Topic of the month....Neuroimaging of posttraumatic stress disorders

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Topic of the month....Neuroimaging of posttraumatic stress disorders

  1. 1. INDEX www.yassermetwally.com  INTRODUCTION  BRAIN REGIONS HYPOTHESIZED AS A PRIORI AS RELEVANT TO PTSD  MRI OF THE HIPPOCAMPUS AND AMYGDAL  FUNCTIONING NEUROIMAGING STUDIES NEUROIMAGING OF POST-TRAUMATIC STRESS DISORDERS We review some of the advances that have been made in understanding the structural, biochemical, and functional neuroanatomy of post-traumatic stress disorder (PTSD). First, we review the primary brain regions that had been hypothesized a priori, from the phenomenology and neurobiology of PTSD, to be implicated in the pathophysiology. Next, we review findings from neuroimaging studies of these brain regions in PTSD and explain the various experimental methods and imaging technologies used in these studies. A broader perspective, including a discussion of additional brain areas that may be involved in PTSD, is synthesized. We conclude with a rationale and approach for studies testing sharply defined hypotheses and those using multidisciplinary strategies that integrate neuroimaging data with other cognitive, biologic, and genetic tools to study this complex disorder.  BRAIN REGIONS HYPOTHESIZED A PRIORI AS RELEVANT TO PTSD  The hippocampus Post-traumatic stress disorder may occur following exposure to situations that induce strong feelings of fear, helplessness, or horror (DSM-IV). One of the core symptoms in trauma survivors with PTSD is a disturbance in memory function [1]. The hippocampus was one of the regions first thought to be implicated in the pathophysiology of PTSD because of its role in both memory and the neuroendocrine response to stress. The first evidence that the hippocampus was involved in memory processing occurred in the late
  2. 2. 1950s with the comprehensive neuropsychological evaluation of patient H.M., who underwent bilateral surgical removal of the medial temporal lobes for treatment of intractable seizures and became unable to acquire new memories [2]. H.M.'s intellectual ability (IQ), immediate memory, knowledge from early life, and personality remained intact, suggesting that memory is a distinct and separable cerebral function. Later, human cases with smaller lesions [3–5] and lesion studies in primates [6–8] confirmed the hippocampus and adjacent cortical areas [9] (i.e., the medial temporal lobe memory system) as essential for declarative memory formation. Declarative or explicit memory entails information that can be recalled and described, such as memories of events, faces, or special layouts [4,10]. Declarative memory is a distinct type of memory that occurs in different brain regions from other types of memory; it includes memories for perceptual and motor skills and other mnemonic processes such as priming, classical conditioning, operant conditioning, habituation, and sensitization. Because the hippocampus is the physical region critical for declarative memory function, one might hypothesize structural abnormalities in the hippocampi of persons with PTSD. In the hippocampi, there is a massive convergence of cortical neurons from various association areas of the brain. Like an old-fashioned central telephone switchboard, the close physical proximity created by this convergence allows for connections to be made. There is a biochemical process by which declarative memories are formed through modification of neuronal connections that is also relevant to the study of PTSD. Hebb was the first to describe memory as the formation of an “assembly of association-area cells,” the synapses of which are more readily traversed by some form of experience-induced synaptic strengthening [11]. Although significant questions remain, it is believed that memories are formed through cellular-level changes in the synaptic coupling between neurons related to an activity-dependent strengthening of that synaptic connection, referred to as long-term potentiation (LTP) [12]. LTP is a form of synaptic plasticity that strengthens the connection between neurons in the formation of networks that constitute an experience, a memory, or learned information. The importance of this concept to PTSD is in providing a putative cellular mechanism that might be disrupted or altered, thereby leading to memory impairments in these individuals, even in the absence of any gross structural hippocampal “damage.” The physical integrity of the hippocampus and the biochemical process of LTP are relevant to PTSD research from a neuroendocrine perspective. Alterations in systemic glucocorticoid (GC) levels (either through direct manipulation or secondary to induced stress) have been shown acutely to interfere with the biochemical processes of LTP and chronically to result in physical damage to the hippocampus [13]. PTSD has been characterized by various alterations in the hypothalamic-pituitary-adrenal (HPA) axis, such as decreased basal and circadian levels of cortisol, decreased urinary excretion of cortisol, increased cortisol suppression following dexamethasone, increased numbers of plasma lymphocyte GC receptors, and hypersecretion of corticotrophin-releasing hormone [14]. Preclinical research has consistently demonstrated that sustained exposure to high GC levels via exogenous GC administration leads to neuronal degeneration confined to the CA3 hippocampal region in rats, tree shrews, and vervet monkeys [15–17]. Increased endogenous GC production as a result of stressful conditions also results in a similar CA3 region hippocampal degeneration in these animals [18–20] and in “dendritic pruning” [21–24]. Neuronal death and dendritic may lead to a similar result in humans under similar high stress and high GC conditions. How GCs mediate neuronal death and atrophy in the above studies is not completely known [13,25]. Possible mechanisms include GC effects of decreasing hippocampal glucose uptake, which may result in lowered ATP stores and heightened vulnerability or “endangerment” to insults [25]; augmenting excitatory amino acid accumulation in the hippocampus [26]; and increasing expression of N-methyl-D-aspartate (NMDA) receptors [27,28]. Increased stimulation of both
  3. 3. NMDA and non-NMDA receptors may result in excitotoxicity, which results from excessive mobilization of cytosolic calcium with overactivation of lipases, proteases, and nucleases and with the generation of oxygen radicals [29]. It is not GCs acting alone but in combination with other neurochemicals that produces dendritic pruning, neuronal atrophy, or neuronal death [13]. Despite our lack of understanding about the exact mechanism through which GCs exert their effects on the hippocampus, there is little doubt that GCs affect not only the physical structure of the hippocampus but also the hippocampus-based mechanism for declarative memory function. Preclinical and human studies have explored the cognitive effects of stress-induced and exogenous increases in GCs on declarative memory function. Healthy subjects given oral steroids display increased errors of commission in verbal memory tasks (incorrectly identifying distractors as target words), impaired verbal declarative memory, and impaired spacial memory (a form of declarative memory) without changes in attention or level of arousal [29–31]. Intravenous infusion of steroids