A new definition of death based on the basic mechanisms of consciousness generation in human beings

Calixto Machado, M.D., Ph.D.

Head of the Department of Clinical Neurophysiology at the Institute of Neurology and Neurosurgery, Havana, Cuba+

For many centuries people were deemed dead when they stopped breathing and when their hearts stopped beating. But during the era of Intensive Care, cessation of brain functions began to be considered the main reason for diagnosing death.1,2 Medical concern over making safe and appropriate diagnosis of BD in respirator-supported patients led to the elaboration of criteria, which reliably established irreversible loss of brain function. This was an operational way of determining that death had occurred.2

The definition or conception of death is on the other side of the subject. According to Shewmon3 there are two basic schools about the definition of human death. Those referring to the "loss of specifically human properties" and those arguing the "loss of integrative unity of the body". Veatch4 has proposed to search for the essential property that characterizes life in humans. "What is it about human life, and that its loss is so essential, that the individual who loses it ought be called dead?" I would complete this question as follows. What is it about human life, which is irreplaceable by any artifice, and that its loss is so essential, that the individual who loses it ought be called dead?5 Bernat1 has also proposed to "define death as the permanent cessation of functioning of the organism as a whole". Some authors combine both schools when presenting their definitions of human death. 3

I have recently discussed that consciousness is the most integrative function of the organism and that it provides the essential human characteristics. Nonetheless, it is fundamental to consider both components of consciousness: arousal and awareness.5

In this paper, I will support a new definition of human death based in the physio-pathological mechanisms of consciousness

2. PHYSIO-PATHOLOGICAL MECHANISMS OF CONSCIOUSNESS GENERATION IN HUMAN BEINGS

Two physiological components control conscious behavior: arousal and content of consciousness.6 The arousal represents a group of behavioral changes that occurs when person awakens from sleep or transits to a state of alertness.7

"Normal consciousness requires arousal, autonomic-vegetative brain function subserved by ascending stimuli from the pontine tegmentum, posterior hypothalamus and thalamus that activate wakefulness".8

The most discernible change that occurs when awaking is the eyes opening.6-8 Arousal is also known as capacity for consciousness5,9

The content of consciousness, also known as awareness, represents the sum of cognitive and affective mental functions, and denotes the knowledge of ones existence, and the recognition of the internal and external worlds.5,6 It has been argued that consciousness has two dimensions: wakefulness and awareness.8 Awareness is the same as the content of consciousness.5,6 Wakefulness is provided by the arousal. 5,8

Plum10 has recently defined not two but three components, subdividing the content of consciousness in two levels or components. According to this author, the second component or level, "which importantly regulates the sustained behavioral state function of affect, mood, attention, cognitive integration, and psychic energy (cathexis) depends on the integrity of the limbic structures including the hypothalamus, the basal forebrain, the amygdala, the hippocampal complex, the cingulun, and the septal area". The third component is considered by Plum as the "cerebral level, along with the thalamus and basal ganglia". This component is related to the processes of higher levels of perception, self-awareness, language, motor skill, and planning. Memory can be impaired by injury of either cerebral or limbic levels.

Summarily, a human being's state of consciousness reflects both his level of arousal that depends on subcortical arousal- energizing systems and, the sum of the cognitive, affective, and other higher brain functions (content of consciousness or awareness), related to "complex physical and psychologic mechanisms by which limbic systems and the cerebrum enrich and individualize human consciousness".10 Therefore, I will use the term arousal when referring to those subcortical arousal- energizing systems, and awareness, to denote the sum of those complex brain functions, related to limbic and cerebrum levels.6,10

Unfortunately, most authors4,11,12 usually mention human consciousness, without considering its two components originally described by Plum and Posner.6 For example, higher brain theorists4,11,12 habitually describe the persistent vegetative state (PVS) as patients with "irreversible loss of consciousness" or "permanent unconscious", but in these patients the arousal is preserved, while the content of consciousness is lost. On the other hand, some authors refer to the higher brain criterion as "the irreversible loss of the capacity for consciousness",11 but they are really referring to the content of consciousness. It is important to take into account these considerations to avoid misunderstandings and to increase precision of terms. As the use of the term "capacity for consciousness",9 could be confusing, I will identify this function with the original term used by Plum and Posner,6 i. e., arousal . I will use awareness as a synonym for content of consciousness.

