NEUROLOGICAL FOUNDATIONS OF COGNITIVE NEUROSCIENCE
Issues in Clinical and Cognitive NeuropsychologyJordan Grafman, series editorNeurological Foundations of Cognitive NeuroscienceMark D’Esposito, editor, 2003The Parallel Brain: The Cognitive Neuroscience of the Corpus CallosumEran Zaidel and Marco Iacoboni, editors, 2002Gateway to Memory: An Introduction to Neural Network Modeling of the Hippocampus and LearningMark A. Gluck and Catherine E. Myers, 2001Patient-Based Approaches to Cognitive NeuroscienceMartha J. Farah and Todd E. Feinberg, editors, 2000
NEUROLOGICAL FOUNDATIONS OF COGNITIVE NEUROSCIENCEedited byMark D’EspositoA Bradford BookThe MIT PressCambridge, MassachusettsLondon, England
Preface ix1 Neglect: A Disorder of SpatialAttention 1Anjan Chatterjee2 Bálint’s Syndrome: A Disorder ofVisual Cognition 27Robert Rafal3 Amnesia: A Disorder of EpisodicMemory 41Michael S. Mega4 Semantic Dementia: A Disorder ofSemantic Memory 67John R. Hodges5 Topographical Disorientation:A Disorder of Way-Finding Ability 89Geoffrey K. Aguirre6 Acquired Dyslexia: A Disorder ofReading 109H. Branch Coslett7 Acalculia: A Disorder ofNumerical Cognition 129Darren R. Gitelman8 Transcortical Motor Aphasia:A Disorder of Language Production 165Michael P. Alexander9 Wernicke Aphasia: A Disorder ofCentral Language Processing 175Jeffrey R. Binder10 Apraxia: A Disorder of MotorControl 239Scott Grafton11 Lateral Prefrontal Syndrome:A Disorder of Executive Control 259Robert T. Knight and Mark D’EspositoContributors 281Index 283Contents
It is an exciting time for the discipline of cogni-tive neuroscience. In the past 10 years we havewitnessed an explosion in the development andadvancement of methods that allow us to preciselyexamine the neural mechanisms underlying cog-nitive processes. Functional magnetic resonanceimaging, for example, has provided markedly im-proved spatial and temporal resolution of brainstructure and function, which has led to answers tonew questions, and the reexamination of old ques-tions. However, in my opinion, the explosive impactthat functional neuroimaging has had on cogni-tive neuroscience may in some ways be responsiblefor moving us away from our roots—the study ofpatients with brain damage as a window into thefunctioning of the normal brain. Thus, my motiva-tion for creating this book was to provide a collec-tion of chapters that would highlight the interfacebetween the study of patients with cognitivedeﬁcits and the study of cognition in normal indi-viduals. It is my hope that reading these chapterswill remind us as students of cognitive neuro-science that research aimed at understanding thefunction of the normal brain can be guided bystudying the abnormal brain. The incredible insightderived from patients with neurological and psy-chiatric disorders provided the foundation for thediscipline of cognitive neuroscience and shouldcontinue to be an important methodological toolin future studies.Each chapter in this book was written by a neu-rologist who also practices cognitive neuroscience.Each chapter begins with a description of a casereport, often a patient seen by the author, anddescribes the symptoms seen in this patient, layingthe foundation for the cognitive processes to beexplored. After the clinical description, the authorshave provided a historical background about whatwe have learned about these particular neurobe-havioral syndromes through clinical observationand neuropsychological investigation. Each chapterthen explores investigations using a variety ofmethods—single-unit electrophysiological record-ing in awake-behaving monkeys, behavioral studiesof normal healthy subjects, event-related potentialand functional neuroimaging studies of both normalindividuals and neurological patients—aimed atunderstanding the neural mechanisms underlyingthe cognitive functions affected in each particularclinical syndrome. In many chapters, there are con-ﬂicting data derived from different methodologies,and the authors have tried to reconcile these differ-ences. Often these attempts at understanding howthese data may be convergent, rather than divergent,has shed new light on the cognitive mechanismsbeing explored.The goal of preparing this book was not to simplydescribe clinical neurobehavioral syndromes.Such descriptions can be found in many excellenttextbooks of behavioral and cognitive neurology.Nor was the goal to provide a primer in cognitiveneuroscience. The goal of this book is to considernormal cognitive processes in the context ofpatients with cognitive deﬁcits. Each of the clinicalsyndromes in this book is markedly heterogeneousand the range of symptoms varies widely acrosspatients. As Anjan Chatterjee aptly states in hischapter on the neglect syndrome: “This hetero-geneity would be cause for alarm if the goal ofneglect research was to establish a uniﬁed andcomprehensive theory of the clinical syndrome.However, when neglect is used to understand theorganization of spatial attention and representation,then the behavioral heterogeneity is actually criticalto its use as an investigative tool.” These wordscapture perfectly my intent for this book.Many neurologists in training and in practicelack exposure to cognitive neuroscience. Similarly,many newly trained cognitive neuroscientistslack exposure to the rich history of investigationsof brain–behavior relationships in neurologicalpatients. I am optimistic that this book will serveboth groups well. It is a privilege to have assembledan outstanding group of neurologists and cognitiveneuroscientists to present their unique perspectiveon the physical basis of the human mind.Preface
Anjan ChatterjeeUnilateral spatial neglect is a fascinating clinicalsyndrome in which patients are unaware of entiresectors of space on the side opposite to their lesion.These patients may neglect parts of their own body,parts of their environment, and even parts of scenesin their imagination. This clinical syndrome is pro-duced by a lateralized disruption of spatial attentionand representation and raises several questions ofinterest to cognitive neuroscientsts. How do humansrepresent space? How do humans direct spatialattention? How is attention related to perception?How is attention related to action?Spatial attention and representation can also bestudied in humans with functional neuroimagingand with animal lesion and single-cell neurophysi-ological studies. Despite the unique methods andapproaches of these different disciplines, there isconsiderable convergence in our understanding ofhow the brain organizes and represents space. Inthis chapter, I begin by describing the clinical syn-drome of neglect. Following this description, Ioutline the major theoretical approaches and bio-logical correlates of the clinical phenomena. I thenturn to prominent issues in recent neglect researchand to relevant data from human functional neuro-imaging and animal studies. Finally, I conclude withseveral issues that in my view warrant furtherconsideration.As a prelude, it should be clear that neglect isa heterogeneous disorder. Its manifestations varyconsiderably across patients (Chatterjee, 1998;Halligan & Marshall, 1992, 1998). This hetero-geneity would be cause for alarm if the goal ofneglect research were to establish a uniﬁed andcomprehensive theory of the clinical syndrome.However, when neglect is used to understand theorganization of spatial attention and representation,then the behavioral heterogeneity is actually criticalto its use as an investigative tool.Distributed neuronal networks clearly mediatespatial attention, representation, and movement.Focal damage to parts of these networks can1 Neglect: A Disorder of Spatial Attentionproduce subtle differences in deﬁcits of thesecomplex functions. These differences themselvesare of interest. A careful study of spatial atten-tion and representations through the syndrome ofneglect is possible precisely because neglect isheterogeneous (Chatterjee, 1998).Case ReportNeglect is more common and more severe with right thanwith left brain damage. I will refer mostly to left-sidedneglect following right brain damage, although similardeﬁcits are seen sometimes following left brain damage.A 65-year-old woman presented to the hospital becauseof left-sided weakness. She was lethargic for 2 days afteradmission. She tended to lie in bed at an angle, orientedto her right, and ignored the left side of her body. Whenher left hand was held in front of her eyes, she suggestedthat the limb belonged to the examiner. As her level ofarousal improved, she continued to orient to her right, evenwhen approached and spoken to from her left. She ate onlythe food on the right side of her hospital tray. Food some-times collected in the left side of her mouth.Her speech was mildly dysarthric. She answeredquestions correctly, but in a ﬂat tone. Although herconversation was superﬁcially appropriate, she seemedunconcerned about her condition or even about being inthe hospital. When asked why she was hospitalized, shereported feeling weak generally, but denied any speciﬁcproblems. When referring to her general weakness, shewould look at and lift her right arm. Over several days,after hearing from her physicians that she had had a strokeand having repeatedly been asked by her physical thera-pist to move her left side, she acknowledged her left-sidedweakness. However, her insight into the practical restric-tions imposed by her weakness was limited. Her therapistsnoted that she was pleasant and engaging for short periods,but not particularly motivated during therapy sessions andfatigued easily.Three months after her initial stroke, obvious signsof left neglect abated. Her left-sided weakness alsoimproved. She had slightly diminished somatosensorysensation on the left, but after about 6 months she alsoexperienced uncomfortable sensations both on the skinand “inside” her left arm. The patient continued to fatigue
easily and remained at home much of the time. Her mag-netic resonance imaging (MRI) scan showed an ischemicstroke in the posterior division of the right middle cerebralartery (ﬁgure 1.1). Her lesion involved the posteriorinferior parietal lobule, Brodmann areas (BA) 39 and 40and the posterior part of the superior temporal gyrus,BA 22.Clinical Examination of NeglectBedside tests for neglect are designed to assesspatients’ awareness of the contralesional parts oftheir own body (personal neglect), contralesionalsectors of space (extrapersonal neglect), and con-tralesional stimuli when presented simultaneouslywith competing ipsilesional stimuli (extinction).Personal NeglectPersonal neglect refers to neglect of contralesionalparts of one’s own body. Observing whetherpatients groom themselves contralesionally pro-vides a rough indication of personal neglect.Patients who ignore the left side of their body mightnot use a comb or makeup, or might not shave theleft side of their face (Beschin & Robertson, 1997).To assess personal neglect, patients are asked abouttheir left arm after this limb is brought into theirview. Patients with left personal neglect do notacknowledge ownership of the limb. When askedto touch their left arm with their right hand, thesepatients fail to reach over and touch their left side(Bisiach, Perani, Vallar, & Berti, 1986).A phenomenon called anosognosia for hemiple-gia can also be thought of as a disorder of personalawareness. In this condition, patients are awareof their contralesional limb, but are not awareof its paralysis (Bisiach, 1993). Anosognosia forhemiplegia is not an all-or-none phenomenon, andpatients may have partial awareness of their con-tralesional weakness (Chatterjee & Mennemeier,1996). Misoplegia is a rare disorder in whichpatients are aware of their own limb, but develop anintense dislike for it (Critchley, 1974).Extrapersonal NeglectExtrapersonal neglect can be assessed using bedsidetasks such as line bisection, cancellation, drawing,and reading. Line bisection tasks assess a patient’sability to estimate the center of a simple stimulus.Patients are asked to place a mark at the midpointof lines (usually horizontal). The task is generallyadministered without restricting head or eye move-ments and without time limitations. Patients withleft-sided neglect typically place their mark to theAnjan Chatterjee 2Figure 1.1Contrast-enhanced magnetic resonance image showing lesion in the posterior division of the right middle cerebral artery,involving the inferior parietal lobule and the posterior superior temporal gyrus.
right of the true midposition (Schenkenberg,Bradford, & Ajax, 1980). Patients make largererrors with longer lines (Chatterjee, Dajani, &Gage, 1994a). If stimuli are placed in space con-tralateral to their lesion, patients frequently makelarger errors (Heilman & Valenstein, 1979). Thus,using long lines (generally greater than 20cm)placed to the left of the patient’s trunk increases thesensitivity of detecting extrapersonal neglect usingline bisection tasks.Cancellation tasks assess how well a patientexplores the contralesional side of extrapersonalspace (ﬁgure 1.2). Patients are presented with arraysof targets which they are asked to “cancel.”Cancellation tasks are also administered withoutrestricting head or eye movements and without timelimitations. Patients typically start at the top rightof the display and often search in a vertical pattern(Chatterjee, Mennemeier, & Heilman, 1992a). Theyneglect left-sided targets (Albert, 1973) and oftentargets close to their body, so that a target in theleft lower quadrant is most likely to be ignored(Chatterjee, Thompson, & Ricci, 1999; Mark &Heilman, 1997). Sometimes patients cancel right-sided targets repeatedly. Increasing the number oftargets may uncover neglect that is not evident onarrays with fewer targets (Chatterjee, Mennemeier,& Heilman, 1992b; Chatterjee et al., 1999). The useof arrays in which targets are difﬁcult to discrimi-nate from distracter stimuli (Rapcsak, Verfaellie,Fleet, & Heilman, 1989) may increase the sensitiv-ity of cancellation tasks. Thus, using arrays with alarge number of stimuli (generally more than ﬁfty)and with distracters that are difﬁcult to discriminatefrom the targets increases the sensitivity of cancel-lation tasks in detecting extrapersonal neglect.In drawing tasks, patients are asked to either copydrawings presented to them or to draw objects andscenes from memory (ﬁgures 1.3 and 1.4). Whenasked to copy drawings with multiple objects, orcomplex objects with multiple parts, patients mayomit left-sided objects in the array and/or omit theleft side of individual objects, regardless of wherethey appear in the array (Marshall & Halligan,1993; Seki & Ishiai, 1996). Occasionally, patientsmay draw left-sided features of target items withless detail or even misplace left-sided details to theright side of their drawings (Halligan, Marshall, &Wade, 1992).Reading tasks can be given by having patientsread text or by having them read single words.Patients with left-sided neglect may have troublebringing their gaze to the left margin of the pagewhen reading text. As a consequence, they may readlines starting in the middle of the page and producesequences of words or sentences that do not makesense. When reading single words, they may eitheromit left-sided letters or substitute confabulatedletters (Chatterjee, 1995). Thus the word “walnut”might be read as either “nut” or “peanut.” Thisreading disorder is called “neglect dyslexia”(Kinsbourne & Warrington, 1962).Extinction to Double Simultaneous StimulationPatients who are aware of single left-sided stimulimay neglect or “extinguish” these stimuli whenleft-sided stimuli are presented simultaneouslywith right-sided stimuli (Bender & Furlow, 1945).Extinction may occur for visual, auditory, or tactilestimuli (Heilman, Pandya, & Geschwind, 1970).Visual extinction can be assessed by asking patientsto count ﬁngers or to report ﬁnger movementsNeglect 3Figure 1.2Example of a cancellation task showing left neglect. Thattask is given without time constraints and without restrict-ing eye or head movements.
presented to both visual ﬁelds compared with singlevisual ﬁelds. Auditory extinction can be assessed byasking them to report which ear hears a noise madeby snapped ﬁngers or two coins rubbed together atone or both ears. Tactile extinction can be assessedby lightly touching patients either unilaterally orbilaterally and asking them to report where theywere touched. Patients’ eyes should be closed whentactile extinction is being assessed since their direc-tion of gaze can modulate extinction (Vaishnavi,Calhoun, & Chatterjee, 1999).Extinction may even be elicited by havingpatients judge relative weights placed in their handssimultaneously (Chatterjee & Thompson, 1998).Patients with extinction may dramatically under-estimate left-sided weights when a weight is alsoplaced on their right hand. Finally, extinction mayalso be observed with multiple stimuli in ipsile-sional space (Feinberg, Haber, & Stacy, 1990;Rapcsak, Watson, & Heilman, 1987).General Theories of NeglectGeneral theories emphasize behaviors commonto patients with neglect and try to isolate the coredeﬁcit, which produces the clinical syndrome.These theories include attentional and representa-tional theories.Anjan Chatterjee 4Figure 1.3Example of a spontaneous drawing by a patient with leftneglect.Figure 1.4Example of a drawing copied by a patient with left neglect.
Attentional TheoriesAttentional theories are based on the idea thatneglect is a disorder of spatial attention. Spatialattention is the process by which objects in certainspatial locations are selected for processing overobjects in other locations. The processing may in-volve selection for perception or for actions. Theidea that objects in spatial locations are selected foraction has given rise to the notion of “intentionalneglect,” in which patients are disinclined to act inor toward contralesional space. (Intentional neglectis discussed more fully later in this chapter.)Attention is generally considered effortful andusually operates serially. Normally, the nervoussystem processes visual information in stages.Visual elements, such as color, movement, andform, are extracted initially from the visual scene.These elements are segregated or grouped together“preattentively,” to parse the visual scene beforeattention is engaged. Preattentive processing isgenerally considered automatic and often operatesin parallel across different spatial locations. Braindamage can produce selective deﬁcits at this preat-tentive level with relatively normal spatial attention(Ricci, Vaishnavi, & Chatterjee, 1999; Vecera &Behrmann, 1997). By contrast, patients with neglectoften have relatively preserved preattentive vision,as evidenced by their ability to separate ﬁgure fromground and their susceptibility to visual illusions(Driver, Baylis, & Rafal, 1992; Mattingley, Davis,& Driver, 1997; Ricci, Calhoun, & Chatterjee,2000; Vallar, Daini, & Antonucci, 2000).In neglect, attention is directed ipsilesionally,and therefore patients are aware of stimuli only inthis sector of space. A major concern of generalattentional theories is to understand why neglectis more common and severe after right than afterleft brain damage. Kinsbourne postulates that eachhemisphere generates a vector of spatial attentiondirected toward contralateral space, and theseattentional vectors are inhibited by the oppositehemisphere (Kinsbourne, 1970, 1987). The lefthemisphere’s vector of spatial attention is stronglybiased, while the right hemisphere produces only aweak vector. Therefore, after right brain damage,the left hemisphere’s unfettered vector of attentionis powerfully oriented to the right. Since the righthemisphere’s intrinsic vector of attention is onlyweakly directed after left brain damage, there isnot a similar orientation bias to the left. Thus, right-sided neglect is less common than left-sidedneglect.Heilman and co-workers, in contrast toKinsbourne, propose that the right hemisphere isdominant for arousal and spatial attention (Heilman,1979; Heilman & Van Den Abell, 1980). Patientswith right brain damage have greater electroen-cephalographic slowing than those with left braindamage. They also demonstrate diminished gal-vanic skin responses compared with normal controlsubjects or patients with left hemisphere damage(Heilman, Schwartz, & Watson, 1978). This dimin-ished arousal interacts with hemispheric biases indirecting attention. The right hemisphere is thoughtto be capable of directing attention into both hemi-spaces, while the left hemisphere directs attentiononly into contralateral space. Thus, after right braindamage, the left hemisphere is ill equipped to directattention into left hemispace. However, after leftbrain damage, the right is capable of directing atten-tion into both hemispaces and neglect does notoccur with the same severity as after right braindamage. Mesulam (1981, 1990), emphasizing thedistributed nature of neural networks dedicatedto spatial attention, also proposed a similar hemi-spheric organization for spatial attention.Posner and colleagues proposed an inﬂuentialmodel of spatial attention composed of elementaryoperations, such as engaging, disengaging, andshifting (Posner, Walker, Friedrich, & Rafal, 1984;Posner & Dehaene, 1994). They reported thatpatients with right superior parietal damage areselectively impaired in disengaging attention fromright-sided stimuli before they shift and engageleft-sided stimuli. This disengage deﬁcit is likely toaccount for some symptoms of visual extinction.In more recent versions of this theory, Posner andcolleagues proposed a posterior and an anteriorattentional network, which bears considerableNeglect 5
resemblance to Heilman’s and Mesulam’s ideas ofdistributed networks. Some parts of this network arepreferentially dedicated to selecting stimuli in spacefor perception and others to selecting stimuli inspace on which to act.Representational TheoriesRepresentational theories propose that the inabilityto form adequate contralateral mental representa-tions of space underlies the clinical phenomenologyin neglect (Bisiach, 1993). In a classic observation,Bisiach and Luzzatti (1978) asked two patients toimagine the Piazza del Duomo in Milan, Italy, fromtwo perspectives: looking into the square toward thecathedral and looking from the cathedral into thesquare (ﬁgure 1.5). In each condition, the patientsonly reported landmarks to the right of their imag-ined position in the piazza. Neglect for imagesevoked from memory may be dissociated fromneglect of stimuli in extrapersonal space (Anderson,1993; Coslett, 1997). In addition to difﬁculty inevoking contralateral representations from memory,patients with neglect may also be impaired informing new contralateral representations (Bisiach,Luzzatti, & Perani, 1979). Rapid eye movementsin sleeping neglect patients are restricted ipsilater-ally (Doricchi, Guariglia, Paolucci, & Pizzamiglio,1993), raising the intriguing possibility that thesepatients’ dreams are spatially restricted.Attentional versus Representational TheoriesAlthough representational theories are often con-trasted with attentional theories, it is not clear thatattentional and representational theories of neglectare really in conﬂict (see the contributions inHalligan & Marshall, 1994, for related discussions).Sensory-attentional and representational theoriesseem to be describing different aspects of the samephenomena. Awareness of external stimuli occursby mentally reconstructing objects in the world.It is therefore not clear that describing attentiondirected in external space avoids the need toconsider mental representations. Similarly, mentalrepresentations, even when internally evoked, areselectively generated and maintained. It is not clearhow describing spatially selective representationavoids the need to consider spatial attention. Atten-tional theories refer to the process and dynamicsthat support mental representations. Representa-tional theories refer to the structural features of thedisordered system. Each theoretical approach seemsinextricably linked to the other.Biological Correlates of NeglectNeglect is seen with a variety of lesions involvingdifferent cortical and subcortical structures. It isalso associated with dysregulation of speciﬁc neuro-transmitter systems.Anjan Chatterjee 6Figure 1.5Two views of the Piazza del Duomo in Milan, Italy.
Cortical LesionsNeglect is more common and more severe in casesof right than left hemisphere damage (Gainotti,Messerli, & Tissot, 1972). The characteristic lesioninvolves the right inferior parietal lobe, Brodmannareas 39 and 40 (Heilman, Watson, & Valenstein,1994). Recently, Karnath and colleagues (Karnath,Ferber & Himmelbach, 2001) have suggested thatlesions to the right superior temporal gyrus are asso-ciated most commonly with extrapersonal neglectin the absence of visual ﬁeld defects. Neglect mayalso be observed after dorsolateral prefrontal(Heilman & Valenstein, 1972; Husain & Kennard,1996; Maeshima, Funahashi, Ogura, Itakura, &Komai, 1994) and cingulate gyrus lesions (Watson,Heilman, Cauthen, & King, 1973). Severe neglectis more likely if the posterior-superior longitudinalfasciculus and the inferior-frontal fasciculus aredamaged in addition to these cortical areas(Leibovitch et al., 1998).The cortical areas associated with neglectare supramodal or polymodal areas into whichunimodal association cortices project (Mesulam,1981). This observation underscores the idea thatneglect is a spatial disorder, not one of primarysensory processing (such as a visual ﬁeld defect).The polymodal nature of the deﬁcit means thatneglect may be evident in different sensory andmotor systems, without necessarily being restrictedto one modality.Subcortical LesionsSubcortical lesions in the thalamus, basal ganglia,and midbrain may also produce neglect. Neglectin humans is associated with decreased arousal(Heilman et al., 1978). Interruptions of ascendingmonoaminergic or cholinergic projections may inpart mediate this clinical manifestation (Watson,Heilman, Miller, & King, 1974).The extension of the reticular system into thethalamus is a thin shell of neurons encasing muchof the thalamus and is called the “nucleus reticu-laris.” The nucleus reticularis neurons inhibit relaysof sensory information from the thalamus to thecortex. In turn, descending projections from thepolymodal association cortices inhibit the nucleusreticularis. Therefore damage to these systems mayresult in a release of the inhibitory action of thenucleus reticularis on thalamic relay nuclei,producing impairment of contralesional sensoryprocessing (Watson, Valenstein, & Heilman, 1981).Damage to the pulvinar, a large nucleus locatedposteriorily in the thalamus, which has reciprocalconnections with the posterior parietal lobule,may result in neglect. Lesions of the basal ganglia,which are tightly linked to prefrontal and cingulatecortices, may also produce neglect (Hier, Davis,Richardson, & Mohr, 1977).Distributed Neural NetworksThe clinical observation that lesions to disparatecortical and subcortical structures produce neglectled Heilman and co-workers to propose that adistributed network mediates spatially directedattention (Heilman, 1979; Watson et al., 1981). Thelimbic connections to the anterior cingulate mayprovide an anatomical basis for poor alertness forstimuli in contralesional locations (Watson et al.,1973) or poor motivation (Mesulam, 1990) inneglect patients.Mesulam (1981, 1990), emphasizing the mono-synaptic interconnectivity of the different brainregions associated with neglect, also proposed asimilar model suggesting that different regionswithin a large-scale network control differentaspects of an individual’s interaction with thespatial environment. He suggested that dorsolateralprefrontal damage produces abnormalities of con-tralesional exploratory behavior and that posteriorparietal damage produces the perceptual disorderseen in neglect.The appealingly straightforward idea that lesionsin different locations within this distributed networkare associated with different behavioral manifesta-tions of neglect is not entirely supported by theevidence (Chatterjee, 1998). The most commonlycited association is that parietal lesions produce theNeglect 7
perceptual aspects of neglect and frontal lesionsproduce the response or motor aspects of neglect.Some studies report this association and others donot (Binder, Marshall, Lazar, Benjamin, & Mohr,1992; Coslett, Bowers, Fitzpatrick, Haws, &Heilman, 1990; McGlinchey-Berroth et al., 1996).One study of a large number of patients even reportsparietal lesions associated with a bias to respondipsilesionally (Bisiach, Ricci, Lualdi, & Colombo,1998a).Neurochemistry of NeglectDistributed neural networks are usually thoughtof in terms of anatomical connections. However,neurotransmitter systems also form distributed net-works with more diffuse effects. Rather than inﬂu-encing speciﬁc cognitive domains, these diffusesystems seem to inﬂuence the state of brain func-tions across many domains. Dopaminergic systemsare of critical importance in neglect. In rats, lesionsto ascending dopaminergic pathways producebehavioral abnormalities that resemble neglect(Marshall & Gotthelf, 1979), and the dopaminergicagonist, apomorphine, ameliorates these deﬁcits.This improvement can be blocked by pretreatmentwith spiroperidol, a dopamine receptor blockingagent (Corwin et al., 1986).These observations led to a small open trialof the dopamine agonist, bromocriptine, in twopatients with neglect (Fleet, Valenstein, Watson,& Heilman, 1987). Both patients’ performancesimproved during bedside assessments of neglect.One patient’s husband reported improvement in heractivities of daily living. Recent reports suggest thatbromocriptine may produce greater improvementthan methylphenidate (Hurford, Stringer, & Jann,1998) and may be more effective in treating themotor aspects of neglect behaviors than strictlyperceptual ones (Geminiani, Bottini, & Sterzi,1998). The efﬁcacy of pharmacological treatmentin the neglect syndrome has not been investigatedsystematically in large-scale studies.Experimental Research on NeglectNeglect has become an important probe in investi-gating several issues in cognitive neuroscience.The topics described next have in common the useof neglect and related disorders as a point of depar-ture, although the issues addressed may be quitedivergent.Intention in Spatial RepresentationsIntentional systems select from among many loca-tions those in which to act. This system is yokedto attentional systems, which select stimuli to beprocessed. There is a growing awareness that muchof perception serves to guide actions in the world(Milner & Goodale, 1995). Some time ago, Watsonand colleagues advanced the idea that neglectpatients may have a premotor intentional deﬁcit, adisinclination to initiate movements or move towardor into contralateral hemispace (Watson, Valenstein,& Heilman, 1978). Similarly, Rizzolatti and co-workers argued that attention facilitates perceptionby activating the circuits responsible for motorpreparation (Rizzolatti, Matelli, & Pavesi, 1983).In most situations, attention and intention areinextricably linked, since attention is usuallydirected to objects on which one acts. Several cleverexperiments have tried to dissociate attentionfrom intention using cameras, pulleys, and mir-rors (Bisiach, Geminiani, Berti, & Rusconi, 1990;Bisiach et al., 1995; Coslett et al., 1990; Milner,Harvey, Roberts, & Forster, 1993; Na et al., 1998;Tegner & Levander, 1991). The general strategy inthese studies is to dissociate where patients arelooking from where their limb is acting. Whenpatients perform tasks in which these two are inconﬂict, in some patients neglect is determined bywhere they are looking and in others by where theyare acting. Some patients behave as though theyhave a combination of the two forms of neglect.Neglect as ipsilesional biases in limb move-ments is sometimes associated with frontal lesions(Binder et al., 1992; Coslett et al., 1990; Tegner &Anjan Chatterjee 8
Levander, 1991). However, patients with lesionsrestricted to the posterior parietal cortex can haveintentional neglect (Mattingley, Husain, Rorden,Kennard, & Driver, 1998; Triggs, Gold, Gerstle,Adair, & Heilman, 1994). Mattingley and col-leagues (Mattingley, Bradshaw, & Phillips, 1992)reported that slowness in the initiation of left-ward movements is associated with right posteriorlesions, whereas slowness in the execution of left-ward movements is associated with right anteriorand subcortical lesions. Most patients with neglectprobably have mixtures of attentional and inten-tional neglect (Adair, Na, Schwartz, & Heilman,1998b), which may be related in quite complexways.One problem in the interpretation of these studiesis that attention versus intention may not be therelevant distinction. Rather, the “attention” experi-mental conditions may reﬂect the link of attentionto eye movement and the “intention” conditionsmay reﬂect the link of attention to limb movements(Bisiach et al., 1995; Chatterjee, 1998). The relevantdistinction may actually be between two perceptual-motor systems, one led by direction of gaze andthe other by direction of limb movements. Such aninterpretation would be consonant with single-cellneurophysiological data from monkeys, whichshow that attentional neurons in the posterior pari-etal cortex are selectively linked to eye or to limbmovements (Colby, 1998).Spatial Attention in Three DimensionsNeglect is usually described along the horizontal(left-right) axis. However, our spatial environmentalso includes radial (near-far) and vertical (up-down) axes. Neglect may also be evident in thesecoordinate systems. Patients with left neglectfrequently have a more subtle neglect for nearspace. On cancellation tasks they are most likelyto omit targets in the left lower quadrant in whichleft and near neglect combine (Chatterjee et al.,1999; Mark & Heilman, 1997). Patients with bilat-eral lesions may have dramatic vertical and radialneglect (Butter, Evans, Kirsch, & Kewman, 1989;Mennemeier, Wertman, & Heilman, 1992; Rapcsak,Fleet, Verfaellie, & Heilman, 1988). Bilaterallesions to temporal-parietal areas may produceneglect for lower and near peripersonal space,whereas bilateral lesions to the ventral temporalstructures are associated with neglect for upper andfar extrapersonal space. Neglect in the vertical axisprobably represents complex interplays between thevisual and vestibular inﬂuences on spatial attention(Mennemeier, Chatterjee, & Heilman, 1994).Left neglect may also vary, depending on whetherthe stimuli are located in close peripersonal spaceor in far extrapersonal space, suggesting that theorganization of space in peripersonal space is dis-tinct from the organization in further extrapersonalspace (Previc, 1998). This notion of concentricshells of space around the body’s trunk was sug-gested initially by Brain (1941), who proposed thatperipersonal space is a distinct spatial constructdeﬁned by the reach of one’s limbs.Spatial Reference FramesObjects in extrapersonal space are anchored to dif-ferent reference frames. These frames are generallydivided into viewer-, object-, and environment-centered reference frames. For example, we canlocate a chair in a room in each of these frames.A viewer-centered frame would locate the chair tothe left or right of the viewer. This frame itselfis divided into retinal, head-centered, or body-centered frames. An object-centered frame refers tothe intrinsic spatial coordinates of the object itself,its top or bottom or right and left. These coordinatesare not altered by changes in the position of theviewer. The top of the chair remains its top regard-less of where the viewer is located.An environment-centered reference frame refersto the location of the object in relation to its envi-ronment. The chair would be coded with respect toother objects in the room and how it is relatedto gravitational coordinates. The vestibular systemthrough the otolith organs probably plays an impor-tant role in establishing the orientation of an objectin relationship to the environmental vertical axisNeglect 9
(Mennemeier et al., 1994; Pizzamiglio, Vallar, &Doricchi, 1997). Several reports demonstrate thatneglect may occur in any of these reference frames(Behrmann, Moscovitch, Black, & Mozer, 1994;Chatterjee, 1994; Driver & Halligan, 1991; Farah,Brun, Wong, Wallace, & Carpenter, 1990; Hillis& Caramazza, 1995; Ladavas, 1987), suggestingthat spatial attention operates across these differentreference frames.Cross-Modal and SensorimotorIntegration of SpaceHumans have a coherent sense of space in whichthey perceive objects and act (Driver & Spence,1998). Neglect studies suggest that multiple spatialrepresentations are embedded within this senseof space. Presumably, multiple sensory modalitiesinteract in complex ways to give rise to multiplerepresentations of space.Rubens and colleagues (Rubens, 1985) de-monstrated that left-sided vestibular stimulationimproves extrapersonal neglect. Presumably, ves-tibular inputs inﬂuence visual and spatial atten-tion in complex ways. Vestibular stimulation canalso improve contralesional somatosensory aware-ness (Vallar, Bottini, Rusconi, & Sterzi, 1993)and may transiently improve anosognosia as well(Cappa, Sterzi, Guiseppe, & Bisiach, 1987). Spatialattention may also be inﬂuenced by changes inposture, which are presumably mediated by otolithvestibular inputs (Mennemeier et al., 1994).Similarly, proprioceptive inputs from neck musclescan inﬂuence spatial attention (Karnath, Sievering,& Fetter, 1994; Karnath, Schenkel, & Fischer, 1991)and serve to anchor viewer-centered referenceframes to an individual’s trunk.Recent studies of patients with tactile extinc-tion have also focused on cross-modal factors inawareness. Visual input when close to the loca-tion of tactile stimulation may improve contra-lesional tactile awareness (di Pellegrino, Basso, &Frassinetti, 1998; Ladavas, Di Pellegrino, Farne, &Zeloni, 1998; Vaishnavi et al., 1999). Similarly, theintention to move may also improve contralesionaltactile awareness (Vaishnavi et al., 1999). Sincepatients with neglect may have personal neglect(Bisiach et al., 1986) or a deﬁcit of their own bodyschema (Coslett, 1998), the question of how bodyspace is integrated with extrapersonal space alsoarises. Tactile sensations are experienced as beingproduced by an object touching the body, an as-pect of peripersonal space. Visual sensations areexperienced as being produced by objects at a dis-tance from the body, in extrapersonal space. Theintegration of tactile and visual stimulation maycontribute to the coordination of extrapersonaland peripersonal space (Vaishnavi, Calhoun, &Chatterjee, 2001).Guiding movements by vision also involvesintegrating visual signals for movement. Thisvisual-motor mapping can be altered if a subjectwears prisms that displace stimuli to the left or rightof their ﬁeld of view. Recent work suggests thatpatients with neglect who are wearing prisms thatdisplace visual stimuli to their right remap ballisticmovements leftward, and that this remapping can beuseful in rehabilitation (Rossetti et al., 1998).Psychophysics, Attention,and Perception in NeglectWhat is the relationship between the magnitude ofstimuli and the magnitude of patients’ representa-tions of these stimuli? This question features promi-nently in psychophysical studies dating back to theseminal work of Gustav Fechner in the nineteenthcentury (Fechner, 1899). How do we understandthe kinds of spatial distortions (Anderson, 1996;Karnath & Ferber, 1999; Milner & Harvey, 1995)and “anisometries” (Bisiach, Ricci, & Modona,1998b) shown in the perception of neglect patients?It turns out that patients are not always aware ofthe same proportion of space. Nor are they alwaysaware of the same quantity of stimuli. Rather,their awareness is systematically related to thequantity of stimuli presented (Chatterjee et al.,1992b).The evidence that neglect patients are systemati-cally inﬂuenced by the magnitude of the stimuliAnjan Chatterjee 10
with which they are confronted has been studiedthe most in the context of line bisection (Bisiach,Bulgarelli, Sterzi, & Vallar, 1983). Patients makelarger errors on larger lines. Marshall and Halligandemonstrated that psychophysical laws could de-scribe the systematic nature of these performances(Marshall & Halligan, 1990). Following this lineof reasoning, Chatterjee showed that patients’performances on line bisection, cancellation,single-word reading tasks, and weight judgmentscan be described mathematically by powerfunctions (Chatterjee, 1995, 1998; Chatterjeeet al., 1994a, 1992b; Chatterjee, Mennemeier, &Heilman, 1994b). In these functions, y = Kfb, frepresents the objective magnitude of the stimuli,and y represents the subjective awareness of thepatient. The constant K and exponent b are derivedempirically.Power function relationships are observed widelyin normal psychophysical judgments of magnitudeestimates across different sensory stimuli (Stevens,1970). An exponent of one suggests that mental rep-resentations within a stimulus range are proportion-ate to the physical range. Exponents less than one,which occur in the normal judgments of luminancemagnitudes, suggest that mental representations arecompressed in relation to the range of the physicalstimulus. Exponents greater than one, as in judg-ments of pain intensity, suggest that mental repre-sentations are expanded in relation to the range ofthe physical stimulus.Chatterjee and colleagues showed that patientswith neglect, across a variety of tasks, have powerfunctions with exponents that are lower than thoseof normal patients. These observations suggestthat while patients remain sensitive to changes insensory magnitudes, their awareness of the size ofthese changes is blunted. For example, the exponentfor normal judgments of linear extension is veryclose to one. By contrast, neglect patients havediminished exponents, suggesting that they, unlikenormal subjects, do not experience horizontal linesof increasing lengths as increasing proportionately.It should be noted that these observations also meanthat nonlinear transformations of the magnitude ofsensations into mental representations occur withinthe central nervous system and not simply at thelevel of sensory receptors, as implied by Stevens(1972).Crossover in NeglectHalligan and Marshall (Halligan & Marshall, 1988;Marshall & Halligan, 1989) discovered that patientswith neglect tended to bisect short lines to theleft of the objective midpoint and seemed to de-monstrate ipsilesional neglect with these stimuli.This crossover behavior is found in most patients(Chatterjee et al., 1994a) with neglect, and is notexplained easily by most neglect theories. In fact,Bisiach referred to it as “a repressed pain in the neckfor neglect theorists.” Using performance on single-word reading tasks, Chatterjee (1995) showed thatneglect patients sometimes confabulate letters tothe left side of short words, and thus read themas longer than their objective length. He arguedthat this crossover behavior represents a contra-lesional release of mental representations. Thisidea has been shown to be plausible in a formalcomputational model (Monaghan & Shillcock,1998).The crossover in line bisection is also inﬂuencedby the context in which these lines are seen. Thus,patients are more likely to cross over and bisectto the left of the true midpoint if these bisectionsare preceded by a longer line (Marshall, Lazar,Krakauer, & Sharma, 1998). Recently, Chatterjeeand colleagues (Chatterjee, Ricci, & Calhoun, 2000;Chatterjee & Thompson, 1998) showed that acrossoverlike phenomenon also occurs with weightjudgments. Patients in general are likely to judgeright-sided weights as heavier than left-sidedweights. However, with lighter weight pairs, thisbias may reverse to where they judge the left sideto be heavier than the right. These results indicatethat crossover is a general perceptual phenomenonthat is not restricted to the visual system.Neglect 11
Implicit Processing in NeglectThe general view of the hierarchical nature of visualand spatial processing is that visual information isprocessed preattentively before attentional systemsare engaged. If neglect is an attentional disorder,then some information might still be processedpreattentively. Neglect patients do seem able toprocess some contralesional stimuli preattentively,as evidenced by their abilities to make ﬁgure-grounddistinctions and their susceptibility to visual illu-sions (Driver et al., 1992; Mattingley et al., 1997;Ricci et al., 2000).How much can stimuli be processed and yet notpenetrate consciousness? Volpe and colleagues(Volpe, Ledoux, & Gazzaniga, 1979) initially re-ported that patients with visual extinction to pic-tures shown simultaneously were still able to makesame-different judgments more accurately thanwould be expected if they were simply guessing.Since then, others have reported that pictures neg-lected on the left can facilitate processing of wordscentrally located (and not neglected) if the picturesand words belong to the same semantic category,such as animals (McGlinchey-Berroth, Milberg,Verfaellie, Alexander, & Kilduff, 1993). Similarly,lexical decisions about ipsilesional words areaided by neglected contralesional words (Ladavas,Paladini, & Cubelli, 1993). Whether neglectedstimuli may be processed to higher levels of se-mantic knowledge and still be obscured from thepatient’s awareness remains unclear (Bisiach &Rusconi, 1990; Marshall & Halligan, 1988).Functional Neuroimaging Studies of SpatialAttention and RepresentationPositron emission tomography (PET) and functionalmagnetic resonance imaging (fMRI) studies offerinsights into neurophysiological changes occurringduring speciﬁc cognitive tasks. Functional imaginghas the advantage of using normal subjects. Thesemethods address several issues relevant to neglect.Hemispheric AsymmetriesHeilman and colleagues (Heilman & Van DenAbell, 1980) as well as Mesulam (1981) postulatedthat the right hemisphere deploys attention diffuselyto the right and left sides of space, whereas the lefthemisphere directs attention contralesionally. Fromsuch a hemispheric organization of spatial attention,one would predict relatively greater right than lefthemisphere activation when attention shifts in eitherdirection. By contrast, the left hemisphere should beactivated preferentially when attention is directed tothe right.Normal subjects do show greater right hemi-spheric activation with attentional shifts to both theright and left hemispaces, and greater left hemi-sphere activations with rightward shifts (Corbetta,Miezen, Shulman, & Peterson, 1993; Gitelmanet al., 1999; Kim et al., 1999). Because intentionalneglect follows right brain damage, one mightexpect similar results for motor movements. Righthemisphere activation is seen with exploratorymovements, even when directed into right hemi-space (Gitelman et al., 1996). Despite these asym-metries, homologous areas in both hemispheres areoften activated, raising questions about the func-tional signiﬁcance of left hemisphere activation inthese tasks.Frontal-Parietal NetworksMost functional imaging studies of visual andspatial attention ﬁnd activation of the intraparietalsulcus (banks of BA 7 and BA 19) and adjacentregions, especially the superior parietal lobule (BA7). Corbetta and colleagues (Corbetta et al., 1993)used PET and found the greatest increases in bloodﬂow in the right superior parietal lobule (BA 7) anddorsolateral prefrontal cortex (BA 6) when subjectswere cued endogenously to different locations.They found bilateral activation, but the activationwas greater in the hemisphere contralateral to theattended targets. The right inferior parietal cortex(BA 40), the superior temporal sulcus (BA 22), andAnjan Chatterjee 12
