Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

Developmental perspectives is the fetus conscious


Published on

Developmental perspectives is the fetus conscious

  • Login to see the comments

  • Be the first to like this

Developmental perspectives is the fetus conscious

  1. 1. Developmental Perspectives: is the Fetus Conscious? Roland Brusseau, MD, FAAP Children’s Hospital Boston Boston, Massachusetts Advances in prenatal care, including diagnostic studies and imagingtechniques, have allowed many serious anatomic fetal anomalies to beidentified in earlier gestation, affording the possibility of fetal therapyand treatment before irreversible damage occurs. Although theanesthetic management for these fetal interventions often depends onthe type of fetal lesion involved, it has been accepted practice to provideanesthesia and analgesia to both the mother, via maternal generalanesthesia and maternal analgesic administration, and to the fetus, viaplacental transfer.1 The general anesthesia and analgesia provide idealsurgical conditions, minimize pain for the mother, reduce the fetal stressresponse, and may potentially ameliorate fetal pain.2 However, thedevelopment of minimally invasive techniques for fetal interventionhave called into question the need to provide any maternal anesthetic atall and, by extension, any fetal anesthetic. This has brought the questionof the potential for fetal pain to the fore.3,4 Although discussions of fetal pain are complicated and controversial,there is little disagreement about the capacity of the fetus to generate aphysiochemical stress response from early gestation. Indeed, humanfetal endocrine responses to stress have been demonstrated from asearly as 18 weeks gestation.5 Such a response to nociceptive stimuli inand of itself would not seem to qualify as a fetal experience of pain. Pain,according to the International Association for the Study of Pain, is anunpleasant sensation which may be associated with actual or potentialREPRINTS: ROLAND BRUSSEAU, MD, FAAP, DEPARTMENT OF ANESTHESIOLOGY, PERIOPERATIVE AND PAIN MEDICINE,CHILDREN’S HOSPITAL BOSTON, 300 LONGWOOD AVENUE, BOSTON, MA 02115. E-MAIL: ROLAND.BRUSSEAU@CHILDRENS.HARVARD.EDUINTERNATIONAL ANESTHESIOLOGY CLINICSVolume 46, Number 3, 11–23r 2008, Lippincott Williams & Wilkins 11
  2. 2. 12 ’ Brusseautissue damage, possibly including physical and emotional components.6Pain is clearly a subjective phenomenon—one that typically accompaniesnociception—but can also arise without any nociceptive stimulus.Nociception, on the other hand, is a neurophysiologic term and denotesspecific activity in nerve pathways. It functions as the transmissionmechanism for physiologic pain, but does not necessarily subserve ordescribe psychologic pain states.7 Pain, as a subjective phenomenon, would seem to require somedegree of conscious activity to separate it from simple nociception and itsconcomitant stress response. Some sort of integrating process, orprocesses, is required to render noxious stimuli into a form ofcoordinated experience. Therefore, an investigation of the generationof fetal pain states may itself serve as a surrogate for an investigation ofconsciousness, or at least the implied possibility of consciousness. Butsimply to demonstrate the possibility of fetal pain is not a satisfactorycriterion for establishing fetal consciousness—clearly one can haveconsciousness without pain but the concept of pain occurring withoutconsciousness would seem to run contrary to our current understandingof pain as a subjective experience. Therefore, a discussion of conscious-ness itself is mandated if we are to suggest that there is such aphenomenon as fetal pain. Subsequently, further investigation of fetalpain may indeed cast light back on some of the mysteries of thedevelopmental aspects of consciousness and help us to appropriately askand then perhaps answer the query: is the fetus conscious?’ Cortex, Subcortex, and Consciousness Working some 5 decades ago, Penfield, a neurosurgeon, and Jasper,a psychologist, demonstrated that the consciousness (as traditionallyunderstood) of some 750 patients undergoing radical cortical excisionsremained continuous and unimpaired both during and after theprocedures. Certain discrete cortical functions might be lost orimpaired, but consciousness remained.8 This led to a critical insight:that the highest integrative functions of the brain are not organized atthe cortical level, but rather within a divergent system of subcorticalstructures that process cortical and subcortical inputs. Subsequently,Jasper found that consciousness might be disrupted in a manner typicalof certain generalized seizures—not by cortical stimulation but rather byexperimental stimulation of the midline thalamus, producing a changefrom the usual adult electroencephalogram (EEG) to the familiar spikeand wave pattern of the absence seizure, suggesting that some form ofconcordant EEG rhythm, or rhythms, is necessary to support theconscious state.9 Consciousness, in their view, at minimum requirescertain (largely subcortical) structures and some form of coordinatingrhythm or rhythms.