produced impairment in both working memory and declarative memory in healthy subjects [32]. Socially stressful situations, which increase endogenous GC levels, have similar effects on declarative memory [33]. These acute effects of elevated GC levels (either through stress or exogenous administration) on declarative memory are not via death or pruning of hippocampal neurons but rather through directly impairing the biochemical process of LTP. Animal studies indicate that GC concentration has an “inverse-U” relationship to hippocampal activity, with extremely low and high GC levels disrupting hippocampal excitability and LTP [34]. Acute stress and GC receptor stimulation impair LTP in a similar fashion [35–37]. In summary, increased GC levels may interfere with declarative memory through various mechanisms of dendritic pruning, neuronal atrophy, neuronal death, and interfering with LTP. However, most studies find decreased basal cortisol levels and increased negative feedback sensitivity in subjects with PTSD. Several investigators have tried to resolve the apparent paradox. The concept of “allostatic load,” for example, has been forwarded as a possible mechanism for GC-mediated alterations in PTSD [38,39]. Allostasis refers to the ability to achieve stability through change and is crucial for proper functioning of the HPA axis and other systems. Accommodation is viewed as a stress that puts wear and tear on the system, eventually leading to a harmful decrease in the system's ability to adapt to change [40]. Chronobiologic analyses of circadian cortisol levels in PTSD have demonstrated a higher signal-to-noise ratio, which indicates a more finely tuned and responsive system [41]. The greater responsiveness of the HPA axis in PTSD may put larger accommodation stresses on the HPA axis, thereby leading to greater wear and tear. Another hypothesis centers on the role of steroid receptors, which are necessary to mediate the effects of GCs. The concept of negative feedback inhibition has also been used to explain the apparent paradox between low cortisol levels and hippocampal-related alterations in PTSD [14]. Under conditions of an increased negative feedback inhibition, GC-mediated effects on hippocampal structure could occur despite lower ambient cortisol levels. It also is possible that increased GC levels are present during and for an unspecified period following the trauma(s), and after some passage of time, susceptible individuals' feedback sensitivity set-point is changed, which then results in lower GC levels. Hence, from a theoretical perspective, a disruption in hippocampal function as a result of endocrine, metabolic, or other agents that interfere with the biochemical process of LTP or that result in neuronal death or pruning could result in consequences that resemble core clinical phenomena of PTSD, such as psychogenic amnesia and chronically impaired declarative memory function [1]. The hippocampus may be a relevant region in the pathophysiology of PTSD, and for this reason, the hippocampus has been widely studied, as reviewed below.
  4. 4.  The amygdala The severe psychological trauma that is an antecedent to the development of PTSD must result in the survivor experiencing fear, helplessness, or horror (DSM-IV). The individual with PTSD often continues to experience marked fear during intrusive recollections, flashbacks, and nightmares. Individuals with PTSD are often hypervigilant and may show an exaggerated startle response to a variety of unexpected stimuli, particularly loud noises. The amygdala has been implicated in the emotion of fear, fear learning, and control of the accompanying behavioral, autonomic, and neuroendocrine correlates. Some of the first evidence that the amygdala may be involved in fear came from the work of Klüver and Bucy [42] in their primate lesion studies. Wild monkeys that were naturally aggressive and fearful of humans underwent bilateral removal of their temporal lobes (which includes the amygdala, hippocampus, and temporal cortex). This resulted in the monkeys becoming nonfearful and docile. Later animal studies with more limited lesions localized the key structure responsible for these behavioral changes as the amygdala [43]. A remarkable amount is known about fear responding and the processing of auditory stimuli before and within the amygdala through preclinical microlesion studies and through the use of the conditioned fear paradigm. Classical fear conditioning is the process by which a neutral stimulus (the conditioned stimulus [CS]) is paired with a fear-inducing stimulus (the unconditioned stimulus), such as a buzzer paired with a shock, and eventually the original neutral stimulus alone will trigger a fearful response. Fear conditioning seems to be an excellent animal model for what is clinically observed in survivors with PTSD who often respond with fear to an increasing number of triggers, which are conditioned stimuli that have been associated with an unconditioned stimulus (the trauma). One of the best studied fear-conditioning pathways is the auditory pathway. The neuronal path of an acoustic CS is through the auditory thalamus, the medial geniculate body, and then the transmission is split. One part goes to the amygdala and the other to the auditory cortex [44]. The auditory thalamus provides a rapid route to the amygdala, along with imprecise information regarding the signal, whereas the signal to the amygdala from the auditory cortex is received later but is more richly analyzed [45]. Fear conditioning to a single tone does not require the auditory cortex, but this brain region appears necessary for fear conditioning to more complex auditory stimuli [46]. Because the fear response is part of what helps to ensure the survival of the organism in potentially lethal situations, it is of survival value to “act first and think later.” The more rapidly transmitted crude signal may activate the amygdala, and the more later-received cortically processed signal may inhibit amygdala activity. Disruption of either the lateral or central amygdala nuclei interferes with animals' ability to acquire new fears (i.e., fear conditioning is impaired) [47]. Although the particulars are beyond the scope of this review, it is important to understand that different modalities of fear-inducing stimuli may be processed in disparate brain regions, and alterations in these brain areas may differentially affect fear responding or fear conditioning to different types of stimuli. Studies in humans parallel animal findings. Functionally, the opposite of physically lesioning or removing a structure is activating it. Epileptic activity is a pathologic activation that may occur in virtually any brain region. In humans, temporal lobe epilepsy is frequently manifest by sudden episodes of fear and poorly directed aggressive behavior. Humans with temporal lobe lesions show deficits in fear conditioning [48], as do individuals with lesions primarily confined to the amygdala [49]. Such individuals also show impairment in perceiving fear in facial expressions [50] and voices [51]. Individuals with a rare disorder resulting in localized bilateral amygdala damage show the above deficits, and although they are able to understand logically that some situations are risky or will most likely have a negative outcome, they are largely unable to use this information to act accordingly [52].
