THE JEREMIAH METZGER LECTURE: DISORDERS OF CONSCIOUSNESS AND THE NORMATIVE UNCERTAINTY OF AN EMERGING NOSOLOGY

I. A NEW NOSOLOGY FOR INNER SPACE

Astronaut and physician Michael Barratt is a hard act to follow (1). He spoke eloquently about outer space and zero gravity physiology and explained how the human body adapts to space flight. Last night, as the Bert and Peggy Dupont Lecturer, Dr. Barratt asked us as physicians to reimagine our thinking for that novel environment and recast our categories so we could diagnose and treat his fellow astronauts.

I will give a different talk with a similar theme (2). Where Dr. Barratt spoke of outer space, I will speak of inner space and share the emerging field of medicine that is categorizing and redefining disorders of consciousness, brain states including brain death, and the vegetative and minimally conscious states (3). Both of our talks speak to the excitement surrounding emerging nosologies at the frontiers of knowledge and the evolution of medical practice (4).

Our story begins in 1972 when Bryan Jennett and Fred Plum described the persistent vegetative state in a landmark article entitled “The Lancet” (5). Jennett is the Scottish neurosurgeon responsible for the Glasgow Coma and Outcome Scales (6). Plum is an American neurologist who first described the Locked in State in 1966 (7) and served as the longtime chair of neurology at Cornell, where he was my teacher (8).

In their seminal paper, Jennett and Plum described the vegetative state as a “syndrome in search of a name” and one of wakeful unresponsiveness, in which the eyes are open but there is no awareness of self, others, or the environment. This condition is reflective of the isolated return of autonomic brain stem function as a patient evolves out a coma, which is notably an eyes closed state of unresponsiveness. If the eyes are the window of the soul, eye opening of a patient in the vegetative state is a paradoxical and heart-wrenching condition for families because it does not reflect the return of sentience.

The vegetative state came to national attention in 1976 when it figured prominently in the right-to-die case of Karen Ann Quinlan, a young woman left in the vegetative state following anoxic brain injury secondary to a drug overdose (9). For the next five decades, medicine has been trying to make sense of the vegetative state, not only because of its biology and clinical presentation, but also due to its normative implications.

In 1977, just two years after the onset of Ms. Quinlan's coma following her overdose, Larry Altman wrote in The New York Times of an outcomes study undertaken by Drs. Plum and Jennett to understand how the brain recovers from grievous injury (10,11). They proposed to study over 1,000 patients in New York and Glasgow over time to discern mechanisms of recovery. As Jennett put it at the time, “We know surprisingly little about recovery.” Plum, ever the straddler of C.P. Snow's two-culture divide between the sciences and the humanities (12), sought clinical understanding in order to make normative sense of this condition and to promote the humane treatment of patients so afflicted. As Altman wrote, “Dr. Plum said all the efforts of the study would take doctors a step forward in setting ‘the scientific basis of tomorrow's medical ethics’ (10).”

What Plum and Jennett aspired to accomplish decades ago took a major step forward in 2018 when the American Academy of Neurology (AAN); the American College of Rehabilitation Medicine (ACRM); and the National Institute of Disability, Independent Living, and Rehabilitation Research (NIDILRR) concluded a five-year systematic review of the diagnosis and treatment of disorders of consciousness (13) and published an evidence-based practice guideline for the care of these patients (14). Both the systematic review and the practice guideline were published concurrently in Neurology and the Archives of Physical Medicine and Rehabilitation along with a commentary on the ethical, palliative, and policy implications of this work which I was honored to write along with my co-author, James L. Bernat, a neurologist from Dartmouth (15).

This was a landmark moment in the history of disorders of consciousness as indicated by the joint publication of the three papers in two journals. The systematic review was done with a rigorous methodology (16), and the practice guideline represented the consensus of leading clinical societies and the relevant NIH institute. The guideline supplanted the 1994 New England Journal of Medicine Multi-Society Task Force on the Vegetative State (17) and affirmed the 2002 Aspen Criteria establishing the Minimally Conscious State (18).

Notably, the practice guideline called for improved standards of care for this population and included improved diagnostic accuracy, the use of serial examinations using the vetted behavioral assessment tool—the Coma Recovery Scale-Revised (CRS-R) (19), and the use of emerging neuroimaging technologies such as functional Magnetic Resonance Imaging (fMRI) and single-photon emission computerized tomography (SPECT) in experienced hands when a bedside diagnosis was equivocal. Crucially, the guideline noted the importance of identifying and treating underlying conditions that could confound diagnosis (e.g., undetected or subclinical seizure disorders that might obscure underlying cognitive function).

The documents also pointed to progress in the treatment of these conditions, highlighting the randomized clinical trial demonstrating the ability of amantadine to accelerate the recovery of consciousness. In my view, the document downplayed the true scope of progress because its methodology only allowed the reporting of studies with more than 20 subjects (15). This evidentiary standard (20) excluded some promising proof of principle diagnostic methods as well as studies utilizing neuromodulation such as deep brain stimulation (DBS), transcranial magnetic stimulation (TMS), and directed ultrasound which have been shown to modulate the circuitry undergirding consciousness. This is a rich pipeline that should not be discounted.

Despite this progress, the guideline remained grounded in the reality of clinical practice. It recognized that patients with disorders of consciousness often succumb to complications of brain injury and inadequate nursing care. And, to that end, it called for the prevention and amelioration of medical complications that can adversely affect morbidity and mortality such as aspiration pneumonia, bedsores, and urinary tract infections. The systematic review also betrayed a quandary: despite the call for the improved diagnosis and treatment of this population, the review revealed that the number of rehabilitation days utilized by this population has declined over the past 15 years (13). Therein lies the tragic paradox: despite all the progress that necessitated the drafting of the first practice guideline for this population, these patients remain underserved. Indeed, utilization data related to brain injury rehabilitation reveal that individuals are more vulnerable to neglect than they were before the aforementioned advances were achieved (21). It is a promising yet sobering story.

For our consideration of the emerging nosology of disorders of consciousness, the real headline from the practice guideline was the redesignation of the permanent vegetative state into the chronic vegetative state. A review of the data by this expert panel suggested that 20% of patients thought to be permanently vegetative might in fact be redesignated at a higher level of function after the temporal milestones associated with permanence had been surpassed. For anoxic brain injury, this was three months; and for traumatic brain injury, it was one year. Patients who were vegetative after these points were considered to be in the permanent vegetative state without hope of additional recovery—that is until now. From an epistemic vantage point, this change in the classification of the vegetative shows the evolution of our knowledge and reminds us that much of what we now think is true is actually contingent and still evolving.

The redesignation of the permanent vegetative into the chronic vegetative state undermined a central catechism of North American bioethics dating to the Quinlan case and on to Cruzan and Schiavo, namely the futility of the vegetative state once it had been characterized as permanent (21). All these right-to-die cases were predicated on the irreversibility of the condition and the futility of any effort to provide treatment. This is captured graphically on Ms. Nancy Cruzan's tombstone (22,23). Above her name where she is characterized as “most loved daughter-sister-aunt” is a depiction of either an EKG or EEG tracing. What begins as something resembling ventricular tachycardia blends into a script “thank you.” This is followed by a flat line. This progression tracks with her vital statistics:

Born July 20, 1957

Departed Jan. 11, 1983

At Peace Dec. 26, 1990

For the Cruzan family, Nancy left them in 1983 when she sustained her brain injury. It was as if she had died then and thus a date worthy of a tombstone. She had “departed” and would never return.

