Network for the Definition of Death |
Brain Death and
End-of-Life Ethics Links
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.
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
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
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
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-
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
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
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
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
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".
220.127.116.11. The potential reversibility of the awareness in the
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
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
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
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