  5. 5. Functional neuroimaging studies in nonpsychiatric subjects show regional changes in brain activity in response to various tasks. The amygdala is selectively activated in processing negative emotional stimuli [53–55] and in fear conditioning [56,57]. The amygdala is also of interest to the study of PTSD not only because of its involvement in the emotional/behavioral manifestation of fear but also because of the autonomic response. Perhaps one of the most pathognomonic signs of PTSD is the increased startle response (related to fear conditioning). The startle response is thought to give an indication of autonomic excitability and can be measured through various means, such as heart rate, blood pressure, skin conductance, and electromyography. The autonomic response also entails increased activity of the major noradrenergic nuclei of the brain—the locus ceruleus. Survivors with PTSD, as compared with normal control subjects and traumatized subjects without PTSD, have shown increased cardiac, skin conductance, and electromyogram responses to loud tones [58,59]. Anatomically, the amygdala is located immediately anterior to the hippocampi, and numerous reciprocal connections exist between these two structures [60]. In one study with nonpsychiatric participants, subjects were shown neutral and emotionally unpleasant film clips while undergoing imaging of brain function. A greater number of the unpleasant film clips were remembered by the subjects 3 weeks later, and the number of unpleasant film clips remembered was highly correlated with right amygdaloid complex activity [61]. Declarative memory has been investigated in humans with a rare condition that results in selective bilateral amygdala damage. Both subjects showed impairments in long-term declarative memory for emotionally arousing material [52]. In a reciprocal fashion, the hippocampi play a role in fear conditioning and response by providing contextual information to the memory (where, when, and other particulars of an traumatic experience) [62,63]. Data indicate that gender and laterality are important considerations. A recent study found that in females, memory for negative emotional film clips was related to left amygdala activation, whereas the association in the male subjects was found with right amygdala activation [64]. These and the aforementioned data support the hypothesis that the human amygdala normally provides the emotional valence to a memory and also enhances acquisition of declarative knowledge regarding emotionally arousing stimuli. It appears that the amygdala, like the hippocampus, uses LTP. With regard to the amygdala, LTP seems to occur in the thalamo-amygdaloid pathways during the process of fear learning [65–67]. It is of interest how various hormones and neurotransmitters modulate efficacy of LTP in the amygdala as compared with the hippocampus. In summary, numerous reasons exist to posit an overactive amygdala in individuals with PTSD. Conversely, one would not anticipate some structural damage or other biologic effect resulting in decreased amygdala activity in subjects with PTSD. The aforementioned studies highlight the importance of stimulus modality, intensity and specific emotion(s) experienced, laterality, and gender as significant experimental factors. MRI OF THE HIPPOCAMPUS AND AMYGDALA  Qualitative and quantitative magnetic resonance imaging Magnetic resonance imaging (MRI) allows for high-resolution imaging of the brain with excellent white and gray matter differentiation. A powerful magnet is used to align proton nuclei of water in body tissues, which are then knocked out of alignment by a radio pulse. A signal is given off by the proton nuclei as they are reverting back to their original disorder, which will be of differing intensity according to the water content of that tissue (which does differ between white and gray brain matter).
  6. 6. The clinical use of brain MRIs is usually of a qualitative nature; specific features (qualities) are evaluated, such a cortical atrophy, infarctions, or neoplasms. In one study, clinical examination of MRIs from PTSD patients revealed focal white matter lesions in a greater percentage of scans on subjects with PTSD as compared with the healthy control subjects [68]. Another study reported an increased incidence of the developmental abnormality cavum septum pellucidum in subjects with PTSD [69]. Of greater applicability to research is the use of quantitative MRI for accurate and precise measurement of the volume and shape of specific brain regions. Such measurements of specific brain regions allow for testing of various pathophysiologic models of PTSD involving structural or neurodevelopmental alterations. The most commonly applied manual method by which the volume of a brain structure is determined is by looking at successive MRI slices through the structure and tracing its perimeter, often termed a “region of interest.” By multiplying the area of the structure on each slice by the number of slices it appears on by the thickness of each slice, the total volume is easily obtained, or the slices can be “stacked” to create a three-dimensional image. To avoid experimental bias, the following conditions must be adhered to: (1) The person(s) tracing the structure should not know the diagnostic group or subject conditions; (2) subject groups should be mixed and not all of one group traced during one time period and the other group at a later time (even if the tracers do not know which group they are tracing) because systematic changes may occur over time in tracing technique; and (3) MRI scans should be obtained on the same scanner type with identical sequence settings, and identical methods for “slicing” the scans should be used (differences, if present, should at least be balanced between groups). Computer- driven automatic tracing programs and automated methods that use alignment of pixel intensities to assess size and shape change [70] are becoming available and decrease tracer bias.  