While these grave markings reflect the tragedy sustained by one family, they also capture a cultural zeitgeist about the vegetative state. To be vegetative was as if being dead, if not in body then at least in soul. As we will see, this became the moral warrant and the legal predicate to remove life-sustaining therapy from such patients, which launched the right-to-die movement in the United States. While this evolution in clinical practice was not without controversy—end-of-life decisions became a central feature of the “culture wars” that would mark the ensuing decades—cases like Quinlan, Cruzan and Schiavo reconfigured prerogatives of patients and families at life's end (24,25).

With the redesignation of the permanent vegetative state as chronic, all this changed. The permanent vegetative state was no longer irrevocable. One of the central pillars upon which the right to die had been anchored had drifted away, raising questions central to clinical practice, bioethics, and the law. In this essay, I will grapple with the implications of this evolution in nosology and suggest that it reflects tremendous progress in our understanding of disorders of consciousness, our ability to diagnose these conditions more accurately using emerging technologies, and our efforts to make fledgling attempts to treat conditions thought for millennia to be beyond our reach. Ultimately, these new scientific developments require our ethics to accommodate this progress. To that end, we need to both preserve the hard-won right to die and affirm the right to care for a population that has labored under the presumption of futility (26). To meet such aspirations, we need to better understand how the nosology characterizing disorders of consciousness evolved and how these developments informed clinical practice, medical ethics, and the law.

To retrace this history, let us begin with the origins of the vegetative state and how this curious brain state was named.

II. THE ORIGINS OF THE VEGETATIVE STATE

Writing in 1998, Fred Plum explained how the vegetative state received its name. The explanation is not what the naïve reader might think it to be. It was neither a pejorative description of patients nor an indication of their worth. Instead, it was a term that had a long philological history dating back to Aristotle with distinguished intermediaries—the French physician, Xavier Bichat (1771–1802) and the American neurologist and endocrinologist, Walter Timme (1874–1956)—along the way. Plum asked:

How did the vegetative state get its name? Not as the reader might think. Patients' families challenge us, implying that we regarded the sufferer as a vegetative. Not so! The conception of a vegetative nervous system goes way back (27).

With Zoe Adams, now a medical student at Yale, I traced the historical origins of the vegetative state, dating it back to Aristotle (28). The astute reader will recall that Aristotle himself was a taxonomist and a botanist who attempted to characterize his world much as we are doing here and Dr. Barratt did last night.

To that end, in Book II of De Anima (On the Soul) (29), Aristotle introduced a taxonomy that consists of vegetative and animalic faculties. The first faculty is nutritive or vegetative and modeled on the plant. The second, seen in animals and humans, consists of sensation, movement, and thought. Like the distinction between autonomic and higher cortical functions as exercised by the brain stem and cortex, these are ascending functions with the higher ones being dependent on the more foundational one. Unlike the give and take between the arousal offered by the reticular activating system in the brain stem which undergirds the conscious thoughts of the cortex, Aristotle's taxonomy was binary and static. The vegetative faculty could neither sense nor perceive.

Because it was descriptive and had this provenance dating to antiquity, Jennett and Plum preferred “vegetative” over other names such as “apallic syndrome” or “coma vigile.” But what about the term “persistent”? Here we see the brilliance and humility of Jennett and Plum who wanted to convey a sense of permanence within the confines of what they knew and the data they possessed. Invoking an admirable degree of conceptual and temporal prudence, they limited themselves to “persistent.” They explained their rationale:

Certainly we are concerned to identify an irrevocable state, although the criteria needed to establish that prediction reliably have still to be confirmed. Until then “persistent” is safer than “permanent” or “irreversible”; but “prolonged” is not strong enough, and unless it is quantified it is meaningless … (5)

Without longitudinal outcome studies, they could not make a claim for permanence; hence, they eschewed a more definite adjective to be “safer.” This was in part what the 1977 study was meant to determine, and I think we should pause to place this paper into historic context. Long before outcomes studies were commonplace, Jennett and Plum were identifying a need for longitudinal studies to better define the duration of the vegetative state. Their caution was rewarded by the new practice guideline of 2018, 46 years after their “Lancet” paper.

But first this nosology took an errant turn. In 1994, the Multi-Society Task Force (MSTF) published a two-part essay in the New England Journal of Medicine further delineating the vegetative state (17). A vegetative state only became persistent once it had lasted a month after a patient transitioned out of coma. It became permanent three months after anoxic brain injury and 12 months if the etiology was traumatic. This distinction reflected the global insult of anoxia versus the variable patterns of traumatic brain injury (TBI) as well as the more favorable prognosis of TBI versus anoxic injury. Once these etiologically informed milestones were reached, the state was considered permanent.

But it was not so simple. James L. Bernat who was part of the MSTF told me in an interview for my book, Rights Come to Mind: Brain Injury, Ethics and the Struggle for Consciousness, that even though “permanent” replaced “persistent” for vegetative states of longer duration, it remained a prognostic statement:

The adjective “persistent” refers only to a condition of the past and continuing disability with an uncertain future, whereas “permanent” implies irreversibility. Persistent vegetative state is a diagnosis; permanent vegetative state is a prognosis (21).

Nonetheless, despite the variability of prognostication, a sense of inevitability about brain injury took hold. Presumptions about the permanent vegetative state were generalized to others with severe brain injury. Outcomes were invariably futile. The presumption was that patients invariably did poorly. At a conceptual level, medicine viewed these brain states as if they were diagnoses and fixed when in fact they were syndromic and, thus, potentially prone to fluidity and recovery to higher levels of function.

Despite his central role as the court-appointed neurologist in the Quinlan case and his association with the vegetative state, Plum did not fall prey to dichotomizing outcomes. Where others simply saw futility Plum considered the utility of additional diagnosis and treatment. For him, it was more than a right or a duty to die but an empirical question. In an unpublished manuscript from the Fred Plum collection at the New York Presbyterian Weill Cornell Medical Center Archives, I found a manuscript that captures Plum's concerns during the late 1970s. He wrote:

We have studied over 100 patients … can identify within 24 hrs. by their neurological signs alone who cannot recover above a vegetative level … who will do well … This leaves a middle group for whom more information is needed but where presenting every effort at treatment must be made to know their maximal potential and how to judge their early signs … (30).

This is an early effort at risk stratification with a focus on the middle third with prognostic uncertainty. The goal was not to simply affirm a right to die but rather achieve proportionate care, realize a patient's “maximal potential,” and importantly assess outcomes in light of initial presenting signs. Early on, Plum was neither naïve nor a nihilist. His admonition to present “every effort” suggests that patients with the same presentation might have different outcomes and categorical conclusions about their prognosis and the utility of care are not warranted.

III. THE VEGETATIVE STATE AND THE RIGHT TO DIE

Despite Plum's scientific caution, broader cultural forces coalesced to make the vegetative state central to nascent efforts to advance a right to die. Bioethics since the 1960s has been predicated on the advance of patient self-determination and autonomy. This took hold in two important spheres: reproductive rights and how we die. Quinlan which was adjudicated in 1976 by the New Jersey Supreme Court (9) was preceded by Roe v. Wade which was decided in 1973 (31). These two cases can be understood as an assertion of bodily dominion and a reflection of the rights movements of that era.