2.1. Arousal

Arousal depends on the integrity of physiological mechanisms that take their origin in the ascending reticular activation system (ARAS), "arising from nonspecific populations of neurons located in the tegmentum of the rostral pons and midbrain as well as the intralaminar nuclei of the thalamus and the posterior hypothalamus".10

Additional important pathways participating in arousal have been recently recognized.7 There are neurotransmitter systems that take origin in the brainstem, hypothalamus and basal forebrain, projecting monosynaptically to the cerebral cortex without relaying through the thalamus. These systems include different neurotransmitter projections: cholinergic from the basal forebrain and mesopontine reticular formation, serotoninergic from the brainstem raphe nuclei, histaminergic from the posterior hypothalamus and noradrenergic from the brainstem locus coeruleus. Experimental studies have also shown that an almost complete destruction of the thalamus does not block cortical activation. Furthermore, the EEG arousal pattern characterized by desynchronization disappears with the administration of drugs to block serotoninergic and cholinergic transmission.6,13

Regarding both the above mentioned experimental data and the anatomopathology of the PVS, it is reasonable that arousal is due to several ascending systems stimulating the cerebral cortex and thalamus in parallel. Thus, "thalamo-cortical transmission may not be sufficient or even necessary to produce cortical activation".6

2.2. Content of consciousness (awareness)

The discovery that the cerebral cortex is organized in vertical columns that represent functional units was crucial for further understanding of the functional organization of the brain. "The basic functional unit of the neocortex is a vertically oriented group of cells extending across the cellular layers and heavily interconnected in the vertical direction, sparsely so horizontally".14 At present there are arguments considering that the functional organization of the entire cerebral cortex is a complex of these vertical columns. Contiguous columns are interconnected by local circuits into "information-processing modules", characterized by specific afferent and efferent connections with other modular units from other cortical and subcortical areas.7, 14

It seems that the brain operates in "parallel processing", because cortical regions are linked in parallel networks with each other and with subcortical structures. Thus, a specific component of a certain cognitive function is scattered among interconnected regions, each one implicated in a distinct aspect of the cognitive ability.7,15

The content of consciousness6 provides the essential properties that individualize a human,10 and enrich his personal identity.16

2.3. Dissociation: arousal - awareness

Normal conscious behavior requires both arousal and awareness.6 Patients in coma are unconscious because both arousal and content of consciousness are disturbed.8 In PVS cases arousal is preserved, being wakeful, but the content of consciousness is lost.5 Thus, in the PVS there is a dissociation of awareness from the arousal.5,7 It has been argued that "separate anatomic pathways mediate arousal and awareness, and that brain diseases can differentially affect each component of consciousness".7

The question is raised: Why in PVS is awareness lacking, while arousal is preserved? The neuropathology in the PVS provides a suitable background to discuss the pathophysiology of consciousness generation. Kinney7 has recently presented a detailed review of this subject.

The Multi-Society Task Force in PVS8 has classified the causes of PVS in 3 main groups: Acute injuries, where the most common causes are traumatic and hypoxic-ischemic encephalopathy; Degenerative and metabolic disorders, including dementia; Developmental malformations, where the most important is anencephaly. Nonetheless, the most prevalent causes of acute PVS in all ages are head trauma and hypoxic-ischemic encephalopathy. These causes have been taken as models to describe the three main patterns of the neuropathological damage in PVS cases.

According to Kinney7 the PVS denotes a "locked-out-syndrome" because "the cerebral cortex is disconnected from the external world, and all awareness of the external world is lost". This author suggested that the loss of awareness in the PVS is caused by three main patterns: widespread and bilateral lesions of the cerebral cortex, diffuse damage of intra- and subcortical connections in the cerebral hemispheres white matter, and necrosis of the thalamus.