Quantitative MRI studies in PTSD The first published study of hippocampal volume in PTSD compared Vietnam veterans with PTSD to healthy comparison subjects with no history of combat or trauma exposure. Right hippocampal volume in the PTSD subjects was a statistically significant 8% less than in comparison subjects [71]. This study, however, did not control for combat exposure, which means that it is impossible to say whether group differences were associated with exposure in itself or specifically with PTSD. Furthermore, hippocampal volume was not adjusted for whole-brain volume. A later study controlled for combat exposure by studying Vietnam veterans with PTSD, combat- exposed Vietnam veterans without PTSD, and eight healthy subjects without a history of trauma [72]. This study found a significant bilateral decrease in hippocampal size (approximately 26% between the PTSD subjects and the other two groups) after controlling for brain volume. The key association with hippocampal volume in these subjects was the diagnosis of PTSD, not trauma exposure in itself. Unfortunately, groups in this study showed significant differences in age, education level, and alcohol use (which has been found to be associated with decreased hippocampal size), and subjects were not intermingled in MRI analysis, which may have resulted in subtle systematic differences in volumetric analysis (particularly during manual tracing). Studies of other trauma survivors provide a more ambiguous picture regarding the associations among hippocampal volume, trauma, and symptoms. Hippocampal volume has also been assessed in adult survivors of severe childhood sexual abuse (CSA). The left hippocampal volume in subjects with a history of CSA was 4.9% smaller than the left hippocampal volume in control subjects without a history of CSA [73]. CSA subjects, however, did not all meet PTSD criteria; 71.4% met diagnostic criteria for PTSD, 71.4% met diagnostic criteria for a dissociative disorder, and 28.6% met criteria for both diagnoses. Six of the subjects were experiencing a current major
  7. 7. depressive episode, and association between recurrent depression and smaller hippocampal volume has been reported. Analyses differentiating the effects of CSA history from PTSD diagnosis were not reported. A second study assessed hippocampal volume in subjects with severe CSA histories (all of whom had current PTSD) compared with healthy comparison subjects without a history of CSA. Comparison regions of the amygdala, caudate, and temporal lobe were also used. Left hippocampal volume was 12% smaller in the PTSD subjects, whereas the volumes of comparison structures did not differ [74]. Preliminary results from recent studies have not found differences in hippocampal volume as associated with trauma or PTSD in subjects with personality disorder [75] or in holocaust survivors [76]. Furthermore, because an intact hippocampus is necessary for declarative memory formation, the logical hypothesis is that GC-mediated hippocampal death and atrophy produces a hippocampal lesion leading to effects similar to those observed in the surgical destruction of hippocampal connects. These gross alterations in CA3 and dentate gyrus size are anticipated to result in a smaller hippocampal volume. Therefore, cognitive deficits in PTSD, particularly declarative memory, should be inversely correlated with hippocampal volume (i.e., greater cognitive deficits with smaller hippocampal volume). The aforementioned studies of hippocampal volume in PTSD assessed for this correlation, yet, despite findings of smaller hippocampal volumes, only one study found a correlation between hippocampal volume and memory deficits [71]. These authors reported a significant correlation between deficits in verbal memory (measured by percent retention subscale of the logical component of the Wechsler Memory Scale) and decreased hippocampal volume in PTSD subjects (r=0.64, df=20, P=0.05). This result was for hippocampal volume uncorrected for brain size, which raises questions about the effect of body size. Smaller body size is associated with smaller brain size but could also be correlated with physical vulnerability and social interaction patterns in combat, which deserve investigation in this context. Furthermore, smaller hippocampal and temporal lobe size has been associated with poorer memory performance in non-PTSD groups, so memory performance per mL of tissue may need to be considered. The specificity of the finding needs to be considered. Patients with schizophrenia and their relatives have been reported to have smaller amygdala and smaller hippocampal volume [77], although this may be less marked in first-episode patients [78]. Patients with panic disorder may also have reduced temporal lobe volumes, although Vythilingam et al. [79] found normal hippocampal volume suggesting some distinction within anxiety disorders. None of the aforementioned studies was longitudinal, and none involved prospective scanning before the trauma. As such, any associations cannot be ascribed a causal relationship (e.g., PTSD or trauma resulted in smaller hippocampi). It is equally plausible that smaller hippocampi may increase vulnerability to developing PTSD following a stressor, lower stress resistance, or increase the risk of encountering stress. Studies of twins have suggested that there is a significant genetic contribution to the development of both PTSD and generalized anxiety disorder (GAD) [80] (see review of genetic factors in PTSD and their relationship to HPA axis abnormalities in [81]). In this unreported study using a novel methodology, twins from the Vietnam registry who were concordant (both trauma exposed or with PTSD) and discordant (one with and one without trauma exposure) were compared in various ways. Of most interest was the comparison among the discordant twin of a soldier with combat-related PTSD (i.e., the subject did not have trauma exposure or PTSD but did have a twin who developed PTSD) as compared with the twin of an individual who had combat exposure but who did not develop PTSD (i.e., the subject had neither exposure nor PTSD). The subject who did not have PTSD but who had a twin with PTSD had significantly smaller hippocampal volumes than the twin of the soldier who did not develop PTSD. Because neither of the subject groups had