  3. 3. Developmental Perspectives ’ 13 Asking a similar question about the minimal requirements forconsciousness, Merker10 cited the example of a common jellyfish, thecubomedusa or Sea Wasp. The cubomedusa serves an example of aprimitive neural network—essentially a group of semi-independentpacemakers with no cephalization or centralization. These pacemakersallow the cubomedusa to respond with directional locomotor responsesto asymmetric sensory inputs. But, Merker asks, is the cubomedusaconscious? He concludes that there is no reason to believe that whatamounts to the environmental guidance system provided by this neuralnetwork involves, or generates, an experience of any kind. But where inthe spectrum of possibility between the cubomedusa and the awakesurgical patients of Penfield and Jasper may we identify a rubicon ofconsciousness? What are the minimal criteria for consciousness? Whatmight a fetus require to be capable of consciousness? Hameroff11 suggests that consciousness, in its most basic form, maybe considered equivalent to a ‘‘minimal awareness’’ without a require-ment for memory, cognition, or organizational sophistication. This iscertainly more rudimentary than the phenomenal consciousness weenjoy in wakefulness. However, Hameroff argues, the interestingquestion lay not in discriminating degrees of self-referential cognition(such as differentiating between human and chimpanzee) but rather inilluminating the distinction between consciousness (understood asminimal awareness) and nonconsciousness. This is the importanttransition. Just as with the eye, where the development of photosensitivepigments that transduce light energy into neural signals is the criticaldevelopment in the natural history of vision,12 here the critical step ingenerating consciousness is bridging the gap between the individualneuron (and concomitant neuroprocessing) and conscious experience.Essentially the brain’s neural networks subdivide processing intomodalities (visual and tactile) and submodalities (temperature andcolor) while perceptions are integrated and unified.13 It is out of suchintegration, it would seem, that conscious states become possible. Recalling Merker’s jellyfish, then, what apparently disqualifies thecubomedusa from participation in conscious states is not so much itssimplicity but rather its lack of specific structural arrangements requiredto support conscious function. It does not integrate or unify subproces-sing modalities; it exists by reflex arc. This, however, raises a question: ifcoordination of such subprocessing is essential to the generation ofconscious states, is its interruption essential to the generation ofunconscious states? Jasper’s induced thalamic seizures certainly suggestsuch, and anesthetics provide further insight. Anesthetics have long been acknowledged as reversible suppressorsof consciousness (as well as memory and movement), yet the mechan-isms of such remain unclearly understood. Although the traditional viewhas been that anesthetics blunt neural function globally, recent evidence
  4. 4. 14 ’ Brusseausuggests that like the unconsciousness of the generalized seizure, theanesthetized brain is anything but silent. Isoflurane has been shown toinhibit pattern recognition (an integrating function) but not componentrecognition, suggesting that subprocessing modalities remain intactwhereas integration fails.14 Indeed, multiple anesthetics have demon-strated electrical uncoupling of rostrocaudal and intrahemispheric brainregions15 and caudorostral information transfer.16 It is not clear,however, whether anesthetics interrupt subcortical integratingfunctions. Certainly, in the fetus or preterm neonate there is currentlyno significant evidence that anesthetics do, or do not, disrupt subcorticalunities. Currently available technologies limit investigation of thisquestion. Nevertheless, the bulk of evidence from anesthesia demon-strates that, as is the case with the cubomedusa, the brain is not silent—itis simply not connected. As such, and in agreement with Penfield andJasper, it would seem that the presence of certain structures andconcordant rhythms become a sort of minimum requirement forconsciousness. Indeed, the very subcortical and cortical structures thatPenfield and Jasper suggest are involved in the generation of consciousstates, and their inherent electrical rhythms, are known to be presentin the term neonate and their development during fetal life is welldocumented.’ Fetal Neurodevelopment I: Structures and Rhythms The development of the human brain and spinal cord begins asearly as the third postconceptual week, when the neural tube formsfrom neuroectoderm. Neural crest cells migrate out laterally to formperipheral nerves from 4 weeks, with the first synapses between themforming a week later. Synapses within the spinal cord begin to develop at8 weeks gestation, suggesting the first spinal reflexes may be presentfrom roughly 8 weeks forward.17 Between 8 and 18 weeks gestation isthe time of maximal neuronal development. After neural proliferation,synaptogenesis occurs, first in peripheral structures and then morecentrally. Cortical development initiates from the subplate zone,developing connections to both the thalamus and the neocortex.Intensive differentiation of these neurons occurs between 17 and 25weeks gestation, a process that is at least partly dependent on sensorystimulation.18 The development of the nociceptive apparatus proceeds in parallelwith basic central nervous system development. The first essentialrequirement for nociception is the presence of sensory receptors, whichdevelop first in the perioral area at around 7 weeks gestation. Fromhere, they develop in the rest of the face and in the palmar surfacesof the hands and soles of the feet from 11 weeks. By 20 weeks, theyare present throughout all of the skin and mucosal surfaces.19 The