2.3.1. Widespread and bilateral lesions of the cerebral cortex

Hypoxic-ischemic encephalopathy is the main etiology of this pattern. It is the consequence of acute hypoxic-ischemic insults after cardio-respiratory arrest, strangulation, suffocation, near-drawing, prolonged hypothension, and perinatal asphyxia in neonates.7 The description of this pattern was the reason that PVS was first known as "apallic syndrome", characterized by the destruction of the "pallium, the cortical gray matter that covers the thelencephalon".17 In the cerebral cortex a laminar necrosis is found that is multifocal or diffuse and extensive. Other ischemic lesions may be superimposed mainly in the border zones of the main intracranial cerebral arteries, as the parasagittal parieto- occipital region, for example.7,2,3

Other damages, such as neuronal loss and small infarcts, are also typically found in the cerebellum, basal ganglia, thalamus and hippocampus; the later being particularly sensitive. Other anatomical structures of the brain are relatively undamaged: brainstem, hypothalamus, basal forebrain and amygdala. The distribution of brain damage reflects the differential vulnerability of brain regions to hypoxia- ischemia.7,17,18

2.3.1.1 Arousal-awareness

In PVS cases with diffuse damage of the cerebral cortex the lack of awareness is understandable. The widespread involvement of the association cortices combined with primary and secondary cortices damage, is the faultfinding anatomical ground.7 It has been suggested that in diffuse cerebral cortical lesions, arousal can be maintained by the brainstem and the thalamus.3, 7 Nonetheless, other parallel pathways projecting monosynaptically to the cerebral cortex without relaying through the thalamus could partake to maintain the arousal in these cases. Thus, arousal could be preserved without a functional cerebral cortex. This has been also supported by experimental data. In animals with a total removal of the cerebral cortex or transection at the rostral midbrain level, arousal is preserved, showing waking/ sleep cycles. Therefore, it has been argued that "the brainstem alone is sufficient for arousal".7, 18,19

2.3.2. Intra- and subcortical connections in the cerebral

hemisphere white matter

The mechanism of this pattern could be explained in head trauma and hypoxic-ischemic injury. After head trauma, a

widespread damage of axons in the cerebral hemispheres white matter occurs, known as diffuse axonal injury (DAI). The DAI is probably caused by the acceleration suffered by the head immediate after the injury.7, 20

The cerebral hemisphere white matter could be also damaged after hypoxic-ischemic accidents in a pattern known as "leukoencephalopathy".21 It is characterized by "extensive symmetrical necrotic lesions in the central white matter of the cerebral hemispheres, with minimal or no damage to gray matter structures".7 These patients yield antecedents of prolonged periods of hypotension, hypoxemia and increased venous pressure.7,20,21

2.3.2.1 Arousal-awareness

This pattern also provides a disconnection of the cerebral cortex from the environment that can explain the lack of awareness in the PVS. Arousal is preserved by the functionally unaltered brainstem and thalamus. The participation of other parallel pathway not relaying through the thalamus has to be also considered.

Reports in PVS patients and experimental data of diffuse axonal injury to cerebral hemispheres with cerebral cortex remaining largely normal suggest that, "acute diffuse disconnection of the cerebral cortex from its subcortical activating mechanisms can block arousal as well as cognitive activity in the primate brain".10

2.3.3. Thalamus

This pattern is characterized by a selective necrosis of the thalamus and, although the cortex is not totally spared, the lesions are focal and restricted.7,22 It has been explained by several possible factors, such as: partial or immediately reversed transtentorial herniation, cerebral edema causing hypoxia-ischemia, and intrinsic metabolic vulnerability of the thalamus.7

2.3.3.1. Arousal-awareness

The lesions of the thalamus provide a disconnection of the cerebral cortex from the external world, and therefore, all awareness from the environment is lost. The lack of awareness in this pattern is not only a consequence of lesions destroying the sensory relay nuclei that block sensory information from the external world, but the damage of the thalamic association nuclei is probably the critical anatomical substratum. These nuclei integrate important pathways to subserve fundamental cognitive and affective functions such as the attention to the external world.7,23 Clinical data support the idea "that lesions in a thalamic nucleus which is heavily interconnected with an association cortex result in functional impairments similar to damage in the cortical region itself".12 For instance, contrary to the generalized expectancy, the neuropathological examination of Karen Ann Quinlans brain showed a disproportional severe damage of the thalamus, as compared with the cerebral cortex. 7,23

