ABSTRACT

Many controversies in the actual discussions on human death concern the lack of rigorous separation and ordered formulation of three distinct elements: the definition of death, the medical criterion (anatomical substratum) for determining that death has occurred, and the tests to prove that the criterion has been satisfied. In this paper I review the three brain-oriented standards of death (whole brain, brainstem and higher brain) according to these three distinct elements, and will propose a new formulation of death, based on the basic physiopathological mechanisms of consciousness generation in human beings. Two physiological components control conscious behavior: arousal and awareness (content of consciousness). We cannot simply differentiate and locate arousal as a function of the ascending reticular activating system, and awareness 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.Therefore,consciousness generation is based on anatomy and physiology throughout the brain.The three brain-oriented standards are inconsistent because they present discrepancies among the elements: definition-criterion-tests. I propose a standard of human death that includes consciousness as the most important function of the body, because it provides the capacity for integrating the main human attributes with an integrative functioning of the body. I have also emphasized that consciousness does not bear a simple one-to-one relationship with higher or lower brain structures, because the physical substratum for consciousness is based on anatomy and physiology throughout the brain. This notion of consciousness as the ultimate integrative function is more consistent with the biologically-based systems than the more philosophically-based notions of personhood

INTRODUCTION

Many controversies in the actual discussions on human death are mainly due to "the lack of rigorous separation and ordered formulation of three distinct elements: the definition of death, the medical criterion (anatomical substratum) for determining that death has occurred, and the tests to prove that the criterion has been satisfied". ^1-7 To define death is mainly a philosophical task, meanwhile the criterion and tests are medical chores. Specific criteria and tests must harmonize with a given definition. The definition must recognize the "quality that is so essentially significant to a living entity that its loss is termed death".^1-3,7

During the last decades, three main brain-oriented formulations of death have been discussed: whole brain, brainstem death and higher brain standards. ^8,9 The whole brain criterion refers to the irreversible cessation of all intracranial structure functions.^1-5,10-19It has been accepted by society mainly for practical reasons. ⁸ Physicians have constructed batteries of bedside tests (and of confirmatory laboratory procedures) to show that this criterion of death has been satisfied. ^{10,12,13,19-21} Until recently, whole brain strategists had not provided a conceptual framework to support specific criteria and tests. ^10-12 Moreover, this view has not answered the key point question about the critical number and location of neurons, subserving the essential brain activities to execute the functioning of the "organism as a whole" ^22-27

Christopher Pallis has powerfully articulated the brainstem death view. ^28-32 There were also practical reasons that promoted this view, ^33-35 because according to Pallis ²⁸ "a dead (i. e, irreversibly non-functioning) brainstem can be diagnosed at bedside, without resort of complicated investigations, and it predicts inevitable asystole within a short while". Therefore, so-called brainstem death was adopted in several Commonwealth countries. ^28-36 Pallis emphasized that the "capacity for consciousness" and “respiration” are the two hallmarks of life of the human being, and that brainstem death predicts an inescapable asystole. ^28-32 The physiopathological review of consciousness generation and respiration will provide a framework for not accepting Pallis' definition of death. ^8,9,37 Moreover, recent clinical cases have shown that brain death will not always predict an "inevitable asystole within a short while". ³⁷

Higher brain theorists have defined human death as the "the loss of consciousness", (definition) related to the irreversible destruction of the neocortex (criterion), or “higher brain”. ^38-44 In this paper, I will explain that consciousness does not bear a simple one-to-one relationship with higher or lower brain structures, and therefore, the higher brain formulation is wrong, because the definition (consciousness) does not correspond directly to the criterion (neocortex). ⁹ I will also review the three brain-oriented standards using to the three distinct elements proposed by Bernat and others,^1-7 and will propose a new formulation of death, based on the basic physiopathological mechanisms of consciousness generation in human beings. ^8,9

PHYSIO-PATHOLOGICAL MECHANISMS OF CONSCIOUSNESS GENERATION IN HUMAN BEINGS

Before proceeding, it is necessary to review the physiopathological mechanisms of consciousness generation.

Plum and Posner ¹⁸ defined consciousness as “the state of awareness of self and the environment”. Two physiological components control conscious behavior: arousal and awareness. ^9,18 Arousal represents a group of behavioral changes that occurs when a person awakens from sleep or transits to a state of alertness. ⁴⁵"Normal consciousness requires arousal, autonomic-vegetative brain function subserved by ascending stimuli from the pontine tegmentum, posterior hypothalamus and thalamus that activate wakefulness". ⁴⁶ The most discernible change that occurs when waking is the eyes opening. ^9,18,45,46 Arousal is also known as capacity for consciousness.^9,28-32

Awareness, also known as content of consciousness, represents the sum of cognitive and affective mental functions, and denotes the knowledge of one's existence, and the recognition of the internal and external worlds. ^9,18 It has been argued that consciousness has two dimensions: wakefulness and awareness. ⁴⁶Awareness is the same as the content of consciousness. ⁹Wakefulness is provided by the arousal. ^9,18,45,46

Plum ⁴⁷ 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 limbic system is important for the homeostasis of the internal milieu, and hence the second component of consciousness is crucial for integrating affective, cognitive and vegetative functions. Plum considers the third component 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.