In the context of Quinlan, the right to die was a negative right to be left alone and to refuse life-sustaining therapy. Judicially, the futility of ongoing care—and notably the loss of a cognitive or sapient state—became the ethical and legal bases for withdrawal of life-sustaining therapy. Drawing upon the testimony of Dr. Plum, who examined Ms. Quinlan at the court's request, Judge Hughes granted the family's request to remove the patient's ventilator. He wrote that:

… It was indicated by Dr. Plum that the brain works in essentially two ways, the vegetative and the sapient. … We have no hesitancy in deciding … that no external compelling interest of the State should compel Karen to endure the unendurable, only to vegetate a few more measurable months with no realistic possibility of returning to any semblance of cognitive or sapient life (9).

Here we see the distinction of the lower autonomic and higher cognitive functions reminiscent of Aristotle's De Anima and, notably for us, the value placed upon the latter rather than the former. Indeed, it was the loss of cognitive or sapient life that led Judge Hughes to offer his landmark ruling with no hesitancy. This loss, coupled with the lack of any “realistic possibility” of its recovery, ushered in a right to die in American jurisprudence.

But there is a curious twist in the decision. Absent a cognitive or sapient state, how could she possibly “endure the unendurable”? Would not that require sentience? Self-awareness would be inconsistent with the vegetative state. We can only surmise that the burden of the vegetative state is experienced by others who have to bear witness and not patients so afflicted. This is another aspect of the vegetative state, the intolerability of imagining oneself or a loved one stripped of that which marks one's personhood. In the context of an emerging right to die, the operative question becomes what kind of life is one that lingers devoid of the self?

Catalyzed by the unique biology of the vegetative state and its clinical implications, over the decades since Quinlan, American medicine has become acculturated to a right to die. The vegetative state became the ultimate in medical futility. Nothing can or should be done because it is an immutable state as graphically illustrated by the Quinlan autopsy results published in the New England Journal of Medicine in 1994 (32). Her brain was a gelatinous gel, 835 g (normal weight, 1300 g), with thinning cortices and hydrocephalus ex vacuo. Structurally, this was not the substrate for consciousness or the persistent self. These perceptions were only reified in the national debates over Nancy Beth Cruzan and Terri Ann Schiavo. Terri was another young woman in the vegetative state who helped to advance the right to die in public perception and clinical practice.

Even as these cases were further solidifying a clinical consensus about the futility of the vegetative state and furthering its linkage to the right to die in America, a number of disturbing outlier cases were gaining attention (21). Starting in the 1980s, patients were recovering consciousness long after permanence should have set in. Initially, these cases were unexpected and inexplicable, but soon a new clinical entity began to emerge. Nestled amongst patients thought to be vegetative, there seemed to be another cohort of patients who were different and were in fact conscious at a liminal level. They had apparently suffered from a nosological neglect syndrome. Simply put, these patients who would come to be identified as being in the minimally conscious state had been out of our gaze.

Instead of seeking to ferret out these patients, first identified by Joseph T. Giacino in 1997 (33,34), medicine and society sought to generalize the futility of the vegetative state to all sorts of severe brain injury. Over 50 families touched by severe brain injury whom I interviewed before writing Rights Come to Mind indicated that patients with severe brain injury encountered a disinterested health care system (21,35). Their narratives painted a picture of therapeutic nihilism. Care was futile, patients did not improve, and, because of this, there was a pattern of neglect. Notwithstanding growing scientific evidence to the contrary, systems of care assumed a static view of brain injury. This led to unconsidered or premature decisions to withhold or withdraw life-sustaining therapies, premature palliative care recommendations, or the prompting of surrogates to consent to organ donation. Patients who survived hospitalization were often discharged to skilled nursing facilities that were ill equipped to handle the sequelae of severe brain injury (36).

The counsel given to practicing clinicians was prescriptive and informed by presumptions of clinical futility. A paper published in 2002 in Neurology entitled, “The Family Conference: End-of-Life Guidelines at Work for Comatose Patients,” captures the prevailing clinical norms. The authors urge that, “The attending physician of a patient with a devastating neurologic illness come to terms with the futility of care.” They continue to advise practitioners that:

… Those families who are unconvinced should be explicitly told they should have markedly diminished expectations for what intensive care can accomplish and that withdrawal of life support or abstaining from performing complex interventions is more commensurate with the neurologic status (37).

Note the language about futility, diminished expectations, and the highly prescriptive suggestion that withholding or withdrawing advanced therapies is proportionate—a recommendation that becomes even more directive when one considers that this counsel is for patients who are still comatose and in a self-limited state of unresponsiveness which only represents the initial couple of weeks following loss of consciousness. Such recommendations are suggested very early in the course of care before patients may have had the chance to declare their actual prognosis.1

This was the cultural zeitgeist and an unintended consequence of the linkage between the futility attached to the vegetative state and the origins of the right to die. In practice, these recommendations have led to premature decisions to withhold or withdraw care. A 2011 Canadian Medical Association Journal article reports that while in-hospital mortality for TBI patients with a disorder of consciousness was 31.7%, a full 70.2% of those deaths were accounted for by a decision to withdraw life-sustaining therapy (38). While many of these decisions were undoubtedly appropriate, the high percentage of deaths associated with decisions to withdraw care suggests a distortion of potentially more salubrious trajectories that might have occurred had these decisions not been made and if patients had access to supportive care and a trial of therapy. Instead of a presumption of clinical utility, I maintain that the high incidence of these decisions points to the presumption that ongoing care would be futile.

A far more nefarious case of neglect was reported in early 2019 when a woman thought to be in the vegetative state gave birth to a baby boy. She had been residing at Hacienda Healthcare, a long-term care facility in Phoenix (39). Her case is troubling on several levels. First, as reported by the Associated Press, until she gave birth, the staff was unaware that she was pregnant. They only became aware that she was pregnant when she started to moan during childbirth. This would indicate that there was neither recognition of the weight gain and increased abdominal girth of pregnancy nor an appreciation that menses had ceased. This would constitute an inexcusable degree of nursing neglect. Second, her pregnancy was the consequence of a sexual assault by a staff nurse whose DNA matched that of the baby. This would be normatively problematic as a patient who is totally dependent needs to be protected. This is a fiduciary obligation and responsibility. And finally, and perhaps most relevant for my thesis of neglect, her caregivers misdiagnosed her.

Let me explain. If she were indeed vegetative and in a state of wakeful unresponsiveness, she would neither have reacted viscerally nor audibly to childbirth. Vegetative patients should neither feel pain nor know distress. They do not have intact pain networks when assessed on neuroimaging (40). Given this, her cries of distress are particularly alarming. They suggest a degree of awareness consistent with the minimally conscious state, a state of liminal consciousness in which patients can perceive pain and intermittently respond to their environment. This misdiagnosis seems probable based on how she reacted to childbirth as well as the comments of an attorney spokesperson for the family who notes that, “Their daughter responds to sound and is able to make facial gestures (39).”

This misdiagnosis is particularly painful in this context. It suggests that she was aware, at some level, during childbirth and potentially so when she was sexually assaulted, the tragedy of that violation now compounded by the additional burden of sentience. And it gets even more problematic because even as she was aware, she was unable to communicate her distress since MCS patients are unable to reliably communicate.