  8. 8. PTSD or combat exposure, the difference in hippocampal volumes would be most parsimoniously described as antedating the trauma and therefore more of a vulnerability factor. In this study, the actual difference in hippocampal volumes between combat-exposed individuals with and without PTSD was not statistically significant. Recently, a longitudinal study was published in which individuals coming to an emergency room after a psychologically traumatic event were given an MRI of the brain and diagnostic testing [82]. These individuals were tested 6 months later to ascertain who had developed PTSD or still had PTSD, and again an MRI was obtained. The researchers did not find a change in hippocampal volume from baseline in those subjects who had PTSD at 6 months, nor did they find a difference in relative hippocampal volumes between those subjects with and those without PTSD at 6 months. This study had sufficient statistical power to find a difference if it were present to the degree found in earlier hippocampal studies. One possibility mentioned by the authors is that the trauma of these subjects occurred in adulthood. By a developmental hypothesis, trauma in childhood and adolescence may interfere with growth and development of the hippocampus, whereas by adulthood this structure is fully formed, and development of PTSD during the adult years would not result in smaller hippocampal volume via impaired hippocampal development. Another longitudinal study assessed hippocampal and other limbic region volumes in adolescent PTSD subjects and control subjects at baseline and 2 years later. No significant volumetric differences either at baseline or upon rescanning 2 years later were found between groups [83]. Many of the aforementioned studies analyzing hippocampal volume also explored amygdala volume, and none found a significant difference in amygdala volume in subjects with PTSD as compared with traumatized and nontraumatized control groups. Assessing for gross volumetric changes in a structure may be a nonsensitive way to detect many if not most physiologically relevant alterations. It is possible that significant biochemical changes affecting the function of a structure might not be reflected in volumetric changes. Furthermore, supportive and connective cells and other structural elements may maintain the general shape or volume of a structure despite significant changes in neuron number, size, or viability. One way to assess these possibilities is through the use of nuclear magnetic spectroscopy (NMS). Nuclear magnetic spectroscopy uses an MRI-type setup, but instead of focusing on the signal emitted by proton nuclei of H2O, the signal from a variety of molecules such as choline, n-acetyl acetate (NAA), glutamate, and others is detected. NMS provides data about the relative concentration of these molecules. The ability to detect various molecules differs according to how strong and unique a signal they emit, the concentration of the compound, the strength of the magnet, and the software being used. This technology is still in its infancy, and the physics of detecting various compounds is still being worked out, as is the ability to create higher-power magnets that allow detection of more compounds and also the ability to sample a smaller region of the brain. NMS does allow for a “virtual” brain biopsy that provides information on behavioral makeup that used to be obtainable only by taking a physical biopsy of the brain. N-acetyl aspartate is an endogenous substance that is believed to be a marker for neuronal density. In investigating whether the hippocampus is somehow smaller because of neuronal death or atrophy, preliminary studies have assessed the NAA signal from the temporal lobe regions. Present technology makes assessment of the hippocampus (which is a relatively small and complex-shaped structure) extremely difficult, and NAA data are from the temporal lobe as a whole and are not limited to the hippocampi. Schuff et al. [84] compared seven veteran PTSD subjects with seven trauma-exposed veterans without PTSD. The right hippocampus in these subjects was a nonsignificant 6% smaller, but there was a significant 18% decrease in NAA signal from this region. Another NMS study also reported a lower NAA-creatine ratio in the right temporal lobe in PTSD subjects compared with combat control veterans [85]. These findings may
  9. 9. indicate that NMS is a more sensitive technique for detecting hippocampal changes caused by neuronal atrophy or degeneration, which, because of the presence of connective and supportive tissues, may not be accompanied by an equal magnitude of change in hippocampal volume. Future studies with higher resolution and using analysis for additional compounds can be anticipated. FUNCTIONING NEUROIMAGING STUDIES  Functional imaging technologies From what was known of the amygdala in animal studies and models of fear and fear conditioning, an overactivation of the amygdala in subjects with PTSD was a reasonable hypothesis. This was a question of neuronal activity that required the use of “functional” imaging technologies or those that allowed data to be gathered on the functioning of the brain through such measures as regional rate of glucose metabolism, blood flow, and oxy/deoxyhemoglobin concentrations. Furthermore, activity, unlike gross structure, is a rapidly changing measure, so it is necessary to control for this factor through various experimental methods.  Positron emission tomography Positron emission tomography (PET) is a functional imaging technique in which a radioisotope is used to measure glucose metabolism (by using 18flouro-deoxyglucose [18FDG]), blood flow ([15O] H2O), or receptor density (using any of an increasing number of radiolabeled ligands). Decay of the radioisotope produces positrons (antimatter electrons), which travel a short but variable distance (one limiting factor in the ultimate resolution of PET data) before striking an electron. The collision between matter and antimatter results in the release of energy in the form of two gamma rays that have the property of being emitted in opposite directions (180° difference). An array of detectors surrounding the subject's head registers the gamma rays, and, through computer analyses, the origin can be calculated, which, when corrected for distance through the brain it must travel, is used to calculate concentration and location of the ligand. Functional imaging techniques provide a picture of the brain that may integrate a period from 1 minute (such as with [15O]H2O), 30 minutes (such as with 18FDG), or hours (such as with ligands that bind to specific receptors or molecules). [15O]H2O is a tracer that allows a map of blood flow to be made, which is useful because blood flow is highly correlated with regional brain activity (metabolism). 18FDG is taken up by the brain like glucose in proportion to the neuron's energy requirements and gets temporarily trapped inside the cell after being acted on by hexokinase. The technique provides a more direct picture of regional brain metabolism but reflects a longer period of activity (approximately 30 minutes).  Functional MRI Functional MRI (fMRI) uses the basic MRI setup with additional sensing hardware and software modifications. fMRI works on the fact that hemoglobin and deoxyhemoglobin have different magnetic properties. Because of this, the deoxygenated blood acts as a type of in situ tracer. This allows for a measure of cerebral blood flow/metabolism that can detect small changes occurring over very short periods (fractions of a second). Like quantitative MRI, the strength of the magnet is a key variable in how high a spatial resolution can be obtained or over how short a period useful data can be acquired. Because these techniques collect data of rapidly changing brain states, it is important to construct experimental conditions that minimize the number of cognitive or physiologic process that differ between the experimental and control conditions. Functional imaging studies can give information regarding blood-flow and metabolism to a region, but the ultimate explanation of the significance of this is unclear. Most significantly, one region