  5. 5. Developmental Perspectives ’ 15nociceptive apparatus is initially involved in local reflex movements atthe spinal cord level without supraspinal integration. As these reflexresponses become more complex, they, in turn, involve brainstemstructures, through which other responses, such as increases in heartrate and blood pressure, are mediated.20,21 The thalamus is the structure responsible for relaying afferentsignals from the spinal cord to various subcortical structures and thecerebral cortex itself.22 Thus, if integrative thalamic function isnecessary for nociceptive perception (ie, pain) or any other higherorder sensory perception as the work of Jasper suggests, arguably itcannot be until the thalamocortical connections are formed andfunctional that the fetus may first attain something approachingHameroff ’s rudimentary consciousness. The thalamus is first identifiedin a primitive form at day 22 or 23 postconception. Its connections growout in phases, initially only as far as the intermediate zone of the cerebralwall, collecting below the cortical plate. Stimulation of the subplate zonesby thalamic neural connections stimulates aspects of cortical develop-ment. As such, thalamic development largely precedes significantcortical development. The final thalamocortical connections are thoughtto be in place by around 26 weeks, although estimates differ.23 In fact,there are thought to be transient cholinergic neurons with functioningsynapses connecting the thalamus and cortical plate from approximately20 weeks.24 This time point could be taken as the absolute earliest timein gestation when a fetus could be aware of nociceptive stimuli, or to feelpain—provided there is some degree of functional maturity in additionto this structural maturity. As suggested by Jasper, the link between consciousness and electricalactivity within the brain can be measured and patterns defined using theEEG. The presence of EEG activity would confirm a degree of functionalmaturation in addition to structural maturation described above.Although sporadic electrical activity has been detected in the fetal brainas early as 43 days gestation,25 more coordinated electrical activity (inthe form of intermittent bursts) has been shown to be present in thebrainstem from 12 weeks, and the later-developing cerebral hemi-spheres at 20 weeks. Before 25 weeks, the electrical activity on EEGrecordings is discontinuous, with periods of inactivity lasting up to 8minutes. From 25 to 29 weeks, the periods of activity increase, such thatby 30 weeks, although EEG activity is still not continuous (indeed, insome infants, it does not become continuous during quiet sleep untilseveral weeks after term), distinct patterns of wakefulness and sleep canbe recognized as the precursors of adult patterns.26 Nevertheless, it is arguable when electrical activity in the fetal brainfirst becomes indicative of a state of consciousness or at least thepossibility thereof. If we require a cortical contribution to the generationof conscious states, then the lack of cortical electrical activity detected
  6. 6. 16 ’ Brusseaubelow 20 weeks sets the lowest possible limit. Given that corticalelectrical activity at this time is exceedingly discontinuous, 20 weekswould seem a very liberal estimate. Should greater continuity of corticalelectrical activity be required, 30 weeks gestation may represent a morereasonable threshold. However, if one were to argue that a minimalform of consciousness might be possible without cortical involvement,then certainly one would have to consider thalamic development as abenchmark for the possible generation of such a state. As describedabove, thalamic structures seem to be in place somewhere between 20and 30 weeks. However, the paucity of evidence demonstratingcontinuous and coordinate thalamic electrical activity makes such adistinction difficult. Nevertheless, the later-developing cortex does allowelectrical interrogation and as such allows indirect evidence of thalamicfunction. Cortical electrical activity suggests intact thalamic function andas such implies that thalamic electrical maturation is at least con-temporaneous with the cortex, and indeed likely precedes corticaldevelopment in this functional regard, as is also the case with itsstructural development. Other evidence, however, points to a muchearlier maturation of thalamic processing function. Thalamic connec-tions are intimately involved in the generation of the physiochemicaland endocrine responses to nociception that are seen as early as 18weeks.20,27 This line of evidence would suggest an earlier threshold forthe possible development of consciousness. In general, however, by 34weeks electrical activity is seen throughout the brain approximately 80%of the time.28 As periods of continuous electrical activity graduallylengthen, it would seem likely that no sudden event marks thebeginning of consciousness but that as the gaps between periods ofelectrical activity gradually shorten, consciousness emerges incrementally.’ Consciousness Without a Cortex Returning to the notion that pain may function as a surrogatemarker for consciousness, inasmuch as an experience of pain pre-supposes at least a minimal degree of consciousness, clinical data mayallow us further insight into the structures and functionalities requiredfor conscious perception. This, in turn, may offer greater insight into thepossibility of fetal consciousness. Consider the possibility that a cortex isnot required at all—what could this tell us about the generation of painstates, and their consequential states of consciousness, in the uterinefetus? In keeping with the critical insights of Penfield and Jasper,clinical evidence suggests that either ablation or stimulation of theprimary somatosensory cortex does not alter pain perception in adults(demonstrated by Penfield and Jasper themselves), whereas boththalamic ablation and stimulation have been shown to interrupt pain
  7. 7. Developmental Perspectives ’ 17perception. Chronic deep brain stimulation of the periventricular gray(PVG) for treatment of chronic pain states clearly demonstrates thelatter point. Stimulation of the PVG that leads to clinically observed painrelief has been shown to attenuate field potentials in the ventroposter-olateral thalamic nucleus for the duration of the stimulation; PVGstimulation that fails to provide pain relief similarly has been shown tofail to attenuate these thalamic field potentials.29 In keeping with thisevidence, we should consider that if cortical activity is not a prerequisitefor pain perception in adults, then by analogy neither would it be anecessary criterion for fetuses. Further, if cortical function is notnecessary for pain perception, then it may not be required for thegeneration of conscious states. Perhaps subcortical structures, includingthe thalamus, are necessary and sufficient to support at least a minimalform of consciousness. As previously discussed, fetal development of thethalamus occurs much earlier than the sensory cortex, but functionalevidence for thalamic sensory processing is currently lacking. Never-theless, significant cortical activity may be demonstrated as early as 28weeks in preterm neonates exposed to tactile or painful stimuli,30suggesting a degree of thalamic function before full gestation and, byextension, implying the possibility of fetal conscious perception by thatgestational age; whether such is possible before 28 weeks, with orwithout cortical contribution, remains an open question. Clinical evidence for conscious perception mediated by such asubcortical system comes from infants and children with hydranence-phaly. These children are born with minimal or no cortical tissue, yethave intact and functional subcortical structures.31–33 Despite the totalor near-total absence of cerebral cortex, these children clearlydemonstrate elements of consciousness: discriminative awareness(including the ability to distinguish familiar from unfamiliar peopleand environments), appropriate social interaction, functional vision,orienting, apparent musical preferences, appropriate affective re-sponses, and associative learning.34 Indeed, many of these childrenare not diagnosed as newborns, as their behavior patterns are oftenindistinguishable from those of unaffected newborns. It is important tonote that these are not hydrocephalic children who possess a thin rim ofintact, functional cortex but rather children with little or no cortex at all,resulting from in utero cortical infarcts that were subsequentlyreabsorbed. What little cortex may remain is generally nonfunctionaland without normal white matter connectivity.35 As such, it would seem these children demonstrate that anatomicdevelopment or functional activity of the cortex may not be required forconscious sensory perception. They may, and do in fact, respond topainful or pleasurable stimuli in what may easily be argued to be aconscious, coordinated manner, similar to intact children.36 Otherevidence for such a subcortical machinery of consciousness may be
  8. 8. 18 ’ Brusseauderived from preterm neonates or adolescents with parenchymal braininjury who have impaired cortical function, yet mount physiochemicaland behavioral responses to pain that are indistinguishable from thoseof unimpaired controls.37,38 Also, patients in persistent vegetative statespresent evidence for the conscious perception of self and environ-ment,39 including the capacity to experience pain.40 Perhaps notsurprisingly, recovery from vegetative states has been shown to beassociated with the restoration of the connectivity of thalamocorticalnetworks,41 again documenting the critical roles of the thalamus andsubcortex in the generation of conscious experience. The neurologic phenomenon of blindsight provides further insightinto the subcortical mechanisms of consciousness. Blindsight occurs inhumans (and has been reproduced in monkeys) when there is extensivedamage to cortical area V1, which produces a hemianopsia.42 In atypical case, the patient can indicate, well above chance level, thedirection of movement of a spot of light over a certain range of speed—all the while denying that he or she sees anything at all. Other patientscan distinguish large, simple shapes, or colors. What is remarkable aboutthis phenomenon is that the patient is, in fact, seeing, but simply is notaware of it. As was the case with acortical pain states, there seems to beno prerequisite for cortical function to produce this discrete, limitedconsciousness. Recent