the anterior cingulate were also active (BA 24), butnot consistently.Nobre and colleagues (Nobre, Sebestyen,Gitelman, & Mesulam, 1997), also using PET,found that an exogenous shift in attention wasassociated with activation around the intraparietalsulcus. Taking advantage of fMRI’s better spatialresolution, Corbetta and colleagues (Corbetta,1998) conﬁrmed activation of the intraparietalsulcus as well as the postcentral and precentralsulcus with shifts of attention. This activation wasfound even when explicit motor responses were notrequired, suggesting that these areas can be atten-tionally engaged without motor preparation. Theyalso found similar blood ﬂow increases in the rightintraparietal sulcus and precentral cortex whenattention was directed at a peripheral location ina sustained manner, rather than just shifting to aperipheral location.The dorsolateral prefrontal cortex is also acti-vated in most studies in which visual attention isshifted to different locations. These activationsseem to center around the frontal eye ﬁelds (BA 6/8)and the adjacent areas. Working memory or in-hibition of eye movement might be associated withdorsolateral prefrontal cortex activity. Gitelmanand co-workers (Gitelman et al., 1999) showed thatactivation of these areas on attentional tasks isprobably not due to these processes. However,the studies did not completely control for eyemovements, which could be contributing to theseactivations. Nonetheless, given that dorsolateralprefrontal cortex lesions also produce disorders ofattention, it is likely that these areas are linked tothe posterior parietal regions involved in directingspatial attention.Supramodal, Space-Based, and Object-BasedAttentionA long-standing question about the organizationof attention is whether there is a supramodal all-purpose attention module, or whether attention isbetter viewed as a collection of different modulestied to distinct sensory and motor systems. Toaddress this question, Wojciulik and Kanwisher(1999) used fMRI in three different tasks of visualattention. These tasks involved shifting attention,matching objects in different locations, and con-joining visual features of an object at a speciﬁc loca-tion. They found that the intraparietal sulcus wasactivated in all three tasks. While one cannot provethe null hypothesis that the intraparietal sulcus isinvolved in all attentional tasks, they suggest thatthis area might mediate a general attention andselection module. Similarly, Coull and Frith (1998)in a PET study found that while the superior pari-etal lobule was more responsive to spatial thannonspatial attention, the intraparietal sulcus wasresponsive to both.The most striking aspect of neglect syndromesis that patients are unaware of contralesional spaceand of objects that inhabit that space. A central tenetof visual neuroscience is the relative segregation ofvisual information into a dorsal “where” stream anda ventral “what” stream (Ungerleider & Mishkin,1982). The dorsal stream processes the spatiallocations of objects of interest, whereas the ventralstream processes features necessary to identify theobject. Somehow humans integrate these streams ofinformation to be aware of both the “where” and“what” of objects.Attention modulates the activity of neural struc-tures in the ventral stream dedicated to identify-ing objects. Patients with prefrontal damage areimpaired in discriminating contralesional visualtargets. This impairment is associated with dimin-ished event-related potentials at 125ms and lastingfor another 500ms (Barcelo, Suwazono, & Knight,2000). These event-related potentials are linked toextrastriate processing, which is associated withtonic activation as well as the selection of featuresand the postselection analyses of objects.The earliest point in visual processing at whichattentional modulation can occur is not clear.Several studies suggest that the primary visualcortex might be modulated by attention(Brefczynski & DeYoe, 1999; Gandhi, Heeger, &Neglect 13
Boynton, 1999; Sommers, Dale, Seiffert, &Tootell, 1999). However, Martinez and colleagues(Martninez et al., 1999) using data from event-related potentials point out that attentional modula-tion in the visual system is evident only after 70–75ms. Since the initial sensory input to the primaryvisual cortex occurs at about 50–55ms, they suggestthat primary visual activation may be due to feed-back activity rather than attentional modulation.The behavioral signiﬁcance of such feedback, if thatis what is being observed, remains to be explored.Activity in neural structures downstream inventral visual processing is clearly modulated byattention. Cognitively demanding tasks can inhibitactivity in visual motion areas, even when themoving stimuli are irrelevant to the task at hand(Rees, Frith, & Lavie, 1997). Baseline activity inthese early visual processing areas can also be mod-ulated by attentional sets. Normally, stimuli sup-press the processing of other stimuli located in closeproximity. Similarly, subjects instructed to attendto color have increased activity in color areas (V4)and when asked to attend to motion have increasedactivity in motion areas (V5), even when the stimulithemselves are not colored or moving (Chawla,Rees, & Friston, 1999). Kastner and colleagues(Kastner, De Weerd, Desimone, & Ungerleider,1998) showed that fMRI activation of areas withinoccipitotemporal regions is associated with thisnormal suppression. This suppression, however,diminishes when spatial attention is directed tolocations encompassing both stimuli, suggesting anoverall enhancement of processing of stimuli inthose areas.The appropriate experimental paradigms andmethods of analysis in functional imaging studies ofspatial attention are still being worked out. In thisearly stage of the ﬁeld’s development, some ﬁnd-ings are difﬁcult to reconcile with the rest of theliterature. One might reasonably surmise that theparietal cortex mediates attention directed in spaceand the occipital and temporal cortices mediateattention directed to features and objects. However,in a PET study, Fink and colleagues (Fink, Dolan,Halligan, Marshall, & Frith, 1997) did not ﬁnd thisfunctional anatomical relationship. They found thatattention directed in space activated the rightprefrontal (BA 9) and inferior temporal-occipital(BA 20) cortex, whereas attention directed atobjects activated the left striate and peristriatecortex (BA 17/18). Both types of attention activatedthe left and right medial superior parietal cortex(BA 7/19), the left lateral inferior parietal cortex(BA 40/7), the left prefrontal cortex (BA 9), and thecerebellar vermis.Animal Studies of Spatial Attention andRepresentationAnimal studies offer insight into mechanisms ofspatial attention that are not obtained easily by study-ing humans. Lesions in animals can be made withconsiderable precision, in contrast to lesions inhumans, which are often determined by vascularanatomy (in the case of stroke) rather than by corticalor functional anatomy. Neurophysiological studiesin animals can address the activity and responsive-ness of single neurons, in contrast to functional neu-roimaging in humans, which offers insight into theneurophysiology at the level of neural networks.Lesion StudiesAnimal lesion studies conﬁrm the idea that dis-tributed neural networks involving the parietal andfrontal cortices mediate spatial attention and aware-ness. In rodents, lesions of the posterior parietal orfrontal cortex (medial agranular cortex) or thedorsolateral striatum produce a syndrome similarto neglect (Burcham, Corwin, Stoll, & Reep, 1997;Corwin & Reep, 1998). These rodents are morelikely to orient ipsilesionally than contralesionallyto visual, tactile, or auditory stimuli. This orienta-tion bias recovers to a considerable degree overdays to weeks. Dopamine antagonists impede spon-taneous recovery and dopamine agonists enhancerecovery (Corwin et al., 1986), probably by inﬂu-encing striatal function (Vargo, Richard-Smith, &Corwin, 1989).Anjan Chatterjee 14
In macaque monkeys, lesions to the frontal peri-arcuate areas and around the inferior parietal lobuleresult in neglect, at least transiently (Duel, 1987;Milner, 1987). These monkeys are more likely toorient toward and act on stimuli in ipsilesionalspace. Single-cell recordings of neurons aroundthe intraparietal sulcus and prefrontal cortices(reviewed later) suggest that these regions are crit-ical in the maintenance of spatial representationsand preparation for actions directed at speciﬁc loca-tions. From this, one would expect that lesions inthese areas would produce profound neglect inanimals. Yet such cortical lesions produce only mildand transient neglect (Milner, 1987). If anything,biased behavior seems more obvious with frontallesions, which seems at odds with human lesionstudies in which posterior lesions are associatedmore often with neglect.In monkeys, cortical lesions with remote meta-bolic abnormalities are more likely to be associatedwith neglect (Duel, 1987). Frontal lesions produc-ing neglect are associated with decreased glucoseutilization in the caudate nucleus and the ventralanterior and dorsomedial thalamic nuclei. Parietallesions producing neglect are associated withdecreased glucose metabolism in the pulvinar andthe lateral posterior thalamic nuclei and in thedeeper layers of the superior colliculus. It is inter-esting that recovery in these animals is also as-sociated with recovery of these remote metabolicabnormalities. This idea that distributed abnormali-ties are needed to produce neglect is reiterated ina more recent study by Gaffan and Hornak (1997).They found in monkeys that transecting whitematter tracts underlying the posterior parietal cortexwas important in producing more persistent neglect.Watson and colleagues (Watson, Valenstein,Day, & Heilman, 1994) reported that damage tomonkeys’ superior temporal sulcus produced moreprofound neglect than damage to the inferior pari-etal lobule. They suggest that the superior temporalsulcus in the monkey may serve as an importantconvergence zone for processing both the dorsal andthe ventral visual streams integrating the “where”and “what” of objects. Damage to this area mightthen be associated with greater contralesionalneglect since the “what” and “where” of contrale-sional objects are no longer conjoined. Thisstudy highlights the difﬁculties in establishing theappropriate homology between the monkey andthe human posterior temporoparietal cortex. Whileneglect in humans is associated most commonlywith lesions to the inferior posterior parietal cortex,Brodmann’s areas 39 and 40, it is not clear which,if any regions, are the appropriate monkey analogto these areas.Finally, Gaffan and Hornak (1997) emphasizethe importance of memory in monkeys’ behavioralmanifestations of overt neglect. They ﬁnd thatneglect is associated with complete commissuro-tomy and optic tract lesions, but not with isolatedoptic tract, parietal, or frontal cortex lesions. Theyinterpret this ﬁnding in the following way: Section-ing the optic tract makes one hemisphere blind tovisual information. This hemisphere acquires visualinformation from the other hemisphere throughinterhemispheric commissures. If each hemispheremaintains a representation of contralateral space,then a monkey without access to information aboutcontralesional space will act as if this space did notexist. With an isolated optic tract lesion, informa-tion about contralesional space is acquired throughthe nonlesioned hemisphere because with multipleocular ﬁxations, objects in contralesional spacesometimes fall on the ipsilesional side of ﬁxation.The idea that short-term memories of contralesionalstimuli inﬂuence spatial behavior had not been con-sidered previously in animal models.Single-Cell Neurophysiological StudiesSingle-cell neurophysiological studies record theactivity of neurons in animals, often monkeys thatare engaged in various perceptual, motor, or cogni-tive tasks. These studies support the idea thatneurons in parietal and frontal association corticesmediate spatial attention and representations. Theseneurons form a distributed network dedicated to avariety of spatial behaviors, including attention andintention regarding spatial locations, memory ofNeglect 15
spatial locations, and facilitation of perception ofobjects in different locations.Parietal NeuronsIn the 1970s, Mountcastle and co-workers foundneurons in the parietal cortex of monkeys thatwere responsive when the animals attended tolights in their peripheral vision despite gazingtoward a central location (Mountcastle, Lynch,Georgopolous, Sakata, & Acuna, 1975). Theyfound that neurons in the posterior parietal cortexresponded to a variety of spatial behaviors, includ-ing ﬁxation, smooth pursuit, saccades, and reaching(Mountcastle, 1976). Neurons in different regions(ventral, medial, lateral) of the posterior intra-parietal sulcus and nearby regions, such as areas5, 7a, and 7b, seem to be critical to the mediationof spatial attention. These neurons form a mosaiclinked to different sensory and motor systems. Forexample, lateral intraparietal (LIP) neurons areless responsive to tactile stimuli or the directionalaspects of moving visual stimuli than ventral in-traparietal (VIP) neurons (Duhamel, Colby, &Goldberg, 1998).Many posterior parietal and frontal neurons areresponsive to combinations of visual and tactilestimuli (Colby & Duhamel, 1991). VIP neurons areresponsive to aligned visual and tactile receptiveﬁelds when they move in speciﬁc directions. Medialintraparietal (MIP) neurons are especially respon-sive to joint rotations and movements of limbs.Other neurons in area 7a integrate visual andvestibular input, and neurons in the lateral intra-parietal area integrate visual and proprioceptiveinput from neck muscles (Andersen, 1995b; Snyder,Grieve, Brotchie, & Andersen, 1998).Generally, neurons within the posterior parietalcortex link speciﬁc sensations to different motorsystems, although there is disagreement on whetherneurons within the LIP sulcus are purely attentionalor whether these neurons are necessarily linkedto eye movements (Andersen, Bracewell, Barash,Gnadt, & Fogassi, 1990; Colby & Goldberg, 1999).Reference FramesThe integration of different sensory modalities inthe posterior parietal cortex is presumably involvedin constructing different kinds of reference frames(Brotchie, Anderson, Snyder, & Goodman, 1995).From studies of people with neglect, we know thatviewer-centered reference frames can be anchoredto retinotopic, head-, or body-centered coordinates.From animal studies it appears unlikely that adifferent pool of neurons code retinal and head-centered coordinates. Andersen and colleaguessuggest that head-centered coordinates are derivedfrom the interaction of retinal and eye positionsignals. The amplitude of a neuron’s response tostimulation of a retinal location is modulated byeye position. Within area 7a, neurons compute thelocation of a stimulus in head-centered coordinatesfrom these interactions (Andersen, Essick, & Siegel,1985). Anderson et al. suggest that other areas,including the lateral intraparietal sulcus, area V3,the pulvinar, nucleus and parts of the premotor andprefrontal cortex may code different kinds of spatialreference frames in a similar fashion (Andersen,1995a). Pouget and Sejnowski (1997) use basisfunctions to offer a slightly different computationalsolution to the mediation of different referenceframes encoded within the same array of neurons.In addition to reference frames divided alongviewer-centered coordinates, space can be parti-tioned as concentric shells around the body, withclose peripersonal space being coded distinctlyfrom distant extrapersonal space (Previc, 1998). Inmonkeys, this segregation of space may be medi-ated by the link between attentional neuronsand multiple motor systems (Snyder, Batista, &Andersen, 1997). Rizzolatti adopts the strong posi-tion that all attentional circuits organize movementsto speciﬁc sectors of space. He claims that the facil-itation of perception by attention is a consequenceof circuits activated in preparation for moving(Rizzolatti & Berti, 1993; Rizzolatti et al., 1988).Neurons within the monkey intraparietal sulcusare tuned to actions involving different motorsystems, such as the mouth, eyes, or hands. InAnjan Chatterjee 16
combination with their connections to frontalregions, these neurons integrate the visual ﬁeldswith the tactile ﬁelds of speciﬁc body parts and withthe actions of these body parts (Gross & Graziano,1995). The parietal and frontal interconnections areanatomically segregated along a ventral-to-dorsalaxis (Petrides & Pandya, 1984). Neurons within theVIP sulcus are responsive to visual stimuli within5cm of the monkey’s face (Colby, Duhamel, &Goldberg, 1993). These neurons project to area F4of area 6 in the premotor cortex, an area that con-tributes to head and mouth movements (Fogassiet al., 1996; Graziano, Yap, & Gross, 1994) and maymediate the construction of very close peripersonalspace. Neurons in the MIP sulcus are responsive tovisual stimuli within reaching distance (Graziano& Gross, 1995). These neurons project to ventralpremotor cortices that mediate visually guided armmovements (Caminiti, Ferraina, & Johnson, 1996;Gentilucci et al., 1988) and are sensitive to stimuliin arm-centered rather than retinotopic coordinates(Graziano et al., 1994). This area has direct con-nections to the putamen, which also has sucharm-centered neurons (Graziano et al., 1994). Theseputamenal neurons may be involved in the decisionprocesses by which different kinds of movementsare selected (Merchant, Zainos, Hernandez, Salinas,& Romo, 1997).Neurons within the monkey LIP sulcus(Duhamel, Colby, & Goldberg, 1992) may be con-nected to saccadic mechanisms of the frontal eyeﬁelds and the superior colliculus. Neurons in thesuperior colliculus are responsive to behaviorallyrelevant stimuli when linked to saccadic eye move-ments (Wurtz & Goldberg, 1972; Wurtz & Munoz,1995). These networks probably link sensations toeye movements and construct distant extrapersonalspace.Space-Based and Object-Based AttentionNeuroimaging studies in humans have shown thatvisual or spatial attention can inﬂuence the pro-cessing of objects in the ventral stream. This inﬂu-ence is presumably involved in binding the “what”and “where” of things. Single-cell monkey physio-logical studies also support such modulation.Neurons in area V4 are sensitive to speciﬁc stimulilocated within their receptive ﬁelds (Moran &Desimone, 1985). Their ﬁring increases when theanimal attends to that location. This strongerresponse to the stimulus for which the neuron isalready tuned, when the animal attends to it, sug-gests a physiological correlate of the enhanced per-ception of objects when attention is directed to thelocation of those objects.Conclusions and Future DirectionsConvergenceThere is a remarkable convergence of some ideasacross different disciplines with highly varied tradi-tions and methods. Four related ideas about spatialattention and representation recur and are summa-rized here.Distributed NetworksNeural networks involving different and noncon-tiguous parts of the brain mediate spatial attention.Rather than being localized to a single brain loca-tion, spatial attention is mediated by the parietal andfrontal and probably cingulate cortices, as well asthe basal ganglia, thalamus, and superior colliculus.Multiple Representations of SpaceThe brain constructs multiple representations ofspace, despite our intuitions of space as a homoge-neous medium that surrounds us. These representa-tions involve the body and different kinds ofextrapersonal space. Extrapersonal space can beviewed as concentric shells around the body, closerto the trunk, within reach of our limbs, or furtheraway in more distant space. Extrapersonal space canalso be partitioned into retinotopic, head-centered,and trunk-centered coordinates that all have theviewer as the primary referent. Viewer-independentreference frames are anchored to the spatial axesNeglect 17
of the object itself or to axes intrinsic to theenvironment.Attention and IntentionAttention and intention are tightly linked. Theextent to which perception and actions are coordi-nated in the formation and sustenance of spatial rep-resentations is remarkable. The actions themselves,whether they are eye movements, head movements,or limb movements in space, are also related tonotions of different kinds of reference frames.Attention and PerceptionAttention and perception may not be as distinctas is often thought. Processing of relatively earlystages of perception seems to be modulated byattention, although the precise boundaries betweenthe two remain to be worked out.Unresolved IssuesDespite this convergence of ideas, I would like tomention some issues that in my view warrant furtherconsideration. Some questions involve research inneglect directly and others involve the relationshipof ﬁndings in neglect and other approaches.Contralesional Hyperorientation in NeglectWhy do patients with right brain damage sometimes“hyperorient” into contralesional space, rather thanneglect contralesional space? We are used to think-ing of neglect as the tendency to orient toward oract in ipsilesional space. However, in some casespatients seem to be drawn contralesionally. Themost robust of these contralesional productivebehaviors is the crossover phenomenon, in whichpatients bisect short lines (usually less than 4cm)to the left of the midline. However, there are otherdramatic instances of contralesional hyperorienta-tion (Chatterjee, 1998). Some patients bisect longlines in contralesional space (Adair, Chatterjee,Schwartz, & Heilman, 1998a; Kwon & Heilman,1991). Some patients will point into contralesionalspace when asked to indicate the environmentalmidline (Chokron & Bartolomeo, 1998). What hashappened to left-sided representations or to motorsystems directed contralesionally to produce thisparadoxical behavior?Memory, Attention, and RepresentationHow does memory interact with attention to affectonline processing of stimuli in neglect? Functionalimaging studies and neurophysiological studiessuggest that there is considerable overlap betweencircuits dedicated to spatial attention and spatialworking memory. Monkey lesion studies indicatean important role for spatial memories in onlineprocessing (Gaffan & Hornak, 1997). We recentlyreported that memory traces of contralesionalstimuli might have a disproportionate inﬂuenceon online representations in patients with neglect(Chatterjee et al., 2000). A conceptual frameworkthat relates spatial memory and attention in inﬂu-encing online perception remains to be articulated.Frontal and Parietal DifferencesHow different are the roles of the frontal and pari-etal cortices in spatial attention? The notion thatparietal neglect is attentional and frontal neglectis intentional has great appeal. Unfortunately, theempirical evidence for such a clear dichotomy ismixed at best. It is not even clear that thesedistinctions make conceptual sense, since whathas been called “attentional neglect” involves eyemovements and what has been called “intentionalneglect” involves limb movements. Single-cell neu-rophysiological studies suggest that neurons withinboth parietal and frontal cortices mediate spatialactions. It may be the case that the actions are moreclearly segregated in the frontal cortex than in theparietal cortex. However, it is not clear that oneshould expect clean behavioral dissociations fromlesions to the frontal and parietal cortices. Perhapseye and limb movements may be coded within thesame array of neurons, as suggested by Andersenand colleagues (Andersen, 1995a) and Pouget andAnjan Chatterjee 18
Sejnowski (1997) for the coding of visual referenceframes. If that were the case, it is not clear howlesions would bias behavior toward different formsof neglect. Furthermore, the ways in which frontaland parietal areas interact based on their intercon-nections is not well understood. In humans, damageto the posterior superior longitudinal fasciculus andthe inferior frontal fasciculus is associated withmore severe and long-lasting neglect. Similarly inmonkeys, transection of the white matter underly-ing the parietal cortex is also associated with greaterneglect.Distinctions within the Parietal CortexWhat are the roles of different regions within theposterior parietotemporal lobes? Lesion studies inhumans suggest that damage to the inferior parietallobule or the superior temporal gyrus produces themost consistent and profound disorder of spatialattention and representation. Lesion studies inhumans suggest that damage to the inferior parietallobule or superior temporal gyrus produces the mostconsistent and profound disorder of spatial attentionand representation. By contrast, functional imagingstudies activate more dersal regions within theintraparietal sulcus and the superior parietal sulcusmost consistently. Why this discrepancy? Per-haps the greater dorsal involvement in functionalimaging studies is related to the design of thestudies, which emphasize shifts of visual attention.Perhaps experimental probes emphasizing theintegration of both “what” and “where” informationwould be more likely to involve the inferior parietalcortex. Recent functional imaging data suggest thatthe temporal-parietal junction may be preferentiallyactivated when subjects detect targets, rather thansimply attend to locations (Corbetta et al., 2000).Monkey lesion studies may not be able to resolvethe discrepancy for two reasons. As mentionedbelow, the appropriate anatomical monkey–humanhomologs are not clear, and neglectlike symptomsoccur only transiently following parietal lesions inmonkeys.Monkey and Human HomologsWhat are the appropriate anatomical homologsbetween humans and monkeys? Human lesionstudies focus on the inferior parietal lobule. It is notclear that an analogous structure exists in monkeys(Watson et al., 1994). Both human functional imag-ing studies and monkey neurophysiology emphasizethe role of the intraparietal sulcus. However, it is notclear that these two structures are homologousacross species.In summary, we know a great deal about spatialattention and representation. Across the varied dis-ciplines there is a remarkable convergence of thekinds of questions being asked and solutions beingproposed. However, many questions remain.Acom-prehensive and coherent understanding of spatialattention and representation is more likely withthe recognition of insights gleaned from differentmethods.AcknowledgmentsThis work was supported by National Institutes & Healthgrout RO1 NS37539. I would like to thank Lisa Santer forher critical reading of early drafts of this chapter.ReferencesAdair, J., Chatterjee, A., Schwartz, R., & Heilman, K.(1998a). Ipsilateral neglect: Reversal of bias or exagger-ated cross-over phenomenon? Cortex, 34, 147–153.Adair, J. C., Na, D. L., Schwartz, R. L., & Heilman, K. M.(1998b). Analysis of primary and secondary inﬂuences onspatial neglect. Brain and Cognition, 37, 351–367.Albert, M. L. (1973). A simple test of visual neglect.Neurology, 23, 658–664.Andersen, R. A. (1995a). Coordinate transformation andmotor planning in parietal cortex. In M. S. Gazzaniga(Ed.), The cognitive neurosciences (pp. 519–532).Cambridge, MA: MIT Press.Andersen, R. A. (1995b). Encoding of intention and spatiallocation in the posterior parietal cortex. Cerebral Cortex,5, 457–469.Neglect 19
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Robert RafalCase ReportR.M. had suffered from two strokes, both due to cardiacemboli from hypertensive heart disease. The ﬁrst occurredin June 1991 at the age of 54 and produced infarction inthe right parietal lobe and a small lesion in the right cere-bellum. He recovered from a transient left hemiparesisand left hemispatial neglect. The second stroke, in March1992, involved the left parietal lobe and left him func-tionally blind. Five months after the second stroke, he wasreferred to a neurologist for headaches. At that time,neurological examination revealed a classical Bálint’ssyndrome without any other deﬁcits of cognitive, motor,or sensory function.The patient had normal visual acuity; he could recog-nize colors, shapes, objects, and faces and could readsingle words. He suffered severe spatial disorientation,however, and got lost easily anywhere except in his ownhome. Although he was independent in all activities ofdaily living, he could not maintain his own household andhad to be cared for by his family. He had to be escortedabout the hospital. When shown two objects, he often sawonly one. When he did report both, he did so slowly andseemed to see them sequentially. Depth perception wasseverely impaired and he could not judge the distance ofobjects from him or tell which of two objects was closerto him. Optic ataxia was pronounced. He could not reachaccurately toward objects, and was unable to use a pencilto place a mark within a circle. He could not make accu-rate saccades to objects and he could not make pursuiteye movements to follow the most slowly moving object.Visual acuity was 20/15 in both eyes. Perimetry at the timeof the initial neurological exam revealed an altitudinalloss of the lower visual ﬁelds. Two years later, however,visual ﬁelds were full. Contrast sensitivity and color visionwere normal. Three-dimensional experience of shapes inrandom dot stereograms was preserved and he experienceddepth from shading.His headaches were controlled with amitriptyline, andanticoagulation treatment with warfarin was instituted toprevent further strokes. By June 1995, the patient was ableto live independently in a duplex next door to his brother’sdaughter, and needed only intermittent help in his dailyactivities. He was able to take unescorted walks in hisneighborhood, to get about in his own house without help,2 Bálint’s Syndrome: A Disorder of Visual Cognitionwatch television, eat and dress himself, and carry on manyactivities of daily living. He was slower than normal inthese activities, but was able to lead a semi-independentlife.A magnetic resonance imaging (MRI) scan in 1994 withthree-dimensional reconstruction revealed nearly symmet-rical lesions in each parieto-occipital region (Friedman-Hill, Robertson, & Treisman, 1995). The lesions wereconcentrated primarily in Brodmann areas 7 and 39, andpossibly included some of areas 5 and 19. In addition,there was a small (volume <0.3cm3) lesion in Brodmannarea 6 of the right hemisphere and asymmetrical cere-bellar lesions (volume = 0.3cm3left hemisphere, 6.0cm3right hemisphere). The damage preserved the primaryvisual cortex and all the temporal lobe. The supramarginalgyri were intact on both sides, as were somatosensory andmotor cortices.The syndrome represented by this patient wasﬁrst described by the Hungarian neurologist RezsöBálint (Bálint, 1909; Harvey, 1995; Harvey &Milner, 1995; Husain & Stein, 1988). While visualacuity is preserved and patients are able to recog-nize objects placed directly in front of them, theyare unable to interact with, or make sense of, theirvisual environment. They are lost in space. Fleetingobjects that they can recognize, but that they cannotlocate or grasp, appear and disappear, and theirfeatures are jumbled together. These patients arehelpless in a visually chaotic world.Holmes and Horax (1919) provided a detailedanalysis of the syndrome that remains deﬁnitive.They emphasized two major components of thesyndrome: (1) simultanagnosia—a constriction, notof the visual ﬁeld, but of visual attention, whichrestricts the patient’s awareness to only one objectat a time and (2) spatial disorientation—a loss ofall spatial reference and memory that leaves thepatients lost in the world and unable to look atobjects (which Bálint called “psychic paralysis ofgaze”) or to reach for them (which Bálint called“optic ataxia”).This chapter reviews the clinical and neuro-psychological aspects of this intriguing syndrome.
It reviews its anatomical basis and some of the dis-eases that cause it. It then details the independentcomponent symptoms of Bálint’s syndrome. It con-cludes with a synthesis that attempts to summarizewhat Bálint’s syndrome tells us about the role ofattention and spatial representation in perceptionand action.Anatomy and Etiology of Bálint’s SyndromeBálint’s syndrome is produced by bilateral lesionsof the parieto-occipital junction. The lesions char-acteristically involve the dorsorostral occipital lobe(Brodmann area 19), and often, but not invariably(Karnath, Ferber, Rorden, & Driver, 2000), theangular gyrus, but may spare the supramarginalgyrus and the superior temporal gyrus. Figure 2.1shows a drawing of the lesions in the patientreported by Bálint in 1909 (Husain & Stein, 1988).The supramarginal gyrus and the posterior part ofthe superior temporal gyrus are affected in the righthemisphere, but spared on the left. The superiorparietal lobule is only minimally involved in eitherhemisphere. Figure 2.2 (Friedman-Hill, Robertson,& Treisman, 1995) shows the reconstructed MRIscan of the patient (R. M.) with Bálint’s syndromedescribed in the case report. The lesion involves theparieto-occipital junction and part of the angulargyrus of both hemispheres, but spares the temporallobe and supramarginal gyrus. A review of otherrecent cases of Bálint’s syndrome emphasizes theconsistent involvement of the posterior parietallobe and parieto-occipital junction as critical inproducing the syndrome (Coslett & Saffran,1991; Pierrot-Deseillgny, Gray, & Brunet, 1986;Verfaellie, Rapcsak, & Heilman, 1990).Thus Bálint’s syndrome is associated with dis-eases in which symmetric lesions of the parieto-occipital junction are typical. For example, Luria(1959) and Holmes and Horax (1919) have reportedthis syndrome after patients received penetratingwounds from projectiles entering laterally andtraversing the coronal plane through the parieto-occipital regions. Strokes successively injuring bothhemispheres in the distribution of posterior parietalbranches of the middle cerebral artery are anothercommon cause (Coslett & Saffran, 1991; Friedman-Hill et al., 1995; Pierrot-Deseillgny et al., 1986).Because the parieto-occipital junction lies in thewatershed territory between the middle and theposterior cerebral arteries, Bálint’s syndrome is acommon sequela of infarction due to global cerebralhypoperfusion. Another symmetrical pathology isthe “butterﬂy” glioma—a malignant tumor origi-Robert Rafal 28Figure 2.1Bálint’s drawing of the brain of the patient he described.(Husain and Stein, 1988).Figure 2.2MRI of patient R.M.
nating in one parietal lobe and spreading across thecorpus callosum to the other side.Radiation necrosis may develop after radiation ofa parietal lobe tumor in the opposite hemisphere inthe tract of the radiation port. Cerebral degenerativedisease, prototypically Alzheimer’s disease, maybegin in the parieto-occipital regions, and there isnow a growing literature reporting cases of classicBálint’s syndrome that are due to degenerative dis-eases (Benson, Davis, & Snyder, 1988; Hof, Bouras,Constintinidis, & Morrison, 1989, 1990; Mendez,Turner, Gilmore, Remler, & Tomsak, 1990).The Symptom Complex of Bálint’s SyndromeBálint’s initial description of this syndrome empha-sized in his patient the constriction of visual atten-tion, resulting in an inability to perceive more thanone object at a time, and optic ataxia, the inability toreach accurately toward objects. Bálint used the termoptic ataxia to distinguish it from the tabetic ataxia ofneurosyphilis; tabetic ataxia is an inability to coordi-nate movements based on proprioceptive input,while optic ataxia describes an inability to coordinatemovements based on visual input. Many similarpatients have since been reported (Coslett & Saffran,1991; Girotti et al., 1982; Godwin-Austen, 1965;Kase, Troncoso, Court, Tapia, & Mohr, 1977;Luria, 1959; Luria, Pravdina-Vinarskaya, &Yarbuss,1963; Pierrot-Deseillgny et al., 1986; Tyler, 1968;Williams, 1970).In addition to noting the simultanagnosia andoptic ataxia reported by Bálint, Holmes and Horaxemphasized spatial disorientation as the cardinalfeature of the syndrome. Holmes and Horax of-fered their case “for the record . . . as an excellentexample of a type of special disturbance of vision. . . which sheds considerable light on . . . thoseprocesses which are concerned in the integrationand association of sensation” (Holmes & Horax,1919, p. 285).Constriction of Visual Attention:SimultanagnosiaIn their 1919 report of a 30-year-old World WarI veteran who had a gunshot wound throughthe parieto-occipital regions, Holmes & Horaxobserved that “the essential feature was his inabil-ity to direct attention to, and to take cognizance of,two or more objects” (Holmes & Horax, 1919,p. 402). They argued that this difﬁculty “must beattributed to a special disturbance or limitation ofattention” (p. 402). Because of this constrictionof visual attention (what Bálint referred to as thepsychic ﬁeld of gaze), the patient could attend toonly one object at a time regardless of the size ofthe object. “In one test, for instance, a large squarewas drawn on a sheet of paper and he recognizedit immediately, but when it was again shown to himafter a cross had been drawn in its center he saw thecross, but identiﬁed the surrounding ﬁgure onlyafter considerable hesitation; his attention seemedto be absorbed by the ﬁrst object on which his eyesfell” (Holmes & Horax, 1919, p. 390).Another useful clinical test uses overlappingﬁgures (ﬁgure 2.3). The degree to which local detailcan capture the patient’s attention and exclude allother objects from his or her attention can be quiteBalint’s Syndrome 29Figure 2.3Overlapping ﬁgures used to test for simultaneous agnosia.
astonishing. I was testing a patient one day, drawinggeometric shapes on a piece of paper and asking herto tell me what she saw. She was doing well atreporting simple shapes until at one point she shookher head, perplexed, and told me, “I can’t see anyof those shapes now, doctor, the watermark on thepaper is so distracting.”The visual experience of the patient with Bálint’ssyndrome is a chaotic one of isolated snapshots withno coherence in space or time. Coslett and Saffranreport a patient whom television programs bewil-dered “because she could only ‘see’ one person orobject at a time and, therefore, could not determinewho was speaking or being spoken to. She reportedwatching a movie in which, after a heated argument,she noted to her surprise and consternation that thecharacter she had been watching was suddenly sentreeling across the room, apparently as a conse-quence of a punch thrown by a character she hadnever seen” (Coslett & Saffran, 1991, p. 1525).Coslett and Saffran’s patient also illustrated howpatients with Bálint’s syndrome are confoundedin their efforts to read: “Although she read singlewords effortlessly, she stopped reading becausethe ‘competing words’ confused her” (Coslett &Saffran, 1991, p. 1525). Luria’s patient reported thathe “discerned objects around him with difﬁculty,that they ﬂashed before his eyes and sometimes dis-appeared from his ﬁeld of vision. This [was] par-ticularly pronounced in reading: the words and linesﬂashed before his eyes and now one, now another,extraneous word suddenly intruded itself into thetext.” The same occurred in writing: “[T]he patientwas unable to bring the letters into correlation withhis lines or to follow visually what he was writingdown: letters disappeared from the ﬁeld of vision,overlapped with one another and did not coincidewith the limits of the lines” (Luria, 1959, p. 440).Coslett and Saffran’s patient “was unable to writeas she claimed to be able to see only a single letter;thus when creating a letter she saw only the tip ofthe pencil and the letter under construction and“lost” the previously constructed letter” (Coslett &Saffran, 1991, p. 1525).Figure 2.4 shows the attempts of one of Luria’spatients to draw familiar objects. When the patient’sattention was focused on the attempt to draw a partof the object, the orientation of that part with regardto the rest of the object was lost, and the renderingwas reduced to piecemeal fragments.Patients are unable to perform the simplest every-day tasks involving the comparison of two objects.They cannot tell which of two lines is longer, norwhich of two coins is bigger. Holmes and Horax’spatient could not tell, visually, which of two pencilswas bigger, although he had no difﬁculty doing soif he touched them. Holmes and Horax made theimportant observation that although their patientcould not explicitly compare the lengths of twolines or the angles of a quadrilateral shape, he hadno difﬁculty distinguishing shapes whose identityis implicitly dependent upon such comparisons:“Though he failed to distinguish any difference inthe length of lines, even if it was as great as 50percent, he could always recognize whether aquadrilateral rectangular ﬁgure was a square or not.. . . [H]e did not compare the lengths of its sides but‘on the ﬁrst glance I see the whole ﬁgure and knowwhether it is a square or not’. . . . He could alsoappreciate . . . the size of angles; a rhomboid evenwhen its sides stood at almost right angles was ‘asquare shoved out of shape’” (Holmes & Horax,1919, p. 394).Holmes and Horax appreciated the importance oftheir observations for the understanding of normalvision: “It is therefore obvious that though he couldnot compare or estimate linear extensions he pre-served the faculty of appreciating the shape of bidi-mensional ﬁgures. It was on this that his abilityto identify familiar objects depended” (Holmes &Horax, 1919, p. 394). “[T]his is due to the rule thatthe mind when possible takes cognizance of unities”(Holmes & Horax, 1919, p. 400).Spatial DisorientationHolmes and Horax considered spatial disorientationto be a symptom independent from simultanag-nosia, and to be the cardinal feature of the syn-Robert Rafal 30
drome: “The most prominent symptom . . . was hisinability to orient and localize correctly objectswhich he saw” (Holmes & Horax, 1919, pp.390–391). Patients with Bálint’s syndrome cannotindicate the location of objects, verbally or by point-ing (optic ataxia, to be discussed later). Holmesand Horax emphasized that the defect in visuallocalization was not restricted to visual objects inthe outside world, but also extended to a defect inspatial memory: “[H]e described as a visualist doeshis house, his family, a hospital ward in which hehad previously been, etc. But, on the other hand, hehad complete loss of memory of topography; he wasunable to describe the route between the house ina provincial town in which he had lived all his lifeand the railways station a short distance away,explaining ‘I used to be able to see the way but Ican’t see it now. . . .’ He was similarly unable to sayhow he could ﬁnd his room in a barracks in whichhe had been stationed for some months, or describethe geography of trenches in which he had served”(Holmes & Horax, 1919, p. 389).This gentleman was clearly lost in space: “On oneoccasion, for instance, he was led a few yards fromhis bed and then told to return to it; after searchingwith his eyes for a few moments he identiﬁed thebed, but immediately started off in a wrong direc-tion” (Holmes & Horax, 1919, p. 395). This patientshowed, then, no recollection of spatial relation-ships of places he knew well before his injury, andno ability to learn new routes: “He was never ableto give even an approximately correct description ofthe way he had taken, or should take, and though hepassed along it several times a day he never ‘learnedhis way’ as a blind man would” (Holmes & Horax,1919, p. 395).Holmes and Horax concluded that “The fact thathe did not retain any memory of routes and topo-graphical relations that were familiar to him beforehe received his injury and could no longer recallBalint’s Syndrome 31DrawingElephantheadearsnoseeyestrunkfeetfeetbody“I can visualize it well ... butmy hands dont move properly”wallsroofwindowdoorwindowsCopyingFigure 2.4Drawing by the patient described by Luria (1959).
them, suggests that the cerebral mechanisms con-cerned with spatial memory, as well as those thatsubserve the perception of spatial relations, musthave been involved” (Holmes & Horax, 1919,p. 404).Impaired Oculomotor BehaviorOculomotor behavior is also chaotic in Bálint’ssyndrome, with striking disturbances of ﬁxation,saccade initiation and accuracy, and smooth-pursuiteye movements. The patient may be unable to main-tain ﬁxation, may generate apparently random sac-cadic eye movements (Luria et al., 1963), and mayseem unable to execute smooth-pursuit eye move-ments. The disorder of eye movements in Bálint’ssyndrome is restricted to visually guided eye move-ments. The patient can program accurate eye move-ments when they are guided by sound or touch:“When, however, requested to look at his own ﬁngeror to any point of his body which was touched hedid so promptly and accurately” (Holmes & Horax,1919, p. 387).Holmes and Horax suggested that the oculomo-tor disturbances seen in Bálint’s syndrome weresecondary to spatial disorientation: “Some inﬂuencemight be attributed to the abnormalities of themovements of his eyes, but . . . these were an effectand not the cause” (Holmes & Horax, 1919, p. 401).“All these symptoms were secondary to anddependent upon the loss of spatial orientation byvision” (Holmes & Horax, 1919, p. 405). Theydescribed, similarly, the behavior of a patient withBálint’s syndrome when he was tested for smooth-pursuit eye movements: “When an object at whichhe was staring was moved at a slow and uniformrate he could keep his eyes on it, but if it was jerkedor moved abruptly it quickly disappeared” (Holmes& Horax, 1919, p. 387).Optic AtaxiaFigure 2.5 shows misreaching in Bálint’s syndrome.Even after the patient sees the comb, he doesn’t lookdirectly at it, and his reaching is inaccurate in depthas well as being off to the side. He groped for thecomb until his hand bumped into it. Given a penciland asked to mark the center of a circle, the patientwith Bálint’s syndrome typically won’t even get themark within the circle—and may not be able to evenhit the paper. In part this may be because the patientcannot take cognizance, simultaneously, of both thecircle and the pencil point; but it is also clear thatthe patient doesn’t know where the circle is.Holmes and Horax considered optic ataxia, likethe oculomotor impairment, to be secondary to thepatient’s “inability to orient and localize correctlyin space objects which he saw. When . . . asked totake hold of or point to any object, he projected hishand out vaguely, generally in a wrong direction,and had obviously no accurate idea of its distancefrom him” (Holmes & Horax, 1919, p. 391).Holmes and Horax again observed that the lackof access to a representation of space was speciﬁcto vision. Their patient was able to localize soundsand he did have a representation of peripersonalspace based on kinesthetic input: “The contrastbetween the defective spatial guidance he receivedfrom vision and the accurate knowledge of spacethat contact gave him, was excellently illustratedwhen he attempted to take soup from a small bowlwith a spoon; if he held the bowl in his own handhe always succeeded in placing the spoon accu-rately in it, . . . but when it was held by a observerRobert Rafal 32Figure 2.5Optic ataxia in Bálint’s syndrome.