As the new AAN/ACRM/NIDDLR practice guideline 14 suggests, the status quo of neglect is no longer tenable. This realization follows 20 years of scientific progress delineating brain states associated with disorders of consciousness through functional neuroimaging and electrophysiology and nascent therapeutic efforts grounded upon a growing understanding of mechanisms of injury, neural circuitry, and brain resilience. This scientific evolution has not only opened our eyes to new ways to view the brain, but it has also helped us appreciate new normative obligations that follow upon new knowledge.

IV. NEW SCIENCE AND OLD PRESUMPTIONS

Previously, I have written that neuroethics is fundamentally an ethics of technology (41). Technology reveals problems that heretofore went unrecognized and unappreciated (e.g., the covert consciousness that might be revealed through neuroimaging). Once we know that patients who appear to be unconscious have the potential to be other than what they seem, our sense of responsibility to them changes. If they are conscious, we ask, might they have feelings? Might they hear what is said in the room? Might they feel pain? Questions that would not have even been considered are now prompted by new technologies that allow us to peer into the brain and into our own hearts.

John Dewey, the great mid-century American pragmatist philosopher, astutely noted the relationship of technology to ethics. In “Common Sense and Scientific Inquiry”, he observed that, “Inventions of new agencies and instruments create new ends; they create new consequences which stir men to form new purposes (42).” So it is with the emerging technologies that are informing vanguard work in the neurosciences. These data have reconfigured our moral universe and helped us appreciate practice patterns that were both uninformed and inequitable. In Obergefell v. Hodges, Justice Kennedy explained how new knowledge can prompt us to appreciate the unfairness of the status quo. He wrote that, “… new insights and societal understandings can reveal unjustified inequality within fundamental institutions that once passed as unnoticed and unchallenged (43).”

Dewey's focus on “new instruments” and Kennedy's conclusion about how new knowledge can transform old presumptions is especially true for the scientific revolution that has catalyzed new knowledge about disorders of consciousness over the past two decades. This revolution was made possible by the new instrumentation afforded by fMRI, which has allowed us to peer into the injured brain and detect variance amongst patients who appear clinically similar at the bedside. A study published by our group in Brain in 2002, for example, revealed that vegetative patients who appeared similar at the bedside had strikingly different scans when metabolic activity was assessed (44). Vegetative states produced by anoxic brain injury had global decreases in metabolic activity on functional neuroimaging where those with multifocal traumatic brain injury had variable patterns, sometimes with retained islands of cortex that were metabolically active. A casual glance at these two classes of scans would suggest that these patients were functionally different even though they were both vegetative (44).

The central common feature was that brains in the vegetative state, whatever the etiology, have lost their integrative function (45). That is, even if there are large metabolically active areas, these regions remain disconnected from the rest of the brain because widely distributed networks and the integrative function of the thalamus have been disrupted. A study by Steven Laureys from Liege in Neuroimage illustrates this point (46). Vegetative patients and controls were exposed to a noxious stimulus. Controls activated a widely distributed pain network in contrast to vegetative patients who only activated the primary sensory area and nothing else. The lack of activation of these widely distributed networks and associated areas is emblematic of the lack of integrative function seen in the vegetative state.

This can be contrasted with patients in the minimally conscious state (MCS) who appear similar to vegetative patients but in fact are conscious and have a distinct neurobiology. First codified in 2002 by a consensus panel (47), MCS patients demonstrate episodic and intermittent awareness of self, others, and the environment. They may look up when a loved one enters the room, respond purposefully to sound, reach for a cup, and even say their name. The difficulty is that they do not produce these behaviors reliably, making accurate diagnosis a challenge. A chilling paper by Caroline Schnakers and colleagues reported that 41% of vegetative patients in chronic care following TBI who were thought to be in the vegetative state were actually minimally conscious (48).

From a functional perspective, these behaviors are undergirded by an integrative capacity that is absent in the vegetative state. In a 2005 study, Nicholas D. Schiff and colleagues demonstrated this network capacity (49). Patients in MCS were played narratives by a loved one as they underwent fMRI. The narratives were played forward and backward so they had the same frequency spectrum. Notably, when the tapes were played in forward mode, these patients, who often appeared unresponsive at the bedside, activated regions of interest in the cortex as did controls. They did not respond to the gibberish when the tapes were played backward. This had profound implications because patients were responding to language, grammar, and syntax. Interviewed by Benedict Carey of The New York Times on February 8, 2005, I said, “This study gave me goose bumps because it shows this possibility of this profound isolation, that these people are there, that they've been there all along, even though we've been treating them as if they're not (50).”

For me, this was further corroboration that MCS was different and that these liminally conscious patients deserved something better than the custodial care that patients with severe brain injury too often receive. It prompted the thought experiment of imagining one's self in a nursing home bed and thought to be in the vegetative state but able to process, at some level, what was said in the room because you were misdiagnosed and actually in MCS. The thought is chilling and even more poignant if we consider that we do not need to imagine that scenario.

V. TERRY WALLIS

In Rights Come to Mind, I profile the case of the Arkansan Terry Wallis who has in many ways become the face of MCS and of the tragedy of being undiagnosed for nearly two decades (21). His story began in 1984 when he was in a car accident that nearly took his life (51). Variously described as being in a coma or the persistent vegetative state since his accident, he had a “miracle awakening” on July 11, 2003, while receiving “custodial care.” His first words were “Mom” and “Pepsi”, and over the ensuing weeks he gained greater fluency.

His story gained international press coverage. But it was a curious awakening. He was stuck in time like Rip Van Winkle. In his mind, Ronald Reagan was still president. Even more disturbing, when I reviewed his medical record, there was behavioral evidence that he was not in the vegetative state all those years but rather in the minimally conscious state. The Wallis family—who gave me permission to tell their story as did all named families who participated in an IRB and HIPPA-compliant narrative study—told me that they asked for a neurologist to reassess Terry. They thought that he might have been aware at times. But they were told that this was impossible, that he was vegetative, and after all those years it wouldn't matter. What was done was done. Mr. Wallis told me that Terry was unassessed by a neurologist for 19 years. And even as his brain recovered, his body deteriorated. He developed contractures. He didn't get physical therapy. Again, what was the point? He was vegetative and never going to recover. So his daughter learned how to do range of motion exercises to help him out.

After he began to speak and I sought to help the family gain access to rehabilitation, I contacted the Office of Marion Barry from the 1st Congressional District in Arkansas for help. Before I called for congressional services, I needed Terry's Social Security number so I called Angilee his mother. After I inquired, she asked me to hold on and asked Terry, “What's your Social Security number?” I heard a muffled voice in the background and then Angilee told me the number. I asked her, “Was that Terry who told you the number?” She said “Yes” and added, “… we thought he was wrong, we looked it up, he was right (21).”

The amazing thing was that Terry during his long “time away” had retained this information, this bit of data so identified with the self. While so many thought he was gone, something of himself persisted for over two decades. In retrospect, the story becomes even more chilling. Angilee told me about an episode in 1993 when I interviewed her for my book. This was a full decade before he started to speak.

As Angilee recounted to me, she received a call from the nursing home where Terry was residing. He was sharing a room with an elderly patient who had advanced dementia. Overnight, that patient, in his confusion, became tangled in his sheet, asphyxiated himself, and died. One of the nurse's aides who did not know that the vegetative state precluded awareness had an intuition that Terry was upset and called his mother. Angilee told me the rest of the story:

… One of the aides called me from work one morning and told me she was not supposed to do that but … that man had passed away that night, and that it had bothered Terry … I needed to be down there … [when she arrived] Terry was lying there with his eyes open wide, he would not go to sleep, I mean he was making no noise at the time. But I stayed there with him most all the day until he finally went to sleep. So I don't know what he saw, but I know he saw something. And I know it had, now, I knew then it had to be something that was really bad (21).