functional magnetic resonance imaging of theblindsight patients directly implicates the superior colliculus as beingactive specifically when such patients correctly discriminate the directionof motion of some stimulus without being aware of it at all.43 Similarevidence for the role of subcortical processing in conscious sensoryperception comes from the related Sprague effect described in cats.44Complete removal of the posterior visual areas of one hemisphererenders the affected cat profoundly and permanently unresponsive tovisual stimuli in the field contralateral to the lesion; however, infliction offurther damage at the midbrain level—particularly at the superiorcolliculus—restores the animal’s ability to orient and localize stimuli inthe formerly blind field.45 Notably, analogous correction of the neglectcaused by frontal cortical damage has been observed in human patientsafter midbrain damage on the opposite side.46 The Sprague effect isthought to be a brainstem-level consequence of unilateral corticalinactivation, likely due to unbalanced cortical input leading tounbalanced inhibitory inputs at the level of the superior colliuculus.47The secondary brain stem lesioning is thought to correct this latterimbalance at least partially, allowing the superior colliculus and relatedstructures to resume their usual contribution to functional behavior.48,49It would seem that the superior colliculus, either by itself or inconjunction with other subcortical structures (eg, the thalamus), iscapable of independent off-line processing and functionality that mayparticipate in a sort of minimal awareness.
  9. 9. Developmental Perspectives ’ 19 Blindsight aptly demonstrates what has been described as a sort ofoff-line consciousness (a consciousness with only minimal awareness, asdescribed by Hameroff, but a form of consciousness nevertheless) that isdistinct from mere reflex; the patient with blindsight is seeing, butsimply is not aware of it. This exists in distinction to what would be anon-line consciousness—which more aptly describes our subjectiveexperience of wakefulness. This has led to the philosophical constructof the zombie, a creature who is supposed to act just as normal peopledo but who is completely unconscious.50 Odd as this construct maysound, there is now suggestive evidence that part of the brain doesbehave like a zombie, such as was the case with blindsight. That is, insome cases, a person uses the current visual input to produce a relevantmotor output, without being able to say what was seen.51 There isanecdotal evidence from sports. It is often stated that a trained tennisplayer reacting to a fast serve has no time to see the ball; the seeingcomes afterward.52 In a similar way, a sprinter is believed to start to runbefore he or she consciously hears the starting pistol; the hearing comesafterward.53 This zombie consciousness may in fact represent aspects ofa subcortical consciousness, that is, the way we process informationwithout having it on-line in consciousness (consider driving a car whilethinking about another topic). Again, this zombie consciousness seems asan example of what Hameroff was describing—that consciousness, in itsmost basic form, may be considered equivalent to minimal awareness.’ The Possibility of Fetal Consciousness This attempt to distinguish an off-line, and hence an on-line,consciousness may be particularly fruitful for investigating the possibilityof fetal consciousness. Such off-line processing may be at play muchearlier in fetal development and provide greater contributions topossible fetal (and neonatal) conscious states than we may think, andfurther help to explain some of the unique phenomena discussed so far.Conscious, or on-line, perception and awareness are associated withgeneralized activation of diverse brain areas.54 The reticular activatingsystem, with numerous subcortical inputs including the basal forebrain,locus coeruleus, substantia nigra, ventral tegmentum, and medianraphe, seems to mediate such activation. Notably, lesions in this system,but not in the thalamus or cortex, lead to a loss of consciousnessawareness.55 This begs the question as to whether such a system as thereticular activating system, by itself or in conjunction with other rhythmssuch as the 40 Hz g oscillation (believed to be a significant contributor toconscious integration56,57), serves as a bridge between the off-line andon-line states of consciousness. Further, a question arises as to whetherdisruption of the on-line consciousness necessarily disrupts off-line
  10. 10. 20 ’ Brusseauconsciousness—could it be that an anesthetized preterm neonate is infact off-line but not on-line? Is a fetus in utero similarly off-line but noton-line? Using pain again as a surrogate marker for consciousness, thequestion remains as to whether the fetus is in any way aware ofnociceptive stimuli. Physiochemical and behavioral data suggest that thefetus remains largely in a sleeplike state while in utero.58 This stateseems to be mediated by substances such as adenosine, steroids, andprostaglandins, as well as a low PO2.59 Evidence for this activelymaintained fetal sleeplike state is based on EEG and other observationsindicating the inhibition of cortical activity. (Perhaps not surprisingly,adult studies of non-rapid eye movement sleep demonstrate that suchsleep is, as was the case with anesthetics, characterized by a loss ofeffective cortical connectivity60). Although mild noxious stimuli