The arousal in this pattern could be preserved by a functionally intact brainstem and the other parallel pathways which project to the cerebral cortex, without relaying through the thalamus. It has been argued that "the thalamus is critical for cognition and awareness and may be less essential for arousal".23

2.4. Is the lack of awareness in the PVS really permanent or irreversible?

The Multi-Society Task Force in PVS8 has defined the precise use of the terms "persistent" and "permanent". "Persistent refers only to a condition of past and continuing disability with an uncertain future, whereas permanent implies irreversibility". The Multi-society Task Force likewise addressed that "A patient in a persistent vegetative state becomes permanently vegetative when the diagnosis of irreversibility can be established with a high degree of clinical certainty". According to the etiology, a period of observation has been proposed to define that a "persistentvegetative state", has become a "permanent vegetative state. 28

PVS patients reflect the only situation in which a clear dissociation of both components of consciousness is found.5 Conversely, recent evidence has shown that cortical-subcortical interactions are necessary to subserve and make both components active.5,10 Regarding the above mentioned subjects, two main questions may arise: Are subcortical structures capable of mediating some form of awareness? Is the lack of awareness in the PVS really permanent or irreversible?

2.4.1. Subcortical structures in awareness

There is striking evidence that subcortical structures are capable of mediating some form of awareness. Plum10 has emphasized that the "non-specific mechanisms ascending from the rostral brainstem and diencephalon importantly and possibly inseparably activate and integrate both the arousal and the cognitive aspects of human consciousness". The participation of the thalamus to provide the awareness has been already mentioned.

Additionally, Shewmon3 has discussed some examples of clear participation of subcortical structures in awareness. Experimental animals with complete decortication have shown to be capable of complex interactions with the environment which is evidence of some awareness.24 In lesions of the somatosensory cortex an evident loss of tactile, vibration and joint position sense is observed; nonetheless, the conscious experience of pain and temperature is preserved, mediated by subcortical structures, probably the thalamus.25 This author also commented that two hydranencephalic patients ("prenatal destruction of the cerebral hemispheres with intact skull and scalp") unquestionably manifested conscious behavior. These two cases are examples of the brainstem "plasticity" in newborns.3 Clinical and experimental evidence convincingly suggests that the brainstem of newborns is potentially capable of much more complex integrative functioning. This includes some functions commonly considered to be cortical, even in animals.3,26 Based on these subjects, the potential presence of some primitive form of awareness in anencephalics, and the possibility of subjective feeling of pain, has been suggested.3,5 Thus, according to Shewmon3 "the human brainstem and diencephalon, in the absence of cerebral cortex, can mediate consciousness and purposeful interaction with the environment".

2.4.1.2. The potential reversibility of the awareness in the PVS

The use of deep brain stimulation (DBS) has shown possible that the cerebral hemispheres could mediate arousal producing some wakefulness behavior, even after complete loss of the brainstems reticular activating system. Hassler,27 used DBS in "apallic" or "coma vigil" cases (PVS patients), stimulating the reticular formation in the thalamus and in the pallidum. It caused these patients to awaken with an undoubted recovery of awareness (recognition of their families and emotional expressions). Katayama et al.,28 also employing DBS of the ARAS (mesencephalic reticular formation and/or non-specific thalamic nuclei) in PVS cases, have reported a persistent increment in pain-related P250, which indicates non-specific cortical activation. Sturm et al.,29 reported the use of DBS at the thalamic level, in a case with probable dysfunction of the mesencephalic reticular formation due to the rupture of a sacular aneurysm at the tip of the basilar artery. DBS resulted in autonomic and behavioral reactions and the patient was able to respond to simple commands. Kohadon and Richer,30 from a series of 25 PVS cases treated by DBS, reported a definitive improvement in arousal with some degree of awareness and interpersonal relationship, in 13 of them. In fact, the possibility of brain function restoration in such patients, by actual or still not developed techniques, is a challenge for the future.5