In retrospect, Angilee now had a sense that even then Terry was aware in a way that she had not then perceived and we could not know. The astute reader will do the math and appreciate that this episode occurred nine years before MCS was codified as an entity. In 1993, there was no diagnostic category into which Terry could be placed. MCS was still nestled as an unrecognized subset of patients within what was then thought to be the permanent vegetative state.

Technology has been a great help in overcoming these limitations. By 2006, my colleagues had demonstrated dynamic changes in Terry's brain that might have been related to his late recovery and regained ability to speak (52). Using diffusion tensor imaging (DTI), they demonstrated axonal sprouting some 19 years after his injury—first in his parietal-occipital region and later in his cerebellum. Over two series of scans about a year and a half apart, both sprouting and pruning of these connections were observed in a process that was reminiscent of the normal developmental process in the maturing brain.

Of course, these two series of scans were but two moments in time decades after Terry was injured. They were simply snapshots that are suggestive, but in no way conclusive, about mechanisms related to the return of language and the recovery process. And what was observed could have been late events that had nothing to do with the disquiet observed in 1993 when his roommate died. These data cannot answer that question, but a more recent study published in 2016 in Science Translational Medicine by Daniel J. Thengone, then a graduate student at Weill Cornell, suggests that changes in network structure can contribute to the recovery of communication late in the course of severe brain injury (53).

In a longitudinal study of Margaret (Maggie) Worthen, the patient who I profile in Rights Come to Mind (21), Thengone and colleagues demonstrated a similar process of white matter changes over a 54-month period in Maggie's brain. Over this period, DTI revealed white matter changes in Broca's area and across the hemispheres essential to the recovery of speech. These two papers are remarkable because they demonstrate brain resilience after a period of latency and dynamic changes in structure which seems to repurpose a developmental process in the service of brain repair. It also suggests that we might reconsider neurorehabilitation more as an educational intervention, given the parallels of brain recovery to normal development (21,54). This would have implications for both the scope and duration of rehabilitation. After all, we send children—and their developing brains—to school for decades to take advantage of their developmental trajectories (55). Should we not do the same now that we appreciate that there is a similar—and eerily parallel—longitudinal process taking place in the injured brain (56)?

Returning to Terry Wallis that fateful night in 1993, with this additional information about brain recovery and resilience, as well as the compelling narrative, there is good reason to believe that Terry was likely aware at some level. While we can neither know for sure that he was aware nor appreciate what he understood, the likelihood that he was conscious at some level must be entertained seriously. The fact that we did not yet have a name for Terry's brain state in 1993 does not mean that he wasn't covertly conscious. The lack of a name also should not blind us to the possibility of evidence that contradicts our priors. If nothing else, this unfolding story should remind us that there are far more diseases and syndromes than we have named, much less been able to understand for want of curiosity and imagination.

As physicians, this realization might be the most important point of this entire lecture. It urges us to have nosological humility when we categorize and organize our diagnostic space. While we need to be careful not to christen disease states before their time, we must likewise be cautious not to reify diagnostic categories that should ideally evolve. We all must remember this point whether we are contemplating diagnostic schema for space medicine as envisioned by Dr. Barratt or musings about the workings of the mind.

VI. NEUROGENOTYPE AND PHENOTYPE: THE EMERGING DISCORDANCE

In the context of brain science, diagnostic schemas are being scrambled by the recognition of covert consciousness. Covert consciousness refers to patients who appear unresponsive at the bedside but who are conscious. Some may respond to volitional tasks when challenged in the scanner. This discordance, if were to analogize to genetics, between genotype and phenotype was first demonstrated in 2006 (57). A paper featured in Science described how a patient who was behaviorally in the vegetative state five months after traumatic brain injury was asked to imagine performing motor, spatial, and linguistic tasks (58). When instructed to imagine playing tennis, walking about her house, and distinguishing similar words, she activated the appropriate regions in the motor cortex, parietal lobe, and language centers. This was big news as vegetative patients were not thought to be capable of doing this, especially after the recent controversy over the fate and moral status of people such as Terri Schiavo.

But as I pointed out at the time (59), the patient featured in the Science article was not vegetative despite the paper's provocative title, “Detecting Awareness in the Vegetative State.” One cannot satisfy the criteria of wakeful unresponsiveness if one is following volitional commands. In a commentary published in the Hasting Center Report, I suggested with my colleague Nicholas Schiff that the patient was in a nonbehavioral minimally conscious state (60). She was following commands in her head if not behaviorally at the bedside. Like the variation seen in the same colored peas in Mendel's garden that were both homozygotes and heterozygotes, what appears the same on the surface may not be equivalent at a deeper level (61). Here the distinction between phenotype and genotype was the difference between apparent unresponsiveness and covert consciousness discernible through the graces of neuroimaging.

Dr. Schiff, with whom I co-direct the Consortium for the Advanced Study of Brain Injury (CASBI) at Weill Cornell and the Rockefeller University, subsequently described this discordance as cognitive motor dissociation(CMD), where patient motor output may not correlate with the patient's cognitive status (62). This observation first made in chronic brain states has since been observed in the acute care setting by applying neuroimaging and electrophysiologic measures to patients who appear unconscious and asking them to perform volitional tasks (63,64). Most recently in 2019, Jan Claassen of Columbia University demonstrated that 15% of unresponsive patients had brain activation on EEG, four days after injury and that this early sign was a favorable prognostic indicator for subsequent functional recovery in this observational study (65).

These emerging data have important clinical, ethical, and conceptual implications. At a clinical level, the possibility of covert conscious and cognitive motor dissociation has normative implications for decisions to withhold or withdraw life-sustaining therapy in patients with acute brain injury (66). Because loss of consciousness is often the predicate to make these irrevocable decisions, it becomes important to know whether what is observed at the bedside accurately reflects the patient's true brain state. If patients have CMD in the acute setting, their outcomes may be more favorable, especially if maximal efforts are made to facilitate recovery and avoid medical complications that often foreshorten the lives of these patients. I predict that an evaluation for CMD will become the standard of care for unresponsive TBI patients in the ICU before a decision to withhold or withdraw care, not so much to preclude such a choice but to make it more informed.

Conceptually, this swathe of papers describing the nonbehavioral brain states of CMD calls into question an effort primarily amongst European neurologists to redesignate the vegetative state as the unresponsive wakefulness syndrome (UWS) (67). These neurologists felt that the use of the term “vegetative” was pejorative. Beyond the origins of the vegetative state we have already addressed that refutes this concern, the redesignation of the vegetative state is highly problematic because patients with covert conscious may appear unresponsive but are not. Why, as science has advanced to allow us to assess a patient's neurological genotype or circuitry, would we want to take a step backward and rely solely on phenotype to characterize patients? It would be like discounting the theory of inheritance when reconsidering Mendel's peas—so much for the work of Avery, MacLeod, and McCarthy or the discoveries of Watson and Crick (68), and lest we forget, Rosalind Franklin (69). It makes very little sense.