do notseem to be perceived during such fetal sleep, major tissue injuryoccurring as a result of fetal trauma or fetal surgical interventiongenerates behavioral and physiologic arousal.61 Nevertheless, given theevidence for a subcortical or off-line consciousness that may be necessaryand sufficient for pain processing (eg, hydrancephalic children) and thelack of evidence suggesting subcortical electrical nonconnectivity duringthis period (indeed, appropriate arousal from sleep seems to suggestsome degree of continuous subcortical connectivity and/or function), thefetus in its latter developmental period may well be capable of painprocessing and thus have at least limited consciousness while in utero—even when apparently asleep. Perhaps the subcortex is necessary and sufficient for at least aminimal, Hameroffian consciousness, one that (if the data regardinganencephalic children are to be believed) may render an integratedexperience of nociception that we might call pain. Multiple lines ofevidence presented herein indicate that the necessary subcorticalstructures are present and functional in the preterm fetus. As discussedabove, it is clear that functionally effective patterns of nociceptive andsensory processing develop during the second trimester in the fetalthalamus. Several lines of evidence indicate that integrative support forconsciousness depends on a subcortical system, whereas the contents ofhigher order, phenomenal consciousness seem to be located in corticalareas. Neither ablation nor stimulation of cortical areas block or causepain perception in adults, whereas thalamic ablation or stimulation does.It would seem, then, that thalamic structures play a central role inconscious pain perception, and therefore in the generation of at leastminimally conscious states. Fetal development of the thalamus occursmuch earlier than the sensory cortex, providing the necessary structuraland functional mechanisms for conscious pain perception during thesecond trimester. If we are to suggest that the fetus can experience pain,then, this would seem to mandate the presence of at least a minimal
  11. 11. Developmental Perspectives ’ 21form of consciousness—a minimal awareness—born out of the integra-tion and unification of diverse sensory, and perhaps other, inputs. Asnoted earlier, although consciousness does not necessarily presupposepain, pain as currently understood does presuppose a consciousness ofsorts. If we are to attribute pain to an anencephalic child, a pretermneonate, or a uterine fetus, then it seems we would be compelled togrant these same individuals at least a limited form of consciousness.’ References 1. Myers LB, Bulich LA. Anesthesia for Fetal Intervention and Surgery. Hamilton: BC Decker Inc; 2005:1–16. 2. Brusseau RR, Myers LB. Anesthesia for fetal surgery and the EXIT procedure. In: ´ Cote C, et al, eds. A Practice of Anesthesia for Infants and Children. 4th ed. Philadelphia, PA: Lippincott William and Wilkins; 2008:473–477, 622–633. 3. Lee SJ, Ralston HJP, Drey EA, et al. Fetal pain: a systematic review of the evidence. JAMA. 2005;294:947–954. 4. Anand KJS. A scientific appraisal of fetal pain and conscious sensory perception. Written testimony offered to the Constitution Subcommittee of the US House of Representatives, US House Committee on the Judiciary, 109th United States Congress on October 1, 2005. Accessioned from anand110105.pdf on 8/31/2006. 5. Giannakoulopoulos X, Sepulveda W, Kourtis P, et al. Fetal plasma cortisol and beta- endorphin response to intrauterine needling. Lancet. 1994;344:77–81. 6. International Association for the Study of Pain; IASP Pain Terminology. A sample list of frequently used terms from: classification of chronic pain. In: Merskey H, Bogduk N. IASP Task Force on Taxonomy. 2nd ed. Seattle: IASP Press; 1994:209–214. 7. Woolf C, Ma Q. Nociceptors—noxious stimulus detectors. Neuron. 2007;55: 353–364. 8. Penfield W, Jasper HH. Epilepsy and the Functional Anatomy of the Human Brain. Boston: Little, Brown & Co; 1954. 9. Hunter J, Jasper HH. Effects of thalamic stimulation in unanaesthetised animals; the arrest reaction and petit mal-like seizures, activation patterns and generalized convulsions. Electroencephalogr Clin Neurophysiol. 1949;1:305–324.10. Merker B. Consciousness without a cerebral cortex: a challenge for neuroscience and medicine. Behav Brain Sci. 2007;30:63–81.11. Hameroff SR. The entwined mysteries of anesthesia and consciousness. Anesthesiology. 2006;105:400–412.12. Gehring WJ. Historical perspective on the development and evolution of eyes and photoreceptors. Int J Dev Biol. 2004;48:707–717.13. DeAngelis GC, Anzai A. A modern view of the classical receptive field: linear and nonlinear spatiotemporal processing by V1 neurons. In: Chalupa LM, Werner JS, eds. The Visual Neurosciences. Cambridge: MIT Press; 2003:704–719.14. Pack CC, Berezovskii VK, Born RT. Dynamic properties of neurons in cortical area MT in alert and anesthetized macaque monkeys. Nature. 2001;94:1058–1065.15. John ER, Prichep LS, Valdes-Sosa P, et al. Invariant reversible QEEG effects of anesthetics. Conscious Cogn. 2001;10:165–183.16. Hudetz AG, Imas OA. Burst activation of the cerebral cortex by flash stimuli during isoflurane anesthesia in rats. Anesthesiology. 2007;107:983–991.17. Okado N, Kakimi S, Kojima T. Synaptogenesis in the cervical cord of the human embryo: sequence of synapse formation in a spinal reflex pathway. J Comp Neurol. 1979;184:491–518.