  10. 10. may serve primarily an inhibitory function; hence, if it is more “active,” it is more actively inhibiting another region(s), and the relationship between these areas and their respective functions is important. An analogy can be made with the human genome. One does not get all the answers by simply knowing the sequence; the useful information resides in the products of the genes, their role in the organism, and their interaction. This is a much more complicated and challenging task.  Symptom provocation One of the first techniques used with functional neuroimaging in the study of PTSD was symptom provocation, which had already been used in the study of other anxiety disorders with an elicitable pathologic response (i.e., obsessive-compulsive disorder and panic disorder). As applied to PTSD, stimuli such as listening to a traumatic script, seeing provocative pictures, or remembering the previously experienced traumatic event often elicit fear, anxiety, flashbacks, and physiologic activation (typically increased heart rate, blood pressure, and skin conductance).  Functional imaging studies in PTSD In a preliminary study, eight subjects with PTSD and high physiologic reactivity to reminders of their trauma were studied using [15O]H2O, which is used to measure cerebral blood flow (CBF). In the traumatic condition, subjects listened to audiotapes of their own accounts of the focal traumas related to their PTSD, whereas subjects in the control condition listened to narratives of neutral life events. Compared with the control subjects, the study subjects showed significantly increased CBF in the anterior cingulate, orbitofrontal, right amygdala, and visual cortex, among other regions. A decrease in CBF was noted in Broca's area [86]. Broca's area is a cortical region found in the posterior superior gyrus of the temporal lobe (on the right side of the brain in the vast majority of individuals) that is involved with language production. Lesions to this area most commonly occur secondary to stroke and result in an inability to put one's thoughts into words (Broca's aphasia). A hallmark of PTSD is the survivor's extreme difficulty in giving a coherent verbal account of the focal trauma. The authors commented that visual cortex and paralimbic activation was similar to the fear response in provocation studies of other anxiety disorders. Activation of these areas optimizes resources for response to a threatening situation; therefore, it was hypothesized that verbal abilities during a crises were of secondary importance (hence, the deactivation of Broca's area). Furthermore, a symptom of PTSD is usually the inability of the patient to give an integrated and coherent verbal description of their trauma. This was also the first study of an anxiety disorder in which amygdala activation was found. The lack of a control group made it impossible to determine to what extent the findings were part of a pathologic response to trauma. A later study by this group used the autobiographic script for traumatic activation (all subjects experienced CSA), but this time approximately half the subjects did not have PTSD, and therefore the effects of trauma versus PTSD per se could be controlled for [87]. As compared with control subjects, those with PTSD showed a greater decrease in Broca's area CBF and significantly larger increases in CBF in the orbitofrontal and anterior temporal regions. The medial prefrontal cortex inhibits the excitatory output of the amygdala in animals, whereas in humans, equivalent regions serving this role are thought to be the medial orbitofrontal cortex and the anterior cingulate gyrus. Therefore, decreased activity in these brain regions could have a disinhibiting effect on the amygdala and again result in an increased fear response through inadequate response inhibition. A process counteracting the effects of fear conditioning is extinction. If the neutral stimulus is no longer paired to the fear-inducing stimulus, the normal animal will show a gradual fading away of the fearful response with successive repetitions of the
  11. 11. neutral stimulus alone. A clinical example of the failure of extinction is a PTSD patient's continued fearful response to various triggers that are reminiscent of the traumatic stressor even after extensive experiences after the traumatic event have presented the traumatic stimulus without the fearful condition (i.e., the veteran feeling terror at the sound of a helicopter more than 30 years after combat and during these 30 years hearing helicopters without being in any physical danger). Like the amygdala, these regions are not known to be structurally damaged by any common neuroendocrine alteration. In the aforementioned study, the anterior cingulate, the area that inhibits amygdala activation, showed a greater CBF increase in response to the traumatic condition in the control subjects as compared with the PTSD subjects. The authors hypothesized that the inability to adequately recruit this structure for the inhibition of amygdala activity may be an important aspect of the pathophysiology of PTSD. This later study did not find amygdala activation in the traumatic condition, and the authors bring up an important consideration: In the second study, the survivors of childhood sexual abuse reported experiencing primarily anger, disgust, and sadness, whereas subjects in the first study reported primarily fear and anxiety. Furthermore, because of the small size of the amygdala, the power for detection of significant differences in activation may be significantly less than other larger brain regions. A SPECT study, using [99mTc]HMPAO in combat veterans with PTSD, combat control subjects, and normal control subjects, found anterior cingulated/middle prefrontal gyrus activation in all groups following hearing tape recordings of combat sounds. Only in the PTSD group was activation of the left amygdala/nucleus accumbens found [88]. Examination of correlations between flashback intensity and CBF during the experience demonstrated