or placed on a table in front of him he could rarelybring his spoon to it at once, but had to grope for ittill he had located it by touch” (Holmes & Horax,1919, pp. 391 and 393).Impaired Depth PerceptionHolmes and Horax (1919) also attributed impaireddepth perception to spatial disorientation. Theyviewed the loss of depth perception in Bálint’s syn-drome as a consequence of the loss of topographicperception, and as a failure to have any appreciationof distance. In their patient they attributed the lossof blinking in response to a visual threat to thepatient’s inability to recognize the nearness of thethreatening object. Difﬁculty in judging distancesalso causes another serious problem for patients—they collide with objects when they walk about.The impairment of depth perception in Bálint’ssyndrome seems to be due to a failure to appreciatethe relative location of two objects, or of the patientand the object he or she is looking at. Size cuesseem not to help the patient judge the distance toan object. However, Holmes and Horax commentedthat their patient’s lack of a sense of distance did notindicate a lack of appreciation of metrics in generalsince he could: “indicate by his two hands the exten-sion of ordinary standards of linear measurement,as an inch, a foot, or a yard . . . and he could indi-cate the lengths of familiar objects, as his riﬂe,bayonet, etc. (Holmes & Horax, 1919, p. 393).Nosological Consideration: Bálint’s Syndrome,Its Neighbors and RelativesThe clinical picture described here is that of Bálint’ssyndrome when it is quite dense and in its pureform. It reﬂects the typical presentation of a pa-tient with bilateral lesions restricted to the parieto-occipital junction. While strokes and head traumamay occasionally cause discretely restricted andsymmetrical lesions, it is more commonly the casethat lesions will not respect these territories andwill cause more extensive damage to the occipital,parietal, and temporal lobes.Coexisting visual ﬁeld deﬁcits, hemispatialneglect, apperceptive or associative agnosia, pro-sopagnosia, alexia, and other cognitive deﬁcits areoften present in association with Bálint’s syndromeor some of its constituent elements.The patient reported by Bálint (1909), forexample, also had left hemispatial neglect, possiblyowing to extension of the lesion into the right tem-poroparietal junction (ﬁgure 2.1): “[T]he attentionof the patient is always directed [by approximately35 or 40 degrees] to the right-hand side of spacewhen he is asked to direct his attention to anotherobject after having ﬁxed his gaze on a ﬁrst one, hetends to the right-hand rather than the left-handside” (cited by Husain and Stein, 1988, p. 90). Inother cases in which a constriction of visual atten-tion is also associated with object agnosia, the ten-dency of the patient to become locked on parts ofobjects may contribute to observed agnosic errorsand may result in diagnostic confusion with inte-grative agnosia (Riddoch & Humphreys, 1987).It is also the case that a given patient may haveoptic ataxia, spatial disorientation, or simultanag-nosia without other elements of Bálint’s syndrome.Thus, spatial disorientation may occur withoutsimultanagnosia (Stark, Coslett, & Saffran, 1996);optic ataxia may occur without simultanagnosiaor spatial disorientation (Perenin & Vighetto, 1988);and simultanagnosia may occur without spatial dis-orientation (Kinsbourne & Warrington, 1962, 1963;Rizzo & Robin, 1990). It should be borne in mindthat in such cases, the observed symptoms mayresult from very different mechanisms than thosethat produce them in Bálint’s syndrome. Thus, whileoptic ataxia and oculomotor impairment may beattributable to a loss of spatial representation inpatients with Bálint’s syndrome caused by bilateralparieto-occipital lesions, optic ataxia from superiorparietal lesions may reﬂect disruption of the neuralsubstrates mediating visuomotor transformations(Milner & Goodale, 1995).Similarly, simultanagnosia may be caused byvery different kinds of lesions for different reasons.The term simultanagnosia was originated speciﬁ-cally to describe a defect in integrating complexBalint’s Syndrome 33
visual scenes (Wolpert, 1924). As deﬁned byWolpert, the term includes, but is more general than,the constriction of attention seen in Bálint’s syn-drome. It is seen in conditions other than Bálint’ssyndrome and may result from unilateral lesions.Hécaen and de Ajuriaguerra describe the difﬁcul-ties of one of their patients (case 1) on being offereda light for a cigarette: “[W]hen the ﬂame wasoffered to him an inch or two away from the ciga-rette held between his lips, he was unable to se theﬂame because his eyes were ﬁxed on the cigarette”(Hécaen & de Ajuriaguerra, 1956, p. 374). How-ever, the mechanism underlying simultanagnosia insuch cases may be different than that which causessimultanagnosia in Bálint’s syndrome.Unlike in Bálint’s syndrome, simultanagnosiacaused by unilateral left temporoparietal lesionsappears to be due to a perceptual bottleneck causedby slowing of visual processing as measured byrapid, serial, visual presentation (RSVP) tasks(Kinsbourne & Warrington, 1962, 1963). In con-trast, patients with Bálint’s syndrome may be ableto recognize a series of individual pictures ﬂashedbrieﬂy in an RSVP test (Coslett & Saffran, 1991).Implications of Bálint’s Syndrome forUnderstanding Visual CognitionBálint’s syndrome holds valuable lessons for under-standing the neural processes involved in control-ling attention, representing space, and providingcoherence and continuity to conscious visual ex-perience: (1) attention makes a selection fromobject-based representations of space; (2) inde-pendent neural mechanisms that operate in parallelorient attention within objects and between objects;(3) the candidate objects on which attention oper-ates are generated preattentively by early vision inthe absence of explicit awareness; and (4) attentionis involved in affording explicit (conscious) accessto the spatial representations needed for goal-directed action and for binding features of objects.Object- and Space-Based AttentionAn appreciation of simultanagnosia in Bálint’ssyndrome has proven inﬂuential in helping toresolve one of the major theoretical controversiesin visual attention research. The issue at stake waswhether visual attention acts by selecting locationsor objects. Work by Michael Posner and others(Posner, 1980; Posner, Snyder, & Davidson, 1980)showed that allocating attention to a location in thevisual ﬁeld enhanced the processing of the visualsignals that appeared at the attended location.Object-based models of attention, in contrast,postulate that preattentive processes parse the visualscene to generate candidate objects (more on thislater) and that attention then acts by selecting onesuch object for further processing that can guidegoal-directed action. These models are supportedby experiments in normal individuals that showbetter discrimination of two features belonging tothe same object than of features belonging to twodifferent objects (Duncan, 1984) and that theseobject-based effects are independent of the spatiallocation of their features (Baylis & Driver, 1995;Vecera & Farah, 1994).Physiological recordings have shown that anobject-based attentional set can modulate process-ing in the extrastriate visual cortex (Chelazzi,Duncan, Miller, & Desimone, 1998). Recent neu-roimaging studies have conﬁrmed that attentionalselection of one of two objects results in activationof brain regions representing other unattendedfeatures of that object (O’Craven, Downing, &Kanwisher, 2000).Object-based models predict that brain lesionscould produce an object-based simultanagnosia thatis independent of location. This is precisely the kindof simultanagnosia that was observed in patientswith Bálint’s syndrome decades before this debatewas joined by psychologists and physiologists.Moreover, recent experimental work by Humphreysand colleagues has shown that simultanagnosia canbe manifest in nonspatial domains. In two patientswith parietal lobe lesions and poor spatial localiza-tion, these authors observed that pictures extin-Robert Rafal 34
guished words and closed shapes extinguishedopen shapes (Humphreys, Romani, Olson, Riddoch,& Duncan, 1994). Thus the object-based attentiondeﬁcit in this syndrome cannot be attributed simplyto the effects of parietal lobe lesions in disruptingaccess to spatial representations.Neural Representations of Objects in SpaceThe spatial representations upon which attentionoperates are determined by objects, or “candidate”objects, derived from a grouped array of featuresby early vision (Vecera & Farah, 1994), and arenot simple Cartesian coordinates of empty spacecentered on the observer (Humphreys, 1998).Humphreys has recently posited that attentionoperates on spatial representations determined byobjects, and that there are separate mechanisms,operating in parallel, for shifting attention withinobjects and between objects (Humphreys, 1998).Shifting attention within an object implies shiftingattention between locations within the object.Figure 2.6 shows stimuli that Cooper andHumphreys (2000) used to study shifts of attentionwithin and between objects in patient G.K. withBálint’s syndrome. In conditions 1 and 2, G.K.’stask was to report whether the upright segmentswere the same or different lengths. For the stimuliin condition 1, in which the comparison wasbetween two parts of the same object, G.K. wascorrect on 84% of the trials, whereas in condition 2in which the judgment required comparison of twoseparate objects, performance was at chance level(54%).Visual Processing Outside of ConsciousAwarenessThe interaction of spatial and object representationsin determining the allocation of attention requiresthat candidate objects be provided by preattentiveprocesses that proceed in the absence of awareness.Cumulative observations in patients with hemispa-tial neglect (see chapter 1) have indeed providedgrowing evidence that early vision does separateﬁgure from ground, group features, and assignprimary axes; it even extracts semantic informationthat can assign attentional priorities for subsequentprocessing. Here some examples are considered inwhich implicit measures of processing in Bálint’ssyndrome have provided strong evidence for exten-sive processing of visual information outside ofawareness.Preattentive Representation of SpaceSpatial disorientation is a cardinal feature ofBálint’s syndrome, and one view of the constrictionBalint’s Syndrome 35Figure 2.6Figures used by Cooper and Humphreys (2000) to demonstrate grouping in Bálint’s syndrome.
of visual attention posits that it, too, is due to a lossof a neural representation of space on which atten-tion may act (Friedman-Hill et al., 1995). However,as we have seen from the work of Humphreyset al. (1994), simultanagnosia may also occur fornonspatial information, such as shifting betweenwords and pictures. Moreover, recent observa-tions in patients with both hemispatial neglect(Danziger, Kingstone, & Rafal, 1998) and Bálint’ssyndrome (Robertson, Treisman, Friedman-Hill,& Grabowecky, 1997) have shown that parietaldamage does not eliminate representations of spatialinformation, but rather prevents explicit access tothis information.Robertson et al. (1997) showed that althoughpatient R.M. could not explicitly report the relativelocation of two objects, he nevertheless exhibited aspatial Stroop interference effect. That is, althoughhe could not report whether the word “up” was inthe upper or lower visual ﬁeld, he was, nevertheless,slower to read “up” if it appeared in the lower visualﬁeld than in the upper visual ﬁeld.Preattentive Grouping of Features andAlignment of Principal AxisAs described earlier, observations by Luria (Luria,1959) and by Humphreys & Riddoch (1993) haverevealed that there is less simultanagnosia whenshapes in the visual ﬁeld are connected. Otherrecent observations by Humphreys and his col-leagues in patient G.K. have conﬁrmed that group-ing based on brightness, collinearity, surroundeness,and familiarity also are generated preattentively, asis grouping based on alignment of a principal axis.Figure 2.7 shows G.K.’s performance in reportingtwo items; it shows that performance is betterwhen the items are grouped on the basis of bright-ness, collinearity, connectedness, surroundness, andfamiliarity (Humphreys, 1998).Preattentive Processing of Meaning of WordsAs is the case in hemispatial neglect, neglectedobjects do appear to be processed to a high levelof semantic classiﬁcation in patients with Bálint’ssyndrome. Furthermore, although this informationis not consciously accessible to the patient, it doesinﬂuence the perception of objects that are seen. Forexample, Coslett & Saffran (1991) simultaneouslypresented pairs of words or pictures brieﬂy to theirpatient, and asked her to read or name them. Whenthe two stimuli were not related semantically, thepatient usually saw only one of them, but when theywere related, she was more likely to see them both.Hence, both stimuli must have been processed to asemantic level of representation, and the meaningof the words or objects determined whether one orboth would be perceived.Words are an example of hierarchical stimuli inwhich letters are present at the local level and theword at the global level. We (Baylis, Driver, Baylis,& Rafal, 1994) showed patient R.M. letter stringsand asked him to report all the letters he could see.Since he could only see one letter at a time, he foundthis task difﬁcult and, with the brief exposure dura-tions used in the experiment, he usually only saw afew of the letters. However, when the letter stringconstituted a word, he was able to report moreletters than when it did not. That is, even when thepatient was naming letters and ignoring the word,the word was processed and helped to bring the con-stituent letters to his awareness.Attention, Spatial Representation, and FeatureIntegration: Gluing the World TogetherI discussed earlier how a single object seen by apatient is experientially mutable in time. It has nopast or future. Any object that moves disappears. Inaddition, objects seen in the present can be per-plexing to the patient, because other objects thatthe patient does not see, and their features, areprocessed and impinge upon the experience of theattended object. Normally, the features of an object,such as its color and its shape, are correctly con-joined, because visual attention selects the locationof the object and glues together all the featuressharing that same location (Treisman & Gelade,1980). For the patient with Bálint’s syndrome,however, all locations are the same, and all theRobert Rafal 36
features that impinge on the patient’s awareness areperceptually conjoined into that object.Friedman-Hill et al. (1995) showed R.M. pairs ofcolored letters and asked him to report the letter hesaw and its color. R.M. saw an exceptional numberof illusory conjunctions (Treisman & Schmidt,1982), reporting the color of the letter that he didnot see as being the color of the letter that he didreport. Lacking access to a spatial representationin which colocated features could be coregisteredby his constricted visual attention, visual featuresthroughout the ﬁeld were free ﬂoating and con-joined arbitrarily. Since a spatial Stroop effect wasobserved in patient R.M. (see earlier discussion),Robertson and her colleagues (1997) argued thatspatial information did exist and that featurebinding relies on a relatively late stage whereimplicit spatial information is made explicitlyaccessible. Subsequent observations in patient R.M.showed, however, that feature binding also occurredimplicitly. Wojciulik & Kanwisher (1998) used amodiﬁcation of a Stroop paradigm in which R.M.was shown two words, one of which was colored,and asked to report the color and ignore the words.Although he was not able to report explicitly whichword was colored, there was nevertheless a largerStroop interference effect (i.e., he was slower toname the color) when a word had an incongruentBalint’s Syndrome 37Figure 2.7Figures used by Humphreys (1998) to demonstrate grouping in Bálint’s syndrome.
color. Thus, there was implicit evidence that theword and its color had been bound, even thoughR.M. had no explicit access to the conjunction offeatures.Conclusions and Future DirectionsLost in space, and stuck in a perceptual present con-taining only one object that he or she cannot ﬁnd orgrasp, the patient with Bálint’s syndrome is helplessin a visually chaotic world. Objects appear and dis-appear and their features become jumbled together.Contemporary theories of attention and percep-tion help us to understand the experience of thesepatients. At the same time, their experience providescritical insights into the neural basis of visual atten-tion and perception, and how they operate togethernormally to provide coherent perceptual experienceand efﬁcient goal-directed behavior.Some of the critical issues remain unresolved andawait future research. It remains unclear whethersimultanagnosia and spatial disorientation are inde-pendent symptoms in Bálint’s syndrome, or whetherthe apparent constriction of visual attention is asecondary consequence of the lack of access to anexplicit representation of space. The identiﬁcationof individual cases in which these two symptomsare dissociated would resolve this question. It is alsoimportant to learn more about the impairment infeature binding that causes the generation of illu-sory conjunctions, and whether this deﬁcit is anintegral component of the syndrome or, rather, ispresent only in some patients with a lesion in a spe-ciﬁc part of the parietal-occipital association cortex.Furthermore, if the component symptoms of thesyndrome are found to be dissociable, we will needto know more about the neural substrates of each.ReferencesBálint, R. (1909). Seelenlahhmung edes “schauens,”optische ataxie, raumliche storung der aufmerksamkeit.Montschrife Pscyhiatrie und Neurologie, 25, 51–81.Baylis, G. C., & Driver, J. (1995). One-sided edge-assignment in vision: 1. Figure-ground segmentation andattention to objects. Current Directions in PsychologicalScience, 4, 201–206.Baylis, G. C., Driver, J., Baylis, L. L., & Rafal, R. D.(1994). Perception of letters and words in Bálint’ssyndrome: Evidence for the unity of words. Neuropsy-chologia, 32, 1273–1286.Benson, D. F., Davis, R. J., & Snyder, B. D. (1988).Posterior cortical atrophy. Archives of Neurology, 45,789–793.Chelazzi, L., Duncan, J., Miller, E. K., & Desimone, R.(1998). Responses of neurons in inferior temporal cortexduring memory-guided visual search. Journal of Neuro-physiology, 80, 2918–2940.Cooper, C. G., & Humphreys, G. W. (2000). Coding spacewithin but not between objects: Evidence from Bálint’ssyndrome. Neuropsychologia 38, 723–733.Coslett, H. B., & Saffran, E. (1991). Simultanagnosia. Tosee but not two see. Brain, 113, 1523–1545.Danziger, S., Kingstone, A., & Rafal, R. (1998). Reﬂex-ive orienting to signals in the neglected visual ﬁeld.Psychological Science, 9, 119–123.Duncan, J. (1984). Selective attention and the organizationof visual information. Journal of Experimental Psychol-ogy: General, 113, 501–517.Friedman-Hill, S. R., Robertson, L. C., & Treisman, A.(1995). Parietal contributions to visual feature binding:Evidence from a patient with bilateral lesions. Science,269, 853–855.Girotti, F., Milanese, C., Casazza, M., Allegranza, A.,Corridori, F., & Avanzini, G. (1982). Oculomotor distur-bances in Bálint’s syndrome: Anatomoclinical ﬁndingsand electrooculographic analysis in a case. Cortex, 16,603–614.Godwin-Austen, R. B. (1965). A case of visual disorien-tation. Journal of Neurology, Neurosurgery and Psychia-try, 28, 453–458.Harvey, M. (1995). Psychic paralysis of gaze, optic ataxia,spatial disorder of attention. Translated from Bálint(1909). Cognitive Neuropsychology, 12, 266–282.Harvey, M., & Milner, A. D. (1995). Bálint’s patient.Cognitive Neuropsychology, 12, 261–264.Hécaen, H., & de Ajuriaguerra, J. (1956). Agnosie visuellepour les objects inanimes par lesion unilaterle gauche.Review Neurologique, 94, 222–233.Robert Rafal 38
Hof, P. R., Bouras, C., Constintinidis, J., & Morrison, J.H. (1989). Bálint’s syndrome in Alzheimer’s disease:Speciﬁc disruption of the occipito-parietal visual pathway.Brain Research, 493, 368–375.Hof, P. R., Bouras, C., Constantinidis, J., & Morrison,J. H. (1990). Selective disconnection of speciﬁc visualassociation pathways in cases of Alzheimer’s diseasepresenting with Bálint’s syndrome. Journal of Neu-ropathology and Experimental Neurology, 49, 168–184.Holmes, G., & Horax, G. (1919). Disturbances of spatialorientation and visual attention, with loss of stereoscopicvision. Archives of Neurology and Psychiatry, 1, 385–407.Humphreys, G. W. (1998). Neural representation ofobjects in space: A dual coding account. PhilosophicalTransactions of the Royal Society of London, Ser. B, 353,1341–1351.Humphreys, G. W., & Riddoch, M. J. (1993). Interactiveattentional systems in unilateral visual neglect. InI. H. Robertson & J. C. Marshall (Eds.), Unilateralneglect: Clinical and experimental studies (pp. 139–168).Hillsdale, NJ: Lawrence Erlbaum Associates.Humphreys, G. W., Romani, C., Olson, A., Riddoch,M. J., & Duncan, J. (1994). Non-spatial extinction fol-lowing lesions of the parietal lobe in humans. Nature,372(6504), 357–359.Husain, M., & Stein, J. (1988). Rezso Bálint and his mostcelebrated case. Archives of Neurology 45, 89–93.Karnath, H.-O., Ferber, S., Rorden, C., & Driver, J. (2000).The fate of global information in dorsal simultanagnosia.NeuroCase 6, 295–306.Kase, C. S., Troncoso, J. F., Court, J. E., Tapia, F. J., &Mohr, J. P. (1977). Global spatial disorientation. Journalof the Neurological Sciences, 34, 267–278.Kinsbourne, M., & Warrington, E. K. (1962). A disorderof simultaneous form perception. Brain, 85, 461–486.Kinsbourne, M., & Warrington, E. K. (1963). The localiz-ing signiﬁcance of limited simultaneous visual formperception. Brain, 86, 461–486.Luria, A. R. (1959). Disorders of “simultaneous percep-tion” in a case of bilateral occipito-parietal brain injury.Brain, 83, 437–449.Luria, A. R., Pravdina-Vinarskaya, E. N., & Yarbuss, A. L.(1963). Disorders of ocular movement in a case ofsimultanagnosia. Brain, 86, 219–228.Mendez, M. F., Turner, J., Gilmore, G. C., Remler, B., &Tomsak, R. L. (1990). Bálint’s syndrome in Alzheimer’sdisease: Visuospatial functions. International Journal ofNeuroscience, 54, 339–346.Milner, A. D., & Goodale, M. A. (1995). The visual brainin action. Oxford: Oxford University Press.O’Craven, K., Downing, P., & Kanwisher, N. (2000).fMRI evidence for objects as the units of attentionalselection. Nature 401, 584–587.Perenin, M.-T., & Vighetto, A. (1988). Optic ataxia: Aspeciﬁc disruption in visuomotor mechanisms. I. Differentaspects of the deﬁcit in reaching for objects. Brain, 111,643–674.Pierrot-Deseillgny, C., Gray, F., & Brunet, P. (1986).Infarcts of both inferior parietal lobules with impairmentof visually guided eye movements, peripheral visualinattention and optic ataxia. Brain, 109, 81–97.Posner, M. I. (1980). Orienting of attention. QuarterlyJournal of Experimental Psychology, 32, 3–25.Posner, M. I., Snyder, C. R. R., & Davidson, B. (1980).Attention and the detection of signals. Journal of Experi-mental Psychology: General, 109, 160–174.Riddoch, M. J., & Humphreys, G. W. (1987). A case ofintegrative visual agnosia. Brain, 110, 1431–1462.Rizzo, M., & Robin, D. A. (1990). Simultanagnosia: Adefect of sustained attention yields insights on visualinformation processing. Neurology, 40, 447–455.Robertson, L. C., Treisman, A., Friedman-Hill, S. R., &Grabowecky, M. (1997). The interaction of spatial andobject pathways: Evidence from Bálint’s syndrome.Journal of Cognitive Neuroscience, 9, 295–317.Stark, M., Coslett, H. B., & Saffran, E. (1996). Impairmentof an egocentric map of locations: Implications forperception and action. Cognitive Neuropsychology, 13,481–523.Treisman, A., & Gelade, G. (1980). A feature integrationtheory of attention. Cognitive Psychology, 12, 97–136.Treisman, A., & Schmidt, N. (1982). Illusory conjunctionsin the perception of objects. Cognitive Psychology, 14,107–141.Tyler, H. R. (1968). Abnormalities of perception withdefective eye movements (Bálint’s syndrome). Cortex, 3,154–171.Balint’s Syndrome 39
Vecera, S. P., & Farah, M. J. (1994). Does visual attentionselect objects or locations? Journal of ExperimentalPsychology: General, 123, 146–160.Verfaellie, M., Rapcsak, S. Z., & Heilman, K. M. (1990).Impaired shifting of attention in Bálint’s syndrome. Brainand Cognition, 12, 195–204.Williams, M. (1970). Brain damage and the mind.Baltimore: Penguin Books.Wojciulik, W., & Kanwisher, N. (1998). Implicit butnot explicit feature binding in a Bálint’s patient. VisualCognition, 5, 157–182.Wolpert, I. (1924). Die simultanagnosie: Storung dergeamtauffassung. Zeitschrift für die gesante Neurologieund Psychiatrie, 93, 397–415.Robert Rafal 40
Michael S. MegaMemory is traditionally divided into implicit andexplicit processes (ﬁgure 3.1). Implicit functionsare not under conscious control, while explicit func-tions are available to our subjective awareness.Implicit processes include classic conditioning orassociative learning (such as the conditioned eye-blink response), procedural memory or skill learn-ing (such as riding a bike or learning the rotarypursuit task), and the effects of priming that facili-tate the acquisition of information in the modalityspeciﬁc to the presentation of the information.Explicit memory includes both our recall of every-thing that has happened to us—called “episodicmemory,” and all the information about the mean-ings of things—called “semantic memory.” Theemphasis here is on patients’ complaints of explicitmemory impairments.Explicit memory is heuristically divided into thesubprocesses of acquisition, storage, and retrievalof information. Disorders of learning are assumedto arise from deﬁcits in either acquisition or storage;thus poor spontaneous recall could arise from twodistinct problems—either a failure in learning newinformation or a deﬁcit in retrieval.Classically, the amnesic syndrome has beendeﬁned as the presence of a signiﬁcant isolatedmemory disorder in the absence of disturbed atten-tion, language, visuospatial, or executive function(executive function is the ability to manipulate pre-viously acquired knowledge). Although the exactdysfunctional subprocess producing amnesia is con-troversial (Bauer, Tobias, & Valenstein, 1993), it isclinically useful to describe amnesia as a failure tolearn new information, which is distinct from aretrieval deﬁcit identiﬁed by normal recognition.Recognition, in turn, may depend on two sub-processes: a feeling of familiarity and an explicitrecollection of some context associated with therecognized item (Gardiner & Parkin, 1990; Horton,Pavlick, & Moulin-Julian, 1993; Mandler, 1980).The recognition tasks that patients with hippo-campal and perirhinal lesions preferentially fail on3 Amnesia: A Disorder of Episodic Memoryare those that make greater demands on the laterrecollection-based subprocess (Aggleton & Shaw,1996; Squire & Shimamura, 1986). Successfulrecognition performance, after spontaneous recallhas failed, also draws on intact prefrontal resources.A profound encoding or recognition impairmentappears to require both medial temporal and pre-frontal disconnection or destruction (Aggleton &Mishkin, 1983; Gaffan & Parker, 2000).Case ReportOn the ﬁrst evaluation a 75-year-old right-handed femalewas accompanied by her husband to our clinic complain-ing of a 3–5-year history of declines in memory. Thehistory was mainly provided by the patient’s husband, whoclaimed that 5 years prior to presentation he ﬁrst noticedabnormalities in his wife’s ability to operate a new video-cassette recorder and new 35-mm camera. There was alsoa decline in her ability to cook large meals for dinnerparties that began 3 years prior to presentation. Approxi-mately 2 years prior to presentation, he began noticingdifﬁculty with his wife’s memory so that she was unableto shop for food without a detailed list. She would fre-quently forget conversations that transpired between themor episodes that might have occurred days prior. Approx-imately 6 months prior to presentation, the patient’shusband noted that she forgot what cards were played intheir bridge club when previously she had been an excel-lent player. The patient agreed with the history of memoryproblems, but felt that her cooking was unaffected. Boththe patient and her husband denied any problems withlanguage function, visuospatial function, or any changein personality or mood. The patient continued to be quiteactive socially, as well as taking part in community activ-ities. Despite her memory problem, she was still capableof functioning almost independently with copious listkeeping.On initial examination the patient had a normal generalmedical exam. The patient was well nourished, coopera-tive, well groomed, and in no apparent distress. Thepatient’s attention was intact with six digits forward, ﬁvedigits in reverse. The Mini Mental State Exam (MMSE)(Folstein, Folstein, & McHugh, 1975) score was 28/30; the
patient missed two of the recall questions. Language wasnormal for ﬂuency, comprehension, and repetition; andnaming was intact, with ﬁfteen out of ﬁfteen items on amodiﬁed Boston Naming Test correctly identiﬁed. Verbalﬂuency showed nineteen animals produced in 1 minute,and reading and writing ability were entirely normal.Memory testing using a ten-word list (Fillenbaum et al.,1997) showed a learning curve of four, six, and eight afterthree trials; and after a 10-minute interval with interfer-ence, the patient spontaneously recalled one out of tenitems. Recognition performance, using ten target itemsand ten foils, produced ﬁve additional items, with threefalse positives.Visuospatial function showed no problems in copyingtwo-dimensional ﬁgures and some mild strategy difﬁcultybut good copying of a three-dimensional cube. Executivefunction showed no problems with calculation abilityfor two-digit addition and multiplication; however, wordproblems showed some hesitancy and difﬁculty inresponse, although the answers were eventually correct.Frontal system evaluation showed no perseveration or lossof set; reciprocal programs, go-no-go, and alternatingprograms were all intact. The rest of the neurologicalexamination, including cranial nerves, motor and sensoryfunction, coordination, reﬂexes, and gait was normal.On the initial evaluation the patient underwent formalneuropsychological testing, functional imaging with[18F]ﬂuorodeoxyglucose positron emission tomography(FDG-PET) and structural imaging with 3-D coronal vol-umetric and double echo magnetic resonance imaging(MRI).Neuropsychological evaluation revealed a normalWechsler Adult Intelligence Scale-Revised (WAIS-R)(Wechsler, 1955), a full-scale IQ with normal scores onall subscales except for arithmetic, which was 1 standarddeviation (S.D.) below age and education norms. Lan-guage evaluation was intact on the Boston Naming Test(Kaplan, Goodglass, & Weintraub, 1984), with a scoreof 59/60. Controlled oral word ﬂuency (FAS) (Benton &Hamsher, 1976 revised 1978) and animal naming wereintact, but in the low average range.Memory testing showed impairments on the CaliforniaVerbal Learning Test (CVLT), which demonstrated encod-ing and storage abnormalities greater than 1.5 S.D. belowage- and education-matched norms. Weschler memory(Wechsler Memory Scale, WMS) (Wechsler, 1945), logicalmemory, and paragraph recall showed signiﬁcant abnor-malities in the ﬁrst and second paragraph delayed-recallscores. Nonverbal memory was also impaired as noted bythe 30-minute delay on the Rey-Osterrieth ComplexFigure Recall (Osterrieth, 1944; Rey, 1941) as well as theBenton Visual Retention Test (Benton, 1974). Executivefunction showed spotty performance, with normal trails Aand B but Stroop B declines at approximately 1 S.D. belowage- and education-matched norms. The Ruff ﬁgural ﬂu-ency task showed low normal performance (Jones-Gotman& Milner, 1977). Interpretation of neuropsychologicaltesting concluded that the patient did not meet the criteriafor dementia according to DSM-IV (APA, 1994); however,the patient did meet the criteria for amnesic disorder.FDG-PET showed essentially normal metabolism inthe frontal, parietal, and occipital cortices as well as sub-cortical structures, but indicated decreased metabolismin medial temporal lobe regions, the loss in the left beinggreater than in the right (ﬁgure 3.2). MRI analysis showedno signiﬁcant cerebrovascular disease either cortically orMichael S. Mega 42MemoryImplicit ExplicitProcedural PrimingAssociativeEpisodic SemanticFigure 3.1Conceptual organization and terminology of general memory function.
subcortically and no masses or cortical atrophy; however,there was mild to moderate volume loss in medial tempo-ral structures as determined by qualitative assessmentof the MRI resliced parallel to the long axis of thehippocampus (de Leon et al., 1997; de Leon et al., 1993)(ﬁgure 3.3) Laboratory evaluation showed a normalchemistry panel-20, complete blood cell count, thyroid-stimulating hormone, B12 and folate levels, a negativeﬂuorescent triponamae antibody absorbed test, and anormal erthrocyte sedimentation rate.The history, examination, and diagnostic studiesat initial evaluation described here are consistentwith an amnesic disorder. The patient met criteriaat that time for mild cognitive impairment (MCI)(Petersen et al., 1999) based on logical memoryperformance (a paragraph recall score of less than8) and other memory scores (<1.5 S.D. below age-and education-matched norms). There were no othersigniﬁcant abnormalities, save for some mild tomoderate executive dysfunction as reﬂected in bothhistory and neuropsychological testing. The possi-bility of incipient Alzheimer’s disease could not beruled out at the time of initial evaluation.A follow-up visit occurred approximately a yearand a half after the time of initial presentation. Theinterim history was signiﬁcant for progressivedeclines in memory function with continued preser-vation of language and visuospatial function. Ques-tionable executive dysfunction evolved, withdifﬁculty in preparing meals, balancing her check-book, and paying household bills. No signiﬁcantchange in personality or mood occurred over thisinterim period. Repeat neuropsychological testingwas signiﬁcant for progressive decline in bothverbal and visual memory, with more than 2standard deviations below age and education meanscores on memory tests, but still relative preserva-tion in executive function and some improvementin visuospatial function, with continued unimpairedlanguage function.In comparison with the initial evaluation, PETshowed progressive bilateral metabolic declines inmedial temporal structures, with continued preser-vation of metabolism in the dorsolateral frontal,high parietal, and occipital cortices (ﬁgure 3.2).Structural imaging showed no evidence of newcerebral vascular disease, but showed progressiveatrophy in medial temporal structures (ﬁgure 3.3).Two years later, the patient collapsed at thebreakfast table. Her husband called paramedics, butthey were unable to revive her and she wasAmnesia 43Figure 3.2Oblique axial slices through the long axis of the hip-pocampus of a FDG-PET scan (registered to the Univer-sity of California at Los Angeles (UCLA) Alzheimer’sDisease Atlas) of a patient at baseline evaluation for anisolated memory complaint (left) and at follow-up 18months later (right), showing progressive left medial(arrow) and lateral temporal dysfunction.Figure 3.3Coronal 3-D MRI at baseline evaluation and at follow-up18 months later (registered to the UCLA Alzheimer’sDisease Atlas) showing progressive atrophy in the lefthippocampus (arrow) for the patient described in thecase report.
pronounced dead on arrival at the local hospital,with pathological evaluation showing a myocardialinfarction. Evaluation of the brain showed no evi-dence of signiﬁcant Alzheimer’s changes, but mod-erate cell loss in the CA1 ﬁelds of the hippocampus,with gliotic change on the left and less so on theright. A diagnosis was made of hippocampalsclerosis.A Historical Perspective on AmnesiaThe case described here illustrates a typical assess-ment strategy for a patient presenting with a pro-gressive memory complaint. When a memoryproblem is reported with no clear etiology onbedside, laboratory, or imaging evaluation, it isoften necessary to follow the patient and repeatthe imaging and neuropsychological evaluation in9 months to a year if the complaints persist. In theabove case, worsening was observed at the follow-up exam compared with the baseline assessmentand thus a degenerative disorder was most likely.The patient’s initial performance on bedsidememory testing using a ten-word list showed a ade-quate learning curve during three presentations ofthe same words revealing normal performanceduring the acquisition phase of learning new infor-mation. After a 10-minute interval with interfer-ence, the patient exhibited poor spontaneous recall,showing a defect in either storage or retrieval. It isimportant not to stop the evaluation at this pointbecause in order to determine which of the abovetwo defects are present, we must prompt the patientwith cues; either category or recognition cues.When a patient with poor spontaneous recall sig-niﬁcantly improves their performance with cues,then we have ruled out a disorder of learning andhave identiﬁed a retrieval deﬁcit as being respon-sible for their memory complaints. Care must betaken not to ignore the number of false positives apatient may produce with cueing. The patientdescribed here correctly recognized half of the itemswith cueing, but had also said yes to several itemsthat were foils (i.e., false-positive responses); thisreveals moderate guessing. When cueing does notimprove recall, or when false positives nearly equalor surpass true positives on the recognition portionof the exam, patients should be considered amnesic.When recognition performance surpasses sponta-neous recall, then patients are said to have aretrieval deﬁcit.The anatomical defects underlying a failure tolearn information (i.e., amnesia) are different fromthose underlying a retrieval deﬁcit. Amnesia resultsfrom damage to the medial temporal encodingsystem and its connections to the prefrontal cortex,whereas a retrieval deﬁcit does not result frommedial temporal damage (Teng & Squire, 1999), butfrom dorsolateral frontal cortical abnormalities.The Medial Temporal Encoding SystemAn understanding of hippocampal anatomy is nec-essary before we attempt to interpret lesion andimaging ﬁndings (ﬁgure 3.4). In a normal adultbrain, the distance from the tip of the temporal poleto the most caudal aspect of the hippocampal for-mation is about 7.5cm, while the intraventricularportion of the hippocampus extends about 4cm. Thecytoarchitecture of the temporal pole (Brodmann’sarea 38) resembles that of the perirhinal cortex(areas 35 and 36) (Amaral & Insausti, 1990). Thetemporal polar portion of the perirhinal cortex iscontinuous with the ventral perirhinal cortex, whichlines the banks of the collateral sulcus. The perirhi-nal cortex extends posteriorly to the anterior bound-ary of the lateral geniculate nucleus, where it isreplaced caudally by the parahippocampal cortex(areas TF and TH). Medially, the amygdaloidcomplex lies posterior to the temporal pole, and thehippocampal formation is inferior to the amygdalain its most anterior extent and then caudal to theamygdala. The hippocampal formation is made upof four components: the dentate gyrus, hippocam-pus, subicular complex, and entorhinal cortex.In 1900, Bechterew found that bilateral lesionsof the hippocampus and diencephalic structures (themamillary bodies and anterior thalamus) resulted inderangements of memory function. Both short- andMichael S. Mega 44
long-term memory remained relatively intact;however, the process of registration of informationwas disturbed (Bechterew, 1900). In 1937, Papezproposed a mechanism of emotion based on amedial circuit (ﬁgure 3.5). He described three divi-sions in the brain through which “man’s volitionalenergies” ﬂow. First a “stream of movement” isconducted through the dorsal thalamus and theinternal capsule to the corpus striatum and then outthe central nervous system to the somatic motorneuron. Second, the “stream of thought” arises fromthe thalamus and ascends the internal capsule to ﬁndexpression in the lateral cerebral cortex involved inexecutive function (the ability to organize a solutionto a complex problem). Third, there are impulsesﬂowing through medial structures in a “stream offeeling” (Papez, 1987).Papez conceived of a two-way circuit for the ﬂowof emotion leading to internal or external expres-sion. Information from external sensory receptorsarrives at the primary sensory cortex and then isrelayed to the hippocampal area and onward to themamillary bodies via the fornix. From the mamil-lary bodies, information spreads throughout thehypothalamus, initiating emotional expression oraffect. Impulses are also directed to the anteriornucleus of the thalamus, via the mamillothalamictract, and then diffusely projected through the ante-rior limb of the internal capsule toward the cingu-late gyrus. There, Papez thought, emotion as aninternal state or mood is consciously perceived.Processing within the cingulate gyrus providesfeedback to the hippocampus via the retrosplenialcortex, completing the circuit.Papez observed that mood may be dissociatedfrom affect since in decorticate subjects emotionalstates were displayed but not perceived by thesubject. For Papez, the integration of emotionalresponsiveness with the dorsolateral frontalAmnesia 45Figure 3.4Anatomy of the hippocampus in relation to other brain regions (left) showing the anterior pes, body, and tail with exten-sion into the fornix near the splenium of the corpus callosum (cc). The coronal section (right) shows the hippocampalﬁelds transitioning from CA3 into CA2 and then CA1, which in turn extends into the subiculum and eventually into theentorhinal and perirhinal cortex within the banks of the collateral sulcus.Figure 3.5The medial circuit of Papez, as depicted by MacLean(1949), was proposed to support emotional processing(Papez, 1937).
executive functions occurred in the medial cortex ofthe cingulate gyrus. There was no anatomicalsupport for the closing connection of the cingulategyrus to the hippocampus in Papez’s circuit until1975, when Shipley and Sørensen (1975) docu-mented that the presubiculum, which receives adense cingulate cortex outﬂow, projects heavily tolayer III of the entorhinal cortex—the origin of theperforant pathway into hippocampal pyramidal cells(Witter & Amaral, 1991). The entorhinal cortex alsois the conduit for highly processed sensory affer-ents. The perirhinal and parahippocampal corticesreceive the result of a chain of feed-forward pro-jections from the unimodal and polymodal sensorycortices (Freeman, Murray, O’Neill, & Mishkin,1986; Mesulam & Mulson, 1982; Pandya &Yeterian, 1985; Suzuki & Amaral, 1994; Tranel,Brady, Van Hoesen, & Damasio, 1988; Van Hoesen,1982; Webster, Ungerleider, & Bachevalier,1991), providing 60% of the cortical input to theentorhinal cortex (Insausti, Amaral, & Cowan,1987).Papez incorrectly conceived his hippocampalcircuit as exclusively subserving emotionalprocesses. Bechterew’s insight was more accurate.He observed that defects in episodic memoryencoding occurred when elements of the hip-pocampal circuit were damaged (Bechterew, 1900).This explicit or conscious encoding of events bythe hippocampal circuit stands in contrast to thesubconscious processing that may occur in theamygdala when objects are imbued with emotionalvalence (Bechara et al., 1995; Blair, Morris, Frith,Perrett, & Dolan, 1999; Ikeda et al., 1998; Moriet al., 1999; Price, 1999).The Dorsolateral Frontal Executive SystemThe superior dorsolateral prefrontal cortex (Brod-mann areas 9 and 10) is the center of an executivecognitive network that links the posterior parietallobe and anterior cingulate gyrus. Functionally, thedorsolateral prefrontal cortex subserves executivefunction (Cummings, 1993) and short-term orworking memory (Baddeley, 1992, 1996, 1998)(See Chapter 11, this volume). These functionsinclude the ability to organize a behavioral responseto solve a complex problem (including the strate-gies used in learning new information and system-atically searching memory), activation of remotememories, self-direction and independence fromenvironmental contingencies, shifting and main-taining behavioral sets appropriately, generatingmotor programs, and using verbal skills to guidebehavior.Damage to the dorsolateral frontal cortex pro-duces deﬁcits in executive function and workingmemory.With regard to long-term memory performance,it is the organization and successful execution ofthe retrieval process during free recall that is mostimpaired by dorsolateral frontal lesions because ofthe disruption of the anatomically distributed dor-solateral network.Regions reciprocally connected to the superiordorsolateral prefrontal areas 9 and 10 are the infe-rior prefrontal area 46 (Selemon & Goldman-Rakic,1985), the superior prefrontal area 8, and area 7aof the caudal superior parietal lobe (Yeterian &Pandya, 1993). Parietal area 7a subserves visualspatial attention, visually guided reaching, andplanning of visuospatial strategies. Major reciprocalconnections with the anterior cingulate cortex(supracallosal areas 24, 24a¢ and b¢, and 32¢) (Mega& Cummings, 1997) also occur with prefrontalareas 8, 9, 10, and 46 (Morecraft & Van Hoesen,1991; Vogt & Pandya, 1987). The anterior cingulatecortex is the center for directing attentional systemsand coordinating the dorsolateral frontal and pari-etal heteromodal association network (Morecraft,Geula, & Mesulam, 1993). Areas reciprocally con-nected to the anterior cingulate cortex include therostral insula and anterior parahippocampal areas.The rostral insular cortex is a transitional para-limbic region that integrates visceral alimentaryinput with olfactory and gustatory afferents(Mesulam & Mufson, 1985). Connections withanterior parahippocampal areas 35 and 36 allow theattentional network to inﬂuence multimodal sensoryafferents entering the hippocampus.Michael S. Mega 46
An understanding of the distributed anatomyof the medial encoding circuit and the dorsolateralexecutive system will aid our interpretation ofthe results of human and nonhuman primate lesionstudies producing memory dysfunction as well asthose of functional neuroimaging studies thatattempt to map explicit encoding and retrievalmechanisms in normal subjects.Experimental Research on Episodic MemoryLesion StudiesMedial Temporal LesionsAlthough Bechterew (1900) ﬁrst noted that bilaterallesions of the medial temporal lobes producedencoding defects, it was the detailed report 57 yearslater by Scoville and Milner (1957) on H.M., whounderwent bilateral temporal lobectomy to relieveintractable seizures, that initiated the modernanatomical search for the encoding, storage, andretrieval systems. Speculation (Horel, 1978) thatlesions outside the hippocampus proper mightexplain H.M.’s memory impairment combined withresults from animal studies (Mishkin & Murray,1994) implicate other medial temporal structuressubserving memory. The perirhinal cortex becamea focus of the medial temporal memory systemin monkeys (Meunier, Bachevalier, Mishkin, &Murray, 1993; Suzuki, Zola-Morgan, Squire, &Amaral, 1993; Zola-Morgan, Squire, Amaral,& Suzuki, 1989c; Zola-Morgan, Squire, Clower, &Rempel, 1993) because the delayed matching andnonmatching-to-sample tasks (which are primarilyrecognition tests) were unimpaired if a hippo-campal lesion did not also extend into the monkey’srhinal cortex (Zola-Morgan, Squire, Rempel,Clower, & Amaral, 1992).In H.M., the surgical lesion included the medialtemporal pole, most of the amygdaloid complex,and bilaterally all of the entorhinal cortex (ﬁgure3.6). In addition, the anterior 2cm of the dentategyrus, hippocampus, and subicular complex wereremoved. Given that the collateral sulcus and thecortex lining its banks are visible, then at least someof the posterioventral perirhinal cortex was intact inH.M. The posterior parahippocampal gyrus (areasTF and TH) was only slightly damaged rostrally.The lingual and fusiform gyri, lateral to the collat-eral sulcus, were also intact.Another surgical case (P.B.) had the entire lefttemporal lobe removed in a two-stage procedure(Penﬁeld & Milner, 1958) and suffered a life-longdense amnesia (Corkin, 1965). At autopsy P.B. alsohad preservation of the posterior 22mm of thehippocampus and parahippocampal cortex (Penﬁeld& Mathieson, 1974). Patients with ischemic lesionsbilaterally conﬁned to the CA1 ﬁeld of the hippo-campus (Cummings, Tomiyasu, Read, & Benson,1984; Zola-Morgan, Squire, & Amaral, 1986) haveclinically signiﬁcant anterograde amnesia that ismilder than that of H.M., and have signiﬁcant ret-rograde amnesia that may last more than 25 years(Rempel-Clower, Zola, Squire, & Amaral, 1996).Isolated hippocampal lesions occurring in child-hood appear to disrupt only the encoding of declar-ative memories about past events, but not theencoding of information about the world (semanticmemory) (Vargha-Khadem et al., 1997) that maydepend upon parahippocampal integrity. Thus, if abilateral lesion includes adjacent structures suchas the temporal pole and the anterior perirhinal andentorhinal cortices (as in the case of H.M.), theamnesic syndrome and the resultant recognitiondeﬁcit (Buffalo, Reber, & Squire, 1998) in humansis much more severe than that resulting from anisolated hippocampal lesion.Similar studies on monkeys, which evaluatedsmall lesions restricted to the hippocampal(Alvarez, Zola-Morgan, & Squire, 1995), entorhinal(Leonard, Amaral, Squire, & Zola-Morgan, 1995),or perirhinal and parahippocampal cortices (Suzukiet al., 1993; Zola-Morgan et al., 1989c), have con-ﬁrmed that all these medial temporal structures—except the amygdale (Murray, 1991; Zola-Morgan,Squire, & Amaral, 1989a)—participate in recogni-tion memory (Meunier et al., 1993; Zola-Morgan,Squire, & Amaral, 1989b; Zola-Morgan et al.,Amnesia 47
1989c; Zola-Morgan, Squire, & Ramus, 1994). Thegreatest recognition memory defect occurs whenthe perirhinal cortex is ablated along with the “Hlesion” (hippocampus, dentate gyrus, and subicularcomplex) (Zola-Morgan et al., 1993), followed bythe combined caudal entorhinal and perirhinalcortices and the H lesion (Mahut, Zola-Morgan, &Moss, 1982; Zola-Morgan et al., 1989c); this defectis greater than that resulting from the H lesion alone(Alvarez et al., 1995).Restricted lesions of the perirhinal and parahip-pocampal (Suzuki et al., 1993; Zola-Morgan et al.,1989c) or entorhinal and perirhinal cortices(Meunier et al., 1993) produce chronic multimodalmemory deﬁcits similar to those of a bilateralmedial temporal lobectomy (Suzuki et al., 1993).Thus each of these medial temporal regions makesa contribution to the mnemonic process, withthe resultant recognition memory defect becomingmore severe with the removal of each additionalprocessing region (Zola-Morgan et al., 1994). Whatthe unique functions are, if any, within each regionis not known (Eichenbaum, Otto, & Cohen, 1994;Gaffan, 1994a).Michael S. Mega 48Figure 3.6A coronal MRI of H.M. from rostral (A) to caudal (C) showing the extent of bilateral hippocampal ablation (left) com-pared with a normal 66-year-old subject (right); note the destruction of the amygdala (A), hippocampus (H), and entorhi-nal cortex (EC) anterior to the level of the mamillary bodies (MMN), with relative sparing of the posterior perirhinalcortex (PR) in the banks of the collateral sulcus(cs). V, temporal horn of lateral ventricle. (Adapted from Corkin et al.,1997.)