  12. 12. 22 ’ Brusseau18. Rabinowicz T, de Courten-Myers GM, Petetot JM, et al. Human cortex development: estimates of neuronal numbers indicate major loss late during gestation. J Neuropathol Exp Neurol. 1996;55:320–328.19. Simons SH, Tibboel D. Pain perception development and maturation. Semin Fetal Neonatal Med. 2006;11:227–231 [Epub April 18, 2006].20. Teixeira JM, Glover V, Fisk NM. Acute cerebral redistribution in response to invasive procedures in the human fetus. Am J Obstet Gynecol. 1999;181:1018–1025.21. Fitzgerald M. Development of pain pathways and mechanisms. In: Anand KJS, ed. Pain Research and Clinical Management. Amsterdam: Elsevier; 1993:19–38.22. Percheron G. Thalamus. In: Paxinos G, May J, eds. The Human Nervous System. 2nd ed. Amsterdam: Elsevier; 2003:592–675.23. Royal College of Obstetricians and Gynecologists. Fetal Awareness: Report of a Working Party. London: RCOG Press; 1997.24. Kostovic I, Rakic P. Developmental history of the transient subplate zone in the visual and somatosensory cortex of the macaque monkey and human brain. J Comp Neurol. 1990;297:441–470.25. Holzman RS, Hickey PR. The development of pain perception and the stress response. In: Bailin MT, ed. Pediatric Anesthesia, in Harvard Electronic Anesthesia Library. New York, NY: Lippincott Williams and Wilkins; 2001 (Chap 2, Section 8).26. Clancy R. Electroencephalography in the premature and fullterm infant. In: Poilin RA, Fox WW, eds. Fetal and Neonatal Physiology. 2nd ed. Philadelphia: WB Saunders; 1998:2147–2165.27. Gitau R, Fisk NM, Teixeira JM, et al. Fetal hypothalamic-pituitary-adrenal stress responses to invasive procedures are independent of maternal responses. J Clin Endocrinol Metab. 2001;86:104–109.28. Ellingson RJ, Guenter HR. Ontogenesis of the electroencephalogram. In: Himwich WA, ed. Developmental Neurology. Springfield, IL: Charles C. Thomas; 1970:441–474.29. Nandi D, Aziz T, Carter H, et al. Thalamic field potentials in chronic central pain treated by periventricular gray stimulation—a series of eight cases. Pain. 2003;101:97–107.30. Bartocci M, Bergqvist LL, Lagercrantz H, et al. Pain activates cortical areas in the preterm newborn brain. Pain. 2006;122:109–117. Epub March 13, 2006.31. Counter SA. Preservation of brainstem neurophysiological function in hydranence- phaly. J Neurol Sci. 2007;263:198–207 [Epub August 27, 2007].32. Marin-Padilla M. Developmental neuropathology and impact of perinatal brain damage. II: White matter lesions of the neocortex. J Neuropathol Exp Neurol. 1997; 56:219–235.33. Takada K, Shiota M, Ando M, et al. Porencephaly and hydranencephaly: a neuropathological study of four autopsy cases. Brain Dev. 1989;11:51–56.34. Shewmon DA, Holmes GL, Byrne PA. Consciousness in congenitally decorticate children: developmental vegetative state as self-fulfilling prophecy. Dev Med Child Neurol. 1999;41:364–374.35. Merker B. Life expectancy in hydranencephaly. Clin Neurol Neurosurg. 2008;110: 213–214 [Epub January 16, 2008].36. McAbee GN, Chan A, Erde EL. Prolonged survival with hydranencephaly: report of two patients and literature review. Pediatr Neurol. 2000;23:80–84.37. Oberlander TF, Grunau RE, Fitzgerald C, et al. Does parenchymal brain injury affect biobehavioral pain responses in very low birth weight infants at 32 weeks’ postconceptional age? Pediatrics. 2002;110:570–576.38. Oberlander TF, Gilbert CA, Chambers CT, et al. Biobehavioral responses to acute pain in adolescents with a significant neurologic impairment. Clin J Pain. 1999; 15:201–209.