In their prescient “Lancet” article, Jennett and Plum understood this (5). When they discussed the finding of the vegetative state at the bedside, they cautiously noted that, “it seems wakefulness without awareness.” This phrase ascribes authorial provenance to Jennett and Plum for UWS but does so with a very salient difference. Jennett and Plum were careful to add the word “seems.” Fred Plum was known to be a superb wordsmith and editor, and this was not an accident. “Seems” was added to convey their hesitancy to assert definitively that the unresponsive wakefulness of the vegetative state is invariably without underlying awareness. They knew the limits of their science, relying as they were on bedside observations. In 1972, they had no way to peer inside the injured brain. Functional imaging was still decades in the future, as was the identification of covert consciousness. But logically, they knew that it could not be precluded. Their careful addition of “seems” presciently accounts for this possibility. Again, Jennett and Plum have been vindicated by developments in neuroscience.

VI. THE CHRONIC VEGETATIVE STATE

Now that we have traversed this long complicated journey and the evolution of disorders of consciousness, we can return to where we started, with the rather dramatic development that the permanent vegetative state has been replaced by the chronic vegetative state. Recall the AAN/ACRM/NIDDLR evidence-based review which found that 20% of patients thought to be permanently vegetative can move on to a higher level of functional status (13,14). Given the tight linkage of the futility of the vegetative state to the evolution of the right to die, this is a dramatic, albeit late, realization. If the right to die is predicated upon “… no realistic possibility of returning to any semblance of cognitive or sapient life,” as Chief Judge Hughes wrote in Quinlan (9), then what is the state of the hard-won right to die? Is that now open to question? Do we have to rethink end-of-life practice patterns and reevaluate our ethics or clinical practice?

I do not think so (39,66). The right to self-determination at life's end is well established in law and ethics. Nonetheless, we do need to be more careful in informing surrogates of their choices and making sure that our best prognostic and diagnostic information is provided as they make critical choices for their loved ones. To better enable these conversations, it would be helpful to discuss the 20% as I did with James Bernat in an essay that accompanied the evidence-based review and practice guideline (15). We should start by noting that for 80% there will be no recovery above the vegetative state and that the 20% who do recover are more heavily tilted toward those with traumatic versus anoxic brain injury. It is also important to recall, following the empirical work of Schnakers cited previously (48), that upwards of 40% of patients thought to be in the vegetative state are misdiagnosed and are in fact minimally conscious. Thus, 4 out of 10 “recoveries” out of the vegetative state are more appropriately considered to be an accurate identification of the minimally conscious state. This is an error in assessment, not a change in a biological process.

Along these lines, some patients who evolve may have a state change when provided with drugs, devices, or some other sort of neuromodulation. These patients have the intact, integrative, neural networks that distinguish MCS from the vegetative state but are behaviorally vegetative because these networks, while present, remain inactive. With the addition of some form of neuromodulation, these networks were activated and behaviors consistent with MCS were manifested. By definition, these patients are better characterized as being in MCS, not the vegetative state. Vegetative patients who lack intact networks do not respond to network activation.

Another category of patients are those who have CMD. They would not be identified by bedside evaluation but only on neuroimaging where a volitional task evoked an appropriate activation in a region of interest. These patients, while appearing to be vegetative, are in fact not in that brain state but are at a minimum in MCS.

A final category is those patients who have had late structural changes in their white matter (as was seen in Terry Wallis and Maggie Worthen) that might undergird a change in brain state. Of course, these changes could result in overt behaviors, activations only seen on neuroimaging as in CMD, or be dependent upon activation via neuromodulation.

It is important to deconstruct who the 20% are lest we overvalue this number and foster a lack of realism about prognosis. The most critical dimension of the redesignation of the permanent into the chronic vegetative state is the clinical and normative mandate to identify MCS and CMD when it exists and also potentially engage in a therapeutic trial with agents that have the potential to prompt state changes via neuromodulation.

VII. NOSOLOGY, COVERT CONSCIOUSNESS, AND CIVIL RIGHTS

One could argue that the foregoing disquisition on nosology was an exercise in semantics, a truly academic exercise without practical or real-world relevance. But as an ethicist working in the American pragmatic tradition (70,71,72,73,74,75,76), the goal was instrumentality and making a difference in the world through diagnostic discernment. Here I am informed by former Harvard University President, Derek Bok's volume, Beyond the Ivory Tower, where he writes of the social responsibility of the modern university (77). These obligations also adhere to academic medicine, especially when it comes to meeting the needs of the underserved, neglected, and unrecognized.

Sadly, as my research and that of others has revealed, patients with severe brain injury are among the most marginalized in modern society. If they survive their initial hospitalization, they are often sent to chronic care facilities where they receive what is euphemistically called “custodial care.” There they are sequestered from the medical mainstream, unassessed and abandoned in ill-equipped facilities that can neither manage the complications of brain injury nor provide a modicum of surveillance to assess a patient's brain state. There they linger, deprived of rehabilitation and often of adequate pain management (78,79).

I have argued in Rights Come to Mind and elsewhere that our failure to meet the needs of patients with severe brain injury is a violation of American disability law which has a mandate to maximally integrate individuals into civil society (21). In a New York Times op-ed, I argued that this is an emerging civil rights issue that we have yet to fully grasp (80).

The Americans with Disabilities Act (ADA) (81) has been hailed as American's last great civil rights legislation. It ended the segregation of people with disabilities and was perhaps the most enduring accomplishment of the George H. W. Bush administration (82). With bipartisan support, the ADA was enacted in 1990 to overcome the same sort of segregation experienced historically by African-American citizens. Emanating from many of the same social forces that informed the Jim Crow laws of the South, discrimination against people with disabilities was motivated by their perceived inferiority and need for protection against the social mainstream (83). These perceptions which were ill-conceived with respect to race were also ill-suited to people with disabilities, and the ADA sought to remedy this. A statement from the Civil Rights Division of the Department of Justice noted that the ADA was a “Mandate for the elimination of discrimination against individuals with disabilities” precisely because “historically, society has tended to isolate and segregate individuals with disabilities (84).” Ruth Bader Ginsburg in an important Supreme Court case Olmstead v. LC upholding the ADA noted in her opinion for the majority that, “Congress explicitly identified unjustified ‘segregation’ of persons with disability as a form of discrimination (85).” Similar arguments can be found in international law, namely the UN Convention on the Rights of Persons with Disabilities which calls for the maximal integration of people with disabilities into society (86,87). A failure to do so constitutes a violation of human rights (88,89).

What constitutes a failure of integration for patients with severe brain injury? Conventionally, when we think of the ADA, we think of mobility and accessibility issues. We imagine people in wheelchairs who cannot gain access to work without a more accommodating public transportation system or work environment. For these folks, accessibility means a cut in the sidewalk so they can overcome the barrier of a curb, an elevator down to a subway in lieu of stairs, and doorways that are wide enough to handle the width of a wheel chair. Basically, it means getting out of the house and into society (80).

When we apply this logic to people with severe brain injury, things become a bit problematic because so many of these individuals will need institutional care due to the severity of their injuries. How then does the ADA apply to them (21)?

There is an old philosophical saying that the only consciousness one can know is one's own. When we speak to others and elicit a nod, a grimace, or a verbal reply in response to what our conscious self is saying, we can infer that we are speaking with another sentient being by their outward signs of understanding. The key to recognition for patients with covert consciousness is the restoration of functional communication. Restoration is the key to reestablishing its cognate, community reintegration. That is, by restoring functional communication, we bring these people back into the room and into the nexus of family, friends, and society. This is how social and biological networks ruptured by severe brain injury are restored. When this happens, the reintegration mandate of the ADA is fulfilled.