Diencephalic LesionsHippocampal output from the subiculum, viathe fornix, enters the mamillary body (primarilythe medial mamillary nucleus) and projects to theanterior thalamic nuclei (Aggleton, Desimone, &Mishkin, 1986). The anterior thalamic region alsoreceives direct hippocampal input via the fornix(Aggleton et al., 1986) and has reciprocal connec-tions with the cingulate gyrus and anterior reticu-larus thalami (Gonzalo-Ruiz, Morte, & Lieberman,1997). The dorsomedial thalamic nucleus receivesmore widespread afferents from the amygdala, basalforebrain, and brainstem, and has reciprocal con-nections with the prefrontal cortex and reticularusthalami (Aggleton & Mishkin, 1984; Ilinsky,Jouandet, & Goldman-Rakic, 1985; Kuroda,Yokofujita, & Murakami, 1998; Russchen, Amaral,& Price, 1987). Lesions of the diencephalon oftenaffect both the anterior and the dorsomedial thala-mus; thus the isolation of hippocampal outﬂowwithin the Papez circuit rarely occurs and the addeddisruption of the frontal subcortical circuits andamygdalo-olfactory system (Mega, Cummings,Salloway, & Malloy, 1997) through the dorsomedialthalamus is common.Wernicke-Korsakoff’s syndrome (Korsakoff,1889), which is often the result of thiamine deﬁ-ciency in alcoholics, drew attention to the dien-cephalon in memory function. These and othercases of amnesia associated with third ventriculartumors (Foerster & Gagel, 1933; Grünthal, 1939;Lhermitte, Doussinet, & de Ajuriaguerra, 1937;Sprofkin & Sciarra, 1952; Williams & Pennybacker,1954) pointed to the mamillary bodies or thalamusas critical to memory function. Mamillary bodydamage was thought to be involved in the amnesiaof alcoholic Korsakoff’s psychosis since this regionsuffers the most concentrated pathology in thedisease (Torvik, 1987). The mamillary bodies andthalamus were evaluated in forty-three cases(Victor, Adams, & Collins, 1971) of Wernicke’sencephalopathy; ﬁve patients who recoveredwithout evidence of memory loss were found tohave mamillary body damage but no thalamicdamage; the remaining thirty-eight cases, withenduring memory disturbance, all had additionaldorsomedial thalamic damage. These ﬁndings iden-tiﬁed the thalamus as the pivotal diencephalicstructure subserving memory function. Further-more, mamillary body damage was not correlatedwith memory impairment in Korsakoff patients(Charness & DeLaPaz, 1987; Davila, Shear, Lane,Sullivan, & Pfefferbaum, 1994; Estruch et al., 1998;Shear, Sullivan, Lane, & Pfefferbaum, 1996), andisolated lesions in animals produced only spatialmemory disturbances, without recognition difﬁculty(Aggleton, Neave, Nagle, & Hunt, 1995; Neave,Nagle, & Aggleton, 1997; Parker & Gaffan, 1997b;Sziklas & Petrides, 1997).A thalamic infarction produces lethargy, confu-sion (Cole, Winkelman, Morris, Simon, & Boyd,1992), apathy (Kritchevsky, Graff-Radford, &Damasio, 1987), and amnesia (Cole et al., 1992;Peru & Fabbro, 1997; Shuren, Jacobs, & Heilman,1997), depending on the lesion size. Severe dorso-medial degeneration occurs in fatal familial insom-nia (Lugaresi, Tobler, Gambetti, & Montagna,1998) and results in failure to generate electroencephalographic (EEG) sleep patterns, underscor-ing its role in arousal. The dorsomedial thalamicdamage in Korsakoff patients, as reﬂected byimaging (Charness, 1993; McDowell & LeBlanc,1984; Shimamura, Jernigan, & Squire, 1988) andhistology (Mair, Warrington, & Weiskrantz, 1979;Mayes, Meudell, & Pickering, 1988; Torvik, 1985;Victor et al., 1989), may require additional neuronalloss in the anterior thalamic nuclei (Harding,Halliday, Caine, & Kril, 2000) to produce perma-nent memory impairment.Lesions of the entire magnocellular divisionof the dorsomedial thalamus in monkeys, whichdisrupt all prefrontal efferents (Russchen et al.,1987), compared with isolated medial magnocellu-lar lesions (Parker, Eacott, & Gaffan, 1997) thatdestroy only the entorhinal and perirhinal inputs(Aggleton et al., 1996), produce signiﬁcant impair-ment of object recognition (Gaffan & Parker, 2000).Amnesia 49
Initial reports of the patient N.A., who developedamnesia from a penetrating injury with a fencing foil(Teuber, Milner, & Vaughan, 1968), suggestedrestricted dorsomedial thalamic damage (Squrie& Moore, 1979). However, with the use of high-resolution magnetic resonance imaging (MRI),N.A.’s lesion was found to affect only the ventralaspect of the dorsomedial nucleus, with more severedamage to the intralaminar nuclei, mamillothalamictract, and internal medullary lamina (Squire,Amaral, Zola-Morgan, Kritchevsky, & Press, 1989).Lesions isolated to the internal medullary laminaand the mamillothalamic tract appear capable ofproducing thalamic amnesia (Cramon, Hebel, &Schuri, 1985; Gentilini, DeRenzi, & Crisi, 1987;Graff-Radford, Tranel, Van Hoesen, & Brandt,1990; Malamut, Graff-Radfore, Chawluk,Grossman, & Gur, 1992; Winocur, Oxbury, Roberts,Agnetti, & Davis, 1984) more severe than lesionsthat affect only the dorsomedial thalamus andspare the former structures (Cramon et al., 1985;Graff-Radford et al., 1990; Kritchevsky et al., 1987).Anterior thalamic lesions on the right, sparingthe dorsomedial nucleus (Daum & Ackermann,1994; Schnider, Gutbrod, Hess, & Schroth, 1996),can cause memory dysfunction similar to that ofKorsakoff’s amnesia. Thus limited damage to theanterior thalamus can produce permanent deﬁcitsin episodic memory, supporting previous studiesemphasizing the importance of this region for thememory deﬁcit in alcoholic Korsakoff’s psychosis(Kopelman, 1995; Mair et al., 1979; Mayes et al.,1988). The lateral dorsal nucleus (a member of theanterior thalamic nuclei) projects to the retrosple-nial cortex and is focally affected in Alzheimer’sdisease (Xuereb et al., 1991). These ﬁndings arealso consistent with the severe memory deﬁcitscaused by lesions of the anterior thalamic nuclei inlaboratory animals (Aggleton et al., 1995; Aggleton& Sahgal, 1993; Aggleton & Saunders, 1997;Parker & Gaffan, 1997a); the degree of memorydysfunction is related to the extent of the lesion(Aggleton & Shaw, 1996).The basal forebrain is also considered part of thediencephalon and includes the nucleus accumbens,olfactory tubercle, nucleus of the stria terminalis,and the preoptic area. It also includes the cell groupsthat provide acetylcholine (ACh) to the telen-cephalon: the septum (Ch1), the vertical (Ch2) andhorizontal (Ch3) diagonal bands of Broca, and thebasal nucleus of Meynert (Ch4) (Mesulam, Mufson,Levey, & Wainer, 1983). These neurons play animportant role in attention (anterior cingulatecortex—vertical diagonal band of Broca), memory(hippocampus—medial septum and diagonal band)(Lewis & Shute, 1967), aversive conditioning(amygdala—nucleus basalis of Meynert, nbM), andthe ability to use learned responses (dorsolateralfrontal cortex—nbM).The basal forebrain was long noted to be damagedin repair or rupture of an aneurysm of an anteriorcommunicating artery (Lindqvist & Norlen, 1966;Talland, Sweet, & Ballantine, 1967), but isolatedlesions are rare. Results from three patients whohad discrete lesions in the basal forebrain suggestthat the critical anatomical lesion may be conﬁnedto the nuclei of the medial septum and diagonalband (Abe, Inokawa, Kashiwagi, & Yanagihara,1998; Damasio, Graff-Radford, Eslinger, Damasio,& Kassell, 1985; Morris, Bowers, Chatterjee, &Heilman, 1992), producing a disconnection ofcholinergic innervation to the hippocampus. Thoughspontaneous recall was impaired in these patients,recognition memory was relatively spared.In summary, for diencephalic lesions to produceprofound abnormalities in recall and recognition,a mamillothalamic—anterior thalamus (Papez’scircuit) disconnection should be combined witha dorsomedial thalamic—prefrontal disconnection.Relatively few human cases have been presentedas exceptions to this generalization (Daum &Ackermann, 1994; Mair et al., 1979; Mayes et al.,1988; Schnider et al., 1996). Future combinedstructural and functional imaging assessments maybe needed to determine if prefrontal disconnectionhas occurred in such cases as well.Retrosplenial and Fornix LesionsLesions of the posterior cingulate gyrus disruptmemory function in animals and humans. TheMichael S. Mega 50
closing link in Papez’s circuit, from the anteriorthalamic efferents traveling through the cingulum toBrodmann areas 23 and 29/30, is the posterior cin-gulate projection sent to the presubiculum. Anteriorcingulotomy will not disrupt this memory circuit,but rarely pathological lesions will extend into, andbeyond, the posterior cingulate gyrus. If the lesionextends inferior to the splenium of the corpus cal-losum, it may also disrupt the fornix, thus discon-necting the efferents from the hippocampus tothe diencephalon. If the lesion extends posteriorly,it may damage the supracommissural portion of thehippocampus—the gyrus fasciolaris and the fasci-ola cinerea. A lesion restricted to the left posteriorcingulate gyrus, the cingulum, and the spleniumof the corpus callosum (possibly sparing the fornix)resulted in a severe amnesia after the bleeding ofan arteriovenous malformation (Valenstein et al.,1987). A left-sided lesion that extended beyondthe posterior cingulate gyrus into the fornix andsupracommissural hippocampus after repair of anarteriovenous malformation resulted in a transientnonverbal but permanent verbal amnesia (Cramon& Schuri, 1992). Disruption of septohippocampalpathways in the cingulum and fornix were thoughtby the authors to play a signiﬁcant role in thepatient’s clinical deﬁcit, but the supracommissuralhippocampus was also damaged. Another caseinvolving the right retrosplenial region produced apredominantly visual amnesia (Yasuda, Watanabe,Tanaka, Tadashi, & Akiguchi, 1997), but verbalmemory was affected.Isolation of the cingulum within the posterior cin-gulate gyrus on the left by a cryptic angioma hem-orrhage produced only a transient encoding deﬁcit(Cramon, Hebel, & Ebeling, 1990), suggesting thatthe supracommissural hippocampus or fornix mustalso be damaged for persistent deﬁcits to occur.Splenial tumors are also capable of producingmemory impairment, perhaps via compression ofthe fornix (Rudge & Warrington, 1991).The questionable effect that fornix lesions inhumans have on memory (Cairns & Mosberg, 1951;Dott, 1938; Garcia-Bengochea, De La Torre,Esquivel, Vieta, & Fernandec, 1954; Garcia-Bengochea & Friedman, 1987; Woolsey & Nelson,1975) has been attributed to the lesions beingpartial, or to poor psychometric evaluations (Gaffan& Gaffan, 1991). Bilateral disruption of the fornix,with ensuing memory decline, has resulted fromtumors (Calabrese, Markowitsch, Harders, Scholz,& Gehlen, 1995; Heilman & Sypert, 1977), trauma(D’Esposito, Verfaellie, Alexander, & Katz, 1995;Grafman, Sclazar, Weingartner, Vance, & Ludlow,1985), vascular disease (Botez-Marquard & Botez,1992), and surgical transection (Aggleton et al.,2000; Hassler & Riechert, 1957; Sweet, Talland, &Ervin, 1959).Unilateral damage to the left fornix has alsoproduced verbal memory impairment (Cameron& Archibald, 1981; Gaffan & Gaffan, 1991;Tucker, Roeltgen, Tully, Hartmann, & Boxell,1988). When memory impairment does occur,recall is usually affected more than simple listrecognition (Aggleton et al., 2000; McMackin,Cockburn, Anslow, & Gaffan, 1995). Recognitiontasks that require the encoding of individual itemswithin a complex scene (“object in place” tasks)are poorly performed in both monkeys (Gaffan,1994b) and humans (Aggleton et al., 2000) withfornix transection.An analysis of rare circumscribed lesions inhumans could not determine if lesions in the poste-rior cingulate cortex, rather than the fornix, cingu-lum, or neighboring members of Papez’s circuit,result in amnesia. Excitotoxic lesions in animalsthat destroy neurons but spare ﬁbers of passage canclarify this issue. Based on posterior cingulatecortical lesions made using the selective cytotoxin,quisqualic acid (Sutherland & Hoesing, 1993),animal studies reveal that posterior cingulate corti-cal neurons are necessary for the acquisition andretention of spatial and nonspatial memory.Lesion SummaryLesion studies in both animals and humans havedemonstrated that the individual components ofPapez’s circuit all contribute to general memoryfunction. As a general rule, however, for signiﬁcantencoding defects to occur (as reﬂected by poorAmnesia 51
performance on generic recognition tasks), eitherperirhinal lesions must be present in isolation orother members of Papez’s circuit must be lesioned incombination with disruption of prefrontal-subcorti-cal circuits. Thus, the combination of relatively pre-served recognition memory with poor spontaneousrecall seems to require an intact perirhinal cortex andat least a partially spared prefrontal system.When recognition memory, using the immediaterecognition memory test (RMT) (Warrington, 1984)for both words and pictures, is evaluated across aspectrum of human lesions that produce isolatedspontaneous memory dysfunction, the most im-paired patients are those that are postencephaliticor have Korsakoff syndrome (Aggleton & Shaw,1996). These data support the combined Papez’scircuit–prefrontal contribution to successful encod-ing since the ﬁrst four lesion groups in that studyoften affect these two circuits; or these data suggestthat the RMT task is a poor test of environmentallyrelevant recognition. Future studies should userecognition tasks that do not have a “ceiling effect”as prominent as that of the RMT to further probethe anatomical basis of recognition and encodingintegrity.Functional Neuroimaging StudiesThe Encoding SystemFunctional imaging studies of normal subjects per-forming tasks of episodic encoding, retrieval, andrecognition also support the importance of Papez’scircuit and frontal lobe function in the memoryprocess. Several reviews have recently summarizedthis ﬁeld (Buckner & Koutstaal, 1998; Cabeza &Nyberg, 2000; Cohen et al., 1999; Gabrieli, 1998,2001; Lepage, Habib, & Tulving, 1998; Schacter &Wagner, 1999).Has functional imaging taught us anything we didnot already know from lesion studies about theneuronal systems supporting encoding andretrieval? The explosive growth in functionalimaging studies over the past 5 years has conﬁrmedthe involvement of medial temporal structures in theencoding process (ﬁgure 3.7). When studies varythe novelty of items presented by increasing the rep-etition of presentations, medial temporal activationis increased for scenes (Gabrieli, Brewer, Desmond,& Glover, 1997; Stern et al., 1996; Tulving,Markowitsch, Craik, Habib, & Houle, 1996), wordsMichael S. Mega 52Figure 3.7Regional mapping of the medial temporal activations found in encoding and retrieval tasks of episodic memory for bothfMRI and PET studies of normal subjects. (Adapted from Schacter Wagner, 1999.)
(Kopelman, Stevens, Foli, & Grasby, 1998), object-noun pairs (Rombouts et al., 1997), and word pairs(Dolan & Fletcher, 1997). Bilateral activationusually occurs for scenes, whereas verbal activa-tions are typically left-sided.The magnitude of medial temporal activation isalso correlated with the effectiveness of encoding,as reﬂected by a subject’s recognition performanceafter the presentation and scanning phase; this cor-relative effect is bilateral for scenes (Brewer, Zhao,desmond, Glover, & Gabrieli, 1998) and left-sidedfor words (Wagner et al., 1998c); it has also beencorrelated with free recall for words even 24 hoursafter presentation (Alkire, Haier, Fallon, & Cahill,1998). Distracter tasks (Fletcher et al., 1995) orvarying the level of cognitive processing during thepresentation of items to be learned can affect encod-ing success (Buckner & Koutstaal, 1998; Dembet al., 1995; Gabrieli et al., 1996).Subsequent recall is signiﬁcantly enhanced byjudging the abstract quality or deeper associationsof words, as opposed to their surface orthographicfeatures. Such strategies of leveraging the associa-tions of items to be remembered has been used sincethe ancient Greek orators. Increased medial tempo-ral activation occurs with deeper semantic process-ing than with shallow letter or line inspectionof words (Vandenberghe, Price, Wise, Josephs, &Frackowiak, 1996; Wagner et al., 1998c) or draw-ings (Henke, Buck, Weber, & Wieser, 1997;Vandenberghe et al., 1996), and with intentionalmemorization versus simple viewing of words(Kapur et al., 1996; Kelley et al., 1998), faces(Haxby et al., 1996; Kelley et al., 1998), or ﬁgures(Schacter et al., 1995).Deep processing also recruits dorsolateralprefrontal regions during encoding (ﬁgure 3.8)(Buckner & Koutstaal, 1998). A differential activa-tion of the prefrontal cortex occurs (Fiez, 1997;Poldrack et al., 1999) with a more posteriorbilateral focus (in BA 6/44) for sensory-speciﬁcfeatures of the encoding task (Klingberg & Roland,1998; Zatorre, Meyer, Gjedde, & Evans, 1996),while a greater anterior left prefrontal focus (inBA 45/47) is found with increasing semanticdemands (Demb et al., 1995; Fletcher, Shallice, &Dolan, 1998).Although a lateralized pattern of activationis generally found for nonverbal (right frontal)(Kelley et al., 1998; McDermott, Buckner, Petersen,Petersen, Kelley, & Sanders, 1999; Wagner et al.,1998b) versus lexical (left frontal) (McDermottet al., 1999; Wagner et al., 1998b) stimuli, if visualstimuli can evoke semantic associations, thenleft anterior prefrontal activation tends to alsooccur (Haxby et al., 1996; Kelley et al., 1998),especially when longer retention times are providedfor these semantic associations to form (Haxby,Ungerleider, Horwitz, Rapoport, & Grady, 1995).Right prefrontal activation is best correlated withsuccessful encoding of scenes, as reﬂected by post-scanning recall performance (Brewer et al., 1998),while left prefrontal activations are best correlatedwith subsequent word recall (Wagner et al.,1998c).Amnesia 53Figure 3.8Functional MRI activation maps for “shallow” and “deep”encoding tasks, contrasted with ﬁxation. Both tasksactivate posterior visual areas, whereas only the deepencoding task shows increased activation of left inferiorand dorsolateral frontal areas (arrows). These activationsare at peak Talairach coordinates. (x, y, z) of -40, 9, 34and -46, 6, 28 for the more dorsal activations and -40,19, 3 and -43, 19, 12 for the more ventral prefrontalactivations. (Adapted from Buckner and Koutstaal, 1998.)
Most functional imaging studies are focused onthe assessment of activity occurring on the same dayof testing. Long-term dynamic changes occur withthe eventual consolidation of learned information.Functional imaging studies have just begun to probethis dynamic consolidation process. After medialtemporal regions are engaged with initial encoding,the anterior cingulate cortex and temporal corticesappear to mediate the retrieval of learned informa-tion. The anterior cingulate cortex has been consis-tently activated in paradigms that require sustainedattention to novel tasks. In a subtraction-basedparadigm of memory encoding combined with amotor task demanding sustained divided attention(Fletcher et al., 1995), the anterior cingulate cortexwas singularly activated by the sustained vigilancedemanded to divide the effort between the twotasks. Position emission topography activationstudies using varied designs (Corbetta, Miezin,Dobmeyer, Shulman, & Petersen, 1991; Frith,Friston, Liddle, & Frackowiak, 1991; Jones, Brown,Friston, Qi, & Frackowiak, 1991; Pardo, Pardo,Haner, & Raichle, 1990; Petersen, Fox, Posner,Mintun, & Raichle, 1988, 1989; Talbot et al., 1991)consistently activated the anterior cingulate cortexwhen subjects were motivated to succeed in what-ever task was given them. When motivation tomaster a task was no longer required, and accurateperformance of a task became routine, the anteriorcingulate cortex returned to a baseline activity level(Raichle et al., 1994).In a radial arm maze task using mice trainedsuccessfully after encoding-associated activation ofPapez’s circuit (hippocampal-posterior cingulatecortex), the anterior cingulate, dorsolateral pre-frontal, and temporal cortices (but not the hip-pocampus) were engaged during retrieval 25 daysafter learning (Bontempi, Laurent-Demir, Destrade,& Jaffard, 1999). Thus the hippocampal formationencodes or maintains new information until theconsolidation process has ended. When the contextof the maze was changed, and new learning had tooccur, the hippocampus-posterior cingulate cortexwas once again activated. In addition to its role inthe consolidation of declarative memory, the post-erior cingulate cortex is also active during associa-tive learning in classic conditioning paradigms(Molchan, Sunderland, McIntosh, Herscovitch, &Schreurs, 1994).The Retrieval SystemThe greater neocortical recruitment during retrievalof remote compared with recent memories seen inthe mouse experiment (Bontempi et al., 1999) sug-gests that there are dynamic hippocampal–corticalinteractions during the consolidation process, witha gradual reorganization of neural substrates result-ing in a shift toward the neocortex during long-termmemory storage (Buzsaki, 1998; Damasio, 1989;Knowlton & Fanselow, 1998; Squire & Alvarez,1995; Teyler & DiScenna, 1986). Most human func-tional imaging studies test retrieval within minutesor hours of presentation. In such studies, the medialtemporal cortex is activated during retrieval com-pared to a resting condition (Ghaem et al., 1997;Grasby et al., 1993; Kapur et al., 1995a; Roland& Gulyas, 1995), passive viewing (Maguire,Frackowiak, & Frith, 1996; Schacter et al., 1995,1997b), or nonepisodic retrieval (Blaxton et al.,1996; Schacter, Alpert, Savage, Rauch, & Albert,1996a; Schacter, Buckner, Koutstaal, Dale, &Rosen, 1997a; Squire et al., 1992).When decisions are required as to whethercurrent items were previously studied, the medialtemporal cortex shows the greatest activation forprior items even though correct judgments aremade about novel items (Fujii et al., 1997; Gabrieliet al., 1997; Maguire et al., 1998; Nyberg et al.,1995; Schacter et al., 1995; Schacter et al., 1997b).This is not the case for frontal lobe activations,which are present during both successful retrieval(Buckner, Koutstaal, Schacter, Wagner, & Rosen,1998; Rugg, Fletcher, Frith, Frackowiak, & Dolan,1996; Tulving, Kapur, Craik, Moscovitch, & Houle,1994a; Tulving et al., 1996) and attempted retrieval(Kapur et al., 1995b; Nyberg et al., 1995; Rugg,Fletcher, Frith, Frackowiak, & Dolan, 1997;Wagner, Desmond, Glover, & Gabrieli, 1998a).The frontal lobe’s contribution to memoryretrieval, as evidenced from functional imagingMichael S. Mega 54
studies, may be related to the sequencing of searchstrategies (Alkire et al., 1998; Gabrieli, 1998;Schacter, Savage, Alpert, Rauch, & Albert, 1996c;Ungerleider, 1995), strategic use of knowledge(Wagner et al., 1998a), and working memoryprocesses that facilitate successful retrieval(Desmond, Gabrieli, & Glover, 1998; Gabrieliet al., 1996; Thompson-Schill, D’Espsito, Aguirre,& Farah, 1997). This multiple processing inter-pretation of frontal lobe activations associatedwith memory retrieval evolved from a reﬁnementof the hemispheric encoding–retrieval asymmetry(HERA) model, which proposed a dichotomybetween left prefrontal activations associated withencoding and right prefrontal activations associatedwith retrieval (ﬁgure 3.9). Although the right pre-frontal cortex is activated in most retrieval taskswhether the tasks are verbal (Blaxton et al., 1996;Buckner et al., 1996; Buckner et al., 1995; Cabeza,Kapur, Craik, & McIntosh, 1997; Flectcher et al.,1998; Kapur et al., 1995b; Nyberg et al., 1995;Petrides, Alivasatos, & Evans, 1995; Rugg et al.,1996; Schacter, Curran, Galluccio, Milberg, &Bates, 1996b; Shallice et al., 1994; Squire et al.,1992; Tulving et al., 1994b; Wagner et al., 1998a),or nonverbal (Haxby et al., 1996; Moscovitch,Kapur, Kohler, & Houle, 1995; Owen, Milner,Petrides, & Evans, 1996), a posterior focus (BA9/46) appears to be stimulus dependent, and ananterior focus (BA 10) may be related to retrievalattempts (McDermott et al., 1999).Event-related functional MRI (fMRI) allows abetter assessment of the activation correlated withindividual trials, and when applied to episodicretrieval tasks, a differential time course of the vas-cular response is observed in the right frontal lobe.A typical transient 4-second peak is noted in theposterior right frontal cortex after item presentationand response, while a sustained 10-second vascularresponse is observed in the right anterior frontalAmnesia 55Figure 3.9Summary of the peak regions of signiﬁcance in functional imaging studies mapping the success and effort in the retrievalof verbal and nonverbal material. (Adapted from Carbeza and Nyberg, 2000.)
cortex after stimulus presentation (Buckner et al.,1998; Schacter et al., 1997a). This sustainedhemodynamic response may represent a differentprocess assisting general retrieval, perhaps ananticipatory mechanism awaiting the next pre-sentation (Buckner et al., 1998) or a successmonitoring process resulting from the last presen-tation (Rugg et al., 1996).The exact contribution of the prefrontal cortexto memory retrieval is not known, but given thatstrategic memory judgments (temporal order,source memory, etc.) yield more extensive bilateralfrontal activations—coupled with results from thelesion literature that demonstrate impaired strategicmemory in patients with focal frontal lesions—itappears that multiple processes are provided bydiscrete frontal regions that combine to assistretrieval of episodic memory (Cabeza et al., 1997;Henson, Rugg, Shallice, Josephs, & Dolan, 1999;Nolde, Johnson, & D’Esposito, 1998a; Nolde,Johnson, & Raye, 1998b). Once consolidation hasoccurred, the retrieval of remotely acquired infor-mation involves the anterior cingulate cortex andother neocortical regions in accessing storedrepresentations (Markowitsch, 1995; Mega &Cummings, 1997). This activation of the anteriorcingulate cortex may be related to increased atten-tion and internal search strategies and be combinedwith other cortical regions, such as temporal cor-tices, which aid the retrieval of autobiographicmemory (Fink, 1996).In summary, functional imaging studies havefurthered our understanding of the neural basis ofthe memory function. It is only through functionalimaging that cognitive neuroscience has begun toexplore the spatially diverse regions simultaneouslyengaged in the encoding and retrieval processes.Thus, functional imaging complements the lesionliterature and in some cases advances our under-standing of the brain regions involved in psycho-logical processes. Caution must be used, however,in interpreting the results from both sources ofinquiry, since the reﬁnement of our understandingof cognition must account for lesion results inpatients and activation results in normal subjects.Utilizing both avenues to test emerging hypotheseswill produce more robust models of cognitiveprocesses.Conclusions and Future DirectionsThe results from clinical, animal, and imagingstudies all support the importance of the medialtemporal region and other components of Papez’scircuit in the spontaneous recall of new information.Variable recognition deﬁcits will be observed, andthus presumed encoding defects, with concomitantdysfunction of prefrontal-subcortical integrity. Themost profound amnesia will occur with perirhinaldestruction, or combined Papez’s-prefrontal circuitdamage. When isolated prefrontal damage ispresent, with Papez’s circuit spared, spontaneousretrieval may be impaired, but recognition willlikely be intact.Future studies of the neuronal basis of normalmemory function will identify the networks respon-sible for the encoding, consolidation, and retrievalof a variety of stimuli with functional imagingparadigms that probe anatomically connected butspatially separate regions. Investigating function-ally coupled distributed brain regions may requirecombining the excellent spatial resolution of fMRIwith the superior temporal resolution of magne-toencephalography along with novel statistical tech-niques that control the search for linked systems.Once a distinct network is identiﬁed that is repro-ducible across individuals for a given memorytask, population-based studies will be necessary todetermine the magnitude and distribution of normalsignal response across demographic variables.Armed with the normal population’s variability inperformance and signal change, abnormalities canbe deﬁned with cross-sectional studies of patientswith memory disorders and longitudinal studies ofnormal subjects who develop memory dysfunction.Such a growing body of data will beneﬁt not onlyour theories of normal memory function but alsoour diagnosis of subtle memory defects, andperhaps their treatment.Michael S. Mega 56
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John R. HodgesMemory, in its broadest sense, refers to the storageand retrieval of any form of information, but whenconsidered as an aspect of human cognition, itclearly does not describe a unitary function. Mem-orizing a new telephone number, recalling thedetails of a past holiday, acquiring the facts neces-sary to practice medicine, learning a new language,or knowing how to drive a car, are all tasks thatdepend on memory, but proﬁciency in one does notguarantee competence in the other. More important,these abilities may break down differentially inpatients with brain disease. There is as yet no uni-versally accepted classiﬁcation of subcomponentsof memory, but virtually all contemporary cognitivemodels distinguish between working (immediate)and longer term memory, and within the latter, rec-ognize both explicit and implicit types.Of the examples given here, the ability to repeata telephone number reﬂects working memory. Theacquisition of motor skills such as driving a carrequires implicit procedural memory.Within explicitlong-term memory, an inﬂuential distinction is thatbetween episodic and semantic memory. The formerrefers to our personal store of temporally speciﬁcexperiences (or episodes), the recall of whichrequires “mental time travel.” In contrast, semanticmemory refers to our database of knowledge aboutthings in the world and their interrelationship; theseinclude words, objects, places, and people (Garrard,Perry, & Hodges, 1997; Hodges & Patterson, 1997).Semantic memory is, therefore, the most centralof all cognitive processes and is fundamental tolanguage production and comprehension, readingand writing, object and face perception, etc. Despitethe central role of semantic memory, its study isrelatively recent, and in the modern era begins in1975 with Warrington’s seminal observation ofselective impairment of semantic memory, nowreferred to as semantic dementia (Warrington,1975), followed a few years later by Warrington andShallice’s ﬁnding of category-speciﬁc semanticimpairment (Warrington & Shallice, 1984).4 Semantic Dementia: A Disorder of Semantic MemoryA breakdown of semantic memory occurs ina number of conditions, most notably afterherpes simplex encephalitis (Pietrini et al., 1988;Warrington & Shallice, 1984), in Alzheimer’sdisease (Hodges & Patterson, 1995), and insemantic dementia (Hodges, Patterson, Oxbury, &Funnell, 1992a). In the former two conditions, thesemantic deﬁcit is almost always accompanied byother major cognitive deﬁcits. For this reason, thestudy of patients with semantic dementia, who havea progressive, yet selective and often profoundbreakdown of semantic memory, provides unparal-leled insights into the organization of semanticmemory and the impact of semantic disintegrationon other cognitive processes.Following the description of a typical case, therest of this chapter consists of an overview of ourwork on semantic dementia over the past decade(Hodges, Garrard, & Patterson, 1998; Patterson &Hodges, 1994), with particular emphasis on whatcan be learned about normal semantic memoryprocesses in the human brain from the study ofpatients with semantic dementia.Case ReportThe following case history of a patient who has beenstudied longitudinally over the past 5 years illustratesthe pattern of cognitive deﬁcits commonly seen in thedisorder (see also Graham & Hodges, 1997; Hodges &Patterson, 1996; Knott, Patterson, & Hodges, 1997).A.M. presented in April 1994 at age 64 with a historyof loss of memory for words that had progressed slowlyover the past 2 years. His wife also noted a decline in hiscomprehension ability that initially affected less commonwords. Despite these problems, he still played golf (to ahigh standard) and tennis. The patient was still driving andable to ﬁnd his way to various golf clubs alone and withoutdifﬁculty. Day-to-day memory was also good and whenseen in the clinic A.M. was able to relate, albeit anomi-cally, the details of their holiday in Australia and his recentgolﬁng achievements. There had been only a slight change
in personality at that time, with mild disinhibition and atendency to stick to ﬁxed routines.The following transcription illustrates that A.M.’sspeech was ﬂuent and without phonological or syntacticerrors, but was strikingly devoid of content. It also showshis recall of undergoing a brain scan some 6 monthsbefore.Examiner: “Can you tell me about a last time you werein hospital?”A.M.: “That was January, February, March, April, yesApril last year, that was the ﬁrst time, and eh, on theMonday, for example, they were checking all my whatsit,and that was the ﬁrst time when my brain was, eh, shown,you know, you know that bit of the brain [indicates left],not that one, the other one was okay, but that was lousy,so they did that, and then like this [indicates scanning bymoving his hands over his head] and probably I was a bitbetter than I am just now.”Formal neuropsychological testing in April 1994revealed that A.M. was severely impaired in tests ofpicture naming. In the category ﬂuency test, in whichsubjects are asked to generate exemplars from a range ofsemantic categories within a set time, he was able to gen-erate a few high-frequency animal names (cat, dog, horse),but no exemplars from more restricted categories such asbirds or breeds of dog. He was only able to name three outof forty-eight black-and-white line drawings of highlyfamiliar objects and animals from the Hodges andPatterson semantic battery (Hodges & Patterson, 1995).Most responses were vague circumlocutions such as“thing you use,” but he also produced some categorycoordinate errors, such as saying “horse” for “elephant.”On a word-picture matching test, based on the sameforty-eight items, in which A.M. had to point out a picturefrom eight other exemplars (e.g., zebra from eight otherforeign animals), he scored 36/48 (twenty-ﬁve age-matched controls score on average 47.4 ± 1.1). Whenasked to provide descriptions of the forty-eight itemsin the battery, from their names, he produced very fewdetails; most were vague or generic responses containingthe superordinate category only (“a musical instrument,”“in the sea,” etc.). A number of examples are shown intable 4.1. On the picture version of the Pyramid and PalmTrees Test, a test of associative semantic knowledge inwhich the subject has to decide which of two pictures (aﬁr tree or a palm tree) goes best with a target picture, apyramid (Howard & Patterson, 1992), A.M. scored 39/52when he ﬁrst presented. Control subjects typically scoreclose to ceiling on this test.On tests of reading, A.M. showed the typical patternof surface dyslexia (Patterson & Hodges, 1992): a normalability to read aloud words with regular spelling-to-soundcorrespondence, but errors when reading aloud irregularwords (pint, island, leopard, etc.)By contrast, on nonsemantic tasks (such as copyingthe Rey Complex Figure, ﬁgure 4.1) A.M.’s performancewas faultless. When asked to reproduce the Rey ComplexFigure after a 45-minute delay, A.M. scored well withinthe normal range (12.5 versus a control mean = 15.2 ±7.4). On nonverbal tests of problem solving, such asRaven’s Colored Matrices, a multiple-choice test of visualpattern matching that requires the subject to conceptualizespatial relationships, A.M. was also remarkably unim-paired. Auditory-verbal short-term memory was alsospared, as judged by a digit span of six forward and fourbackward.John R. Hodges 68Figure 4.1Patient A.M.’s copy (bottom) of the Rey Complex Figure(top).