Some reports of misdiagnosis or recuperation in PVS have also appeared in recent literature. Unexpected and well-documented recoveries of cognitive functions have been described in patients, where it was believed that the criteria were correctly applied by neurologists experienced and skilled in the diagnosis of this condition.31,32

2.5. Interaction arousal-awareness to provide consciousness

The PVS provides a "model" in which arousal is preserved and awareness is lacking.5 Therefore, it has been suggested that both component of consciousness "are mediated by distinct anatomic, neurochemical and/or physiological systems".7 Nonetheless, the potential "plasticity" of the brain has demonstrated that subcortical structures could mediate awareness, even with the complete absence of the cerebral cortex..3 Thus, awareness is not only related to the function of the neocortex (although it is primary important), but to complex physical and psychologic mechanisms, due to the interrelation of the ARAS, limbic system, and the cerebrum.5,10

Plum has emphasized that the ARAS substantially and inseparably activates ahe arousal and the cognitive aspects of human consciousness. He recognized a brainstem-diencephalic participation not only in arousal, but in cognitive function. In lesions affecting thalamic- mesencephalic structures that comprise the ARAS, the presence of important cognitive and affective deficits can be found.10 Alterations in the cerebral cortex after severe damage restricted to mesencephalic-diencephalic activating systems have been reported. They reflect transneural degeneration, and suggest that these pathways not only activate the cerebral cortex but they also trophically influence cortical neurons.

Therefore, it can be concluded that we cannot simply differentiate and locate arousal as a function of the ARAS, and the content of consciousness as a function of the cerebral cortex. Substantial interconnections among the brainstem, subcortical structures and the neocortex, are essential for subserving and integrating both components of human consciousness.3, 5,10

The above considerations lead one to conclude that there is no single anatomical place of the brain "necessary and sufficient for consciousness".3 The existence of a "physiological kernel of consciousness"9 or a "reticular formation/cortical unit" has been discussed by Shewmon.3 In a broad sense this "physiological kernel of consciousness" or "reticular formation/cortical unit" (RF/CU) is conformed by the widespread interconnections among the ARAS, subcortical structures, and the neocortex.

3. DEFINITION OF DEATH BASED IN THE BASIC MECHANISMS OF CONSCIOUSNESS GENERATION IN HUMAN BEINGS

According to these important facts that shows the relevance of the interaction of both components of consciousness (arousal and awareness) to govern conscious behavior in humans, I have recently presented a definition of human death.5 I used the term capacity for consciousness as synonym for arousal. To prevent possible nomenclature misunderstandings, it is better to use the term arousal. Awareness is a synonym for content of consciousness.

"The irreversible loss of both components of consciousness, arousal and awareness"

4. FINAL REMARKS

It is obvious that substantial interconnections among the brainstem, subcortical structures, and the neocortex, are essential for subserving and integrating both components of human consciousness.3,5,10 These interconnections are

delineated in the so-called "reticular formation/cortical unit" (RF/CU).3 Moreover, the remarkable technological advances provided by civilization permit the technological substitution of body functions, possibility increasing on a daily basis.5 Thus, a question remains: Is there any brain function that could be replaced technologically without abolishing the essential human characteristics, and being still possible to integrate the organism as a whole.

We could discuss this subject based on a hypothetical experiment. Lets consider that we have all the technological possibilities to substitute progressively all functions of a human. When then would this human become a robot ? Which is the last function that could be replaced without abolishing the essential human characteristics?