Fundamentally, the restitution of communication is about the restoration of relationality. This is seen in Pedro Almodovar's Academy Award-winning film, Talk to Her (90), about two women with severe brain injury: one succumbs and the other regains the ability to communicate by establishing a connection with the patient. This is captured in the original Spanish title of the Academy Award-winning film, Hable con Ella, or talk with her. The errant preposition speaks volumes. You speak with someone to reestablish a relationship; with that conversation, you achieve reintegration (21,91,92) .

Following this logic, the restoration of functional communication has been the holy grail for those threating patients with disorders of consciousness. It is to this population what the achievement of mobility is for patients with motor impairments and helps to overcome barriers and promote social integration.

VIII. DEEP BRAIN STIMULATION IN THE MINIMALLY CONSCIOUS STATE

To that end, my colleagues and I restored functional communication in a patient in the minimally conscious state. In a paper published in Nature, we reported on the first use of thalamic deep brain stimulation in the minimally conscious state in a 38-year-old man who had sustained closed head trauma following an assault six years prior to study enrollment (93,94). The subject sustained blunt trauma to the right frontal lobe with subsequent bilateral hematomas, significant mass effect, and elements of subfalcine and central herniation. His initial Glasgow Coma Scale score was 3, which is the lowest score compatible with life. He transitioned from the vegetative state to MCS within two to three months of injury. He received rehabilitation. His highest level of function was inconsistent command following with eye movements which had been stable and without improvement when he was enrolled in the study and assessed comprehensively with a vetted behavioral assessment instrument.

Electrodes were implanted bilaterally in the intralaminar nuclei of the thalamus in a six-month double blind crossover study. During the ensuing period, he regained cognitively mediated behaviors including the recovery of fluent language and improved limb control, and his ability to eat by mouth and manage secretions returned for the first time in the six years since his injury. He was able to say six- or seven-word sentences, tell his mother he loved her, and voice a preference when taken shopping at Old Navy (21). This improvement in functional status correlated with stimulation and constituted first evidence that DBS can promote late recovery in severe TBI.

From an ethical point of view, the restoration of decisional voice was remarkable. As a co-investigator, I was responsible for designing the ethical framework for this phase I study with more than minimal risk in a patient who was unable to give consent (21,95,96) . Given prevailing views and ethical norms concerning research in a decisionally incapacitated subject, this sort of intervention was generally deemed impermissible because informed consent could not be obtained from the patient. For nearly a decade, I argued in the literature that such research should be permissible and pointed out that we were conflating and confusing informed consent with respect for persons. It was one thing to do a study without a competent subject's consent or over their objection. It was quite another thing to demand consent when consent cannot be obtained and the object of the intervention is to restore the subject's ability and agency. Eventually, this argument won the day, and we proceeded with our study with approval of multiple IRBs and an investigational device exemption (IDE) from the Food and Drug Administration (21).

We designed the consent document seeking authorization from legally authorized representatives with the caveat that should neuromodulation restore the subject's decisional capacity the subject should be reconsented for continued enrollment in the trial. I remember positing this scenario to my colleagues as we formulated the IRB protocol, and I got the sense that “we should be so lucky.” But they respected my arguments and the need for closure. If I was arguing for the legitimacy of the intervention based on its potential to restore the patient's voice, then it was only right to respect that voice when it returned. So a reconsent provision became part of the plan (21).

It was a remarkable day after the study concluded when we were reprogramming the stimulator and the subject became fatigued. It was a hot summer day and the process was laborious (21). There are four contacts on each electrode and every time a charge or field was changed for each contact, the subject would need to undergo a behavioral assessment. Both staff and the subject were exhausted. At one point, a physiatrist on our team asked the subject if he wanted to stop and he said he did. I looked at my watch and recorded the time for my book as we had restored the subject's ability to participate in medical decisions. I thought it was agency ex machina—the restoration of decision making via a neuroprosthetic device. It wasn't at the level of consent and refusal but at a lesser standard of assent and dissent. Nonetheless, it was a major step forward and a remarkable moment to witness. A spark of personhood that seemingly had been lost forever had now been retrieved by electrical stimulation of the brain.

Needless to say, my colleagues and I felt pretty good about what we had accomplished. We knew there was far more to do, but the journey had begun. But not everyone agreed. Grant Gillett, a prominent neurosurgeon and bioethicist, wrote an essay in the Journal of Bioethical Inquiry entitled, “Minimally conscious states, deep brain stimulation and what is worse than futility (97).” He argued that we had made the subject worse because he is now “awakened” and more aware than he had been of the tragedy of his life and the burden of his existence. It would have been better if he had been left alone. What we did was worse than futility, it was harm. He even created an acronym. With a nod to Shakespeare, he noted that there's the “RUBB,” the risk of unbearable badness. It was a tough critique to read.

And then Corinth Pecco, the mother of Greg Pearson who was the subject in the study, told me in an interview that Greg had become sad. With Gillett's commentary fresh in mind, Ms. Pecco told me that Greg had been crying:

She continues, “He was crying one day I was visiting him and I said, ‘Greg why are you crying?’”

“He says, ‘I’m crying for Cory.’”

Innocently, I asked, “Who's Cory?”

“That's his brother. That's his brother that does not come to see him, that's in denial.”

“And even I started crying because here he is, he's aware, he knows what's going on.” (21)

It's a remarkable exchange. One could infer, as Gillett did, that Greg's tears were from self-pity and despair for his plight. But the narrative does not support this. When Corinth asked her son why he was crying, he told her he was crying for Cory, his brother. Simply put, he misses him. And later in the transcript, there is the inference that he may be saddened that his brother can't bear to see him this way and so stays away. These are not tears of self-pity but of yearning and loss for the “brother that does not come to see him, that's in denial.” The power of the revelation causes Corinth herself to cry. She realizes that her child is aware and knows what is going on.

Gillett also presupposes that Greg was unaware because he could not speak. While this may be true, it is also possible that he was aware but unable to verbalize because he was in CMD. We cannot know for sure. But if he were aware and unable to talk, he would be better off if his voice was restored so he could express his distress or defend his interests. This is consistent with the disability rights mantra, “nothing about us without us (98).” When decisions and choices need to made for people with disabilities, let's not presume to know what they are thinking or what they might want. We could look at Greg's tears and think one thing, only to be wrong.

This is a central premise in my book, which is captured in its title Rights Come to Mind (21). Drawing on a disability rights paradigm, the argument was to give voice to the voiceless, who had been silenced by severe brain injury, and recognize the rights of the conscious. While it has been a long slow argument, I am gratified that it is taking hold. Even a former critic, Professor Gillett, wrote a laudatory review of the book in The Hastings Center Report (99).

IX. A LEGAL DEFENSE FUND FOR SEVERE BRAIN INJURY

Although I was pleased by this turn of events, the object was not to win an academic argument but rather to a make difference in the lives of a most vulnerable population. As I reflect on the past couple of decades of learning about and advocating for patients and families touched by severe brain injury, I have come to the conclusion that there are profound inequities that must be addressed. My work in medical ethics has helped me understand that this is a fundamental question of human rights and distributive justice. Ethics has helped provide clarity on the diagnosis but unfortunately has done little more than elucidate a complex clinical and normative space.