A.M. was tested approximately every 6 months over thenext 3 years. He was so profoundly anomic when he ﬁrstpresented that there was little room for further decline. Ontests of comprehension, by contrast, there was a relentlessdecline; for instance, on the word-picture matching test,A.M.’s score fell from 36 to 5/48 in November 1996 (con-trols = 47.4 ± 1.1). Likewise on the pictorial version of thePyramid and Palm Trees Test, his score fell progressivelyfrom 39/52 to chance.Despite this rapid loss of semantic knowledge, A.M.showed no signiﬁcant decline on tests of nonverbalproblem solving or visuospatial ability over the same timeperiod. For instance, on Raven’s Colored Matrices, he stillscored perfectly in November 1996.A.M.’s impairment in semantic knowledge had a con-siderable impact on his everyday activities. On variousoccasions he misused objects (e.g., he placed a closedumbrella horizontally over his head during a rainstorm),selected an inappropriate item (e.g., bringing his wife, whowas cleaning in the upstairs bathroom, the lawnmowerinstead of a ladder), and mistook various food items (e.g.,on different occasions, A.M. put sugar into a glass of wine,orange juice on his lasagne, and ate a raw defrostingsalmon steak with yoghurt). Activities that used to be com-monplace acquired a new and frightening quality to him:on a plane trip early in 1996 he became clearly distressedat his suitcase being X-rayed and refused to wear a seat-belt in the plane.After 1996, the behavioral changes became more pro-minent, with increasing social withdrawal, apathy, anddisinhibition. Like another patient described by Hodges,Graham, and Patterson (1995), A.M. showed a fascinatingmixture of “preserved and disturbed cognition.” Hodges etal.’s patient, J.L., would set the house clocks and his watchforward in his impatience to get to a favorite restaurant, notrealizing the relationship between clock and actual time.A.M. made similar apparently “insightful” attempts toget his own way. For example, his wife reported that shesecretly removed his car keys from his key ring to stophim from taking the car for a drive. At this point, A.M.was obsessed with driving and very quickly noticed themissing keys. He solved the problem by taking his wife’sSemantic Dementia 69Table 4.1Examples of deﬁnitions provided by patient A.M. from reading the wordCrocodile I can’t remember it at all . . . not in the sea is it?Swan Is it a duck, it’s a bird . . . can’t recall anything else.Ostrich Is it an animal, don’t know what kind . . . I never see it in Sainsbury’s [a super market].Zebra I’ve no idea what it is.Lion A very violent animal, it’s a lion in Africa, got a very big mouth, eat lots of animals and humans. Theybite on the back of the neck etc.Deer They’re owned by farmers, in the ﬁelds of course, we shave their fur off . . . or is it a sheep? Do we dothat too, with deer? I’m not sure.Frog I think I’ve seen them on the ground, they’re very small, I think they might be a bit in the water too, Icouldn’t describe them.Seahorse I didn’t know they had horses in the sea.Harp I don’t know what a harp is, not a kind of musical instrument is it?Trumpet Yes, I do seem to remember the word trumpet. If only I had a dictionary I could tell you what it is.Toaster We put bread in the toaster to make toast for breakfast. It heats the bread up, makes it a bit dark, then itejects the bread up to the top etc.Sledge A sledge? . . . A sledge we use in the snow. You slide on the snow in a sledge.Aeroplane It has wings and takes off at the airport into the sky. I know I’ve been in an aeroplane. It has wings anda jet etc.
car keys off her key ring without her knowledge and goingto the locksmiths, successfully, to get a new set cut. At nopoint did A.M. realize his wife had taken the keys fromhis key ring. Despite virtually no language output andprofound comprehension difﬁculties, he still retainedsome skills; for example, he continued to play sports (par-ticularly golf) regularly each week, remembering correctlywhen he was to be picked up by his friends, until 1998,when he entered permanent nursing care.Figure 4.2 shows three coronal magnetic resonanceimages (MRIs) through A.M.’s temporal lobes that wereobtained in 1995. The striking asymmetric atrophy ofthe anterior temporal lobes is clearly visible, involvingparticularly the temporal pole and fusiform gyrus andinferolateral region, but with relative sparing of thehippocampus.In summary, A.M.’s case history illustrates a numberof the characteristic features of semantic dementia: (1)selective impairment of semantic memory, causing severeanomia, impaired single-word comprehension, reducedgeneration of exemplars on category ﬂuency tests, and animpoverished fund of general knowledge; (2) surfacedyslexia; (3) relative sparing of syntactic and phonologi-cal aspects of language; (4) normal perceptual skills andnonverbal problem-solving abilities; (5) relatively pre-served recent autobiographical and day-to-day (episodic)memory; (6) anterolateral temporal lobe atrophy.A Historical Perspective on Semantic DementiaThe last decades of the nineteenth century and theearly twentieth century were a golden age for neu-rologists interested in higher cognitive function.During this period most of the classic syndromes ofbehavioral neurology were ﬁrst clearly deﬁned. Oneof the stars of this era was Arnold Pick, a neuro-logist, psychiatrist, and linguist. In a remarkableseries of papers (now available in translation; Pick,1892, in Girling & Berrios, 1994; Pick, 1901, inGirling & Markova, 1995; Pick, 1904, in Girling &Berrios, 1997), he described patients who presentedwith unusually severe ﬂuent aphasia in the contextof a dementia and at postmortem had markedatrophy of the cortical gyri of the left temporal lobe.Pick wanted to call attention to the fact that pro-gressive brain atrophy can lead to focal symptomsthrough local accentuation of the disease process.He also made speciﬁc and highly perceptive pre-dictions regarding the role of the midtemporalregion of the left hemisphere in the representationJohn R. Hodges 70Figure 4.2Coronal T1-weighted MRI images showing profoundatrophy of the temporal pole (left > right) and inferolateralcortex, with relative sparing of the hippocampus.
of word meaning. Unfortunately Pick’s contribu-tions to understanding the neural basis of meaningsystems in the brain were largely forgotten and hisname became associated with his later discoveriesrelated to focal degeneration of the frontal lobes. Aswe will see later, patients with focal anterior tem-poral and frontal degeneration are part of the samespectrum that is often referred to as Pick’s diseaseor more recently, frontotemporal dementia.Following a dark age of dementia studies, a ren-aissance of interest—particularly in the syndromesassociated with focal lobar atrophy—occurred inthe 1970s and 1980s. This revival occurred almostsimultaneously in the ﬁelds of cognitive neuro-psychology and behavioral neurology, but onlysome time later were the two strands united.Elizabeth Warrington (1975) was the ﬁrst toclearly delineate the syndrome of selective seman-tic memory impairment. She reported three patients,two of whom were subsequently shown to havethe histological changes of Pick’s disease at autopsy(Cummings & Duchen, 1981 and personal commu-nication from E. Warrington). Drawing on the workof Tulving (1972, 1983), Warrington recognizedthat the progressive anomia in her patients was notsimply a linguistic deﬁcit, but reﬂected a funda-mental loss of semantic memory (or knowledge)about items, which thereby affected naming, wordcomprehension, and object recognition. Suchpatients would previously have been described ashaving a combination of “amnesic, or transcorticalsensory, aphasia” and “associative agnosia.”A very similar syndrome was reported bySchwartz, Marin, and Saffran (1979), who observeda profound loss of knowledge for the meaning ofa word with preservation of phonological and syn-tactic aspects of language in a patient, W.L.P., whocould also read aloud words that he no longer com-prehended. These ﬁndings had a profound impacton contemporary models of reading processes(Patterson & Lambon Ralph, 1999).The major contribution in neurology came fromMarsel Mesulam, who in 1982 reported on sixpatients with a long history of insidiously worseningaphasia in the absence of signs of more generalizedcognitive failure. Over the next 15 years it becameclear that within the broad category of primary pro-gressive aphasia, two distinct syndromes could beidentiﬁed: progressive nonﬂuent aphasia and pro-gressive ﬂuent aphasia (for a review see Hodges& Patterson, 1996; Mesulam & Weintraub, 1992;Snowden, Grifﬁths, & Neary, 1996a).In the nonﬂuent form, speech is faltering and dis-torted, with frequent phonological substitutions andgrammatical errors, but the semantic aspects of lan-guage remain intact. The latter syndrome presentsin many ways the mirror image: speech remainsﬂuent, grammatically correct, and well articulated,but becomes progressively devoid of content words,with semantic errors and substitution of genericsuperordinate terms (animal, thing, etc.). As illus-trated earlier, the deﬁcit involves word productionand comprehension, but is not conﬁned to wordmeaning (performance on nonverbal tests of seman-tic knowledge, such as the Pyramid and Palm TreesTest, is invariably affected). To reﬂect this funda-mental breakdown in the knowledge system under-lying the use of language, Snowden, Goulding, andNeary (1989) coined the term semantic dementiawhich we have adopted in our studies of thesyndrome (Hodges & Patterson, 1996; Hodges etal., 1992a; Hodges et al., 1999a; Hodges, Spatt, &Patterson, 1999b).There are a number of compelling reasons to con-sider semantic dementia as part of a spectrum thatincludes dementia of the frontal type, collectivelynow most often referred to as frontotemporaldementia. The ﬁrst is pathological; of the fourteenclinicopathological studies of cases fulﬁlling crite-ria for semantic dementia, all had either classicPick’s disease (i.e., Pick bodies and/or Pick cells) ora nonspeciﬁc spongiform change of the type foundin the majority of cases with other forms of fron-totemporal dementia (Hodges et al., 1998). Thesecond is the evolution of the pattern of cognitiveand behavioral changes over time. As illustratedearlier, semantic dementia patients present withprogressive anomia and other linguistic deﬁcits, buton follow-up, the behavioral changes characteristicof orbitobasal frontal lobe dysfunction invariablySemantic Dementia 71
emerge (Edwards-Lee et al., 1997; Hodges &Patterson, 1996). Third is the fact that modern neu-roimaging techniques demonstrate subtle involve-ment of the orbitofrontal cortex in the majority ofcases presenting prominent temporal atrophy andsemantic dementia (Mummery et al., 2000;Mummery et al., 1999).Structural and Functional Imaging Studies inSemantic DementiaThe most striking, and consistent, ﬁnding in seman-tic dementia is focal, and often severe, atrophy ofthe anterior portion of the temporal lobe (see A.M.’sMRI, ﬁgure 4.2). Early studies based upon visualinspection suggested involvement of the polar andinferolateral regions, with relative sparing of thesuperior temporal gyrus and the hippocampal for-mation (Hodges & Patterson, 1996; Hodges et al.,1992a). All cases involved the left side, but somehad bilateral atrophy. Functional position emissiontomography (PET) activation studies in normal sub-jects, which typically employed paradigms similarto the Pyramids and Palm Trees Test, also pointedto a key role for the left temporal lobe in both verbaland visual semantic knowledge (Martin, Wiggs,Ungerleider, & Haxby, 1996; Mummery, Patterson,Hodges, & Wise, 1996; Vandenberghe, Price, Wise,Josephs, & Frackowiak, 1996). It appeared, there-fore, that despite a large body of work on split-brainsubjects and normal controls using tachisoscopictechniques, knowledge systems in the brain aresurprisingly lateralized.More recent ﬁndings cast doubt on this simpleconclusion. We have recently employed methodsof quantiﬁcation (both automated voxel-basedmorphometry and manual volumetry of deﬁnedanatomical structures) of brain atrophy. Thesestudies conﬁrm the profound involvement of thetemporal pole, the fusiform gyrus, and the infero-lateral cortex, but have shown that in virtually allcases these changes are bilateral and in a number ofthem the right side is more severely affected thanthe left (Galton et al., 2001; Mummery et al., 2000).The status of the hippocampus and parahip-pocampal structures (notably the entorhinal andperirhinal cortices) has also become less certain.Despite previous reports of relative sparing of thehippocampus, a recent volumetric analysis of tencases of semantic dementia (including that of A.M.)has shown asymmetric atrophy of the hippocampus,which on the left was actually more marked thanin a group of ten Alzheimer’s disease patients,matched for disease duration, but was equivalent inseverity on the right side. The appearance of the“relative” preservation of medial temporal struc-tures is due to the profound atrophy of surroundingstructures compared with the hippocampus. Theaverage volume loss of the temporal pole, fusiform,and inferolateral gyri was 50%, and in some casesup to 80% compared with an average 20% loss ofhippocampal volume. In Alzheimer’s disease the20% loss of the hippocampi stands out against thenormal polar and inferolateral structures (Galtonet al., 2001).There was also considerable variability amongsemantic dementia cases. The entorhinal cortex,which constitutes a major component of theparahippocampal gyrus, is also severely affectedin semantic dementia. The perirhinal cortex has acomplex anatomy in humans, occupying the banksof the collateral sulcus and the medial aspect of thetemporal lobe (Corkin, Amaral, Gonzalez, Johnson,& Hyman, 1997). The rostral part is almost certainlyaffected in semantic dementia, although the caudalpart might be partially spared (Simons, Graham, &Hodges, 1999).Functional imaging in semantic dementia andother disorders is in its infancy, in part owing to thestill only partially resolved problems of analyzingand normalizing brains with signiﬁcant lesions. It is,however, clear that functional imaging will forman essential and increasingly prominent researchtool in our attempts to understand functional–anatomical relationships.As argued by Price (1998),functional imaging studies of normal participantscan yield vital information about the various brainregions activated during the performance of somecognitive task, but these studies cannot on their ownJohn R. Hodges 72
identify which of multiple activations constitute thesine qua non of that cognitive function. Structurallesion data have typically been thought to provideevidence of this nature. However, even greateradvances should be possible if we can also identifystructurally intact regions of the patient’s brainthat—presumably because of reduced input from thedamaged areas to which they are normally con-nected—no longer function adequately.The ﬁrst activation study of semantic dementia(Mummery et al., 1999) used a combination ofstructural MRI and PET. The behavioral activationtask required associative semantic judgments abouttriplets of pictures of common objects or printedwords corresponding to the names of the pictures.Four patients at early to middle stages of semanticdecline were able to perform this task at rates that,although impaired relative to controls, were signif-icantly above chance. For the normal participants,the semantic task (compared with a visual judgmentbaseline) activated the expected network of lefttemporal, temporoparietal, and frontal regions previ-ously demonstrated by Vandenberghe et al. (1996).This distributed set of regions included the leftanterior and middle temporal areas that reveal con-sistent atrophy in semantically impaired patients.A logical conclusion—and indeed one that weendorse—is therefore that this territory is somehowthe core, the sine qua non, of the semantic process-ing required by this task. There was, however, anunexpected PET result: signiﬁcant hypometabolism(lack of activation), for all four patients relativeto normal controls, in a more posterior temporalregion, Brodmaum area (BA) 37, the posterior infe-rior temporal gyrus on the left.Morphometric analysis of MR images from thesame four patients revealed no signiﬁcant atrophyin BA 37. This is therefore a functional abnormal-ity, not a structural one, but it raises at least the pos-sibility that the patients’ semantic deﬁcit is relatedto this functional posterior-temporal lesion. Asomewhat different interpretation, supported by asubstantial number of PET results from normalindividuals (for a review see Price, 1998) is thatBA 37 is critical for translating semantic (and other)representations into a phonological code. Althoughthe task employed in this study did not require overtnaming, it is plausible that the normal subjectsautomatically generated internal phonologicalcodes for the stimulus items. Since patients withsemantic dementia are signiﬁcantly anomic, theirlack of activation in BA 37 might reﬂect a mal-function of the procedure for computing the phono-logical code of a stimulus (see Foundas, Daniels,& Vasterling, 1998, for evidence of anomia arisingfrom a focal vascular lesion in left BA 37). Thisis our preferred interpretation of the PET resultfor semantic dementia, because of the consistentﬁndings of semantic deﬁcits in conjunction withanterior temporal damage, plus the absence ofreports (at least that we have seen) of any notablesemantic impairments following selective posteriortemporal lesions.Insights from Behavioral Studies of SemanticDementiaOur behavioral studies of semantic dementia canbe divided into those dealing with spared versusaffected cognitive abilities. These studies have pro-vided valuable insights into both the modularity ofcognitive processes and the organization of seman-tic memory.Cognitive Abilities That Are RelativelyIndependent of Semantic MemoryThe spared abilities can be divided into threedomains: (1) memory systems other than semanticmemory, (2) aspects of language processing otherthan those that are necessarily disrupted by a seman-tic impairment, and (3) cognitive abilities outsidethe domains of memory and language.Working MemoryThere is good evidence for normal operation ofworking memory in semantic dementia. Forexample, it is clear from clinical observations,beginning with Warrington (1975), that theseSemantic Dementia 73
patients do not forget what they or others have justdone or said. In terms of formal measures of short-term memory, patients with semantic dementiademonstrate completely normal digit span (e.g.,Knott et al., 1997; Patterson, Graham, & Hodges,1994), as in our patient A.M., at least until very latein the course of decline, and also demonstratenormal performance on the nonverbal Corsi span(Lauro-Grotto, Piccini, & Shallice, 1997).Episodic MemoryInitial clinical descriptions of patients with seman-tic dementia suggested that this syndrome providedcompelling evidence for a dissociation betweenpreserved episodic and impaired semantic memory.Patients are well oriented and can relate the details,albeit anomically, of recent life events. They alsoretain broad facts about their own life, such as pastoccupation, whether they are married, and numbersof children and grandchildren (Hodges, Salmon, &Butters, 1992b). More detailed exploration reveals,however, a major confound of time of memoryacquisition. While patients with the amnesic syn-drome, as a result of hippocampal damage (follow-ing anoxic brain damage or in the early stags ofAlzheimer’s disease), typically show preservationof autobiographical memory for their early lifecompared with the more recent past (Greene,Hodges, & Baddeley, 1995; for a review seeHodges, 1995), patients with semantic dementiashow the opposite pattern, that is to say, a reversalof the usual temporal gradient effect, with memoryfor remote events the most vulnerable (Graham &Hodges, 1997; Hodges & Graham, 1998; Snowden,Grifﬁths, & Neary, 1996b).This phenomenon of reversal of the usualtemporal gradient was explored in a detailed casestudy of A.M. (described earlier) using the so-calledCrovitz technique (Crovitz & Shiffman, 1974) inwhich subjects are asked to recount speciﬁcepisodes in response to cue words, such as boator baby, from particular life periods (Graham &Hodges, 1997). The richness of each memory wasthen scored by two independent assessors blind tothe hypothesis under investigation. A.M. was ableto produce fairly speciﬁc episodes from the past5 years, but his early life memories were all vaguegeneric descriptions (ﬁgure 4.3). This ﬁndingexplains the ability of patients with semanticdementia to relate recent life events and reveals theshortcomings of clinical observations.We have demonstrated, therefore, that patientswith semantic dementia show impairment on bothsemantic and autobiographical memory when theage of acquisition of the memories is equated. Testsof semantic memory typically tap knowledge aboutthings learned in early life, and patients’ auto-biographical memory from this era is poor. Onesimple interpretation of these ﬁndings is that oldepisodic and semantic memories are essentially thesame type of memory. A number of theorists haveargued that repeatedly rehearsed episodes have thestate of semantic knowledge and that general seman-tic information is merely the residue of numerousepisodes (Baddeley, 1976; Cermak, 1984; McClel-land, McNaughton, & O’Reilly, 1995). It should bepointed out, however, that patients with semanticJohn R. Hodges 74Figure 4.3Performance of patient A.M. and three age- and education-matched controls on the Crovitz test (Crovitz, Diaco,Apter, 1992) over four different life periods.
dementia have a profound loss of knowledge; forexample, they typically call all animals “dog” or“cat” (the equivalent of the knowledge level of a2-year-old) and, while it is true that their auto-biographical memory is impoverished, they retain aconsiderable amount of personal information.We conclude, therefore, that although distantepisodic memory is affected, it is less severelyimpaired than semantic memory. By contrast,patients with diffuse brain damage—for instance,patient J.M., who sustained patchy cerebral damagefrom cerebral vasculitis (Evans, Breen, Antoun, &Hodges, 1996)—show the opposite pattern, i.e.,preserved semantic memory and severe auto-biographical amnesia.To explain these patterns, we have suggested thatwhile semantic memory is segregated to particularbrain regions (particularly the inferolateral tem-poral lobes), autobiographical memories are multi-modal and distributed (Kitchener & Hodges, 1999).Patients with semantic dementia can compensatewhile damage remains conﬁned to one temporallobe, but suffer from severe loss of autobiographi-cal memory when the damage extends to multipleor bilateral brain regions. This also explains whyautobiographical memory is devastated fairly earlyin the course of Alzheimer’s disease, which affectsthe medial and lateral temporal lobes bilaterally(Greene et al., 1995). A similar hypothesis wasproposed by Eslinger, who found impaired auto-biographical memory following herpes simplexencephalitis only in those patients with bilateraldamage (Eslinger, 1998).The relatively preserved recent autobiographicalmemory clearly suggests that the mechanisms forencoding new episodic memories may be function-ing adequately in semantic dementia. If true, thiswould run counter to Tulving’s (1983, 1995) inﬂu-ential theory of long-term memory organization,which asserts that episodic memory is essentiallya subsystem of semantic memory, and that newepisodic learning is dependent upon semanticknowledge of the items and concepts to beremembered. Until recently, this claim that episodicmemory is dependent upon semantic memory andthat patients should not be able to establish normalepisodic memory for stimuli they fail to compre-hend had not been addressed. Our recent studies ofanterograde memory function in semantic dementiahave begun to explore the relationship betweensemantic and episodic memory in more detail.Performance on tests of verbal anterogradememory, such as logical memory (story recall) andword-list learning tests, is uniformly poor, which wehave interpreted in the context of the patient’s poorsemantic knowledge of the words to be encoded. Bycontrast, patients, like A.M., often score within thenormal range on nonverbal memory tests such asrecall of the Rey Complex Figure (Hodges et al.,1999a). They also show excellent recognitionmemory when color pictures are used as the stimuli,although recently it has been demonstrated that theyrely heavily upon perceptual information. Graham,Simons, Pratt, Patterson, and Hodges (2000a)compared recognition memory for “known” and“unknown” items (known items were pictures thatsubjects were able to name or correctly identify andvice versa) in two different conditions. In one, theitem was perceptually identical at study and test(e.g., it was the same telephone), while in the othercondition a different exemplar was presented atstudy and test (e.g., a different telephone). Patientswith semantic dementia showed near-perfect recog-nition memory for both known and unknown itemsin the former, perceptually identical condition, butin the latter (perceptually different) condition,recognition memory for the unknown items wasvery impaired. Together with the ﬁndings of thestudies described earlier, these data suggest thatepisodic memory is not solely reliant upon theintegrity of semantic knowledge and that perceptualinformation regarding events plays a comple-mentary role in providing a basis for recognitionmemory.Turning to the anatomical basis for the preserva-tion of recent autobiographical memory and ofanterograde memory in semantic dementia, ourinitial explanation for this phenomenon—in termsof the apparent sparing of the hippocampal complex(Graham & Hodges, 1997)—also requires someSemantic Dementia 75
revision in light of the recent anatomical ﬁndingof asymmetric hippocampal atrophy in at least aportion of patients with semantic dementia (seeearlier discussion).Most theories of long-term memory posit a time-limited role for the hippocampus (Graham &Hodges, 1997; McClelland et al., 1995). Accordingto such theories, the hippocampal complex providesvital support for recent but not for old memory.“Recent” in this context still means long-termmemory, over periods of weeks or months. Over thisperiod, the hippocampus is vital for linking piecesof sensory information in the cortex, but withrepeated rehearsals, connections develop in thecortex—a process referred to as long-term consoli-dation—and gradually the memory trace becomesindependent of the hippocampus. We had explainedthe preservation of recent autobiography andanterograde memory in terms of hippocampalsparing in semantic dementia, but as we will seelater, there is now evidence that the hippocampusis involved in this disorder. It may be that althoughthe hippocampus is affected, the cellular pathologyis distinct and less disruptive than that found inAlzheimer’s disease. There is also considerablevariability in the extent of hippocampal atrophy, andthe asymmetrical involvement (typically the left isgreater than the right) might be an important factor.Current studies are pursuing these aspects.LanguageAs indicated earlier, two prominent symptoms ofsemantic dementia are degraded expressive andreceptive vocabulary; this is only to be expectedsince, of all aspects of language processing, the abil-ities to produce and to comprehend content wordsrely most obviously on activation of semantic rep-resentations. Apart from the semantic system, thetwo other major components of language—phonol-ogy and syntax—seem to function reasonably wellin semantic dementia.Phonology There is a striking absence of phono-logical errors in the patients’ spontaneous speech orin their performance of more controlled tasks ofspeech output such as naming objects, repeatingsingle words, and reading aloud. Virtually allaphasic stroke patients, whatever their classiﬁcationin schemes of aphasic syndromes (e.g., Broca’s,Wernicke’s, conduction, anomic aphasia), makesome errors in naming objects that are phonologi-cal approximations to the correct name; the same istrue of patients with nonﬂuent progressive aphasia(Croot, Patterson, & Hodges, 1998; Snowden et al.,1996a). In contrast, anomic errors in patients withsemantic dementia take the form of single-wordsemantic errors (category coordinates or superordi-nates), circumlocutions (often with very impover-ished content), and omissions (“I don’t know”), butthese patients almost never make phonologicalerrors (Hodges & Patterson, 1996; Snowden et al.,1996a). The speech-production deﬁcit in semanticdementia is therefore probably the result of thepatient having insufﬁcient semantic informationto activate the correct, or often any, phonologicalrepresentation, rather than a disruption of thephonological system itself.The skills of reading aloud and writing to dicta-tion are well preserved for stimuli consisting ofhigh-frequency words and/or words with typicalcorrespondences between spelling and pronun-ciation. The great majority of patients, however,show a striking pattern of surface dyslexia andsurface dysgraphia, making “regularization” errorsto lower-frequency words with an unpredictablerelationship between spelling and sound; this hasbeen frequently reported in English-speakingpatients (e.g., Knott et al., 1997; Patterson &Hodges, 1992), but also in other languages that arecharacterized by a variety of levels and degrees ofconsistency in spelling-sound correspondences (seefor example, Lauro-Grotto et al., 1997, for Italian;Diesfeldt, 1992, for Dutch; Patterson, Suzuki,Wydell, & Sasanuma, 1995, for Japanese kanji). Wehave attributed these “surface” patterns of readingand spelling disorders to the reduction in normalsemantic constraints on deriving the correct pro-nunciation or spelling of previously known wordsJohn R. Hodges 76
(Graham, Hodges, & Patterson, 1994; Graham, Pat-terson, & Hodges, 2000b).Syntax Comprehension of the syntactic aspects oflanguage is also well preserved, at least until latein the course of semantic dementia (Hodges &Patterson, 1996). On a test of sentence–picturematching designed to assess the processing ofvarious syntactic structures (the Test for the Recep-tion of Grammar; Bishop, 1989), patients typicallyscore within the normal range; and where thenumber of errors exceeds normal limits, the errorsare often lexical rather than syntactic in nature(Hodges et al., 1992a).On the expressive side, the grammatical accuracyof aphasic patients’ spontaneous speech is reallyrather difﬁcult to judge (except in the case of ﬂa-grant impairments, as in the syndrome of agram-matism); this is mainly because normal speakers’spontaneous speech is often grammatically illformed, full of starts and stops and repairs thatlargely go unnoticed by the listener because thecomprehension process is so automatic and soforgiving. On the basis of other researchers’ reports(e.g., Snowden et al., 1996a) and our own experi-ence of listening to patients with this disorderover the past decade, the striking abnormality ofspeech is always word-ﬁnding difﬁculty and almostnever any major syntactic anomaly. As the con-dition worsens and the vocabulary deteriorationbecomes very marked, speech output not surpris-ingly becomes reduced in quantity and often ratherstereotyped in quality. Even the stock phrases thattend to emerge, however—such as the distressinglyaccurate ones used by P.P. (Hodges, Patterson, &Tyler, 1994): “I don’t understand at all” or M.C.(Hodges et al., 1992a): “I wish I knew what youmeant”—are usually well-formed utterances.Visuospatial Abilities and Nonverbal ProblemSolvingPatients score within the normal range on tests ofvisuospatial function such as Judgment of Line Ori-entation, the Rey Complex Figure test, and objectmatching (the latter test requires a decision aboutwhich of two photographs shows the same object,but viewed from a different angle, as a target pho-tograph) (Hodges & Patterson, 1996). As describedearlier, when asked to copy the Rey ﬁgure, thesepatients produce excellent reproductions (Hodges etal., 1992a), indicating not only good visuospatialskills but also competent planning and organization.Scores on the Raven’s Matrices are almost alwaysnormal (Hodges et al., 1992a; Snowden et al.,1996a; Waltz et al., 1999), demonstrating thatproblem solving is unimpaired as long as it does notrequire knowledge of speciﬁc concepts. Waltz andColleagues (1999) have also recently shown thatunlike patients with frontal dementia, semanticdementia patients are able to solve complex deduc-tive and inductive reasoning puzzles.Insights into the Organization of SemanticMemoryThe following sections deal with our studies ofsemantic breakdown in semantic dementia. The ﬁrstsection addresses the overall architecture of knowl-edge and whether the evidence from patients sug-gests a hierarchical (knowledge tree) or distributed(network) model. The following sections then turnto the internal structure and whether knowledge isorganized according to semantic categories, modal-ities of input (words versus pictures), or output(language versus action).Pruning the Semantic Tree or Holes in theSemantic Net?The pattern of naming responses made by patientswith semantic dementia shows a characteristicevolution with progression of the condition (Hodgeset al., 1995). In the early stages, their responses(e.g., “elephant” for “hippopotamus”) indicate aninability to distinguish between individual membersof a category, but indicate preservation of broadcategory-level information. Later in the course ofSemantic Dementia 77
the disease, they produce prototypical (e.g., “horse”for “hippopotamus” and for any other large animal)or superordinate responses (“animal”), but onlyin very advanced cases are cross-category errorsproduced.This characteristic progression appears mostreadily interpretable in terms of a hierarchicallystructured semantic system, in which speciﬁcinformation is represented at the extremities of abranching “tree of knowledge.” More fundamentaldistinctions, such as the division of animate beingsinto land animals, water creatures, and birds, arethought to be represented closer to the origin ofthe putative hierarchy, with living versus nonlivingthings at the very top. The deﬁning characteristicsof higher levels are inherited by all lower points(Collins & Quillian, 1969). Such a model has intu-itive appeal and the deﬁcits of semantic dementiacan be seen as a progressive pruning back of thesemantic tree (Warrington, 1975).An alternative account, which we favor, is basedon the concept of microfeatures in a distributedconnectionist network (McClelland et al., 1995;McClelland & Rumelhart, 1985). The basic idea isillustrated in ﬁgure 4.4. An advantage of such amodel is that the low-level “features” of individualconcepts need only be represented once, while ahierarchical model requires distinctive features tobe represented separately for every concept forwhich they are true (e.g., “has a mane” for both lionand horse). Category membership is then under-stood as an emergent property of the sharing of ele-ments of these patterns between concepts and thusbecomes a matter of degree—another intuitivelyappealing property. A distributed feature networkcould predict preservation of superordinate at theexpense of ﬁner-grained knowledge, as seen insemantic dementia, because even in a network thathad lost the representations of many individualattributes, category coordinates would continue topossess common elements, allowing judgmentsabout category membership to be supported longafter more ﬁne-grained distinctions had becomeimpossible.John R. Hodges 78uprighteats fish webbed feetlarge likes coldhas feathershas legshas a beaklays eggshootspredatornocturnalfliessmalleats insectsred breastFigure 4.4Distributed representation (microfeature) model illustrating penguin (thin line), owl (dashed line), and robin (thick line).
Do Patients with Semantic Dementia ShowCategory-Speciﬁc Loss of Knowledge?Living versus Nonliving ThingsSemantic memory impairment that selectivelyaffects some categories of knowledge and sparesothers has been most extensively documented inpatients with herpes simplex virus encephalitis, whotypically demonstrate a memory advantage for non-living over living and natural things (animals, fruit,etc.) (Pietrini et al., 1988; Warrington & Shallice,1984). The complementary dissociation, whicheffectively rules out any explanation based exclu-sively on either lower familiarity or a greater degreeof visual similarity among the exemplars of livingcategories, has also been described, typically inpatients who have suffered ischemic strokes in theterritory of the left middle cerebral artery (for areview see Caramazza, 1998; Gainotti, Silveri,Daniele, & Giustolisi, 1995).The simplest interpretation of this phenomenonwould be that the neural representations of differentcategories are located in separate cortical regions(Caramazza, 1998; Caramazza & Shelton, 1998).An alternative hypothesis is, however, that theattributes critical to the identiﬁcation of itemswithin these two broad domains differ in kind.According to this view, one group of items, domi-nated by living things, depends more stronglyon perceptual attributes, while another, mostlyartifacts, depends on their functional properties(Warrington & Shallice, 1984). Support for thesensory–functional dichotomy as a basis for cate-gory speciﬁcity came initially from a group studyof patients showing this phenomenon. In thesepatients the impaired categories did not alwaysrespect the living versus manmade distinction(Warrington & McCarthy, 1987). In particular, bodyparts were found to segregate with nonliving thingswhile fabrics, precious stones, and musical instru-ments behaved more like living things. The divisionof knowledge into these fundamental subtypes hasbeen supported by positron emission tomographyactivation studies of normal volunteers (Martin etal., 1996; Mummery et al., 1999), but studies exam-ining the status of perceptual and functional knowl-edge in patients with category-speciﬁc impairmentshave provided only limited endorsement of thehypothesis (DeRenzi & Lucchelli, 1994; Silveri &Gainotti, 1988).The picture in semantic dementia presents asimilar inconsistency. When asked to provide deﬁ-nitions of common concepts, these patients volun-teer very little visuoperceptual information. Forinstance, when asked to describe a horse, theytypically produce phrases such as “you ride them,”“they race them,” and “you see them in ﬁelds,” butonly rarely comment on their size, shape, color, orconstituent parts (Lambon Ralph, Graham,Patterson, & Hodges, 1999). In view of the strikingtemporal lobe involvement, the sensory–functionaltheory might be conﬁdently expected to predict asigniﬁcant advantage for artifact categories on testsof naming or comprehension. When considered asa group, the expected pattern does emerge in thesepatients (albeit to a rather modest degree), but astriking category effect is only rarely seen in indi-vidual cases (Garrard, Lambon Ralph, & Hodges,2002).It seems, therefore, that lesion location and typeof information are not the sole determinants ofcategory speciﬁcity. Whether the additional factorsrelate mainly to brain region (it has been hypo-thesized, for instance, that involvement of medialtemporal structures may be important) (Barbarotto,Capitani, Spinnler, & Trivelli, 1995; Pietrini et al.,1988) or to some unidentiﬁed aspect of cognitiveorganization, is as yet unclear.Knowledge of People versus Objects: The Role ofRight and Left Temporal LobesA number of earlier authors had suggested anassociation between right temporal atrophy and theselective loss of knowledge of persons (DeRenzi,1986; Tyrrell, Warrington, Frackowiak, & Rossor,1990), but the ﬁrst fully documented case, V.H., wasreported by our group in 1995 (Evans, Heggs,Antoun, & Hodges, 1995). Initially, V.H. appearedSemantic Dementia 79
to have the classic features of modality-speciﬁcprosopagnosia, i.e., a severe inability to identifyfamiliar people from their faces, but much betterperformance on names and voices. With time,however, it became clear that the deﬁcit was oneof a loss of knowledge about people affecting allmodalities of access to knowledge. V.H. was unableto identify a photograph of Margaret Thatcher (thepatient was English) or to provide any informationwhen presented with the name, yet general seman-tic and autobiographical memory remained intact(Kitchener & Hodges, 1999). We hypothesized aspecial role for the right temporal lobe in the repre-sentation of knowledge about people (Evans et al.,1995). As with most clear predictions, subsequentstudies have produced rather conﬂicting data. Whilefurther patients with predominantly right-sidedatrophy have all shown a severe loss of knowledgeof persons, we have also observed signiﬁcant(though not selective) impairments of such knowl-edge in patients with a predominantly left-sidedabnormality, suggesting that knowledge of people isespecially vulnerable to temporal atrophy on eitherside (Hodges & Graham, 1998).With regard to familiar objects rather than people,our working hypothesis is that conceptual knowl-edge is represented as a distributed network acrossboth the left and right temporal neocortex. This con-clusion is supported by some, but not all, sources ofrelevant evidence. For example, PET results withnormal participants would lead one to believe thatessentially all of the semantic action occurs in theleft hemisphere (Mummery et al., 1999; Vanden-berghe et al., 1996). Our tentative claim forbilateral representation of general conceptual know-ledge is based on evidence from semanticdementia. Deﬁcits in semantic tests (such as namingobjects, matching words and pictures, sorting, ormaking associative semantic judgments) are seennot only in patients with predominantly lefttemporal atrophy (e.g., Breedin, Saffran, & Coslett,1994; Hodges et al., 1994; Lauro-Grotto et al.,1997; Mummery et al., 1999; Snowden, Grifﬁths,& Neary, 1994; Tyler & Moss, 1998; Vandenbergheet al., 1996) but also in those with mainly right-sided damage (e.g., Barbarotto et al., 1995; Hodgeset al., 1995; Knott et al., 1997).V.H., the patient just described whose unilateralanterior right temporal atrophy produced a selectivedeﬁcit for recognition and knowledge of people(Evans et al., 1995), went on to develop a moregeneralized semantic deﬁcit in conjunction with thespread of atrophy to the left temporal region(Kitchener & Hodges, 1999). The opposite scenariohas occurred in two patients whose semanticdementia began with a phase of unilateral leftanterior temporal changes in association with onlyminimal semantic abnormality. Both cases wereshown to have a progressive anomia and developedmore pervasive semantic breakdown only whenthe pathology spread to involve both temporallobes.The most dramatic cognitive difference that hasemerged from our analyses of patients with greaterleft than right atrophy (L > R), in contrast to thosewith greater abnormality on the right (R > L), is notin the extent or pattern of the semantic impairmentper se, but rather in its relationship to anomia. Thisrelationship was explored in a combined cross-sectional and longitudinal analysis in which weplotted the patient’s picture-naming score for theforty-eight concrete concepts in our semanticbattery as a function of the corresponding level ofsemantic deﬁcit—deﬁned for this purpose as thepatient’s score on a word-picture matching test forthe same forty-eight items. This analysis revealsthat for a given level of semantic impairment, the L> R patients are substantially more anomic onaverage than the R > L cases. The nature of thenaming errors is also different in the two subgroups;although all patients make some of each of the threemain naming-error types seen in semantic dementia(which, as noted earlier, are single-word semanticerrors, circumlocutions, and omissions), there arerelatively more semantic errors in the R > L patientsand relatively more failures to respond at all in theL > R group.Our account of this pattern is that semanticrepresentations of concrete concepts are distributedacross left and right temporal regions, but becauseJohn R. Hodges 80
speech production is so strongly lateralized to theleft hemisphere, the semantic elements on theleft side are much more strongly connected tothe phonological representations required to namethe concepts. This explains how a patient in theearly stages of semantic dementia with atrophyexclusively on the left side can be signiﬁcantlyanomic, with only minor deﬁcits on semantic tasksthat do not require naming (Lambon Ralph et al.,1999).Modalities of Input and OutputOne of the continuing debates in the ﬁeld has relatedto the issue of whether knowledge is dividedaccording to the modality of input or output. Putsimply, when you hear or see the word “asparagus,”is the semantic representation activated by this inputthe same as or different from the conceptual knowl-edge tapped by seeing or tasting it? Likewise, whenyou speak about or name a hammer, is the concep-tual representation that drives speech production thesame as or different from the semantic knowledgethat guides your behavior when pick up and usea hammer? The latter kind of knowledge is oftenreferred to, by theorists who hold that it is aseparate system, as action semantics (Buxbaum,Schwartz, & Carew, 1997; Lauro-Grotto et al.,1997; Rothi, Ochipa, & Heilman, 1991).Our hypothesis, based upon work in semanticdementia, is that central semantic representationsare modality free. We tend to side with the theoristsarguing for one central semantic system (e.g.,Caramazza, Hillis, Rapp, & Romani, 1990; Howard& Patterson, 1992), rather than those proposingseparate modality-speciﬁc semantic systems (e.g.,Lauro-Grotto et al., 1997; McCarthy & Warrington,1988; Rothi et al., 1991; Shallice & Kartsounis,1993). This view has been formed mainly by thefact that none of the cases of semantic dementiathat we have studied have demonstrated a strikingdissociation between different modalities of inputor output and the following studies.Are There Two Separate Systems for Words andObjects?To address this question, we recently (LambonRalph et al., 1999) evaluated deﬁnitions of concreteconcepts provided by nine patients with semanticdementia (including A.M.) (table 4.1). The stimulusmaterials consisted of the forty-eight items fromthe semantic battery described earlier (Hodges &Patterson, 1995). Each patient was asked, on dif-ferent occasions, to deﬁne each concept both inresponse to a picture of it and in response to itsspoken name. The deﬁnitions were scored in avariety of ways, including an assessment of whetherthe patient’s deﬁnition achieved the status of “coreconcept”: that is, the responses provided sufﬁcientinformation for another person to identify theconcept from the deﬁnition.The view that there are separate verbal and visualsemantic systems predicts no striking item-speciﬁcsimilarities across the two conditions. In keepingwith our alternative expectation, however, there wasa highly signiﬁcant concordance between deﬁnitionsuccess (core concept) and words and pictures refer-ring to or depicting the same item. The numberof deﬁnitions containing no appropriate semanticinformation was signiﬁcantly larger for words thanfor the corresponding pictures. This differencemight be taken by theorists preferring a multiple-systems view as indicating the relative preservationof visual semantics, but we argue that it is open tothe following alternative account: The mappingbetween an object (or a picture of it) and its con-ceptual representation is inherently different fromthe mapping between a word and its central concept.Although not everything about objects can beinferred from their physical characteristics, thereis a systematic relationship between many of thesensory features of an object or picture and itsmeaning. This relationship is totally lacking forwords; phonological forms bear a purely arbitraryrelationship to meaning. Expressed another way,real objects or pictures afford certain properties(Gibson, 1977); words have no affordances. Unlessone is familiar with Turkish, there is no way ofSemantic Dementia 81
knowing whether piliç describes a chicken, anaubergine, or a ﬁsh (actually it is a chicken). Whenconceptual knowledge is degraded, it thereforeseems understandable that there should be a numberof instances where a patient would be able toprovide some information, even though it isimpoverished, in response to a picture, but woulddraw a complete blank in response to the object’sname.When the nine patients were analyzed as indi-vidual cases and deﬁnitions were scored for thenumber of appropriate features that they contained,seven patients achieved either equivalent scores forthe two stimulus conditions or better performancefor pictures than words, but the remaining twopatients in fact scored more highly in response towords than to pictures. Furthermore, these latter twowere the only two cases whose bilateral atrophy onMRI was clearly more severe in the right temporallobe than on the left.This outcome might be thought to provide evenstronger support for separable verbal and visualsemantic systems, with verbal representationsmore reliant on left hemisphere structures, andvisual representations based more on a right hemi-sphere semantic system. Once again, this was notour interpretation. In any picture–word dissociation,one must consider the possibility that the patienthas a presemantic deﬁcit in processing the stimulustype, yielding poorer performance. For the twopatients who provided more concept attributes forwords than pictures, their clear central semanticimpairment (indicated by severely subnormal deﬁ-nitions for words as well as pictures) was combinedwith abnormal presemantic visuoperceptual pro-cessing. For example, both had low scores onmatching the same object across different views;and one of the cases (also reported in Knott et al.,1997) was considerably more successful in nam-ing real objects (21/30) than line drawings of thesame items (2/30), reﬂecting difﬁculty in extractingthe necessary information for naming from thesomewhat sparse visual representation of a linedrawing. We have concluded that none of ourresults require an interpretation in terms of separatesemantic representations activated by words andobjects.Is There a Separate Action Semantic System?Our recent investigations addressing this generalissue were motivated by the claim (e.g., Buxbaumet al., 1997; Lauro-Grotto et al., 1997; Rothi et al.,1991) that there is a separate “action semantic”system that can be spared when there is insufﬁcientknowledge to drive other forms of response—notonly naming, but even nonverbal kinds of respond-ing such as sorting, word–picture matching, orassociative matching of pictures or words. Thisview is promoted by frequent anecdotal reportsthat patients with semantic dementia, who fail awhole range of laboratory-based tasks of the latterkind, function normally in everyday life (e.g.,Snowden, Grifﬁths, & Neary, 1995). We too haveobserved many instances of such correct object usein patients, although there are also a number ofcounterexamples (see A.M. above). Nevertheless,the documented successes in object use by patientswith severe semantic degradation require explana-tion. We have recently tried to acquire someevidence on this issue (Hodges, Bozeat, LambonRalph, Patterson, & Spatt, 2000; Hodges et al.,1999b).The ability of six patients with semanticdementia to demonstrate the use of twenty everydayobjects such as a bottle opener, a potato peeler, or abox of matches was assessed. The patients also per-formed a series of other semantic tasks involvingthese same objects, including naming them, match-ing a picture of the object with a picture of the loca-tion in which it is typically found (a potato peelerwith a picture of a kitchen rather than a garden)or to the normal recipient of the object’s action (apotato peeler with a potato rather than an egg). Inaddition, the patients performed the novel tool testdesigned by Goldenberg and Hagmann (1998) inwhich successful performance must rely on problemsolving and general visual affordances of the toolsand their recipients, since none of these correspondto real, familiar objects.John R. Hodges 82
The results of these experiments can be summa-rized in terms of the questions that we framed. (1)Are patients with semantic dementia generallymuch more successful in using real objects thanwould be expected from their general semantic per-formance? No. (2) If a patient’s success in objectuse varies across different items, can this usually bepredicted on the basis of his or her success in other,nonusage semantic tasks for the same objects? Onthe whole, yes. (3) Where there is evidence forcorrect use of objects for which a patient’s knowl-edge is clearly impaired, can this dissociation beexplained by preservation of general mechanicalproblem-solving skills combined with real-objectaffordances, rather than requiring an interpretationof retained object-speciﬁc action semantics? Yes.In other words, we have obtained no convincingevidence for a separate action semantic systemthat is preserved in semantic dementia.The patient successes appear to be explicable interms of two main factors. The ﬁrst is that thepatients have good problem-solving skills and thatmany objects give good clues to their function. Thesecond is that success with objects is signiﬁcantlymodulated by factors of exemplar-speciﬁc familiar-ity and context. As demonstrated by the ingeniousexperiments of Snowden et al. (1994), a patient whoknows how to use her own familiar teakettle in thekitchen may fail to recognize and use both theexperimenter’s (equally kettlelike but unfamiliar)teakettle in the kitchen and her own teakettle whenit is encountered out of a familiar context (e.g., inthe bedroom). Our experimental assessments ofobject use involved standard examples of everydayobjects, but these were not exemplars previouslyused by and known to the patients, and moreoverthey were presented in a laboratory setting, not intheir normal contexts.Conclusions and Future DirectionsClearly, a great deal has been learned aboutthe neural basis of semantic memory, and therelationship between semantic and other cognitiveprocesses, from the study of patients with semanticdementia. Despite this, much remains to be done. Inparticular, there is a dearth of clinicopathologicalstudies that combine good in vivo neuropsycholog-ical and imaging data with postmortem brainanalysis. The role of left and right temporal lobestructures in speciﬁc aspects of semantic memoryremains controversial, but can be addressed by thelongitudinal analysis of rare cases who present withpredominant left over right temporal lobe atrophy.The recent ﬁnding of asymmetrical medial tempo-ral (hippocampal and/or entorhinal) atrophy despitegood episodic memory processing in early seman-tic dementia also raises a number of importantissues for future study.Until very recently, the study of memory in non-human primates has focused almost exclusively onworking memory and paradigms thought to mirrorhuman episodic memory. It is now believed thatsome object-based tasks (e.g., delayed matchingand nonmatching-to-sample) more closely resemblehuman semantic memory tests, and that animalsfailing such tasks after perirhinal ablation havedeﬁcits in object recognition and/or high-levelperceptual function (see Murray & Bussey, 1999;Simons et al., 1999). This radical departure hasstimulated interest in the role of the human perirhi-nal cortex in semantic memory and the relationshipbetween perception and knowledge in humans. Anumber of projects exploring parallels betweenmonkey and human semantic memory are alreadyunder way and promise to provide further excitinginsights over the next few years.AcknowledgmentThis chapter is dedicated to my neuropsychology col-league and friend, Karalyn Patterson, who has inspiredmuch of the work described in this chapter; and to theresearch assistants, graduate students, and postdoctoralresearchers who have made the work possible. We havebeen supported by the Medical Research Council, theWellcome Trust, and the Medlock Trust.Semantic Dementia 83