positive correlations with the hippocampus, insula, putamen, somatosensory, and cerebellar regions and negative correlations with the prefrontal cortex, fusiform, and medial temporal cortices [89]. Decreased cortical and increased thalamic blood flow during an intense flashback was also seen in a single patient study [90] and suggests a thalamocortical mechanism; thalamic involvement in startle response was seen in a recent fMRI activation study [91]. Fernandez et al. [92] imaged a patient with torture-related PTSD before and after treatment with fluoxetine. Before treatment, trauma reminders resulted in decreased rCBF in the insula, prefrontal, and inferior frontal cortices consistent with the Osuch et al. [89] and Fernandez et al. [92] studies. Increased activity was evident in the cerebellum, precuneus, and supplementary motor cortex. This pattern was normalized after SSRI administration. Another symptom provocation method in PTSD involves presenting startling auditory stimuli and observing heightened eye-blink and skin conductance response [93,94] or even reduced reactivity in chronic stress [95]. Because startle activates orbitofrontal cortex (a target area for PTSD symptoms) in fMRI [91] and FDG-PET [96] studies, this provocation method may be useful in PTSD imaging studies.  Cognitive activation studies Cognitive neuroscientists studying basic elements of various cognitive processes in normal brain function pioneered activation paradigms. In this technique, an experimental and a control task differ in one element, and subjects undergo functional imaging in each condition. The image in one condition is subtracted from the other, presumably revealing the differences in regional brain activity between the two conditions. Studying one group of essentially identical subjects can provide information on the differences between conditions. Studying a control and experimental group in the two conditions can provide information on differences in regional brain activity as a function of condition, group, and group-by-condition interaction. In studying a disorder such as PTSD, one would pick a cognitive task that activates a system believed to be abnormal (e.g., attention, processing of emotional stimuli, etc.). One group studied PTSD in six male veterans (five
  12. 12. with alcohol abuse) and acquired data during conditions of baseline, a continuous perfomance task, and a verb generation task to evaluate brain activity as related to attention, reaction time, response selection, and language/speech production. PET data on regional cerebral blood flow (rCBF) were collected using 15O and published in two reports [97,98]. As compared with the control group, the PTSD group showed a reduced left-to-right ratio of rCBF in the hippocampal region and greater orbitofrontal cortex activation. On the continuous performance task, which measures attention and reaction time, the PTSD group made more errors on the task and showed less activation in parietal cortex. The abnormal functional asymmetry for the hippocampal regions found in these studies may parallel some of the earlier reported findings of smaller hippocampal volumes. Alcohol use in the subjects limits the generalizability of the findings. Because the control group was not traumatized, it is also not possible to know if these differences were associated with trauma alone or actual PTSD. A later [15O]H2O study addressed these methodologic problems by using subjects without alcohol dependence and controlling for combat exposure by studying 14 veterans, all of whom were combat exposed but only seven of whom had PTSD [99]. Six conditions were studied: viewing pictures and imagining neutral, negative, and combat related material. Group-by-condition analyses showed that only the PTSD group showed a significant rCBF increase in the combat versus neutral condition in the anterior cingulate and right amygdala and decreased activation in Broca's area in the combat versus negative condition. A methodologic problem in all such activation studies is the problem that the combat or fear-inducing material does not have an equal psychologic impact in both groups. This is to be anticipated to some extent because reacting with intense fear or having a flashback upon exposure to traumatic triggers is a criterion for PTSD. It is unclear if the differences reported in such a study are related to the degree of fear (and would therefore be observed in the control group if the stimulus was strong enough) or if they are unique to PTSD pathophysiology. To address the question of the amygdala's native reactivity, a novel method for selective activation of the amygdala that does not activate the usual inhibitory anterior cingulate was used with fMRI in combat-exposed veterans with and without PTSD. In this masked-faces method, neutral and fearful faces are shown briefly to the subject and are followed by a neutral face (mask). The subject is only consciously aware of seeing the mask, but the amygdala, which receives input directly from the thalamus, is able to register the “danger/fear” without inhibitory influences from the anterior cingulate gyrus. PTSD symptom severity correlated with amygdala activation, and the PTSD group showed greater amygdala activation as compared with the combat control subjects [100]. This argues for a state of amygdala hyper-responsivity in PTSD, even without diminished anterior cingulate inhibitory activity. Consistent with this, Semple et al. [101] found higher brain blood flow in the amygdala in PTSD patients than in normal subjects, although cocaine addiction in these subjects limits generalizeability of the findings. Evidence for amygdala hyper-responsivity in stress-related memory dysfunctions is also presented in a PET case study of a psychogenic amnesic patient who showed amygdala activation during a facial memory test, whereas control subjects showed only hippocampal activation [102].  Pharmacologic challenges This paradigm involves a pharmacologic agent that produces an effect on a brain system or region that is believed to be implicated in the pathophysiology of a disorder. The effect in the control is compared with the experimental group with regard to changes in blood flow or glucose metabolism. As opposed to symptom provocation, which in the case of PTSD activates a myriad of endocrine, biochemical and autonomic events, the pharmacologic challenge may be used as a way to pharmacologically dissect the separate components of the response or systems. Pharmacologic challenges can be paired to any neuroimaging technique that provides a functional picture of the brain but is most frequently used with PET.