  13. 13. Developmental Perspectives ’ 2339. Schiff NDM, Rodriguez-Moreno DM, Kamal AM, et al. fMRI reveals large-scale network activation in minimally conscious patients. Neurology. 2005;64:514–523.40. Shewmon DA. A critical analysis of conceptual domains of the vegetative state: sorting fact from fancy. Neurorehabilitation. 2004;19:343–347.41. Laureys S, Faymonville ME, Luxen A, et al. Restoration of thalamocortical connectivity after recovery from persistent vegetative state. Lancet. 2000;355: 1790–1791. Erratum in Lancet. 2000;355:1916.42. Weiskrantz L. Blindsight. In: Chalupa LM, Werner JS, eds. The Visual Neurosciences. Cambridge: MIT Press; 2003:704–719.43. Leh SE, Johansen-Berg H, Ptito A. Unconscious vision: new insights into the neuronal correlate of blindsight using diffusion tractography. Brain. 2006;129: 1822–1832 [Epub May 19, 2006].44. Sprague JM. Interaction of cortex and superior colliculus in mediation of visually guided behavior in the cat. Science. 1966;153:1544–1547.45. Wallace SF, Rosenquist AC, Sprague JM. Recovery from cortical blindness mediated by destruction of nontectotectal fibers in the commissure of the superior colliculus in the cat. J Comp Neurol. 1989;284:429–450.46. Weddell RA. Subcortical modulation of spatial attention including evidence that the Sprague effect extends to man. Brain Cogn. 2004;55:497–506.47. McHaffie JG, Norita M, Dunning DD, et al. Corticotectal relationships: direct and ‘‘indirect’’ pathways. Prog Brain Res. 1993;95:139–150.48. Wallace SF, Rosenquist AC, Sprague JM. Ibotenic acid lesions of the lateral substantia nigra restore visual orientation behavior in the hemianopic cat. J Comp Neurol. 1990;296:222–252.49. Durmer JS, Rosenquist AC. Ibotenic acid lesions in the pedunculopontine region result in recovery of visual orienting in the hemianopic cat. Neuroscience. 2001;106:765–781.50. Chalmers DJ. The Conscious Mind. New York: Oxford University Press; 1996:93–308.51. Koch C, Crick F. The zombie within. Nature. 2001;411:893.52. Milner DA, Goodale MA. The Visual Brain in Action. Oxford: Oxford University Press; 1995:68–86.53. Libet B. Mind TIME: The Temporal Factor in Consciousness. Cambridge: Harvard University Press; 2004:33–122.54. Smythies J. The functional neuroanatomy of awareness: with a focus on the role of various anatomical systems in the control of intermodal attention. Conscious Cogn. 1997;6:455–481.55. Edelman GE, Tononi G. A Universe of Consciousness. New York, NY: Basic Books; 2000:37–78, 176–192.56. Womelsdorf T, Fries P, Mitra PP, et al. Gamma-band synchronization in visual cortex predicts speed of change detection. Nature. 2006;439:733–736 [Epub December 21, 2005].57. Plourde G, Garcia-Asensi A, Backman S, et al. Attenuation of the 40-hertz auditory steady state response by propofol involves the cortical and subcortical generators. Anesthesiology. 2008;108:233–242.58. Pillai M, James D. Are the behavioural states of the newborn comparable to those of the fetus? Early Hum Dev. 1990;22:39–49.59. Mellor DJ, Diesch TJ, Gunn AJ, et al. The importance of ‘‘awareness’’ for understanding fetal pain. Brain Res Brain Res Rev. 2005;49:455–471.60. Massimini M, Ferrarelli F, Huber R, et al. Breakdown of cortical effective connectivity during sleep. Science. 2005;309:2228–2232.61. Williams C. Framing the fetus in medical work: rituals and practices. Soc Sci Med. 2005;60:2085–2095.