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Geoffrey K. AguirreTopographical disorientation (hereafter, TD) refersto the selective loss of way-ﬁnding ability withinthe locomotor environment. Despite sharing thisgeneral impairment and a diagnostic label, patientswith TD present in a rather heterogeneous manner,with considerable variability in the precise natureof their cognitive deﬁcit and lesion site. This vari-ability in clinical presentation might be expected,given the tremendous complexity of way-ﬁndingand the multifaceted solutions that are brought tobear on the challenge. It should further be clear thatmany general impairments, which have little to dowith representation of environmental informationper se (e.g., blindness, global amnesia, paralysis)might prevent a person from successfully travelingfrom their home to a well-known destination.Historically, the treatment of TD as a neurologicaldisorder has been a bit of a muddle, with con-siderable debate regarding the singular, “essentialnature” of the disorder and confusion regardingthe terminology used to describe the cases. (For ahistorical review see Barrash, 1998, or Aguirre andD’Esposito, 1999.)Despite these challenges, the complexities of TDyield to an understanding of the behavioral elementsof way-ﬁnding and an appreciation of the parcella-tion of cognitive function within the cortex. Iconsider here a framework that can be used to cat-egorize cases of TD based upon the behavioralimpairment and the location of the responsiblelesion. I begin with four cases of TD, which providea sense of the range of disabilities seen. Next,I consider the cognitive processes involved inway-ﬁnding and the interpretation of clinical testsof disoriented patients. The cases presented initiallyare then revisited in greater detail, and a four-part “taxonomy” of TD explored. Finally, I dis-cuss the results of recent neuropsychological andfunctional neuroimaging studies of environmentalrepresentation.5 Topographical Disorientation: A Disorder of Way-Finding AbilityCase ReportsCase 1: A patient reported by Levine and colleagues(Levine, Warach, & Farah, 1985) presented with severespatial disorientation following development of intracere-bral hemorrhages. He would become lost in his own houseand was unable to travel outside without a companionbecause he was completely unable to judge which direc-tion he needed to travel. The patient demonstrated a righthomonymous hemianopia, but had intact visual acuity andno evidence of prosopagnosia, object agnosia, or achro-matopsia. His disabilities were most strikingly spatial. Hehad difﬁculty ﬁxating on individual items within an array,demonstrated right-left confusion for both external spaceand his own limbs, and could not judge relative distance.He became grossly disoriented in previously familiarplaces; was unable to learn his way around even simpleenvironments; and provided bizarre descriptions of routes.A computed tomography (CT) scan revealed bilateralposterior parietal lesions extending into the posterioroccipital lobe on the left.Case 2: Patient T.Y. (Suzuki, Yamadori, Hayakawa, &Fujii, 1998) presented with severe difﬁculties in ﬁndingher way to her doctor’s ofﬁce, a route which she had rou-tinely walked over the previous 10 years. Although T.Y.initially demonstrated unilateral spatial neglect and con-structional apraxia, these resolved over the followingweeks. She did have a stable, incomplete, left lower quad-rantanopsia. She was without object agnosia or prosopag-nosia, and had intact visual and spatial memory asmeasured by standard table-top tests. Despite an intactability to recognize her house and famous buildings, T.Y.was unable to state the position from which the photo-graphs of these structures were taken. She was also utterlyunable to judge her direction of heading on a map whileperforming a way-ﬁnding task through a college campus.In contrast to these deﬁcits, T.Y. was able to draw accu-rate maps and provide verbal directions to places familiarto her prior to her disability. A magnetic resonanceimaging (MRI) scan revealed a subcortical hemorrhageinvolving primarily the right posterior cingulate.Case 3: Patient A.H. (Pallis, 1955) woke one morning toﬁnd that he could not recognize his bedroom and becamelost trying to return from the toilet to his room. In
addition to a central scotoma, he developed achromatop-sia and marked prosopagnosia. He was without neglect,left-right confusion, or apraxia. His primary and most dis-tressing complaint was his inability to recognize places.While he could intuit his location within his hometownfrom the turns he had taken and the small details he mightnotice (i.e., the color of a particular park bench), he wasunable to distinguish one building from another, forexample, mistaking the post ofﬁce for his pub. His troubleextended to new places as well as previously familiarlocales. Vertebral angiography revealed defective ﬁlling ofthe right posterior cerebral artery.Case 4: Patient G.R. (Epstein, DeYoe, Press, Rosen, &Kanwisher, 2001) developed profound difﬁculties learninghis way around new places following cardiac surgery. Inaddition to his way-ﬁnding complaints, G.R. demonstrateda left hemianopsia, right upper quadrantanopsia, anddyschromatopsia. He had no evidence of neglect, left-rightconfusion, or apraxia, and no prosopagnosia or objectagnosia. G.R. did have subtle memory impairments onformal testing, with greater disability for visual than verbalmaterial. Despite being able to follow routes marked onmaps, G.R. was totally unable to learn new topographicalinformation, including the appearance of environmentalfeatures and exocentric spatial relationships. He wasunimpaired in navigating through environments familiarto him prior to the onset of his symptoms. An MRI scanrevealed bilateral damage to the parahippocampal gyri,with extension of the right lesion posteriorly to involvethe inferior lingual gyrus, medial fusiform gyrus, andoccipital lobe.Normative Way-Finding and Clinical TestsPeople employ a variety of strategies and repre-sentations when solving way-ﬁnding tasks. Thesevariations have been attributed to subject variables(e.g., gender, age, length of residence), differencesin environmental characteristics (e.g., density oflandmarks, regularity of street arrangements), anddifferences in knowledge acquisition (e.g., naviga-tion versus map learning). One basic tenet ofenvironmental psychology studies is that these dif-ferences are largely the result of differences inrepresentation; a subject not only improves his orher knowledge of the environment with increasingfamiliarity, for example, but comes to representthat knowledge in qualitatively different ways withexperience (Appleyard, 1969; Piaget, Inhelder, &Szeminska, 1960; Siegel, Kirasic, & Kail, 1978;Siegel & White, 1975). This shift in representationin turn supports the ability to produce more accu-rate, ﬂexible, and abstract spatial judgments. Speci-ﬁcally, a distinction has frequently been drawnbetween representations of the environment that areroute based and those that are more “maplike.” Thisgross division has appeared under many labels(i.e., taxon versus locale, O’Keefe & Nadel, 1978;procedural versus survey, Thorndyke & Hayes,1982; route versus conﬁgural, Siegel & White,1975; network versus vector map, Byrne, 1982), butthey generally possess the same basic structure.Most environmental representation is predicatedon the ability to recognize speciﬁc locations wherenavigational decisions are executed. This perceptualability is called “landmark (or place) recognition”and is thought to be the ﬁrst “topographic” abilityacquired in developing infants (Piaget et al., 1960).Subjects improve in their ability to successfullyidentify environmental features with developmen-tal age and there is considerable between-subjectagreement as to what constitutes a useful landmark(Allen, Kirasic, Siegel, & Norman, 1979). Forexample, buildings located at street intersectionsseem to provide primary anchor points for real-world navigational learning (Presson, 1987).Route knowledge describes the information thatencodes a sequential record of steps that lead froma starting point, through landmarks, and ﬁnally to adestination. This representation is essentially linear,in that each landmark is coupled to a given instruc-tion (i.e., go right at the old church), which leads toanother landmark and another instruction, repeateduntil the goal is reached. Indeed, the learning oflandmark-instruction paths has been likened tothe learning of stimulus-response pairs (Thorndyke,1981). While more information can be storedalong with a learned route—for example, distances,the angles of turns and features along the routeGeoffrey K. Aguirre 90
(Thorndyke & Hayes, 1982)—there is evidence thatsubjects often encode only the minimal necessaryrepresentation (Byrne, 1982).Descriptions of route learning also emphasize itsgrounding in an egocentric coordinate frame. It isassumed that a set of transformations take place bywhich the retinal position of an image is combinedwith information regarding the position of the eyesin the orbits and the position of the head upon theneck in order to represent the location of an objectwith reference to the body. This is called an “ego-centric (or body-centered) space” and is the domainof spatial concepts such as left and right. Orienta-tion is maintained within a learned route by repre-senting an egocentric position with respect to alandmark (i.e., pass to the left of the grocery store,then turn right). A ﬁnal, and crucial, aspect of routeknowledge is its presumed inﬂexibility. Because aroute encodes only a series of linear instructions, therepresentation is fragile in that changes in cruciallandmarks or detours render the learned pathuseless.Whereas route learning is conducted within ego-centric space, maplike representations are locatedwithin the domain of exocentric space, in whichspatial relations between objects within the envi-ronment, including the observer, are emphasized(Taylor & Tversky, 1992). A developmental disso-ciation between egocentric and exocentric spatialrepresentation has been demonstrated in a seriesof experiments by Acredolo (1977), indicating thatthese two coordinate frames are represented byadult subjects. In order to generate a representationof exocentric space, egocentric spatial decisionsmust be combined with an integrated measure ofone’s motion in the environment. While a tree maybe to my right now, if I walk forward ten pacesand turn around, the tree will now be to my left.Though the egocentric position of the landmark haschanged, I am aware that the tree has not moved;the exocentric position has remained invariant. Arepresentation of this invariance is made availableby combining the egocentric spatial judgments witha measure of the vector motion that was undertaken.An important lesson from this cursory review isthat the particular type of representation that asubject generates of his or her environment can bedependent upon (1) the subject’s developmentalage, (2) the duration of a subject’s experience witha particular environment, (3) the manner in whichthe subject was introduced to the environment(i.e., self-guided exploration, map reading), (4) thelevel of differentiation (detail) of the environment,and (5) the tasks that the subject is called upon toperform within the space. The multiplicity andredundancy of strategies that may be brought to bearupon way-ﬁnding challenges make the interpreta-tion of standard clinical tests of topographical ori-entation problematic. For example, asking a patientto describe a route in his or her town is not guaran-teed to evoke the same cognitive processes fordifferent routes, let alone different subjects. Sincethese commonly employed tests of topographicalorientation (i.e., describing a route, drawing a map)are poorly deﬁned with regard to the cognitiveprocesses they require, it is always possible toprovide a post hoc explanation for any particulardeﬁcit observed.This inferential complication is further con-founded by the ability of patients to store a partic-ular representation in any one of several forms.Consider, for example, the frequently employedbedside test of producing a sketch map. Patients areasked to draw a simple map of a place (e.g., theirhome, their town, the hospital) with the intentionof revealing intact or impaired exocentric (i.e.,maplike) representations of space. It is possiblehowever, to produce a sketch map of a place withoutpossessing an exocentric representation (Pick,1993). For example, complete route knowledge ofa place, combined with some notion of the relativepath lengths composing the route segments, is suf-ﬁcient to allow the construction of an accuratesketch map. Thus, while a subject may be able toproduce a sketch map of a place, this does not nec-essarily indicate that the subject ever possessedor considered an exocentric representation of thatplace prior to the administration of the test (Byrne,Topographical Disorientation 91
1982). Alternatively, it is possible that considerableexperience with map representations of a placewould lead a subject to develop a “picturelike” rep-resentation. If, for example, a subject has had theopportunity to consult or draw maps of his home orhometown several times previously, then he mightbe able to draw a map of that place in the samemanner that he might draw a picture of an object.In a similar manner, impairments in one area oftopographical representation might lead to poor per-formance on tests that ostensibly probe a differentarea of competence. For example, if a patient isasked to describe a route through a well-knownplace, it is frequently assumed that the patient isrelying only upon intact egocentric spatial knowl-edge. However, it is entirely possible that if pro-ducing a verbal description of a route is not awell-practiced behavior, the subjects engage inan imaginal walk along the route to produce thedescription (Farrell, 1996). In this case, deﬁcits inthe ability to represent and manipulate informationabout the appearance of landmarks would alsoimpair performance. Thus, given that subjects mighthave to generate maplike representations only at thetime of testing, and given that this process can bedependent upon route representations which them-selves may require intact representations of envi-ronmental landmarks, it is conceivable that tertiaryimpairments in producing a sketch map mightbe produced by primary impairments in landmarkrecognition!How then are we to proceed in interpreting theclinical tests given to patients with TD? The onlypossible means of gaining inferential knowledge ofthese disorders is to obtain additional informationregarding the nature of the impairment. One simpleapproach is to attach credence to the patient’sdescription of their disability. As will be examinedlater, some categories of TD give rise to rather con-sistent primary complaints across patients. Whenthese reports are sufﬁciently clear and consonant,they provide a reasonable basis for theorizing. Nat-urally, there are limitations to this approach as well.Patient reports might simply be wrong (Farrell,1996); the case reported by DeRenzi and Faglioni(1962) offers an example in which the patient’sclaim of intact recognition for buildings and envi-ronmental features was at odds with his actualperformance.Additional clinical tests, with more transparentinterpretations, may also be used to help inter-pret topographical impairments. Demonstrations ofstimulus-speciﬁc deﬁcits in visual memory and im-pairments of egocentric spatial representation havebeen particularly helpful. For example, Whiteleyand Warrington (1978) introduced tests of visualrecognition and matching of landmarks, which haveled to a deeper understanding of one type of TD. Ofcourse, such tests themselves require careful inter-pretation and monitoring. As has been demonstratedfor general object agnosia, patients can maintainintact performance on such tasks by using markedlyaltered strategies (Farah, 1990).While more complex clinical tests have beenemployed, these frequently are as subject to variousinterpretations as the original patient deﬁcit. Forexample, the stylus-maze task (Milner, 1965), inwhich the subject must learn an invisible paththrough an array of identical bolt heads, has beenwidely applied. Despite the vague similarity ofmaze learning and real-world navigation, it is con-ceivable that failure to successfully complete thetask might be due to a number of cognitive impair-ments that are unrelated to way-ﬁnding; indeed,neuropsychological studies that have employed thistest have noted that many patients who are impairedon the stylus maze task have no real-world orienta-tion difﬁculties whatsoever (Newcombe & Ritchie,1969) and vice versa (Habib & Sirigu, 1987). Othertests that have been applied with varying degreesof success include the Semmes ExtrapersonalOrientation Test, which requires retention andupdating of right-left orientation, and tests of geo-graphical knowledge (i.e., is Cincinnati east or westof Chicago?), which seem to bear no relationship toTD per se.The ability of patients to compensate for theirdeﬁcits and the techniques that they use are alsoinformative. For example, it has long been notedthat some patients navigate by reference to an exten-Geoffrey K. Aguirre 92
sive body of minute environmental features, such asdistinctive doorknobs, mailboxes, and park benches(Meyer, 1900). As discussed later, this compensa-tory strategy speaks both to the nature of the impair-ment and to the intact cognitive abilities of thepatient.Finally, the traditional sketch map productionand route description tests can provide useful infor-mation in some situations. Consider the case of apatient who is able to generate accurate sketch mapsof places that were unfamiliar prior to sustaining thelesion and that the patient has only experiencedthrough direct exploratory contact. In this situation,the patient must have an intact ability to representspatial relationships (either egocentric or exocen-tric) to have been able to generate this representa-tion. In a similar vein, the demonstration of intactrepresentational skills using these “anecdotal” clin-ical measures may be interpreted with slightly moreconﬁdence than impairments.Neuropsychological Studies of Way-FindingWhile the early neurological literature regarding TDcontains almost exclusively case studies, the 1950sand 1960s witnessed the publication of a number ofgroup and neuropsychological studies. The researchfrom this era has been ably reviewed and evaluatedby Barrash (1998). Essentially, these studies empha-sized that lesions of the “minor hemisphere” (right)were most frequently associated with topographicaldifﬁculties and the studies initiated the process ofdistinguishing types of disorientation. The modernera of neuropsychological investigation of TDbegan with Maguire and colleagues’ (Maguire,Burke, Phillips, & Staunton, 1996a) study of theperformance of patients with medial temporallesions on a standardized test of real-world way-ﬁnding. One valuable contribution of this studywas to emphasize the importance of evaluatingTD within the actual, locomotor environment, asopposed to the use of table-top tests.Twenty patients who had undergone medial tem-poral lobectomy (half on either side) were testedon a videotaped route-learning task. While thesepatients denied frank TD and did not have anymeasurable general memory impairments, theywere impaired relative to controls on tests of route-learning and judgment of exocentric position. It isinteresting that patients with left or right excisionshad roughly equivalent impairments.Another report (Bohbot et al., 1998) also exam-ined the involvement of the hippocampal formationin topographical learning. Fourteen patients withwell-deﬁned thermocoagulation lesions of the me-dial temporal lobes were tested on a human analogof the Morris (Morris, Garrud, Rawlins, & O’Keefe,1982) water maze task. Patients with lesions con-ﬁned to the right parahippocampal cortex wereimpaired more than those with lesions of the leftparahippocampal cortex, right or left hippocampus,and epileptic controls.The focus on the medial temporal lobes in general(and the hippocampus in particular) in these studiesderives from the compelling ﬁnding in rodents of“place cells” within the hippocampus. Consideredin more detail later, these neurons are “tuned” to ﬁremaximally when the rodent is within a particularposition within an exocentric space. The existenceof these neurons led to the proposal that the hip-pocampus is the anatomical site of the “cognitivemap” of exocentric space emphasized by O’Keefeand Nadel (1978). As we will see, the role of thehippocampus and its adjacent structures in humannavigation is still rather uncertain, but the studies ofMaguire (1996a) and Bohbot (1998) demonstratedthat lesions within the medial temporal lobes couldimpair real-world navigation.The neuropsychological study by Barrash andcolleagues (Barrash, Damasio, Adolphs, & Tranel,2000) is notable for its comprehensive examinationof patients with lesions distributed throughoutthe cortex on a real-world route-ﬁnding test. Onehundred and twenty-seven patients with stable,focal lesions were asked to learn a complex, one-third-mile route through a hospital. The primaryﬁnding was that lesions to several discrete areasof the right hemisphere were frequently associated(>75% of the time) with impaired performance onTopographical Disorientation 93
the route-learning test. The identiﬁed area extendedfrom the inferior medial occipital lobe (lingual andfusiform gyri) to the parahippocampal and hip-pocampal cortices, and also included the intrapari-etal sulcus and white matter of the superior parietallobule. A much smaller region of the medial occip-ital lobe and parahippocampus on the left was alsoidentiﬁed. This study is valuable in that it identiﬁesthe full extent of cortical areas that are necessary insome sense for the acquisition of new topographi-cal knowledge.There are two important caveats, however, whichwere well recognized and discussed by the authorsof the study. First, the patients were studied usinga comprehensive navigation task. As has been dis-cussed, there are many different underlying cogni-tive impairments that might lead to the ﬁnalcommon pathway of route-learning deﬁcits. There-fore, the various regions identiﬁed as being neces-sary for intact route learning might each be involvedin the task in a very different way. Second, becausethe patients have “natural” as opposed to experi-mentally induced lesions, the identiﬁcation of thenecessary cortical regions cannot be accepted un-critically. For example, while lesions of the righthippocampus were associated with impaired per-formance, a high proportion of patients with hip-pocampal damage also have parahippocampaldamage because of the distribution of the vascularterritories. If so, it is possible that damage to theparahippocampus alone is sufﬁcient, and that theﬁnding of an association between hippocampallesions and impaired performance is the erroneousresult of an anatomical confound.Both of these objections can be addressed byusing alternative approaches. By studying theprecise cognitive deﬁcits present in patients withlocalized lesions, the cognitive, way-ﬁnding respon-sibility of each identiﬁed region can be more pre-cisely deﬁned. In addition, functional neuroimagingstudies in humans (although strictly providing fordifferent kinds of inference) can be used to reﬁneanatomical identiﬁcations without reliance uponthe capricious distributions of stroke lesions. Wediscuss this in greater detail later.A Taxonomy of Topographical DisorientationNow armed with the distribution of cortical lesionsites known to be associated with route-learningimpairments and with an understanding of thebehavioral basis of way-ﬁnding, we can return tothe cases presented originally. As we will see, thesefour cases each serve as an archetype for a particu-lar variety of TD. These four varieties of TD aresummarized in table 5.1, and the lesion site prima-rily responsible for each disorder is illustrated inﬁgure 5.1.Egocentric Disorientation (Case 1)The patient described by Levine, Warach, and Farah(1985) demonstrated profound way-ﬁnding difﬁcul-ties within his own home and new places followingbilateral damage to the posterior parietal cortex.While he (and a number of similar patients: M.N.N.,Kase, Troncoso, Court, & Tapia, 1977; Mr. Smith,Hanley, & Davies, 1995; G.W., Stark, Coslett, &Saffran, 1996; and the cases of Holmes & Horax,1919) has been described as topographically disori-ented, it is clear that his impairments extended farbeyond the sphere of extended, locomotor space. Toquote Levine and Farah:[His] most striking abnormalities were visual and spatial.. . . He could not reach accurately for visual objects,even those he had identiﬁed, whether they were presentedin central or peripheral visual ﬁelds. When shown twoobjects, he made frequent errors in stating whichwas nearer or farther, above or below, or to the right orleft. . . .He could not ﬁnd his way about. At 4 months after thehemorrhages, he frequently got lost in his own house andnever went out without a companion. . . . Spatial imagerywas severely impaired. He could not say how to get fromhis house to the corner grocery store, a trip he had madeseveral times a week for more than 5 years. In contrast, hecould describe the store and its proprietor. His descriptionsof the route were frequently bizarre: “I live a block away.I walk direct to the front door.” When asked which direc-tion he would turn on walking out of his front door, hesaid, “It’s on the right or left, either way.” . . . When,Geoffrey K. Aguirre 94
seated in his room, he was blindfolded and asked to pointto various objects named by the examiner, he responded[very poorly]. (Levine, Warach, & Farah, 1985, p. 1013)These patients, as a group, had severe deﬁcits inrepresenting the relative location of objects withrespect to the self. While they were able to gesturetoward objects they could see, for example, thisability was completely lost when their eyes wereclosed. Performance was impaired on a wide rangeof visual-spatial tasks, including mental rotationand spatial span tasks. It thus seems appropriate tolocate the disorder within the egocentric spatialframe. Indeed, Stark and colleagues (1996) havesuggested that one of these patients (G.W.) had sus-tained damage to a spatial map that represents in-formation within an egocentric coordinate system.It is interesting that these cases suggest that neuralsystems capable of providing immediate informa-tion on egocentric position can operate independ-ently of systems that store this information (Starket al., 1996).These patients were uniformly impaired in way-ﬁnding tasks in both familiar and novel environ-ments. Most remained conﬁned to the hospital orhome, willing to venture out only with a compan-ion (Kase et al., 1977; Levine et al., 1985). Routedescriptions were impoverished and inaccurate(Levine et al., 1985; Stark et al., 1996) and sketchmap production disordered (Hanley & Davies,1995). In contrast to these impairments, visual-object recognition was informally noted to be intact.Patient M.N.N. was able to name objects correctlywithout hesitation, showing an absence of agnosicfeatures in the visual sphere. Patient G.W. had nodifﬁculty in recognizing people or objects and case2 of Levine et al. (1985) was able to identifycommon objects, pictures of objects or animals,familiar faces, or photographs of the faces of familymembers and celebrities.Unfortunately, these patients were not speciﬁ-cally tested on visual recognition tasks employinglandmark stimuli. As noted earlier, Levine andcolleagues reported that their case 2 was able todescribe a grocery store and its proprietor, but thisTopographical Disorientation 95Figure 5.1Locations of lesions responsible for varieties of topo-graphical disorientation: (1) the posterior parietal cortex,associated with egocentric disorientation; (2) the posteriorcingulate gyrus, associated with heading disorientation;(3) the lingual gyrus, associated with landmark agnosia;and (4) the parahippocampus, associated with anterogradedisorientation. These sites are illustrated in the right hemi-sphere since the great majority of cases of topograph-ical disorientation follow damage to right-sided corticalstructures.
does not constitute a rigorous test. It is possible thatdespite demonstrating intact object and face recog-nition abilities, patients with egocentric disorienta-tion will be impaired on recognition tasks thatemploy topographically relevant stimuli. Thus, untilthese tests are conducted, we can offer only the pos-sibility that these patients are selectively impairedwithin the spatial sphere.It seems plausible that the way-ﬁnding deﬁcitsthat these patients display are a result of their pro-found disorientation in egocentric space. As notedearlier, route-based representations of large-scalespace are formed within the egocentric spatialdomain. This property of spatial representation waswell illustrated by Bisiach, Brouchon, Poncet, &Rusconi’s 1993 study of route descriptions in apatient with unilateral neglect. Regardless of thedirection that the subject was instructed to imaginetraveling, turns on the left-hand side tended to beignored. Thus, the egocentric disorientation thatthese patients display seems sufﬁcient to accountfor their topographical disorders. In this sense, it isperhaps inappropriate to refer to these patients asselectively topographically disoriented—their dis-ability includes forms of spatial representation thatare clearly not unique to the representation of large-scale, environmental space.Barrash (1998) has emphasized the variable dura-tion of the symptoms of TD. In particular, manypatients who demonstrate egocentric disorientationin the days and weeks following their lesion gradu-ally recover near-normal function. Following thisinitial period, patients can demonstrate a patternof deﬁcits described by Passini, Rainville, & Habib(2000) as being conﬁned to “micro” as opposed to“macroscopic” space. Their distinction is perhapsmore subtle than the egocentric versus exocentricclassiﬁcation made here, because the recoveredpatients may demonstrate impairments in the mani-pulation of technically nonegocentric spatial infor-mation (e.g., mental rotation), but do not show grossway-ﬁnding difﬁculties.Those egocentrically disoriented patients forwhom lesion data are available all have either bilat-eral or unilateral right lesions of the posterior pari-etal lobe, commonly involving the superior parietallobule. Studies in animals (both lesion and electro-physiologically based) support the notion thatneurons in these areas are responsible for the repre-sentation of spatial information in a primarily ego-centric spatial frame. Homologous cortical areas inmonkeys contain cells with ﬁring properties thatrepresent the position of stimuli in both retinotopicand head-centered coordinate spaces simultane-Geoffrey K. Aguirre 96Table 5.1A four-part taxonomy of topographical disorientationLesion site Disorder label Proposed impairment Model casePosterior parietal Egocentric Unable to represent the location G.W. (Stark, Coslett, Saff,disorientation of objects with respect to self 1996)Posterior cingulate Heading Unable to represent direction of T.Y. (Suzuki, Yamador,gyrus disorientation orientation with respect to external Hayakawa, Fujii, 1998)environmentLingual gyrus Landmark Unable to represent the appearance A.H. (Pallis, 1955)agnosia of salient environmental stimuli(landmarks)Parahippocampus Anterograde Unable to create new representations G.R. (Epstein, Deyoe, Press,disorientation of environmental information Rosen, Kanwisher 2001)
ously (i.e., planar gain ﬁelds; Anderson, Snyder, Li,& Stricanne, 1993). Notably, cells with exocentricﬁring properties have not been identiﬁed in therodent parietal cortex, although cells responsiveto complex conjunctions of stimulus egocentricposition and egomotion have been reported(McNaughton et al., 1994).Heading Disorientation (Case 2)While the previous group of patients evidenced aglobal spatial disorientation, rooted in a fundamen-tal disturbance of egocentric space, a second groupof patients raises the intriguing possibility thatexocentric spatial representations can be selectivelydamaged. These are patients who are both able torecognize salient landmarks and who do not havethe dramatic egocentric disorientation describedearlier. Instead, they seem unable to derive direc-tional information from landmarks that they dorecognize. They have lost a sense of exocentricdirection, or “heading” within their environment.Patient T.Y. (Suzuki et al., 1998) presented withgreat difﬁculty in way-ﬁnding following a lesionof the posterior cingulate gyrus. She showed noevidence of aphasia, acalculia, or right-left disori-entation, object agnosia, prosopagnosia, or achro-matopsia. She also had intact verbal and visualmemory as assessed by the Wechsler MemoryScale, intact digit span, and normal performance onRaven’s Progressive Matrices. Her spatial learningwas intact, as demonstrated by good performanceon a supraspan block test and the Porteus Maze test.In contrast to these intact abilities, T.Y. was unableto state the position from which photographs offamiliar buildings were taken. Or judge her direc-tion of heading on a map while performing a way-ﬁnding task through a college campus.Three similar patients have been reported byTakahashi and colleagues (Takahashi, Kawamura,Shiota, Kasahata, & Hirayama, 1997). Like patientT.Y., they were unable to derive directional infor-mation from the prominent landmarks that theyrecognized. The patients were able to discriminateamong buildings when several photographs weredisplayed and were able to recognize photographsof familiar buildings and landscapes near theirhomes. The basic representation of egocentricspace, both at immediate testing and after a 5-minute delay, was also demonstrated to be pre-served. In contrast to these preserved abilities,Takahashi et al.’s patients were unable to describeroutes between familiar locations and could notdescribe the positional (directional) relationshipbetween one well-known place and another. In addi-tion, the three patients were unable to draw a sketchmap of their hospital ﬂoor. A patient (M.B.) reportedby Cammalleri et al. (1996) had similar deﬁcits.Takahashi and colleagues suggested that theirpatients had lost the sense of direction that allowsone to recall the positional relationships betweenone’s current location and a destination within aspace that cannot be fully surveyed in one glance.This can also be described as a sense of heading, inwhich the orientation of the body with respect toexternal landmarks is represented. Such a represen-tation would be essential for both route-followingand the manipulation of maplike representations ofplace. The possibility of isolated deﬁcits in therepresentation of spatial heading is an intriguingone. These patients have a different constellation ofdeﬁcits from those classiﬁed as egocentrically dis-oriented, and the existence of these cases suggeststhat separate cortical areas mediate different framesof spatial representation.Patient T.Y., Takahashi’s three patients, andpatient M.B. had lesions located within the rightretrosplenial (posterior cingulate) gyrus. Figure5.2 shows the lesion site in patient T.Y. It is inter-esting that this area of the cortex in the rodent hasbeen implicated in way-ﬁnding ability. Studies inrodents (Chen, Lin, Green, Barnes, & McNaughton,1994) have identiﬁed a small population of cellswithin this area that ﬁre only when the rat is main-taining a certain heading, or orientation withinthe environment. These cells have been dubbed“head-direction” cells (Taube, Goodridge, Golob,Dudchenko, & Stackman, 1996), and most likelyTopographical Disorientation 97
generate their signals based upon a combination oflandmark, vestibular, and idiothetic (self-motion)cues. Representation of the orientation of the bodywithin a larger spatial scheme is a form of spatialrepresentation that might be expected to be drawnupon for both route-based and map-based naviga-tion. Neuroimaging studies in humans (consideredlater) have also added to this account.Landmark Agnosia (Case 3)The third class of topographically disorientedpatient can be described as landmark agnosic, inthat the primary component of their impairment isan inability to use prominent, salient environmentalfeatures for orientation. The patients in this categoryof disorientation are the most numerous and beststudied.Patient A.H. described by C. A. Pallis in 1955,woke to ﬁnd that he could not recognize hisbedroom and became lost trying to return from thetoilet to his room. He also noted a central “blindspot,” an inability to see color, and that all facesseemed alike. He quickly became lost upon leavinghis house, and was totally unable to recognize whathad previously been very familiar surroundings.Upon admission, the patient was found to havevisual ﬁeld deﬁcits consistent with two adjacent,upper quadrantic scotomata, each with its apex atthe ﬁxation point. A.H. had no evidence of neglect,was able to localize objects accurately in both theleft and right hemiﬁelds and had intact stereognos-tic perception, proprioception, and graphaestheticsense. There was no left-right confusion, acalculia,or apraxia. General memory was reported as com-pletely intact. A.H.’s digit span was eight forwardand six backward, and he repeated the Babcocksentence correctly on his ﬁrst try.The patient had evident difﬁculty recognizingfaces. He was unable to recognize his medical atten-dants, wife, or daughter, and failed to identify pic-tures of famous, contemporary faces. He had similardifﬁculty identifying pictures of animals, althougha strategy of scrutinizing the photos for a criticaldetail that would allow him to intuit the identity ofthe image was more successful here than for the pic-tures of human faces. For example, he was able toidentify a picture of a cat by the whiskers.His primary and most distressing complaint washis inability to recognize places:In my mind’s eye I know exactly where places are, whatthey look like. I can visualize T . . . square without difﬁ-culty, and the streets that come into it. . . . I can draw youGeoffrey K. Aguirre 98Figure 5.2MRI scan of patient T.Y., revealing a right-sided, posterior cingulate gyrus lesion. (Images courtesy of Dr. K. Suzuki.)
a plan of the roads from Cardiff to the Rhondda Valley.. . . It’s when I’m out that the trouble starts. My reasontells me I must be in a certain place and yet I don’t rec-ognize it. It all has to be worked out each time. . . . Forinstance, one night, having taken the wrong turning, I wasgoing to call for my drink at the Post Ofﬁce. . . . I have tokeep the idea of the route in my head the whole time, andcount the turnings, as if I were following instructions thathad been memorized. (Pallis, 1955, p. 219)His difﬁculty extended to new places as well as pre-viously familiar locales: “It’s not only the places Iknew before all this happened that I can’t remem-ber. Take me to a new place now and tomorrowI couldn’t get there myself” (Pallis, 1955, p. 219).Despite these evident problems with way-ﬁnding,the patient was still able to describe and draw mapsof the places that were familiar to him prior to hisillness, including the layout of the mineshafts inwhich he worked as an engineer.Patient A.H. is joined in the literature by anumber of well-studied cases, including patientsJ.C. (Whiteley & Warrington, 1978), A.R. (Hécaen,Tzortzis, & Rondot, 1980), S.E. (McCarthy, Evans,& Hodges, 1996), and M.S. (Rocchetta, Cipolotti,& Warrington, 1996); several of the cases reportedby Landis, Cummings, Benson, & Palmer (1986);and the cases reported by Takahashi, Kawamura,Hirayama, & Tagawa (1989); Funakawa, Mukai,Terao, Kawashima, & Mori (1994), and Suzuki,Yamadori, Takase, Nagamine, & Itoyama (1996).These patients have several features in common: (1)disorientation in previously familiar and novelplaces, (2) intact manipulation of spatial informa-tion, and (3) an inability to identify speciﬁc build-ings. In other words, despite a preserved ability toprovide spatial information about a familiar envi-ronment, the patient is unable to ﬁnd his or her waybecause of the inability to recognize prominentlandmarks.This loss of landmark recognition, and its relativespeciﬁcity, has been formally tested by severalauthors, usually by asking the subject to iden-tify pictures of famous buildings. Patient S.E.(McCarthy et al., 1996) was found to be markedlyimpaired at recalling the name or information aboutpictures of famous landmarks and buildings com-pared with the performance of control subjects andhis own performance recalling information aboutfamous people.Patient M.S. (Rocchetta et al., 1996) performedat chance level on three different delayed-recognition memory tests that used pictures of (1)complex city scenes, (2) previously unfamiliarbuildings, and (3) country scenes. M.S. was alsofound to be impaired at recognizing Londonlandmarks that were familiar before his illness.Takahashi and colleagues (1989) obtained seven-teen pictures of the patient’s home and neighbor-hood. The patient was unable to recognize any ofthese, but he could describe from memory the treesplanted in the garden, the pattern printed on hisfence, the shape of his mailbox and windows, andwas able to produce an accurate map of his houseand hometown.In contrast, tests of spatial representation havegenerally shown intact abilities in these patients.Patients S.E., M.S., and J.C. were all found to havenormal performance on a battery of spatial learningand perceptual tasks that included Corsi span,Corsi supraspan, and “stepping-stone” mazes(Milner, 1965). (Patient A.R., however, was foundto be impaired on the last of these tests.) In general,the ability to describe routes and produce sketchmaps of familiar places is intact in these patients.As discussed previously, these more anecdotalmeasures of intact spatial representation should betreated with some caution because there is con-siderable ambiguity as to the speciﬁc nature of thecognitive requirements of these tasks. Nonetheless,the perfectly preserved ability of patients A.R. andA.H. to provide detailed route descriptions, and thedetailed and accurate maps produced by S.E., A.H.,and Takahashi’s patient (Takahashi et al., 1989),are suggestive of intact spatial representations ofsome kind. (Patient M.S., however, was noted tohave poor route description abilities.) Particularlycompelling, moreover, are reports of patients pro-ducing accurate maps of places that were not famil-iar prior to the lesion event (Cole & Perez-Cruet,1964; Whiteley & Warrington, 1978). In this case,Topographical Disorientation 99
the patient can only be drawing upon preservedspatial representational abilities to successfullytransform navigational experiences into an exocen-tric representation.Several neuropsychological deﬁcits have beennoted to co-occur with landmark agnosia, speciﬁ-cally, prosopagnosia (Cole & Perez-Cruet, 1964;Landis et al., 1986; McCarthy et al., 1996; Pallis,1955; Takahashi et al., 1989) and achromatopsia(Landis et al., 1986; Pallis, 1955), along with somedegree of visual ﬁeld deﬁcit. These impairments donot invariably accompany landmark agnosia (e.g.,Hécaen et al., 1980), however, and are known tooccur without accompanying TD (e.g., Tohgi et al.,1994). Thus it is unlikely that these ancillary im-pairments are actually the causative factor of TD.More likely, the lesion site that produces landmarkagnosia is close to, but distinct from, the lesion sitesresponsible for prosopagnosia and achromatopsia.There is also evidence that landmark agnosicshave altered perception of environmental features,in addition to the loss of familiarity (as is the casewith general-object agnosics and prosopagnosics;Farah, 1990). For example, Hécaen’s patient A.R.was able to perform a “cathedral matching” taskaccurately, but “he [AR] spontaneously indicatedthat he was looking only for speciﬁc details ‘awindow, a doorway . . . but not the whole.’ . . .Places were identiﬁed by a laborious process ofelimination based on small details” (Hécaen et al.,1980, p. 531).An additional hallmark feature of landmarkagnosia is the compensatory strategy employed bythese patients. The description of patient J.C. istypical:He relies heavily on street names, station names, andhouse numbers. For example, he knows that to get to theshops he has to turn right at the trafﬁc lights and then leftat the Cinema. . . . When he changes his place of work hedraws a plan of the route to work and a plan of the inte-rior of the “new” building. He relies on these maps andplans. . . . He recognizes his own house by the numberor by his car when parked at the door. (Whiteley &Warrington, 1978, pp. 575–576)This reliance upon small environmental details,called variously “signs,” “symbols,” and “land-marks” by the different authors, is common to all ofthe landmark agnosia cases described here and pro-vides some insight into the cognitive nature of theimpairment. First, it is clear that these patients arecapable of representing the strictly spatial aspect oftheir position in the environment. In order to makeuse of these minute environmental details for way-ﬁnding, the patient must be able to associate spatialinformation (if only left or right turns) with partic-ular waypoints. This is again suggestive evidenceof intact spatial abilities. Second, although thesepatients are termed “landmark agnosics,” it is notthe case that they are unable to make use of anyenvironmental object with orienting value. Instead,they seem speciﬁcally impaired in the use of high-salience environmental features, such as buildings,and the arrangement of natural and artiﬁcial stimuliinto scenes. Indeed, these patients become disori-ented within buildings, suggesting that they are nolonger able to represent a conﬁguration of stimulithat allows them to easily differentiate one placefrom another. It thus seems that careful studyof landmark agnosics may provide considerableinsight into the normative process of selection andutilization of landmarks.The parallels between prosopagnosia and land-mark agnosia (which we might refer to as synorag-nosia, from the Greek for landmark) are striking.Prosopagnosic patients are aware that they areviewing a face, but do not have access to the effort-less perception of facial identity that characterizesnormal performance. They also develop compensa-tory strategies that focus on the individual partsof the face, often distinguishing one person fromanother by careful study of the particular shape ofthe hairline, for example.The lesion sites reported to produce landmarkagnosia are fairly well clustered. Except for patientJ.C. (who suffered a closed head injury and forwhom no imaging data are available) and patientM.S. (who suffered diffuse small-vessel ischemicdisease), the cases of landmark agnosia reviewedhere all had lesions either bilaterally or on the rightGeoffrey K. Aguirre 100
side of the medial aspect of the occipital lobe,involving the lingual gyrus and sometimes theparahippocampal gyrus. The most common mecha-nism of injury is an infarction of the right posteriorcerebral artery.The type of visual information that is representedin this critical area of the lingual gyrus is an openquestion. Is this a region involved in the represen-tation of all landmark information, or simply certainobject classes that happen to be used as landmarks?How would such a region come to exist? Oneaccount of the “lingual landmark area” (Aguirre,Zarahn, & D’Esposito, 1998a) posits the existenceof a cortical region predisposed to the representa-tion of the visual information employed in way-ﬁnding. Through experience, this area comes torepresent environmental features and visual conﬁg-urations that have landmark value (i.e., that tend toaid navigation). We might imagine that such a spa-tially segregated, specialized area would developbecause of the natural correlation of some landmarkfeatures with other landmark features (Polk &Farah, 1995). Furthermore, such a region mightoccupy a consistent area of cortex from person toperson as a result of the connection of the area withother visual areas (e.g., connections to areas withlarge receptive ﬁelds or to areas that process “opticﬂow”).We have a sense from environmental psychologystudies of the types of visual features that wouldcome to be represented in such an area: large,immobile things located at critical, navigationalchoice points in the environment. Certainly build-ings ﬁt the bill for western, urban dwellers. Wemight suspect that in other human populations thatnavigate through entirely different environments,different kinds of visual information would be rep-resented. In either case, lesions to this area wouldproduce the pattern of deﬁcits seen in the reportedcases of landmark agnosia. Evidence for such anaccount has been provided by neuroimaging studiesin intact human subjects, which are consideredbelow.Anterograde Disorientation and the MedialTemporal Lobes (Case 4)Our discussion so far has focused on varieties ofTD that follow damage to neocortical structures.The posterior parietal cortex, the posterior cingulategyrus, and areas of the medial fusiform gyrus haveall been associated with distinct forms of naviga-tional impairments. Despite this, much of the extantTD literature has been concerned with an area ofthe paleocortex: the medial temporal lobes. Asmentioned previously, this focus on the medial tem-poral lobes derives from the compelling neuro-physiological ﬁnding that hippocampal cells in therodent ﬁre selectively when the freely movinganimal is in certain locations within the environ-ment. The existence of these place cells is thebasis for theories that offer the hippocampus as arepository of information about exocentric spatialrelationships (O’Keefe & Nadel, 1978). Additionalevidence regarding the importance of the hip-pocampus in animal spatial learning was providedby Morris and colleagues (1982), who reported thatrats with hippocampal lesions were impaired on atest of place learning, the water maze task. Thespeciﬁcity of the role played by the hippocampus(i.e., Ammon’s horn, the dentate gyrus, and thesubiculum) in spatial representation has subse-quently been debated at length (e.g., Cohen &Eichenbaum, 1993).At the very least, it is clear that selective (neuro-toxic), bilateral lesions of this structure in the rodentgreatly impair performance in place learning taskssuch as the water maze (Jarrard, 1993; Morris,Schenk, Tweedie, & Jarrard, 1990). The central roleof the hippocampus in theories of spatial learning inanimals has inﬂuenced the neurological literature onTD to some extent. For example, many case reportsof topographically disoriented patients with neocor-tical damage are at pains to relate the lesion loca-tion to some kind of disruption of hippocampalfunction (e.g., through disconnection or loss ofinput).In recent decades, the “cognitive map” theoryhas come to be contrasted with models of medialTopographical Disorientation 101
temporal lobe function in the realm of long-termmemory. In this account, which is supported prima-rily through lesion studies in human patients, thehippocampus is responsible for the initial formationand maintenance of “declarative” memories, whichover a period of months are subsequently consoli-dated within the neocortex and become independ-ent of hippocampal function.What of the impact of medial temporal lesionsupon navigational ability? It is clear that unilaterallesions of the hippocampus do not produce anyappreciable real-world way-ﬁnding impairments inhumans (DeRenzi, 1982). While one study (Vargha-Khadem et al., 1997) has reported anterograde way-ﬁnding deﬁcits in the setting of general anterogradeamnesia following bilateral damage restricted tothe hippocampus, this obviously cannot be consid-ered a selective loss. Other studies of patients withbilateral hippocampal damage have not commentedupon anterograde way-ﬁnding ability (Rempel-Clower, Zola, Squire, & Amaral, 1996; Scoville& Milner, 1957; Zola-Morgan, Squire, & Amaral,1986). Retrograde loss of way-ﬁnding knowledge inthese patients is not apparently disproportionate tolosses in other areas (Rempel-Clower et al., 1996)and this knowledge can be preserved (Milner,Corkin, & Teuber, 1968; Teng & Squire, 1999).Cases have been reported, however, of topo-graphical impairment that is primarily conﬁned tonovel environments, although it is not associatedwith lesions to the hippocampus per se. It is inter-esting that this anterograde TD, described in twopatients by Ross (1980), one patient by Pai (1997),the patient of Luzzi, Pucci, Di Bella, & Piccirilli(2000), and the ﬁrst two cases of Habib and Sirigu(1987), appears to affect both landmark and spatialspheres. By far the most comprehensive study hasbeen provided by Epstein and colleagues (2001) intheir examination of patients G.R. and C.G.At the time of testing, G.R. was a well-educated,60-year-old man who had suffered right and leftoccipital-temporal strokes 2 years previously.Figure 5.3 shows the lesion site in this patient.These strokes had left him with a left hemianopsiaand right upper quadrantanopsia and dyschro-matopsia. He had no evidence of neglect, left-rightGeoffrey K. Aguirre 102Figure 5.3MRI scan of patient G.R., revealing bilateral damage to the parahippocampal gyri, with extension of the right lesionposteriorly to involve the inferior lingual gyrus, medial fusiform gyrus, and occipital lobe. (Images courtesy of Dr. R.Epstein.)