Lets suppose that Mark is a terminal patient, affected by a terminal methastatic cancer. Whenever, a methastasis is found, the affected organ, function, or system is replaced by an artifice. By this way, the lungs, the heart, the stomach, the four limbs are progressively substituted. The replacement will continue even into the brain. The visual pathways are completely substituted by specially designed electronic- cameras. Something similar occurred with the auditory system, because electronic ears are wired into the brain. At the end, the body is a complete electronic-mechanical artifice. All the brainstem, diencephalic, and other subcortical functions have been swapped. The only remaining functional structure is a unit conformed by the activating reticular formation and the cerebral cortex, which is fully interconnected with the rest of the electronic brain and the artificial body. A question arises: Is this "electro-mechanic complex" a human?

Of course, it is a human being. The RF/CU will still provide both components of a conscious behavior, i.e., arousal and awareness. In Mark, nothing about his personhood has changed: his thoughts, his memories, his affections, etc. Thus, his RF/CU will maintain his essential human characteristics and will command and integrate the functioning of the rest of his "electronic brain" and his "artificial body".

To discuss a crucial difference of the two basic schools3 regarding the definition of human death: those referring to the "loss of integrative unity of the body"1 and those arguing the "loss of roperties",4 a new

experiment will be conducted. Lets consider that the RF/CU could be surgically extracted from Marks brain. Moreover, a special laboratory preparation allows us to supply blood and oxygen to the RF/CU. A question arises: Will the preserved RF/CU will be Mark? Of course, it will be Mark, because his RF/CU will still render both components of his conscious behavior, i.e., arousal and awareness. This condition has to be considered as extreme "locked-out" and "locked-in" syndromes. Mark will be totally disconnected from the outer world, and he will not be able to express his thoughts and his feelings. In this condition there is nothing to integrate. Thus, his organism is not functioning "as a whole", but he is not dead, his essential human attributes remain.

Therefore, to define human death, the crucial point is to define the function that provides the essential human properties. I have no doubts to affirm that consciousness characterizes human existence and that the irreversible loss of consciousness defines human death (considering its two components, arousal and awareness). Moreover, I also consider that at the same time, consciousness is the most integrative function of the body. No other function could integrate as consciousness, the functioning of the organism as a whole, when it is possible.

Thus, the definition of human death I proposed takes as its hallmarks both components of consciousness that first, provide the essential human characteristics, and that also control the functioning of the organism as a whole.5

REFERENCES

1. Bernat, JL. Ethical issues in Neurology. In Joynt, RJ, ed. Clinical Neurology. Philadelphia: JB Lippincott Company, 1991:1- 105.

2. Machado, C. Criterios Cubanos para el Diagn"stico de la dicas, 1992.

3. Shewmon, D.A. "Brain Death": A valid theme with invalid variations, blurred by semantic ambiguity. In: Angstwurm, H and Carrasco de Paula, I., ed. Working Group on The Determination of Brain Death and its Relationship to Human Death: Vatican City: Pontificia Academia Scientiarum, 1992; pp:23-51.

4. Veatch, RM. The definition of death: ethical, philosophical, and policy confusion. In: Korein, J, ed. Brain Death: Interrelated Medical and Social Issues. New York: Ann NY Acad. Sci., 1977; 315:307-317.

5. Machado, C. Death on neurological grounds. J. Neurosurg. Sciences (in press).

6. Plum, F, Posner, JB. The Diagnosis of Stupor and Coma. Philadelphia: FA Davis Company, 1980.

7. Kinney, H.C., Samuels, M.A. Neuropathology of the persistent vegetative state: A Review. J. Neuropathology and Experimental Neurology 53:548-558, 1994.

8. The Multi-Society Task Force on PVS. Medical aspects of the persistent vegetative state. N. Engl. J. Med. 330:1499- 1508, 1994.

9. Pallis, C. ABC of brain stem death: from brain death to brain stem death. Br. Med. J. 28:1487-1490, 1982.

10. Plum, P. Coma and related global disturbances of the human conscious state. In: Peters A, ed. Cerebral Cortex, Vol 9. New York: Plenum Publishing Corporation, 1991:359-425.

11. Truog, RD, Flacker, JC. Rethinking brain death. Critical Care Medicine 1992; 20:1705-1713.

12. Wikler, D. Not dead, not dying? Ethical categories and the persistent vegetative state. Hastings Center Rep 1988; 18:41- 47.