In summary, a human being's state of consciousness reflects both his or her 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". ⁴⁸Therefore, 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. ^9,18,48

Unfortunately, most authors ^38,41,43 mention human consciousness, without considering its two components originally described by Plum and Posner. ¹⁸ For example, higher brain theorists ^38-44 habitually describe the persistent vegetative state (PVS) as patients with "irreversible loss of consciousness" or "permanent unconscious", but in these patients arousal is preserved, while awareness is apparently lost. On the other hand, some authors refer to the higher brain criterion as "the irreversible loss of the capacity for consciousness", ⁴¹but they are really referring to awareness. As the use of the term "capacity for consciousness", ^28-32 could be confusing, I will identify this function with the original term used by Plum and Posner, ¹⁸ i. e., arousal. I will use awareness as a synonym for content of consciousness. ^8,9

Arousal depends on the integrity of physiological mechanisms that take their origin in the ascending reticular activating system (ARAS): "it originates in the upper brainstem reticular core and projects through synaptic relays in the thalamus to the cerebral cortex, where it increases excitability". ⁴⁸ Moruzzi and Magoun, ⁴⁹ in their pioneer studies, discovered “the presence in the brainstem of a system of ascending reticular relays, whose direct stimulation activates or desynchronizes the EEG, replacing high-voltage low waves with low voltage fast activity”. Nonetheless, Steriade et al. ^48,50-59have recently emphasized that this desynchronization related to wakefulness “is now more apparent than real”, because although large slow waves disappear during waking, the EEG shows high frequency oscillations (30-40 Hz), known as gamma oscillations, that reflect synchronized and enhanced intracortical and corticothalamic activity.

Bogen ⁶⁰ has emphasized that the intralaminar nuclei complex of the thalamus is a cardinal component of the ARAS. The thalamic intralaminar neurons receive inputs from many sensory modalities and widely project to the cerebral cortex. Moreover, these nuclei are a major target for the brainstem reticular formation involved in waking. Recent reports strengthen the idea that intralaminar nuclei are thus essential in coordinating activity among cortical areas, and contribute to the formation of global perception to complex stimuli. ^60,61

The connections from the brainstem to the cerebral cortex, relayed through intralaminar and other thalamic nuclei, and their main neurotransmitters (acetylcoline and glutamate) have been identified. ⁴⁸ Additional important pathways participating in arousal have been recently recognized. ⁴⁵There 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. ^18,62Therefore, it is reasonable that arousal is due to several ascending systems stimulating the cerebral cortex and thalamus in parallel. ^9,45 Thus, "thalamo-cortical transmission may not be sufficient or even necessary to produce cortical activation". ¹⁸

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". ⁶³ At present there are arguments 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. ^45,63

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. ^45,64 According to Feinberg, ⁶⁵ one of the most remarkable peculiarities of the brain is "the seemingly enormous redundancy, parallelism, and distributiveness" of its connections.

The cerebral cortex and thalamus make up "a unified oscillatory machine" that exhibit spontaneous rhythms and that are conditional to behavioral state and vigilance. ⁵¹ The brain uses spatiotemporally distributed systems to "capture high-order perceptual features".⁶⁵ Singer and Gray ⁶⁶have argued that fast rhythms of corticothalamic neurons, known as gamma oscillations, are probably implicated in synchronizing mechanisms that respond to different features of the same perceptual object, leading to several hypothesis of high cognitive mechanisms.

Normal conscious behavior requires both arousal and awareness.¹⁸ Patients in coma are unconscious because both arousal and awareness are disturbed. ^9,18

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.

In persistent vegetative state (PVS) cases arousal is preserved (the PVS has periods of wakefulness), but awareness is seemingly is lost.⁹ Thus, in PVS there is an apparent dissociation of awareness from arousal. ^9,45 It has been argued that "separate anatomic pathways mediate arousal and awareness, and that brain diseases can differentially affect each component of consciousness". ⁴⁵

This raises the question: Why is awareness lacking in PVS, while arousal is preserved? The neuropathology in the PVS provides a suitable background to discuss the pathophysiology of consciousness generation. Kinney ⁴⁵ has recently presented a detailed review of this subject. According to this author, PVS denotes a "locked-out-syndrome" because "

ABSTRACT

INTRODUCTION

PHYSIO-PATHOLOGICAL MECHANISMS OF CONSCIOUSNESS GENERA­TION IN HUMAN BEINGS

PHYSIO-PATHOLOGICAL MECHANISMS OF CONSCIOUSNESS GENERATION IN HUMAN BEINGS