confusion or apraxia, and no prosopagnosia orobject agnosia. His primary disability was a dra-matic inability to orient himself in new places:According to both GR and his wife, this inability to learnnew topographical information was typical of his experi-ence since his strokes, as he frequently gets lost in his dailylife. Soon after his injury, he moved to a neighborhoodwith many similar-looking houses. He reported that inorder to ﬁnd his new house after a walk to a market 6–7blocks away, he had to rely on street signs to guide him tothe correct block, and then examine each house on theblock in detail until he could recognize some feature thatuniquely distinguished his home. Subsequently, GR andhis wife moved to a different house in a different country.He reported that for the ﬁrst six months after the move,his new home was like a “haunted house” for him insofaras he was unable to learn his way around it. (Epstein etal., 2001, p. 5)Epstein noted the inability of the patient to learnhis way about the laboratory testing area despiterepeat visits, and described the results of a landmarklearning test in which the subject performed ratherpoorly. In contrast, G.R. was able to successfullyfollow a route marked on a map, indicating intact,basic spatial representation. In addition, G.R. wasable to draw accurate sketch maps of places knownto him prior to his stroke and performed the sameas age-matched controls on a recognition test offamous landmarks. These ﬁndings suggest that G.R.had intact representation of previously learnedspatial and landmark topographical information.Epstein and colleagues report the results of addi-tional tests that suggest that G.R.’s primary deﬁcitwas in the encoding of novel information on theappearance of spatially extended scenes.The patients reported by Habib and Sirigu (1987)and those of Ross (1980) had similar impairments.All four patients displayed preserved way-ﬁnding inenvironments known at least 6 months before theirlesion. Ross’s patient 1 was able to draw a veryaccurate map of his parent’s home. Both case 1 andcase 2 of Habib and Sirigu reported that followingan initial period of general impairment, no orienta-tion difﬁculties were encountered in familiar partsof town.The lesion site in common among these cases isthe posterior aspect of the right parahippocampus.Figure 5.3 shows the lesion site in patient G.R.This ﬁnding is in keeping with the results of thegroup neuropsychological studies reported earlier.Both Bohbot and Barrash found that lesions of theright parahippocampus were highly associated withdeﬁcits in real-world topographical ability. Onecaveat regarding localization of this lesion site isthat lesions of the parahippocampus typically occurin concert with lesions of the medial lingual gyrus,the area described earlier as consistently involvedin landmark agnosia. Can we be certain that land-mark agnosia and anterograde disorientation actu-ally result from lesions to two differentiable corticalareas? The report by Takahashi and Kawamura (inpress), who studied the performance of four patientswith TD, is helpful in this regard. They observedthat the patient with damage restricted to theparahippocampus was impaired in the acquisition ofnovel topographical information (they tested scenelearning), while the other patients with lesions thatincluded the medial lingual gyrus displayed difﬁ-culty recognizing previously familiar scenes andbuildings, in addition to an anterograde impairment.Despite the case literature that argues for theprimacy of the parahippocampus within the medialtemporal lobe for way-ﬁnding, other lines of evi-dence continue to raise intriguing questions regard-ing the role of the hippocampus proper. Maguireand colleagues (2000) recently reported thatLondon taxicab drivers, who are required to assim-ilate an enormous quantity of topographical infor-mation, have larger posterior hippocampi thancontrol subjects. Moreover, the size of the posteriorhippocampus across drivers was correlated with thenumber of years they had spent on the job! Theneuroimaging literature reviewed in the next sectionhas also found neural activity within hippocampalareas in the setting of topographically relevanttasks.Topographical Disorientation 103
Functional Neuroimaging StudiesFunctional neuroimaging studies of topographicalrepresentation fall into two broad categories: (1)those that have sought the neural substrates of theentire cognitive process of topographical represen-tation and (2) those that have examined subcompo-nents of environmental knowledge.In the ﬁrst category, one of the earliest studieswas that by Aguirre, Detre, Alsop, & D’Esposito(1996). The subjects were studied with functionalMRI (fMRI) while they attempted to learn their waythrough a “virtual reality” maze. When the signalobtained during these periods was compared withthat obtained while the subjects repetitively tra-versed a simple corridor, greater activity wasobserved within the parahippocampus bilaterally,the posterior parietal cortex, the retrosplenial cor-tex, and the medial occipital cortex. This study didnot attempt to isolate the different cognitive ele-ments that are presumed to make up the complexbehavior of way-ﬁnding. Thus, the most we canconclude from this study (and studies of its kind) isthat the regions identiﬁed are activated by someaspect of way-ﬁnding.Since then, Maguire and colleagues have pub-lished a number of neuroimaging studies thatpresent clever reﬁnements of this basic approach:presenting subjects with virtual reality environ-ments in which they perform tasks (Maguire,Frackowiak, & Frith, 1996b, 1997; Maguire, Frith,Burgess, Donnett, & O’Keefe, 1998a; Maguire etal., 1998b). A consistent ﬁnding in their work hasbeen the presence of activity within the hippocam-pus proper, particularly in association with success-ful navigation in more complex and realistic virtualreality environments. Parahippocampal activity hasalso been a component of the activated areas,although Maguire has argued that this is drivenmore by the presence of landmarks within thetesting environment than the act of navigation itself.The interested reader is referred to Maguire,Burgess, & O’Keefe (1999) for a cogent review.Clearly, something interesting is happening in thehippocampus proper in association with navigationtasks. What is intriguing, however, is the absence ofclinical or even neuropsychological ﬁndings of top-ographical impairments in association with lesionsof this structure. The existence of this seeming con-ﬂict points to the inferential limitations of func-tional neuroimaging studies. The behaviors understudy are enormously complicated, making anyattempt to isolate them by cognitive subtraction(a standard technique of neuroimaging inference)questionable.It will always be possible that activity in the hip-pocampus (or any other area) is the result of con-founding and uncontrolled behaviors that differbetween the two conditions. Even if we could becertain that we have isolated the cognitive processof navigation, it would still be possible to observeneural activity in cortical regions that are notnecessary for this function (Aguirre, Zarahn, &D’Esposito, 1998b). Regardless, the individual con-tributions of areas of the medial temporal lobes tonavigational abilities in humans remains an area ofactive investigation.The second class of neuroimaging study hassought the neural correlates of particular subcom-ponents of environmental representation. At themost basic level of division, Aguirre and D’Esposi-tio (1997) sought to demonstrate a dorsal-ventraldissociation of cortical responsiveness for manipu-lation of judgments about landmark identity anddirection in environmental spaces. Their subjectsbecame familiar with a complex virtual reality townover a period of a few days. During scanning, thesubjects were presented with scenes from the envi-ronment and asked to either identify their currentlocation or, if given the name of the place, to judgethe compass direction of a different location.Consistent with the division of topographical repre-sentation outlined earlier, medial lingual areasresponded during location identiﬁcation, whileposterior cingulate and posterior parietal areasresponded during judgments about heading.Further studies have reﬁned this gross division.Aguirre and colleagues (1998a) tested the hypothe-sis that the causative lesion in landmark agnosiadamages a substrate specialized for the perceptionGeoffrey K. Aguirre 104
of buildings and large-scale environmental land-marks. Using functional MRI, they identiﬁed acortical area that has a greater neural response tobuildings than to other stimuli, including faces, cars,general objects, and phase-randomized buildings.Across subjects, the voxels that evidenced “build-ing” responses were located straddling the anteriorend of the right lingual sulcus, which is in goodagreement with the lesion sites reported for land-mark agnosia. The ﬁnding of a “building-sensitive”cortex within the anterior, right lingual gyrus hasbeen replicated by other groups (Ishai, Ungerlieder,Martin, & Schouten, 1999).Epstein and his colleagues have studied the con-ditions under which parahippocampal activity iselicited. Their initial ﬁnding (Epstein & Kanwisher,1998) was that perception of spatially extendedscenes (either indoor or outdoors) elicited robustactivation of the parahippocampus. These responseswere equivalent whether the pictured rooms con-tained objects or were simply bare walls! In a seriesof follow-up studies (Epstein, Harris, Stanley, &Kanwisher, 1999), Epstein has found that activity inthe parahippocampus is particularly sensitive to theencoding of new perceptual information regardingthe appearance and layout of spatially extendedscenes. These ﬁndings dovetail nicely with thepattern of anterograde deﬁcits that have beenreported in patients with parahippocampal damage.Conclusions and Future DirectionsThe past decade has seen the development ofseveral key insights into the nature of TD. Drivenby the success of the cognitive neuroscienceprogram, it is now possible to attribute varieties oftopographical disorientation to particular impair-ments in cognitive function. When presented witha patient with TD, a series of simple questionsand tests should be sufﬁcient to place the patientwithin one of the four categories of disorientationdescribed. Is the patient grossly disoriented withinegocentric space? Can he ﬁnd his way about placesknown to him prior to his injury? Does he makenow use of a different set of environmental cues, inplace of large-scale features like buildings? Canhe recognize landmarks but is uncertain of whichdirection to travel next? When the cognitive cate-gorization is consonant with the lesion observed, theclinician can be fairly conﬁdent of the type of TDexperienced by the patient.In many cases, the degree of impairment im-proves over the months following the lesion, par-ticularly in the case of egocentric and anterogradedisorientation (Barrash, 1998). For those patientswith landmark agnosia, encouragement in the use ofenvironmental features other than large-scale land-marks may be helpful in returning the patient to anormal way-ﬁnding function.The clinical syndrome of topographical disorien-tation remains an area of active investigation forseveral groups. More generally, the tools andmodels of cognitive neuroscience are now beingapplied to the problems of normative way-ﬁnding.Unresolved issues concern the relative contributionsof areas of the medial temporal lobes, explicitdemonstration of the representation of heading inthe posterior cingulate gyrus and a better under-standing of the development and representationalproperties of the lingual gyrus.ReferencesAcredolo, L. P. (1977). Developmental changes in theability to coordinate perspectives of a large-scale space.Developmental Psychology, 13, 1–8.Aguirre, G. K., & D’Esposito, M. (1997). Environmentalknowledge is subserved by separable dorsal/ventral neuralareas. Journal of Neuroscience, 17, 2512–2518.Aguirre, G. K., & D’Esposito, M. (1999). Topographicaldisorientation: A synthesis and taxonomy. Brain, 122,1613–1628.Aguirre, G. K., Detre, J. A., Alsop, D. C., & D’Esposito,M. (1996). The parahippocampus subserves topographicallearning in man. Cerebral Cortex, 6, 823–829.Aguirre, G. K., Zarahn, E., & D’Esposito, M. (1998a).An area within human ventral cortex sensitive to “build-ing” stimuli: Evidence and implications. Neuron, 21,373–383.Topographical Disorientation 105
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H. Branch CoslettCase ReportFamily members of the patient (W.T.), a 30-year-old right-handed woman, noted that she suddenly began to speakgibberish and lost the ability to understand speech. Neu-rological examination revealed only Wernicke’s aphasia.Further examination revealed ﬂuent speech, with frequentphonemic and semantic paraphasias. Naming was rela-tively preserved. Repetition of single words and phonemeswas impaired. She repeated words of high imageability(e.g., desk) more accurately than words of low imageabil-ity (e.g., fate). Occasional semantic errors were noted inrepetition; for example, when asked to repeat “shirt,” shesaid “tie.” Her writing of single words was similar to herrepetition in that she produced occasional semantic errorsand wrote words of high imageability signiﬁcantly betterthan words of low imageability. A computed axial tomo-graphy (CAT) scan performed 6 months after the onset ofher symptoms revealed a small cortical infarct involvinga portion of the left posterior superior temporal gyrus.W.T.’s reading comprehension was impaired; sheperformed well on comprehension tests involving high-imageability words, but was unable to reliably derivemeaning from low-imageability words that she correctlyread aloud. Of greatest interest was that her oral readingof single words was relatively preserved. She read approx-imately 95% of single words accurately and correctly readaloud ﬁve of the commands from the Boston DiagnosticAphasia Examination (Goodglass & Kaplan, 1972). It isinteresting that the variables that inﬂuenced her readingdid not affect her writing and speech. For example, herreading was not altered by the part of speech (e.g., noun,verb, adjective) of the target word; she read nouns, mod-iﬁers, verbs, and even functors (e.g., words such as that,which, because, you) with equal facility. Nor was herreading affected by the imageability of the target word;she read words of low imageability (e.g., destiny) as wellas words of high imageability (e.g., chair). W.T. alsoread words with irregular print-to-sound correspondences(e.g., yacht, tomb) as well as words with regularcorrespondence.W.T. exhibited one striking impairment in her reading,an inability to read pronounceable nonword letter strings.For example, when shown the letter string “ﬂig,” W.T.could reliably indicate that the letter string was not a word.6 Acquired Dyslexia: A Disorder of ReadingAsked to indicate how such a letter string would bepronounced or “sounded out,” however, she performedquite poorly, producing a correct response on only approx-imately 20% of trials. She typically responded by produc-ing a visually similar real word (e.g., ﬂag) while indicatingthat her response was not correct.In summary, W.T. exhibited Wernicke’s aphasiaand alexia characterized by relatively preservedoral reading of real words, but impaired readingcomprehension and poor reading of nonwords.Her pattern of reading deﬁcit was consistent withthe syndrome of phonological dyslexia. Her per-formance is of interest in this context becauseit speaks to contemporary accounts of the mecha-nisms mediating reading. As will be discussed later,a number of models of reading (e.g., Seidenberg& McClelland, 1989) invoke two mechanisms asmediating the pronunciation of letter strings; one isassumed to involve semantic mediation whereasthe other is postulated to involve the translation ofprint into sound without accessing word-speciﬁcstored information—that is, without “looking up” aword in a mental dictionary. W.T.’s performanceis of interest precisely because it challenges suchaccounts.W.T.’s impaired performance on reading compre-hension and other tasks involving semantics sug-gests that she is not reading aloud by means of asemantically based procedure. Similarly, her inabil-ity to read nonwords suggests that she is unableto reliably employ print-to-sound translation pro-cedures. Her performance, therefore, argues foran additional reading mechanism by which word-speciﬁc stored information contacts speech produc-tion mechanisms directly.Historical Overview of Acquired DyslexiaDejerine provided the ﬁrst systematic descriptionsof disorders of reading resulting from brain lesionsin two seminal manuscripts in the late nineteenth
century (1891, 1892). Although they were not theﬁrst descriptions of patients with reading disorders(e.g., Freund, 1889), his elegant descriptions of verydifferent disorders provided the general theoreticalframework that animated discussions of acquireddyslexia through the latter part of the twentiethcentury.Dejerine’s ﬁrst patient (1891) manifested im-paired reading and writing in the context of amild aphasia after an infarction involving the leftparietal lobe. Dejerine called this disorder “alexiawith agraphia” and argued that the deﬁcit wasattributable to a disruption of the “optical imagefor words,” which he thought to be supported bythe left angular gyrus. This stored information wasassumed to provide the template by which familiarwords were recognized; the loss of the “opticalimages,” therefore, would be expected to producean inability to read familiar words. Althoughmultiple distinct patterns of acquired dyslexiahave been identiﬁed in subsequent investigations,Dejerine’s account of alexia with agraphia repre-sented the ﬁrst well-studied investigation of the“central dyslexias” to which we will return.Dejerine’s second patient (1892) was quite dif-ferent. This patient exhibited a right homony-mous hemianopia and was unable to read aloud orfor comprehension, but could write and speak well.This disorder, designated “alexia without agraphia”(also known as agnosic alexia and pure alexia), wasattributed by Dejerine to a disconnection betweenvisual information presented to the right hemisphereand the left angular gyrus, which he assumed to becritical for the recognition of words.During the decades after the contributions ofDejerine, the study of acquired dyslexia languished.The relatively few investigations that were reportedfocused primarily on the anatomical underpinningsof the disorders. Although a number of interestingobservations were reported, they were often eitherignored or their signiﬁcance was not appreciated.For example, Akelaitis (1944) reported a left hemi-alexia—an inability to read aloud words presentedin the left visual ﬁeld—in patients whose corpuscallosum had been severed. This observation pro-vided powerful support for Dejerine’s interpretationof alexia without agraphia as a disconnectionsyndrome.In 1977, Benson sought to distinguish a thirdalexia associated with frontal lobe lesions. Thisdisorder was said to be associated with a Brocaaphasia as well as agraphia. These patients weresaid to comprehend “meaningful content words”better than words playing a “relational or syntactic”role and to exhibit greater problems with readingaloud than reading for comprehension. Finally,these patients were said to exhibit a “literal alexia”or an impairment in the identiﬁcation of letterswithin words (Benson, 1977).The study of acquired dyslexia was revitalized bythe elegant and detailed investigations of Marshalland Newcombe (1966, 1973). On the basis ofcareful analyses of the words their subjects readsuccessfully as well as a detailed inspection of theirreading errors, these investigators identiﬁed dis-tinctly different and reproducible types of read-ing deﬁcits. The conceptual framework developedby Marshall and Newcombe (1973) has motivatedmany subsequent studies of acquired dyslexia (seeColtheart, Patterson, & Marshall, 1980; Patterson,Marshall, & Coltheart, 1985), and “information-processing” models of reading have been based toa considerable degree on their insights.Experimental Research on Acquired DyslexiaReading is a complicated process that involvesmany different procedures and cognitive faculties.Before discussing the speciﬁc syndromes of ac-quired dyslexia, the processes mediating wordrecognition and pronunciation are brieﬂy reviewed.The visual system efﬁciently processes a compli-cated stimulus that, at least for alphabet-based lan-guages, is composed of smaller meaningful units,letters. In part because the number of letters is smallin relation to the number of words, there is oftena considerable visual similarity between words(e.g., same versus sane). In addition, the position ofletters within the letter string is also critical to wordH. Branch Coslett 110
identiﬁcation (consider mast versus mats). In lightof these factors, it is perhaps not surprising thatreading places a substantial burden on the visualsystem and that disorders of visual processing orvisual attention may substantially disrupt reading.The fact that normal readers are so adept at wordrecognition has led some investigators to suggestthat words are not processed as a series of distinctletters but rather as a single entity in a process akinto the recognition of objects. At least for normalreaders under standard conditions, this does notappear to be the case. Rather, normal readingappears to require the identiﬁcation of letters asalphabetic symbols. Support for this claim comesfrom demonstrations that presenting words in anunfamiliar form—for example, by alternating thecase of the letters (e.g., wOrD) or introducingspaces between words (e.g., food)—does not sub-stantially inﬂuence reading speed or accuracy (e.g.,McClelland & Rumelhart, 1981). These data arguefor a stage of letter identiﬁcation in which thegraphic form (whether printed or written) is trans-formed into a string of alphabetic characters (W-O-R-D), sometimes called “abstract letter identities.”As previously noted, word identiﬁcation requiresnot only that the constituent letters be identiﬁedbut also that the letter sequence be processed. Themechanism by which the position of letters withinthe stimulus is determined and maintained is notclear, but a number of accounts have been proposed.One possibility is that each letter is linked to aposition in a word “frame” or envelope. Finally, itshould be noted that under normal circumstancesletters are not processed in a strictly serial fashion,but may be analyzed by the visual system in paral-lel (provided the words are not too long). Disordersof reading resulting from an impairment in theprocessing of the visual stimulus or the failure ofthis visual information to access stored knowledgeappropriate to a letter string are designated “periph-eral dyslexias” and are discussed later.In “dual-route” models of reading, the identity ofa letter string may be determined by a number ofdistinct procedures. The ﬁrst is a “lexical” proce-dure in which the letter string is identiﬁed by match-ing it with an entry in a stored catalog of familiarwords, or a visual word form system. As indicatedin ﬁgure 6.1 and discussed later, this procedure,which in some respects is similar to looking up aword in a dictionary, provides access to the mean-ing and phonological form of the word and at leastsome of its syntactic properties. Dual-route modelsof reading also assume that the letter string canbe converted directly to a phonological form bythe application of a set of learned correspondencesbetween orthography and phonology. In this ac-count, meaning may then be accessed from thephonological form of the word.Support for dual-route models of reading comesfrom a variety of sources. For present purposes,perhaps the most relevant evidence was provided byMarshall and Newcombe’s (1973) ground-breakingdescription of “deep” and “surface” dyslexia. Theseinvestigators described a patient (G.R.) who readapproximately 50% of concrete nouns (e.g., table,doughnut), but was severely impaired in the readingof abstract nouns (e.g., destiny, truth) and all otherparts of speech. The most striking aspect of G.R.’sperformance, however, was his tendency to produceerrors that appeared to be semantically related tothe target word (e.g., speak read as talk). Marshalland Newcombe designated this disorder “deepdyslexia.”These investigators also described two patientswhose primary deﬁcit appeared to be an inabilityto reliably apply grapheme-phoneme correspon-dences. Thus, J.C., for example, rarely applied the“rule of e” (which lengthens the preceding vowel inwords such as “like”) and experienced great difﬁ-culties in deriving the appropriate phonology forconsonant clusters and vowel digraphs. The disor-der characterized by impaired application of print-to-sound correspondences was called “surfacedyslexia.”On the basis of these observations, Marshalland Newcombe (1973) argued that the meaning ofwritten words could be accessed by two distinct pro-cedures. The ﬁrst was a direct procedure by whichfamiliar words activated the appropriate stored rep-resentation (or visual word form), which in turnAcquired Dyslexia 111
H. Branch Coslett 112Figure 6.1An information-processing model of reading illustrating the putative reading mechanisms.
activated meaning directly; reading in deepdyslexia, which was characterized by semanticallybased errors (of which the patient was oftenunaware), was assumed to involve this procedure.The second procedure was assumed to be a phono-logically based process in which grapheme-to-phoneme or print-to-sound correspondences wereemployed to derive the appropriate phonology (or“sound out” the word); the reading of surfacedyslexics was assumed to be mediated by this non-lexical procedure. Although a number of Marshalland Newcombe’s speciﬁc hypotheses have subse-quently been criticized, their argument that readingmay be mediated by two distinct procedures hasreceived considerable empirical support.The information-processing model of readingdepicted in ﬁgure 6.1 provides three distinct pro-cedures for oral reading. Two of these procedurescorrespond to those described by Marshall andNewcombe. The ﬁrst (labeled “A” in ﬁgure 6.1)involves the activation of a stored entry in the visualword form system and the subsequent access tosemantic information and ultimately activation ofthe stored sound of the word at the level of thephonological output lexicon. The second (“B” inﬁgure 6.1) involves the nonlexical grapheme-to-phoneme or print-to-sound translation process; thisprocedure does not entail access to any stored infor-mation about words, but rather is assumed to bemediated by access to a catalog of correspondencesstipulating the pronunciation of phonemes.Many information-processing accounts of thelanguage mechanisms subserving reading incorpo-rate a third procedure. This mechanism (“C” inﬁgure 6.1) is lexically based in that it is assumedto involve the activation of the visual word formsystem and the phonological output lexicon. Theprocedure differs from the lexical procedure de-scribed earlier, however, in that there is no inter-vening activation of semantic information. Thisprocedure has been called the “direct” readingmechanism or route. Support for the direct lexicalmechanism comes from a number of sources,including observations that some subjects readaloud words that they do not appear to comprehend(Schwartz, Saffran, & Marin, 1979; Noble, Glosser,& Grossman, 2000; Lambon Ralph, Ellis, &Franklin, 1995).As noted previously, the performance of W.T. isalso relevant. Recall that W.T. was able to readaloud words that she did not understand, suggestingthat her oral reading was not semantically based.Furthermore, she could not read nonwords, sug-gesting that she was unable to employ a sounding-out strategy. Finally, the fact that she was unable towrite or repeat words of low imageability (e.g.,affection) that she could read aloud is importantbecause it suggests that her oral reading was notmediated by an interaction of impaired semanticand phonological systems (cf. Hills & Caramazza,1995). Thus, data from W.T. provide support for thedirect lexical mechanism.Peripheral DyslexiasA useful starting point in the discussion of acquireddyslexia is provided by the distinction made byShallice and Warrington (1980) between “peri-pheral” and “central” dyslexias. The former are con-ditions characterized by a deﬁcit in the processingof visual aspects of the stimulus, which preventsthe patient from achieving a representation of theword that preserves letter identity and sequence. Incontrast, central dyslexias reﬂect impairment tothe “deeper” or “higher” reading functions by whichvisual word forms mediate access to meaning orspeech production mechanisms. In this section wediscuss the major types of peripheral dyslexia.Alexia without Letter-by-Letter Agraphia (PureAlexia; Letter-by-Letter Reading)This disorder is among the most common of theperipheral reading disturbances. It is associated witha left hemisphere lesion that affects the left occipi-tal cortex (which is responsible for the analysis ofvisual stimuli on the right side of space) and/or thestructures (i.e., left lateral geniculate nucleus of thethalamus and white matter, including callosal ﬁbersfrom the intact right visual cortex) that provideinput to this region of the brain. It is likely that theAcquired Dyslexia 113
lesion either blocks direct visual input to the mech-anisms that process printed words in the left hemi-sphere or disrupts the visual word form systemitself (Geschwind & Fusillo, 1966; Warrington &Shallice, 1980; Cohen et al., 2000). Some of thesepatients seem to be unable to read at all, whileothers do so slowly and laboriously by a processthat involves serial letter identiﬁcation (often called“letter-by-letter” reading). Letter-by-letter readersoften pronounce the letter names aloud; in somecases, they misidentify letters, usually on the basisof visual similarity, as in the case of N Æ M (seePatterson & Kay, 1982). Their reading is also ab-normally slow and is often directly proportionalto word length. Performance is not typicallyinﬂuenced by variables such as imageability,part of speech, and regularity of print-to-soundcorrespondences.It was long thought that patients with purealexia were unable to read, except letter by letter(Dejerine, 1892; Geschwind & Fusillo, 1966).There is now evidence that some of them do retainthe ability to recognize letter strings, although thisdoes not guarantee that they will be able to readaloud. Several different paradigms have demon-strated the preservation of word recognition. Somepatients demonstrate a word superiority effect inthat a letter is more likely to be recognized whenit is part of a word (e.g., the R in WORD) thanwhen it occurs in a string of unrelated letters (e.g.,WKRD) (Bowers, Bub, & Arguin, 1996; Bub,Black, & Howell, 1989; Friedman & Hadley, 1992;Reuter-Lorenz & Brunn, 1990).Second, some of them have been able to performlexical decision tasks (determining whether a letterstring constitutes a real word) and semantic catego-rization tasks (indicating whether a word belongsto a category, such as foods or animals) at abovechance levels when words are presented too rapidlyto support letter-by-letter reading (Shallice &Saffran, 1986; Coslett & Saffran, 1989a). Brevityof presentation is critical, in that longer exposure tothe letter string seems to engage the letter-by-letterstrategy, which appears to interfere with the abilityto perform the covert reading task (Coslett, Saffran,Greenbaum, & Schwartz, 1993). In fact, the patientmay show better performance on lexical decisionsin shorter (e.g., 250ms) than in longer presentations(e.g., 2 seconds) that engage the letter-by-letterstrategy, but do not allow it to proceed to comple-tion (Coslett & Saffran, 1989a).A compelling example comes from a previouslyreported patient who was given 2 seconds toscan the card containing the stimulus (Shallice &Saffran, 1986). The patient did not take advantageof the full inspection time when he was performinglexical decision and categorization tasks; instead, heglanced at the card brieﬂy and looked away, perhapsto avoid letter-by-letter reading. The capacity forcovert reading has also been demonstrated in twopure alexics who were unable to employ the letter-by-letter reading strategy (Coslett & Saffran, 1989b,1992). These patients appeared to recognize words,but were rarely able to report them, although theysometimes generated descriptions that were relatedto the word’s meaning (for example, cookies Æ“candy, a cake”). In some cases, patients haveshown some recovery of oral reading over time,although this capacity appears to be limited to con-crete words (Coslett & Saffran, 1989a; Buxbaum &Coslett, 1996).The mechanisms that underlie “implicit” or“covert” reading remain controversial. Dejerine(1892), who provided the ﬁrst description of purealexia, suggested that the analysis of visual input inthese patients is performed by the right hemisphere,as a result of the damage to the visual cortex on theleft. (It should be noted, however, that not all lesionsto the left visual cortex give rise to alexia. A criti-cal feature that supports continued left hemisphereprocessing is the preservation of callosal input fromthe unimpaired visual cortex on the right.)One possible explanation is that covert readingreﬂects recognition of printed words by the righthemisphere, which is unable to either articulate theword or (in most cases) to adequately communicateits identity to the language area of the left hemi-sphere (Coslett & Saffran, 1998; Saffran & Coslett,1998). In this account, letter-by-letter reading iscarried out by the left hemisphere using letterH. Branch Coslett 114
information transferred serially and inefﬁcientlyfrom the right hemisphere. Furthermore, the ac-count assumes that when the letter-by-letter strategyis implemented, it may be difﬁcult for the patientto attend to the products of word processing inthe right hemisphere. Consequently, the patient’sperformance in lexical decision and categorizationtasks declines (Coslett & Saffran, 1989a; Coslettet al., 1993). Additional evidence supporting theright hemisphere account of reading in pure alexiais presented later.Alternative accounts of pure alexia have also beenproposed (see Coltheart, 1998, for a special issuedevoted to the topic). Behrmann and colleagues(Behrmann, Plaut, & Nelson, 1998; Behrmann &Shallice, 1995), for example, have proposed thatthe disorder is attributable to impaired activationof orthographic representations. In this account,reading is assumed to reﬂect the “residual function-ing of the same interactive system that supportednormal reading premorbidly” (Behrmann et al.,1998, p. 7).Other investigators have attributed pure dyslexiato a visual impairment that precludes activationof orthographic representations (Farah & Wallace,1991). Chialant & Caramazza (1998), for example,reported a patient, M.J., who processed single, visu-ally presented letters normally and performed wellon a variety of tasks assessing the orthographiclexicon with auditorily presented stimuli. In con-trast, M.J. exhibited signiﬁcant impairments inthe processing of letter strings. The investigatorssuggest that M.J. was unable to transfer informa-tion specifying multiple letter identities in parallelfrom the intact visual processing system in the righthemisphere to the intact language-processing mech-anisms of the left hemisphere.Neglect DyslexiaParietal lobe lesions can result in a deﬁcit thatinvolves neglect of stimuli on the side of space thatis contralateral to the lesion, a disorder referred toas hemispatial neglect (see chapter 1). In mostcases, this disturbance arises with damage to theright parietal lobe; therefore attention to the left sideof space is most often affected. The severity ofneglect is generally greater when there are stimulion the right as well as on the left; attention is drawnto the right-sided stimuli at the expense of those onthe left, a phenomenon known as extinction. Typicalclinical manifestations include bumping into objectson the left, failure to dress the left side of the body,drawing objects that are incomplete on the left,and reading problems that involve neglect of the leftportions of words, i.e., “neglect dyslexia.”With respect to neglect dyslexia, it has beenfound that such patients are more likely to ignoreletters in nonwords (e.g., the ﬁrst two letters inbruggle) than letters in real words (such as snuggle).This suggests that the problem does not reﬂect atotal failure to process letter information but ratheran attentional impairment that affects consciousrecognition of the letters (e.g., Sieroff, Pollatsek,& Posner, 1988; Behrmann, Moscovitch, & Moser,1990a; see also Caramazza & Hills, 1990b). Per-formance often improves when words are presentedvertically or spelled aloud. In addition, there is evi-dence that semantic information can be processedin neglect dyslexia, and that the ability to readwords aloud improves when oral reading followsa semantic task (Ladavas, Shallice, & Zanella,1997).Neglect dyslexia has also been reported inpatients with left hemisphere lesions (Caramazza &Hills, 1990b; Greenwald & Berndt, 1999). In thesepatients the deﬁciency involves the right side ofwords. Here, visual neglect is usually conﬁned towords and is not ameliorated by presenting wordsvertically or spelling them aloud. This disorderhas therefore been termed a “positional dyslexia,”whereas the right hemisphere deﬁcit has beentermed a “spatial neglect dyslexia” (Ellis, Young, &Flude, 1993).Attentional DyslexiaAttentional dyslexia is a disorder characterized byrelatively preserved reading of single words, butimpaired reading of words in the context of otherwords or letters. This infrequently described disor-der was ﬁrst described by Shallice and WarringtonAcquired Dyslexia 115
(1977), who reported two patients with brain tumorsinvolving (at least) the left parietal lobe. Bothpatients exhibited relatively good performance withsingle letters or words, but were signiﬁcantlyimpaired in the recognition of the same stimuliwhen they were presented as part of an array. Sim-ilarly, both patients correctly read more than 90%of single words, but only approximately 80% ofthe words when they were presented in the contextof three additional words. These investigators at-tributed the disorder to a failure of transmission ofinformation from a nonsemantic perceptual stage toa semantic processing stage (Shallice & Warrington,1977).Warrington, Cipolotti, and McNeil (1993)reported a second patient, B.A.L., who was ableto read single words, but exhibited a substantialimpairment in the reading of letters and words in anarray. B.A.L. exhibited no evidence of visual dis-orientation and was able to identify a target letterin an array of “X”s or “O”s. He was impaired,however, in the naming of letters or words whenthese stimuli were ﬂanked by other members of thesame stimulus category. This patient’s attentionaldyslexia was attributed to an impairment arisingafter words and letters had been processed as units.More recently Saffran and Coslett (1996) reporteda patient, N.Y., who exhibited attentional dyslexia.The patient had biopsy-proven Alzheimer’s diseasethat appeared to selectively involve posterior corti-cal regions. N.Y. scored within the normal range onverbal subtests of the Wechsler Adult IntelligenceScale-Revised (WAIS-R), but was unable to carryout any of the performance subtests. He performednormally on the Boston Naming Test. N.Y. per-formed quite poorly in a variety of experimentaltasks assessing visuospatial processing and visualattention. Despite his visuoperceptual deﬁcits, how-ever, N.Y.’s reading of single words was essen-tially normal. He read 96% of 200 words presentedfor 100ms (unmasked). Like previously reportedpatients with this disorder, N.Y. exhibited a substan-tial decline in performance when asked to read twowords presented simultaneously.Of greatest interest, however, was the fact thatN.Y. produced a substantial number of “blend”errors in which letters from the two words werecombined to generate a response that was notpresent in the display. For example, when shown“ﬂip shot,” N.Y. responded “ship.” Like the blenderrors produced by normal subjects with brief stim-ulus presentation (Shallice & McGill, 1977), N.Y.’sblend errors were characterized by the preservationof letter position information; thus, in the precedingexample, the letters in the blend response (“ship”)retained the same serial position in the incorrectresponse. A subsequent experiment demonstratedthat for N.Y., but not controls, blend errors wereencountered signiﬁcantly less often when the targetwords differed in case (desk, FEAR).Like Shallice (1988; see also Mozer, 1991),Saffran and Coslett (1996) considered the centraldeﬁcit in attentional dyslexia to be impaired controlof a ﬁltering mechanism that normally suppressesinput from unattended words or letters in thedisplay. More speciﬁcally, they suggested that as aconsequence of the patient’s inability to effectivelydeploy the “spotlight” of attention to a particularregion of interest (e.g., a single word or a singleletter), multiple stimuli fall within the attentionalspotlight. Since visual attention may serve to inte-grate visual feature information, impaired modula-tion of the spotlight of attention would be expectedto generate word blends and other errors reﬂectingthe incorrect concatenation of letters.Saffran and Coslett (1996) also argued thatloss of location information contributed to N.Y.’sreading deﬁcit. Several lines of evidence supportsuch a conclusion. First, N.Y. was impaired rela-tive to controls, both with respect to accuracy andresponse time in a task in which he was required toindicate if a line was inside or outside a circle.Second, N.Y. exhibited a clear tendency to omit onemember of a double-letter pair (e.g., reed > “red”).This phenomenon, which has been demonstrated innormal subjects, has been attributed to the loss oflocation information that normally helps to differ-entiate two occurrences of the same object.H. Branch Coslett 116
Finally, it should be noted that the well-documented observation that the blend errors ofnormal subjects as well as those of attentionaldyslexics preserve letter position is not inconsistentwith the claim that impaired location informationcontributes to attentional dyslexia. Migration orblend errors reﬂect a failure to link words or lettersto a location in space, whereas the letter positionconstraint reﬂects the properties of the word-processing system. The latter, which is assumed tobe at least relatively intact in patients with atten-tional dyslexia, speciﬁes letter location with respectto the word form rather than to space.Other Peripheral DyslexiasPeripheral dyslexias may be observed in a varietyof conditions involving visuoperceptual or atten-tional deﬁcits. Patients with simultanagnosia, a dis-order characterized by an inability to “see” morethan one object in an array, are often able to readsingle words, but are incapable of reading text (seechapter 2). Other patients with simultanagnosiaexhibit substantial problems in reading even singlewords.Patients with degenerative conditions involvingthe posterior cortical regions may also exhibitprofound deﬁcits in reading as part of their moregeneral impairment in visuospatial processing (e.g.,Coslett, Stark, Rajaram, & Saffran, 1995). Severalpatterns of impairment may be observed in thesepatients. Some patients exhibit attentional dyslexia,with letter migration and blend errors, whereasother patients exhibiting deﬁcits that are in certainrespects rather similar do not produce migration orblend errors in reading or illusory conjunctions invisual search tasks. We have suggested that at leastsome patients with these disorders suffer from aprogressive restriction in the domain to which theycan allocate visual attention. As a consequence ofthis impairment, these patients may exhibit an effectof stimulus size so that they are able to read wordsin small print, but when shown the same word inlarge print see only a single letter.Central DyslexiasDeep DyslexiaDeep dyslexia, initially described by Marshall andNewcombe in 1973, is the most extensively inves-tigated of the central dyslexias (see Coltheart et al.,1980) and in many respects the most dramatic. Thehallmark of this disorder is semantic error. Shownthe word “castle,” a deep dyslexic may respond“knight”; shown the word “bird,” the patient mayrespond “canary.” At least for some deep dyslexics,it is clear that these errors are not circumlocutions.Semantic errors may represent the most frequenterror type in some deep dyslexics whereas in otherpatients they comprise a small proportion of readingerrors. Deep dyslexics make a number of othertypes of errors on single-word reading tasks as well.“Visual” errors in which the response bears a strongvisual similarity to the target word (e.g., book readas “boot”) are common. In addition, “morphologi-cal” errors in which a preﬁx or sufﬁx is added,deleted, or substituted (e.g., scolded read as“scolds”; governor read as “government”) are typi-cally observed.Another deﬁning feature of the disorder is aprofound impairment in the translation of printinto sound. Deep dyslexics are typically unable toprovide the sound appropriate to individual lettersand exhibit a substantial impairment in the readingof nonwords. When confronted with letter stringssuch as ﬂig or churt, for example, deep dyslexicsare typically unable to employ print-to-soundcorrespondences to derive phonology; nonwordsfrequently elicit “lexicalization” errors (e.g., ﬂigread as “ﬂag”), perhaps reﬂecting a reliance onlexical reading in the absence of access to reliableprint-to-sound correspondences. Additional featuresof the syndrome include a greater success in readingwords of high compared with low imageability.Thus, words such as table, chair, ceiling, and but-tercup, the referent of which is concrete or image-able, are read more successfully than words suchas fate, destiny, wish, and universal, which denoteabstract concepts.Acquired Dyslexia 117