13. Villablanca, J., Salinas-Ceballos, M.E. Sleep-wakefulness, EEG and behavioral studies of chronic cats without the thalamus. The athalamic cat. Arch. Ital. Biol. 110:383-411, 1972.

14. Mountcastle, V.B.: An organization principle for cerebral function: the unit module and the distributed system. In: Edelman, G.M., Mouncastle, V.B., eds. The mindful brain. Cambridge, M.A.: The MIT Press, 1978:7-50.

15. Goldman-Rakic, P.S. Topography of cognition: Parallel distributed networks in primate association cortex. Ann. Rev. Neurosci. 11:137-156, 1988.

16. Green, MB, Wikler, D. Brain death and personal identity. Philosophy and Public Affairs 1980; 2:105-133.

17. Ingvar, DH, Brun, A, Johansson, L, Sammuelsson, SM. Survival after severe cerebral anoxia with destruction of the cerebral cortex: the apallic syndrome. In: Korein, J, ed. Brain Death: Interrelated Medical and Social Issues. New York: Ann. NY Acad. Sci., 1977; 315:184-214.

18. Brierley, J.B., Adams, J.H., Graham, D.I., Simpsom, J.A. Neocortical death after cardiac arrest. A clinical, neurophysiological, and neuropathological report of two cases. Lancet 2:560-565, 1972.

19. Villablanca, J.R. Independent forebrain and brainstem controls for arousal and sleep. Behav. Brain Sci. 4:494-496, 1981.

20. Adams, J.H., Grahan, D.I., Murray, L.S., Scott, G. Diffuse axonal injury due to nonmisile head injury in humans: An analysis of 45 cases. Ann. Neurol. 12:557-563, 1982.

21. Ginsberg, M.D., Hedley,-Whyte, E.T., Richardson, E.P. Hypoxic-ischemic leukoencephalopathy in man. Arch. Neurol. 33:5- 14, 1976.

22. Relkin, N.R., Petito, C.K., Plum, F. Coma and the vegetative state associated with thalamic injury after cardiac arrest.

23. Kinney, H.C., Korein, J., Panigraphy, A., Dikkes, P., Goode, R. Neuropathologic findings in the brain of Karen Ann Quinlan: The role of the thalamus in the persistent vegetative state. N. Engl. J. Med. 330:1469-1475, 1994.

24. Villablanca, J.R., Burgess, J.W., Olmstead, C.E., Levine, M.S. Recovery of function after neonatal or adult hemispherectomy in cats: I-III. Behav. Brain Res. 19:205-226, 20:1-18, 20:217-230, 1986.

25. Brodal, A., ed. Neurological Anatomy in Relation to Clinical Medicine, 3rd ed., New York: Oxford University Press, pp:394-447, 1981.

26. Shewmon, D. A., Holmes, G.L. Brainstem plasticity in congenitally decerebrated children. Brain & Devel. 12:664, 1990.

27. Hassler, R, Dalle Ore, G, Bricolo, OA, et al. Behavioral and EEG arousal induced by stimulation of unespecific projection systems in a patient with post-traumatic apallic syndrome. Electroencephalogr. Clin. Neurophysiol. 1969; 27:306- 310.

28. Katayama, Y, Tsubokawa, T, Yamamoto, T, et al. Characterization of brain activity with deep brain stimulation in patients in a persistent vegetative state: pain-related late positive component of cerebral evoked potential. Pace 1991; 14:116-121.

29. Sturm, V., K|Hner, A., Schmitt, H.P., Assmus, H., Stock, G. Chronic electrical stimulation of the thalamic unspecific activating system in a patient with coma due to midbrain and upper brain stem infarction. Acta Neurochirurgica 47:235-244, 1979.

31. Rosenberg, GA, Johnson, SF, Brenner, RP. Recovery of cognition after prolonged vegetative state. Ann. Neurol. 1977; 2:167-168.

32. Steinbock, B. Recovery from persistent vegetative state? The case of Carrie Coons. Hastings Cent Rep 1989; 19:14-15.