  13. 13. Yohimbine is an ?2 receptor antagonist that increases noradrenergic discharge. In one study, yohimbine was used as a probe to assess whether individuals with PTSD have greater autonomic/noradrenergic reactivity [103]. Ten combat veterans with PTSD and ten normal control subjects were administered yohimbine and shortly thereafter underwent 18FDG PET scanning. The PTSD subjects had a significantly higher incidence of flashbacks and panic attacks in response to the yohimbine. The authors found that the PTSD group exhibited a widespread decrease in cortical metabolism. Prior studies indicated that, at higher concentrations, noradrenaline decreases rCBF, whereas CBF is increased at lower an intermediate noradrenaline concentrations. One might ask why the locus ceruleus, the primary nucleus for noradrenergic neurons in the brain, was not differentially activated. The findings from this study suggest that it was, and one would anticipate that the greatest effects of norepinepherine release are to areas to which locus ceruleus neurons project (not within the structure itself). The authors interpreted their findings as an indication that noradrenergic activity is heightened in PTSD. Of course, such a bimodal response makes interpretation of the results difficult. Nonetheless, this is consistent with a model of inadequate activity in cortical regions paired with limbic overactivation. Central sensitivity to GCs in PTSD is currently being assessed by studying changes in memory function and regional glucose metabolism using 18FDG following a hydrocortisone challenge. GCs cause a decrease in cell-surface glucose transporters, presumably paralleling the sensitivity of the GC receptors to steroids. Because 18FDG looks like glucose to the neuron, one can measure to what extent GCs inhibit the uptake of 18FDG. In preliminary analyses, we found that the PTSD group, as compared with the non-PTSD control group, showed a greater decrease in glucose uptake in the hippocampal regions following hydrocortisone [104]. Although preliminary, these findings lend support to the hypothesis of increased central GC sensitivity in PTSD. We will also be able to analyze this data in comparison to psychological testing results obtained after the hydrocortisone-versus-placebo challenge.  Radioligand studies By using a cyclotron, radiochemists can create isotopes of various elements and then incorporate them into a ligand. A variety of radiolabeled compounds can be designed to have specific affinities for various neuronal receptors, binding sites, or other targets. In conjunction with a PET scanner, the ligand acts as a tag and can provide such useful information as receptor numbers, location, and affinity. The GABA receptor is comprised of various combinations of subunits, on one of which a benzodiazepine binding site is located. GABA is the main inhibitory neurotransmitter of the brain, and, as such, it would be of interest if there were some alteration of this receptor in subjects with PTSD. One PET study used a radioligand for the benzodiazepine binding site with PET scanning and found decreased binding in the frontal cortex of PTSD subjects [105]. DISCUSSION Quantitative MRI studies of hippocampal volume in subjects with PTSD have shown mixed results. The majority of studies report a smaller hippocampal volume in PTSD subjects, but negative findings are less frequently published. Recent preliminary reports from well controlled studies with adequate power have not found significant differences in hippocampal volume. Association does not imply cause and effect, and the possibility that smaller hippocampal volume is a vulnerability factor for the development of PTSD following a trauma is just as plausible. Three other possible relationships between smaller hippocampal volume and PTSD have been enumerated [106]. Longitudinal studies can address this issue, and two published studies (one in adults, the other in adolescents) did not find any significant changes in hippocampal volume either
  14. 14. at baseline or at 2-year follow-up in control and PTSD subjects. Factors such as longer follow-up time, age at which the focal trauma was sustained, duration/severity of PTSD symptomatology, and neurodevelopmental period of symptom evolution have not been adequately studied. Hippocampal volumetric changes may be one of the measures least sensitive to the type of alterations or dysfunction that may be present in subjects with PTSD. Preliminary studies of NAA signal using NMS indicate a decreased number or integrity of temporal lobe neurons. Advances in both magnet strength and computer software are anticipated to increase sensitivity, spatial resolution, and the number of compounds that can be assayed through this noninvasive technique. Studies of excitatory (primarily glutamate) and inhibitory (primarily GABA) neurotransmitter concentration and location would be relevant. Functional neuroimaging studies are beginning to show certain consistencies and have been synthesized to form the constellation of a hyper-responsive amygdala and associated limbic structures leading to heightened fear-conditioning, fearful response, and emotional learning, in conjunction with a hypoactive anterior cingulate area that fails to properly inhibit amygdala activity [107]. Decreased hippocampal function may impair the process of habituation or extinction of the fearful response and may also lead to increased tendency for stimulus generalization secondary to a decreased in contextual constraints that the hippocampus usually may supply. Longitudinal studies and twin studies would be of great use in understanding the progression, causal relationships, and genetic contribution of these findings. Radioligand studies are in their infancy, but with the availability of a cyclotron and experienced radiochemists, a great number of selective ligands should be possible to synthesize. Because PTSD is perhaps the paradigmatic example of a disorder involving the complex interaction of genes and environment, a deeper appreciation of this syndrome will require longitudinal studies (which are best for sorting out cause-and-effect relationships) and investigations that use a combination of modalities. The reason for the latter is that in the analysis of a complex system, each additional modality of information provides a synergistic rather than merely additive value to the data obtained. Such multidisciplinary or multimodal approaches may combine, in various ways, structural, functional, and ligand neuroimaging, NMS, pharmacologic challenges, neuropsychological testing, symptom provocation, cognitive activation, and naturalistic and genetic data in the effort to understand interactions between these systems that increase or decrease vulnerability or expression of particular signs or symptoms of PTSD. As technology and methods improve, it is likely that additional brain regions will be found to be relevant to the pathophysiology of this complex disorder. References [1]. Golier J, Yehuda R. Neuropsychological processes in post-traumatic stress disorder. Psychiatr Clin N Am. 2002;25:in press [2]. Scoville W, Milner B. Loss of recent memory after bilateral hippocampal lesions. J Neuropsychiatry Clin Neurosci. 2000;12:103-113 [3]. Reed JM, Squire LR. Impaired recognition memory in patients with lesions limited to the hippocampal formation. Behav Neurosci. 1997;111:667-675 [4]. Squire LR. Memory and the hippocampus: a synthesis from findings with rats, monkeys, and humans. Psychol Rev. 1992;99:195-231
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  22. 22.  To download the current version of topic of the month publication follow the link quot;http://neurology.yassermetwally.com/topic.zipquot;  You can also download the current version of topic of the month publication from within the publication or go to my web site at: quot;http://yassermetwally.comquot; to download it.  At the end of each year, all the publications are compiled on a single CD-ROM, please author to know more details.  Screen resolution is better set at 1024*768 pixel screen area for optimum display  For an archive of the previously published topics in downloadable PDF format go to http://yassermetwally.net, then under pages in the right panel, scroll down and click on the text entry quot;topic of the monthquot;  In order to view a list of the previously published topics in downloadable PDF format, follow the link: http://wordpress.com/tag/neurological-topic-of-the-month/ The author: Professor Yasser Metwally, professor of neurology, Ain Shams university, Cairo, Egypt  www.yassermetwally.com

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