Another characteristic feature of deep dyslexia isa part-of-speech effect in which nouns are typicallyread more reliably than modiﬁers (adjectives andadverbs), which in turn are read more accuratelythan verbs. Deep dyslexics manifest particular dif-ﬁculty in the reading of functors (a class of wordsthat includes pronouns, prepositions, conjunctions,and interrogatives including that, which, they,because, and under). The striking nature of the part-of-speech effect may be illustrated by the patientwho correctly read the word “chrysanthemum” butwas unable to read the word “the” (Saffran & Marin,1977)! Most errors in functors involve the substitu-tion of a different functor (that read as “which”)rather than the production of words of a differentclass, such as nouns or verbs. Since functors are ingeneral less imageable than nouns, some investiga-tors have claimed that the apparent effect of part ofspeech is in reality a manifestation of the pervasiveimageability effect. There is no consensus on thispoint because other investigators have suggestedthat the part-of-speech effect is observed even ifstimuli are matched for imageability (Coslett,1991).Finally, it should be noted that the accuracy oforal reading may be determined by context. This isillustrated by the fact that a patient was able to readaloud the word “car” when it was a noun, butnot when the same letter string was a conjunction.Thus, when presented with the sentence, “Le carralentit car le moteur chauffe” (The car slowsdown because the motor overheats), the patientcorrectly pronounced only the ﬁrst instance of“car” (Andreewsky, Deloche, & Kossanyi, 1980).How can deep dyslexia be accommodated by theinformation-processing model of reading illustratedin ﬁgure 6.1? Several alternative explanations havebeen proposed. Some investigators have arguedthat the reading of deep dyslexics is mediated by adamaged form of the left hemisphere-based systememployed in normal reading (Morton & Patterson,1980; Shallice, 1988; Glosser & Friedman, 1990).In such an account, multiple processing deﬁcitsmust be hypothesized to accommodate the fullrange of symptoms characteristic of deep dyslexia.First, the strikingly impaired performance inreading nonwords and other tasks assessing phono-logical function suggests that the print-to-soundconversion procedure is disrupted. Second, the pres-ence of semantic errors and the effects of image-ability (a variable thought to inﬂuence processingat the level of semantics) suggest that these patientsalso suffer from a semantic impairment (but seeCaramazza & Hills, 1990a). Finally, the productionof visual errors suggests that these patients sufferfrom impairment in the visual word form system orin the processes mediating access to the visual wordform system.Other investigators (Coltheart, 1980, 2000;Saffran, Bogyo, Schwartz, & Marin, 1980) haveargued that reading by deep dyslexics is mediatedby a system not normally used in reading—that is,the right hemisphere. We will return to the issue ofreading with the right hemisphere later. Finally,citing evidence from functional imaging studiesdemonstrating that deep dyslexic subjects exhibitincreased activation in both the right hemisphereand nonperisylvian areas of the left hemisphere,other investigators have suggested that deepdyslexia reﬂects the recruitment of both right andleft hemisphere processes.Phonological Dyslexia: Reading withoutPrint-to-Sound CorrespondencesFirst described in 1979 by Derouesne and Beauvois,phonological dyslexia is perhaps the “purest” of thecentral dyslexias in that, at least in some accounts,the syndrome is attributable to a selective deﬁcitin the procedure mediating the translation fromprint into sound. Single-word reading in this dis-order is often only mildly impaired; some patients,for example, correctly read 85–95% of real words(Funnell, 1983; Bub, Black, Howell, & Kartesz,1987). Some phonological dyslexics read all dif-ferent types of words with equal facility (Bubet al., 1987), whereas other patients are relativelyimpaired in the reading of functors (Glosser &Friedman, 1990).Unlike the patients with surface dyslexiadescribed later, the regularity of print-to-soundH. Branch Coslett 118
correspondences is not relevant to their perform-ance; thus, phonological dyslexics are as likelyto correctly pronounce orthographically irregularwords such as colonel as words with standardprint-to-sound correspondences such as administer.Most errors in response to real words bear a visualsimilarity to the target word (e.g., topple read as“table”). The reader is referred to a special issue ofCognitive Neuropsychology for a discussion of thisdisorder (Coltheart, 1996).The striking and theoretically relevant aspect ofthe performance of phonological dyslexics is a sub-stantial impairment in the oral reading of nonwordletter strings. We have examined patients with thisdisorder, for example, who read more than 90% ofreal words of all types yet correctly pronouncedonly approximately 10% of nonwords. Most errorsin nonwords involve the substitution of a visuallysimilar real word (e.g., phope read as “phone”) orthe incorrect application of print-to-sound corre-spondences (e.g., stime read as “stim” to rhymewith “him”).Within the context of the reading model depictedin ﬁgure 6.1, the account for this disorder is rela-tively straightforward. Good performance with realwords suggests that the processes involved innormal “lexical” reading—that is, visual analysis,the visual word form system, semantics, and thephonological output lexicon—are at least relativelypreserved. The impairment in reading nonwordssuggests that the print-to-sound translation proce-dure is disrupted.Recent explorations of the processes involvedin reading nonwords have identiﬁed a number ofdistinct procedures involved in this task (see Colt-heart, 1996). If these distinct procedures may beselectively impaired by brain injury, one mightexpect to observe different subtypes of phonologi-cal dyslexia. Although the details are beyond thescope of this chapter, Coltheart (1996) has recentlyreviewed evidence suggesting that different sub-types of phonological dyslexia may be observed.Finally, it should be noted that several investiga-tors have suggested that phonological dyslexia isnot attributable to a disruption of a reading-speciﬁccomponent of the cognitive architecture, but ratherto a more general phonological deﬁcit. Supportfor this assertion comes from the observation thatthe vast majority of phonological dyslexics areimpaired on a wide variety of nonreading tasks thatassess phonology.Phonological dyslexia is, in certain respects,similar to deep dyslexia, the critical differencebeing that semantic errors are not observed inphonological dyslexia. Citing the similarity ofreading performance and the fact that deep dyslex-ics may evolve into phonological dyslexics as theyimprove, it has been argued that deep and phono-logical dyslexia are on a continuum of severity(Glosser & Friedman, 1990).Surface Dyslexia: Reading without LexicalAccessSurface dyslexia, ﬁrst described by Marshall andNewcombe (1973), is a disorder characterized bythe relatively preserved ability to read words withregular or predictable grapheme-to-phoneme corre-spondences, but substantially impaired readingof words with “irregular” or exceptional print-to-sound correspondences. Thus, patients with surfacedyslexia typically are able to read words suchas state, hand, mosquito, and abdominal quite well,whereas they exhibit substantial problems readingwords such as colonel, yacht, island, and borough,the pronunciation of which cannot be derived bysounding-out strategies. Errors in irregular wordsusually consist of “regularizations”; for example,surface dyslexics may read colonel as “kollonel.”These patients read nonwords (e.g., blape) quitewell. Finally, it should be noted that all surfacedyslexics that have been reported to date read atleast some irregular words correctly. Patients willoften read high-frequency irregular words (e.g.,have, some), but some surface dyslexics have beenreported to read such low-frequency and highlyirregular words as sieve and isle.As noted earlier, some accounts of normalreading postulate that familiar words are read aloudby matching a letter string to a stored representationof the word and retrieving the pronunciation by aAcquired Dyslexia 119
mechanism linked to semantics or by a direct route.Since this process is assumed to involve the activa-tion of the sound of the whole word, performancewould not be expected to be inﬂuenced by theregularity of print-to-sound correspondences. Thefact that this variable signiﬁcantly inﬂuences per-formance in surface dyslexia suggests that thedeﬁcit in this syndrome is in the mechanisms medi-ating lexical reading, that is, in the semanticallymediated and direct reading mechanisms. Similarly,the preserved ability to read words and nonwordsdemonstrates that the procedures by which wordsare sounded out are at least relatively preserved.In the context of the information-processingmodel discussed previously, how would one ac-count for surface dyslexia? Scrutiny of the modeldepicted in ﬁgure 6.1 suggests that at least three dif-ferent deﬁcits may result in surface dyslexia. First,this disorder may arise from a deﬁcit at the levelof the visual word form system that disrupts theprocessing of words as units. As a consequenceof this deﬁcit, subjects may identify “sublexical”units (e.g., graphemes or clusters of graphemes) andidentify words on the basis of print-to-sound corre-spondences. Note that in this account, semanticsand output processes would be expected to be pre-served. The patient J.C. described by Marshall andNewcombe (1973) exhibited at least some of thefeatures of this type of surface dyslexia. Forexample, in response to the word listen, JC said“Liston” (a former heavyweight champion boxer)and added “that’s the boxer,” demonstrating that hewas able to derive phonology from print and sub-sequently access meaning.In the model depicted in ﬁgure 6.1, one mightalso expect to encounter surface dyslexia withdeﬁcits at the level of the output lexicon (see Ellis,Lambon Ralph, Morris, & Hunter, 2000). Supportfor such an account comes from patients who com-prehend irregular words yet regularize these wordswhen asked to read them aloud. For example, M.K.read the word “steak” as “steek” (as in seek) beforeadding, “nice beef” (Howard & Franklin, 1987). Inthis instance, the demonstration that M.K. was ableto provide appropriate semantic information indi-cates that he was able to access meaning directlyfrom the written word and suggests that the visualword form system and semantics were at leastrelatively preserved.One might also expect to observe surfacedyslexia in patients exhibiting semantic loss.Indeed, most patients with surface dyslexia (oftenin association with surface dysgraphia) exhibit asigniﬁcant semantic deﬁcit (Shallice, Warrington,& McCarthy, 1983; Hodges, Patterson, Oxbury, &Funnell, 1992). Surface dyslexia is most frequentlyobserved in the context of semantic dementia, a pro-gressive degenerative condition characterized by agradual loss of knowledge in the absence of deﬁcitsin motor, perceptual, and, in some instances, ex-ecutive function (see chapter 4).Note, however, that the information-processingaccount of reading depicted in ﬁgure 6.1 also incor-porates a lexical but nonsemantic reading mecha-nism by which patients with semantic loss wouldbe expected to be able to read even irregular wordsnot accommodated by the grapheme-to-phonemeprocedure. In this account, then, surface dyslexia isassumed to reﬂect impairment in both the semanticand lexical, but not nonsemantic mechanisms. Itshould be noted in this context that the “triangle”model of reading developed by Seidenberg andMcClelland (1989; also see Plaut, McClelland,Seidenberg, & Patterson, 1996) provides an alter-native account of surface dyslexia. In this account,to which we brieﬂy return later, surface dyslexia isassumed to reﬂect the disruption of semanticallymediated reading.Reading and the Right HemisphereOne controversial issue regarding reading concernsthe putative reading capacity of the right hemi-sphere. For many years investigators argued thatthe right hemisphere was “word-blind” (Dejerine,1892; Geschwind, 1965). In recent years, how-ever, several lines of evidence have suggested thatthe right hemisphere may possess the capacity toread (Coltheart, 2000; Bartolomeo, Bachoud-Levi,Degos, & Boller, 1998). Indeed, as previouslyH. Branch Coslett 120
noted, a number of investigators have argued thatthe reading of deep dyslexics is mediated at least inpart by the right hemisphere.One seemingly incontrovertible ﬁnding demon-strating that at least some right hemispheres possessthe capacity to read comes from the performanceof a patient who underwent a left hemispherec-tomy at age 15 for treatment of seizures causedby Rasmussen’s encephalitis (Patterson, Varga-Khadem, & Polkey, 1989a). After the hemispherec-tomy, the patient was able to read approximately30% of single words and exhibited an effect of partof speech; she was unable to use a grapheme-to-phoneme conversion process. Thus, as noted by theauthors, this patient’s performance was similar inmany respects to that of patients with deep dyslexia,a pattern of reading impairment that has beenhypothesized to reﬂect the performance of the righthemisphere.The performance of some split-brain patients isalso consistent with the claim that the right hemi-sphere is literate. These patients may, for example,be able to match printed words presented to the righthemisphere with an appropriate object (Zaidel,1978; Zaidel & Peters, 1983). It is interesting thatthe patients are apparently unable to derive soundfrom the words presented to the right hemisphere;thus they are unable to determine if a word pre-sented to the right hemisphere rhymes with a spokenword.Another line of evidence supporting the claimthat the right hemisphere is literate comes from anevaluation of the reading of patients with purealexia and optic aphasia. We reported data, forexample, from four patients with pure alexia whoperformed well above chance in a number of lexicaldecision and semantic categorization tasks withbrieﬂy presented words that they could not explic-itly identify. Three of the patients who regained theability to explicitly identify rapidly presented wordsexhibited a pattern of performance consistent withthe right hemisphere reading hypothesis. Thesepatients read nouns better than functors and wordsof high imageability (e.g., chair) better than wordsof low imageability (e.g., destiny). In addition, bothpatients for whom data are available demonstrateda deﬁcit in the reading of sufﬁxed (e.g., ﬂowed)compared with pseudo-sufﬁxed (e.g., ﬂower)words. These data are consistent with a version ofthe right hemisphere reading hypothesis, which pos-tulates that the right hemisphere lexical-semanticsystem primarily represents high imageabilitynouns. In this account, functors, afﬁxed words, andlow-imageability words are not adequately repre-sented in the right hemisphere.An important additional ﬁnding is that magneticstimulation applied to the skull, which disrupts elec-trical activity in the brain below, interfered with thereading performance of a partially recovered purealexic when it affected the parieto-occipital area ofthe right hemisphere (Coslett & Monsul, 1994). Thesame stimulation had no effect when it was appliedto the homologous area on the left. Additional datasupporting the right hemisphere hypothesis comefrom the demonstration that the limited whole-wordreading of a pure alexic was lost after a rightoccipito-temporal stroke (Bartolomeo et al., 1998).Although a consensus has not yet been achieved,there is mounting evidence that at least for somepeople, the right hemisphere is not word-blind, butmay support the reading of some types of words.The full extent of this reading capacity and whetherit is relevant to normal reading, however, remainunclear.Functional Neuromaging Studies ofAcquired DyslexiaA variety of experimental techniques includingposition emission tomography (PET), functionalmagnetic resonance imaging (fMRI), and evokedpotentials have been employed to investigate theanatomical basis of reading in normal subjects.As in other domains of inquiry, differences inexperimental technique (e.g., stimulus duration)(Price, Moore, & Frackowiak, 1996) and designhave led to some variability in the localization ofputative components of reading systems. Attemptsto precisely localize components of the cognitiveAcquired Dyslexia 121
architecture of reading are also complicated by theinteractive nature of language processes. Thus,since word recognition may lead to automatic acti-vation of meaning and phonology, tasks such aswritten-word lexical decisions, which in theory mayrequire only access to a visual word form system,may also activate semantic and phonologicalprocesses (see Demonet, Wise, & Frackowiak,1993). Despite these potential problems, thereappears to be at least relative agreement regardingthe anatomical basis of several components of thereading system (see Fiez & Petersen, 1998; Price,1998).A number of studies suggest that early visualanalysis of orthographic stimuli activates Brodmannareas 18 and 19 bilaterally (Petersen, Fox, Snyder,& Raichle, 1990; Price et al., 1996; Bookheimer,Zefﬁro, Blaxton, Gaillard, & Theodore, 1995;Indefrey et al., 1997; Hagoort et al., 1999). Forexample, Petersen et al. (1990) reported extrastriateactivation with words, nonwords, and even falsefonts.As previously noted, most accounts of readingpostulate that after initial visual processing, famil-iar words are recognized by comparison with acatalog of stored representations that is often termedthe “visual word-form system.” A variety of recentinvestigations involving fMRI (Cohen et al., 2000,Puce, Allison, Asgari, Gore, & McCarthy, 1996),PET (e.g., Beauregard et al., 1997), and directrecording of cortical electrical activity (Nobre,Allison, & McCarthy, 1994) suggest that the visualword-form system is supported by the inferioroccipital or inferior temporo-occipital cortex; theprecise localization of the visual word form systemin cortex, however, varies somewhat from study tostudy.Recent strong support for this localization comesfrom an investigation by Cohen et al. (2000) of ﬁvenormal subjects and two patients with posteriorcallosal lesions. These investigators presentedwords and nonwords for lexical decision or oralreading to either the right or left visual ﬁelds. Theyfound initial unilateral activation in what wasthought to be area V4 in the hemisphere to whichthe stimulus was projected. More important, how-ever, in normal subjects, activation was observed inthe left fusiform gyrus (Talairach coordinates -42,-57, -6), which was independent of the hemisphereto which the stimulus was presented. The twopatients with posterior callosal lesions were moreimpaired in the processing of letter strings presentedto the right than to the left hemisphere; fMRI inthese subjects demonstrated that the region of thefusiform gyrus described earlier was activated in thecallosal patients only by stimuli presental to the lefthemisphere. As noted by the investigators, theseﬁndings are consistent with the hypothesis that thehemialexia demonstrated by the callosal patients isattributable to a failure to access the visual word-form system in the left fusiform gyrus.It should be noted, however, that alternativelocalizations of the visual word-form systemhave been proposed. Petersen et al. (1990) andBookheimer et al. (1995), for example, have sug-gested the medial extrastriate cortex as the relevantsite for the visual word-form system. In addition,Howard et al. (1992), Price et al. (1994), andVandenberghe, Price, Wise, Josephs, & Frackowiak(1996) have localized the visual word-form systemto the left posterior temporal lobe. Evidence againstthis localization has been presented by Cohen et al.(2000).Several studies have suggested that retrieval ofphonology for visually presented words may acti-vate the posterior superior temporal lobe or the leftsupramarginal gyrus. For example, Vandenbergheet al. (1996), Bookheimer et al. (1995), and Menard,Kosslyn, Thompson, Alpert, & Rauch (1996)reported that reading words activated Brodmannarea 40 to a greater degree than naming pictures,raising the possibility that this region is involved inretrieving phonology for written words.The left inferior frontal cortex has also beenimplicated in phonological processing with writtenwords. Zatorre, Meyer, Gjedde, & Evans (1996)reported activation of this region in tasks involvingdiscrimination of ﬁnal consonants or phonememonitoring. In addition, the contrast between read-ing of pseudo-words and regular words has beenH. Branch Coslett 122
reported to activate the left frontal operculum (Priceet al., 1996), and this region was activated by alexical decision test with written stimuli (Rumsey etal., 1997).Deriving meaning from visually presented wordsrequires access to stored knowledge or semantics.While the architecture and anatomical bases ofsemantic knowledge remain controversial and arebeyond the scope of this chapter, a variety of linesof evidence reviewed by Price (1998) suggests thatsemantics are supported by the left inferior tempo-ral and posterior inferior parietal cortices. The roleof the dorsolateral frontal cortex in semantic pro-cessing is not clear; Thompson-Schill, D’Esposito,Aguirre, & Farah (1997) and other investigators(Gabrieli, 1998) have suggested that this activationis attributable to “executive” processing, includingresponse selection rather than semantic processing.Conclusions and Future DirectionsOur discussion to this point has focused on a“box-and-arrow” information-processing accountof reading disorders. This account has not onlyproven useful in terms of explaining data fromnormal and brain-injured subjects but has also pre-dicted syndromes of acquired dyslexia. One weak-ness of these models, however, is the fact that theaccounts are largely descriptive and underspeciﬁed.In recent years, a number of investigators havedeveloped models of reading in which the architec-ture and procedures are fully speciﬁed and im-plemented in a fashion that permits an empiricalassessment of their performance. One computa-tional account of reading has been developed byColtheart and colleagues (Coltheart & Rastle, 1994;Rastle & Coltheart, 1999). Their “dual-route cas-caded” model is a computational version of thedual-route theory similar to that presented in ﬁgure6.1. This account incorporates a “lexical” route(similar to “C” in ﬁgure 6.1) as well as a “nonlexi-cal” route by which the pronunciation of graphemesis computed on the basis of position-speciﬁc corre-spondence rules. This model accommodates a widerange of ﬁndings from the literature on normalreading.A fundamentally different type of reading modelwas developed by Seidenberg and McClelland andsubsequently elaborated by Plaut, Seidenberg, andcolleagues (Seidenberg & McClelland, 1989; Plaut,Seidenberg, & McClelland, Patterson 1996). Thisaccount belongs to the general class of parallel dis-tributed processing or connectionist models. Some-times called the “triangle” model, this approachdiffers from information-processing accounts in thatit does not incorporate word-speciﬁc representa-tions (e.g., visual word forms, output phonologicalrepresentations). In this account, the subjects areassumed to learn how written words map ontospoken words through repeated exposure to famil-iar and unfamiliar words. Word pronunciations arelearned by the development of a mapping betweenletters and sounds generated on the basis of experi-ence with many different letter strings. The pro-babilistic mapping between letters and sounds isassumed to provide the means by which bothfamiliar and unfamiliar words are pronounced.This model not only accommodates an impres-sive array of the classic ﬁndings in the literature onnormal reading but also has been “lesioned” in anattempt to reproduce the reading patterns charac-teristic of dyslexia. For example, Patterson et al.(1989b) have attempted to accommodate surfacedyslexia by disrupting semantically mediatedreading, and Plaut and Shallice (1993) generated aperformance pattern similar to that of deep dyslexiaby lesioning a somewhat different connectionistmodel.A full discussion of the relative merits of thesemodels as well as approaches to understandingreading and acquired dyslexia is beyond the scopeof this chapter. It would appear likely, however, thatinvestigations of acquired dyslexia will help us tochoose between competing accounts of readingand that these models will continue to offer criticalinsights into the interpretation of data from brain-injured subjects.Acquired Dyslexia 123
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Darren R. GitelmanArithmetic is being able to count up to twenty withouttaking off your shoes.—Mickey MouseAlthough descriptions of calculation deﬁcits datefrom the early part of this century, comprehensiveneuropsychological and neuroanatomical modelsof this function have been slow to develop. Thislag may reﬂect several factors, including an initialabsence of nomenclature accurately describingcalculation deﬁcits, difﬁculty separating calculationdisorders from disruptions in other domains, and,more fundamentally, the multidimensional nature ofnumerical cognition, which draws upon perceptual,linguistic, and visuospatial skills during both child-hood development and adult performance. The goalof this chapter is to review the cognitive neuro-science and behavioral neuroanatomy underlyingthese aspects of numerical processing, and thelesion-deﬁcit correlations that result in acalculia.Recommended tests at the bedside are outlined atthe end of the chapter since the theoretical motiva-tions for those tests will have been discussed by thatpoint.Case ReportC.L., a 55-year-old right-handed woman, sought an eval-uation for problems with writing and calculations. Thesesymptoms had been present for approximately 1 year andhad led her to resign from her position as a second-gradeteacher. In addition to writing and calculation deﬁcits, bothspelling and reading had declined. Lapses of memoryoccurred occasionally. Despite these deﬁcits, daily livingactivities remained intact.Examination revealed an alert, cooperative, and pleas-ant woman who was appropriately concerned about herpredicament. She was fully oriented, but had only a vagueknowledge of current events. She could not recite themonths in normal order and her verbal ﬂuency wasreduced for lexical items (ﬁve words). After ten trials shewas able to repeat four words from immediate memory,7 Acalculia: A Disorder of Numerical Cognitionand could then recall all four words after 10 minutes. Thisperformance suggested that she did not have a primarymemory disorder. There was mild hesitancy to her spon-taneous speech, but no true word-ﬁnding pauses. She didwell on confrontation naming, showing only mild hesita-tion on naming parts of objects. Only a single phonemicparaphasia was noted. Her comprehension was preserved,and reading was slow but accurate, including readingnumbers. Writing was very poor. She had severe spellingdifﬁculties, even for simple words, including regular andirregular forms. Calculations were severely impaired. Forexample, she said that 8 + 4 was 11 and could not calcu-late 4 ¥ 12. Mild deﬁcits were noted for ﬁnger namingand left-right orientation. Thus she manifested all fourcomponents of Gerstmann’s syndrome (acalculia, agra-phia, right-left confusion, and ﬁnger agnosia). Difﬁcultiesin target scanning and mild simultanagnosia were present.Clock drawing showed minimal misplacement of num-bers, but she could not copy a cube. Lines were bisectedcorrectly. Her general physical examination and elemen-tary sensorimotor neurological examination showed nofocal deﬁcits.Because of her relatively young age and unusual pre-sentation, an extensive workup was performed. A varietyof laboratory tests were unremarkable. A brain magneticresonance imaging (MRI) scan showed moderate atrophicchanges. Single-photon emission computed tomographyshowed greater left than right parietal perfusion deﬁcits(ﬁgure 7.1).The patient in this case report clearly had difﬁ-culty with calculations. The most signiﬁcant othercognitive deﬁcits were in writing and certain re-stricted aspects of naming (e.g., ﬁnger naming). Thedescription of this case reports a simple, classic neu-rological approach to the evaluation of her calcula-tion deﬁcit. However, it will soon be shown that theexamination barely touched upon the rich cognitiveneurology and neuropsychology underlying humannumerical cognition. The case also illustrates twoimportant points regarding calculations that willbe expanded upon later: (1) Calculation deﬁcits donot necessarily represent general disturbances inintellectual abilities; for example, in this patient,language functions (outside of writing) and memory
were generally preserved. (2) The cerebral perfu-sion deﬁcits, particularly in the left parietal cortex,and the patient’s anarithmetia are consistent withthe prominent role of this region in several aspectsof calculations.Historical Perspective and Early Theoriesof CalculationThe development of numerical cognitive neuro-science has paralleled that of many other cognitivedisorders. Early on in the history of this ﬁeld,lesion-deﬁcit correlations suggested the presence ofdiscrete centers for calculation. Subsequently, viewsbased on equipotentiality prevailed, and calculationdeﬁcits were thought to reﬂect generalized disrup-tions of brain function (Spiers, 1987). Current viewspreserve the concepts of regional specializationand multiregional integration through the theoreti-cal formulation that complex cognitive functions,such as calculations, are supported by large-scaleneural networks.1The phrenologist Franz Josef Gall was probablythe ﬁrst to designate a cerebral source for numbers,in the early 1800s, which he attributed to the infe-rior frontal regions bilaterally (Kahn & Whitaker,1991). No patient-related information, however,was provided for this conjecture. The ﬁrst patient-based description of an acquired calculation dis-order was provided in 1908 by Lewandowskyand Stadelman. Their patient developed calcula-tion deﬁcits following removal of a left occipitalhematoma. The resulting calculation disturbanceclearly exceeded problems in language or deﬁcits inother aspects of cognition. Thus, these authors werethe ﬁrst to report that calculation disturbances couldbe distinct from other language deﬁcits.Subsequently, several cases were reported inwhich calculation disturbances appeared to followleft retrorolandic lesions or bilateral occipitaldamage (Poppelreuter, 1917; Sittig, 1917; Peritz,1918, summarized by Boller & Grafman, 1983).Peritz also speciﬁcally cited the left angular gyrusas a center for calculations (Boller & Grafman,1983).Henschen ﬁrst used the term acalculia to refer toan inability to perform basic arithmetical operations(Henschen, 1920; Boller & Grafman, 1983; Kahn &Whitaker, 1991). He also postulated that calcula-tions involved several cortical centers, including theinferior frontal gyrus for number pronunciation,both the angular gyrus and intraparietal sulcus fornumber reading, and the angular gyrus alone forwriting numbers. Signiﬁcantly, he also recognizedthat calculation and language functions are associ-ated but independent (Boller & Grafman, 1983;Kahn & Whitaker, 1991).Several subsequent analyses have documentedthe distinctions between acalculia and aphasia, andhave demonstrated that calculation deﬁcits areunlikely to be related to a single brain center (i.e.,they are not simply localized to the angular gyrus).Berger, for example, documented three cases ofacalculia that had lesions in the left temporal andoccipital cortices but not in the angular gyrus(Berger, 1926; Boller & Grafman, 1983; Kahn &Whitaker, 1991). Berger also suggested that thevarious brain areas underlying calculation workedtogether to produce these abilities, thus heraldinglarge-scale network theories of brain organization(Mesulam, 1981; Selemon & Goldman-Rakic,1988; Alexander, Crutcher, & Delong, 1990;Darren R. Gitelman 130Figure 7.1Two representative slices from the single-photon emissioncomputed tomography scan for C.L. The areas of pre-dominant left frontoparietal hypoperfusion are indicatedby arrows. Perfusion was also reduced in similar areas onthe right compared with normal subjects, but the extentwas much less dramatic than the abnormalities on the left.
Dehaene & Cohen, 1995). Another important dis-tinction noted by Berger was the difference betweensecondary acalculia (i.e., those disturbances due tocognitive deﬁcits in attention, memory language,etc.), and primary acalculia, which appeared to beindependent of other cerebral disorders (Boller &Grafman, 1983).Other early authors postulated a variety of addi-tional deﬁcits that could interfere with calculations,such as altered spatial cognition (Singer & Low,1933; Krapf, 1937; Critchley, 1953), disturbedsensorimotor transformations (possibly having todo with the physical manipulation of quantities)(Krapf, 1937), altered numerical mental representa-tions and calculation automaticity (Leonhard, 1939;Critchley, 1953), and abnormal numerical and sym-bolic semantics (Cohn, 1961; Boller & Grafman,1983; Kahn & Whitaker, 1991). Consistent with thisplethora of potential cognitive deﬁcits, an increas-ing number of cognitive processes (e.g., ideational,verbal, spatial, and constructional) were hypothe-sized to support numerical functions, and corre-spondences were developed between cortical areasand the cognitive functions they were thought toserve (Boller & Grafman, 1983; Kahn & Whitaker,1991).The parietal lobes have long been considered tobe a fundamental cortical region for calculationprocesses. From 1924 to 1930, Josef Gerstmannpublished a series of articles describing a syndromethat now bears his name. He described the associa-tion of lesions in the left parietal cortex with deﬁcitsin writing, ﬁnger naming, right-left orientationand calculations (Gerstmann, 1924, 1927, 1930).Gerstmann attributed this disorder to a disturbanceof “body schema,” which he thought was coordi-nated through the parietal lobes. The existenceand cohesiveness of this syndrome has been bothpraised (Strub & Geschwind, 1974) and challenged(Benton, 1961; Poeck & Orgass, 1966; Benton,1992).It has also been unclear how disturbances in bodyschema would explain acalculia except at a superﬁ-cial level (e.g., children learn calculations by count-ing on their ﬁngers; therefore a disturbance in ﬁngernaming may lead to a disturbance in calculations).More recently, it has been suggested that theGerstmann syndrome may represent a disconnec-tion between linguistic and visual-spatial systems(Levine, Mani, & Calvanio, 1988). This explanationmay be particularly important for understandinghow neural networks supporting language or sym-bolic manipulation and those supporting spatialcognition interact with each other and contributeto calculations. This particular point is discussedfurther in the section on network models ofcalculations.Aside from the parietal contributions to numberprocessing, other authors, focusing on the visualaspects of numerical manipulation, have consideredthe occipital lobes to be particularly important(Krapf, 1937; Goldstein, 1948). Another debate hasconcentrated on the hemispheric localization ofarithmetical functions. Although calculation deﬁcitsoccur more commonly with lesions to the left hemi-sphere, they can also be seen with right hemisphereinjury (Henschen, 1919; Critchley, 1953; Hécaen,1962). Others, such as Goldstein (1948), doubtedthe right hemisphere’s involvement in this function.More recently, Collignon et al. and Grafmanet al. documented calculation performance in seriesof patients with right or left hemisphere damage(Collingnon, Leclercq & Mahy, 1977; Grafman,Passaﬁume, Faglioni, & Boller, 1982). In bothreports, disturbances of calculation followed injuryto either hemisphere; however, acalculia occurredmore often in patients with left hemisphere lesions.Grafman et al. (1982) also demonstrated that leftretrorolandic lesions impaired calculations morethan left anterior or right-sided lesions.In 1961, Hècaen et al. published a report ona large series of patients (183) with posterior corti-cal lesions and calculation disorders (Hécaen,Angelergues, & Hovillier, 1961). Three main typesof calculation deﬁcits were noted: (1) One grouphad alexia and agraphia for digits with or withoutalexia and agraphia for letters. In this group, calcu-lations appeared to be impaired secondary to dis-turbances in visual aspects of numerical input andoutput. (2) A second group showed problems withAcalculia 131
the spatial organization of numbers and tended towrite numbers in the wrong order or invert them.(3) The third group had difﬁculty performing arith-metical operations, but their deﬁcits were notsimply attributable to problems with the compre-hension or production of numbers. This group wasdeﬁned as having anarithmetia.The importance of this report was severalfold:It conﬁrmed the distinctions between aphasia andacalculia; it demonstrated the importance of theparietal cortex to calculations (among other retro-rolandic regions); it demonstrated the separabilityof comprehension, production, and computationaloperations in the calculation process; and it sug-gested that both hemispheres contribute to thisfunction (Boller & Grafman, 1983). This report wasalso the ﬁrst to attempt a comprehensive cognitivedescription of calculation disorders, rather thanconsidering them as disconnected and unrelatedsyndromes.Grewel (1952, 1969) stressed the symbolic natureof calculation and that abnormalities in the seman-tics and syntax of number organization could alsodeﬁne a series of dyscalculias. He noted that theessential aspects of our number system are based onthe principles underlying the Hindu system: (1) tensymbols (0–9) are all that is necessary to deﬁne anynumber; (2) a digit’s value in a number is basedon its position (place value); and (3) zero indicatesthe absence of power (Grewel 1952, 1969; Boller& Grafman, 1983). Therefore calculation disordersmight reﬂect abnormalities of digit selection or digitplacement. These features are particularly importantin modern concepts of numerical comprehensionand production (McCloskey, Caramazza, & Basili,1985).Grewel also suggested several additional typesof primary acalculia. For example, asymbolic acal-culia referred to problems in comprehending ormanipulating mathematical symbols, while asyntac-tic acalculia described problems in comprehendingand producing numbers (Grewel, 1952, 1969).Although many of the anatomical associations hereported are not in use today, they illuminated themultiple cortical areas associated with this function(Grewel, 1952, 1969).Comprehensive NeuropsychologicalTheories of CalculationBy the early 1970s, a variety of case reports andgroup lesion studies had suggested a number ofbasic facts about arithmetical functions: (1) It waslikely that calculation abilities represented a collec-tion of cognitive functions separate from but inter-dependent with other intellectual abilities such aslanguage, memory, and visual-spatial functions.Therefore, signiﬁcant calculation deﬁcits couldoccur, with less prominent disturbances acrossseveral other cognitive domains. (2) A number ofbrain regions appeared to be important for calcula-tions, including the parietal, posterior temporal, andoccipital cortices, and possibly the frontal cortex.2Additional lesion sites are discussed further later.(3) Both hemispheres were thought to contributeto calculation performance, but lesions of the lefthemisphere more often produced deﬁcits in cal-culations and resulted in greater impairments inperformance. (4) There were likely to be several dif-ferent types of deﬁcits that resulted in acalculia, forexample, the asymbolic and asyntactic acalculias ofGrewel (Grewel, 1952, 1969).Despite these theoretical advances, there was stilldebate about the distinctness and localizabilityof calculations as a function (Collingnon et al.,1977; Spiers, 1987). More problematic had beenthe lack of a coherent theoretical framework toexplain either the operational principles or thefunctional–anatomical correlations underlying cal-culation abilities. Further understanding of theneuropsychology and functional anatomy of calcu-lations beneﬁted from the development of theoreti-cally constrained case studies (Spiers, 1987) and theuse of mental chronometry to specify the underly-ing neuropsychological processes (Posner, 1986).In recent years, a variety of brain mapping methodshave also contributed to our understanding of thebrain regions subserving this function.Darren R. Gitelman 132
Current psychological approaches to numericalcognition have attempted to incorporate manyof these aspects of numerical processing into acomprehensive theoretical framework. This foru-mulation includes how numbers are perceived(visually, verbally, etc.), the nature of numericalrepresentations in the brain, the variety of numericaloperations (number comparison, counting, approxi-mation, and arithmetical computations), and howthese perceptual, representational, and operationalfunctions relate to one another.McCloskey formulated one of the ﬁrstcomprehensive calculation theories by outliningnumber processing and computational mechanisms(McCloskey et al., 1985). However, Dehaene hasargued that approximation and quantiﬁcation pro-cesses constitute an important aspect of the calcula-tion system and were not explicitly modeled inMcCloskey’s formulations (McCloskey et al.,1985; Dehaene & Cohen, 1995, 1997; Dehaene,Dehaene-Lambertz, & Cohen, 1998).A general schematic representing a synthesis ofvarious models for calculations is shown in ﬁgure7.2. Most current calculation theories include eachof the systems in ﬁgure 7.2, although the nature ofthe interrelationships among these processes hasbeen debated considerably. Recent theories, such asthe popular triple-code model of Dehaene, attemptto integrate neuropsychological theories of calcula-tion with network theories of the associated brainanatomy (Dehaene & Cohen, 1995). Details of theseneurocognitive systems and the nature of deﬁcitsfollowing their injury are reviewed later.Number ProcessingAs illustrated in ﬁgure 7.2, a number-processingsystem is central to our ability to comprehend andproduce a variety of numerical formats.3Numberscan be written as numerals or words (e.g., 47 versusforty-seven) or they can be spoken. There are alsolexical and syntactic aspects of number processingAcalculia 133Figure 7.2Schematic of systems supporting calculations and number processing. The functions concerned with quantiﬁcation andapproximation were not explicitly included in the original model outlined by McCloskey Caramazzza, Basili (1985), buthave been added because of their demonstrated importance to numerical cognition (Dehaene & Cohen, 1995). The posi-tions of quantiﬁcation and approximation operations in the model represent both a foundation supporting the develop-ment of numerical cognition and an important numerical resource used by adults in number processing and calculations.
(McCloskey et al., 1985). Lexical processinginvolves the identiﬁcation of individual numeralswithin a number. For example, lexical processingof the number 447 establishes that there are two 4sand one 7. An example of a lexical error would beto interpret this number as 457. This demonstratesmaintenance of the overall number quantity (asopposed to saying “forty-ﬁve”), but an individualdigit has been misidentiﬁed.Syntactic processing deﬁnes the order and re-lationship of the numerical elements to each otherand is closely associated with the concept of placevalue. An example of a syntactic error would bewriting the number four-hundred forty seven as40047. Although this answer contains the elements400 and 47, combining them in this manner violatesthe syntactic relationships in the original number(McCloskey et al., 1985).As part of the set of lexical functions, mecha-nisms have also been posited for the phonologicalprocessing of numbers (i.e., processing spokenwords for numbers), and the graphemic processingof numbers (i.e., processing written number forms).However, phonological and graphemic mechanismshave not been attributed to syntactic functions sincespoken and written verbal number forms appearto require similar syntactic processing (i.e., thesyntactic relationships among the elements offorty-four and 44 are identical). Phonological andgraphemic mechanisms have also not been distin-guished for Arabic numerals, which occur only inwritten form (McCloskey et al., 1985). An outlineof possible cognitive subcomponents for numberprocessing is shown in ﬁgure 7.3.General support for the functions delineatedin this schema has been neuropsychologicallydemonstrated by ﬁnding patients who show dis-sociations in their number-processing abilities fol-lowing various brain lesions (traumatic, vascular,etc.). Unfortunately, in the acalculia literature,precise localization of lesions for most patients islacking. Over the past several years, however, datafrom functional neuroimaging studies have startedto provide more precise information on brain–behavior relationships in this area.In order to illustrate these deﬁcits in number pro-cessing, speciﬁc aspects of patients’ case historiesare provided here. However, room does not permita complete elaboration of each report, and the inter-ested reader is encouraged to review the sourcematerial for this detail. Patients are identiﬁed asthey were in the original publication. Some patientsDarren R. Gitelman 134Figure 7.3Outline of proposed neuropsychological mechanisms subserving number processing. (Adapted from McCloskey,Caramazza, & Basili, 1985.)