Five years ago, I was privileged to complete a sabbatical at Yale University as the Dwight H. Terry Scholar in Bioethics and while there was asked to teach at Yale Law School. Since then, I have taught a writing seminar that produces legal scholarship related to the needs of severe brain injury. This has grown into CASBI@YLS (100). Through this effort, I have come to the conclusion that, if ethics is the diagnosis, the law is the therapy. It is through legal advocacy that patients will secure their rights and gain access to the care that is their due. While working with talented law students at Yale, I have expanded upon my earlier work outlining and deepening the legal scholarship that will utilize disability law to advance the needs of this population (101).

After establishing this scholarly predicate, we hope to emulate the immensely successful Legal Defense Fund (LDF) of the NAACP and create an LDF for severe brain injury. The NAACP LDF was instrumental in helping to overcome segregation and advance equity for all Americans, notably people of color (102). The historic efforts of the LDF culminated in the landmark Brown v. Board of Education decision in 1954 (103). This case was the impetus for the Civil Rights Act of 1964 (104), which was the antecedent for important advances in disability law such as the Rehabilitation Act of 1973 (105) and the Americans with Disability Act that was subsequently enacted (81). The NAACP Legal Defense Fund's experience is also instructive because patients with severe brain injury suffer from a degree of societal segregation that is reminiscent of the Jim Crow era.

At this juncture, an LDF for severe brain injury remains aspirational, but the need is real. Our aspirations must come to pass; after all, what is the sense of progress in the neurosciences if those who might benefit remain in the shadows. At a minimum, our goals should be to assure a proper diagnosis, identify covert consciousness when it exists, tend to the pain and symptom management of those who are sensate, and help to restore functional communication. This is a heady agenda but certainly one that is within our reach.

X. ANTIQUITY AND AEQUANIMITAS

Some will remain naysayers who are stuck in a paradigm of futility, a vestige of the right-to-die movement, and ask why we should try in the face of such overwhelming odds. This is understandable as genuine challenges remain. But as our generation clarifies its values and sets priorities, it is important to appreciate that these questions are as old as medicine itself. The issue of what to do with respect to brain injury goes back to a schism between Hippocrates and Galen, the fourth century physician from Pergamum, who was the master's greatest disciple. On brain injury, the master and student diverged.

Wilder Penfield (106), the great neurosurgeon and epileptologist who founded the Montreal Neurological Institute (MNI), captured these differing views in a ceiling he designed for the MNI (21,107). Against a backdrop of Golgi cells are ancient symbols of the brain including hieroglyphics and a ram's head. Around this is a Galenic refutation of the Hippocratic aphorism that all brain injuries are invariably fatal. As translated from Greek by Osler's nephew, W. W. Francis—about whom Charles Bryan writes in this volume of the Transactions (108)—Galen wrote, “But I have seen the injured brain healed.” (107) Galen offers an alternate view countering the Hippocratic corpus and even prevailing modern-day notions that brain injuries are immutable.

As a medical ethicist, I might be expected to side with the Hippocratics. But on this one I am squarely in the Galenic camp, a position that members of the Climatological should also embrace. As has been presented here, brains can be dynamic and resilient in their recoveries. The diffusion tensor images of patients such as Terri Wallis and Maggie Worthen—with their sprouting and pruning of white matter long after injury—are proof positive of the Galenic retort to Hippocrates.

At a deeper epistemic level, these discernable changes speak to the importance of accepting and embracing an evolving nosology. While this will lead to diagnostic and prognostic uncertainty as paradigms shift, we can do nothing less. We must give up our clinical catechisms and follow the facts even if they lead to inconvenient truths. As William Osler reminds us in The Leaven of Science, “The determination of structure with a view to the discovery of function has been the foundation of progress (109).”

DISCUSSION

Crowley, Boston: That was an outstanding lecture … just fabulous … you do wonderful work. What is to be learned from these circumstances? For example, in Awakenings by Oliver Sacks, he relates such stories. I've heard several times now that in schizophrenics suddenly somebody dies and the patient comes back to a perfectly normal state for weeks. Has any PET scanning or CT scanning been done that might add something here?

Fins, New York: Right … so there's another drug I didn't mention, zolpidem, the sleeping pill … it activates the mesocircuit. Interestingly, as with patients suffering from Parkinson's disease, people would initially respond to L-dopa and then would stop responding as the brain normalizes. Similar results happen with zolpidem. Initially, it stimulates the mesocircuit, which restores evidence of consciousness. But as the brain normalizes, it begins to act like a sleeping pill and the positive effects wear off. If I had more time and more slides, I could show you a slide before and after the use of zolpidem. Patients with a consciousness disorder have a sort of a hypoactive frontal cortex … when you give them zolpidem and then scan their bran the frontal cortex lights up. This affects 14% of people. When they respond to zolpidem, their frontal cortex is activated … those mesocircuit networks are then turned on. We were unable to perform an fMRI when we did our deep brain stimulation study because the technology was unavailable for a functional scan with electrodes in the brain which could have caused injury. But that's one response to your question. The other thing with respect to Awakenings is that patients who have undergone neuromodulation have to now re-equilibrate. My colleagues and I have a brain initiative grant looking a thalamic stimulation in moderate to severe TBI, and I just got an R01 to study patients and families before and after neuromodulation. Subjects will have to now equilibrate to their new reality in which they have more functionality. More importantly, Helen Mayberg worked on depression and deep brain stimulation in which she activated Brodmann area 25. As patients come out of their depressed state, they get better. They're more active and aware, which forces them to deal with the problems that put them into their depressed state in the first place. I have much more to say, but … there are physiological and psychological dimensions to this awakening as it were. Thank you.

Wolf, Boston: That was a terrific talk, and I thought your point about paying attention to pain in these patients is very crucial. I am going to ask a difficult question: Have you or your colleagues ever looked at the cost of increasing the quality of life in these patients?

Fins, New York: Thank you. I think one way of looking at this, given that the health care system is very parsimonious, is how to deal with the fixed costs already associated with this population. So let's say deep brain simulation for this population works, it remains investigational, and it costs $50,000 to put the stimulator in. That's a cost. But what are the offsets? These patients no longer need tube feeds, and they're more mobile so they don't get bed sores. What's the cost of a bed sore? If a family is disinclined to withdraw ongoing care, I think there may be a cost-benefit analysis to this intervention. But as you know, when you do experimental work, you do not look at a cost-benefit analysis early on because everything is more costly at the beginning. If you focused on costs at the outset, it would stifle innovation. As for the question of what counts as quality of life, it is complicated and a matter of perspective. In the introduction of my book, Rights Come to Mind, I was very careful not to romanticize these brain stakes. This is not something anyone would aspire to. But that is not the right way to think about it. What we're trying to do is meet patients where they are … the condition to where they have evolved. If you look at the family narratives from my research, first the families want their loved ones to survive, they want them to wake up, they want their eyes to open, they want those eyes to be seeing eyes, and then they want to be able to communicate. Unfortunately, we will all need to face this complexity. We dichotomize outcomes … patients either die or they totally recover. In our work, we're trying to meet people where they are because these people suffer and we can attend to their suffering. I think families need to know about these subtleties and what the possibilities are to make an informed decision. I am in favor of informed consent and informed refusal, but I think we need to provide information to enable sound choices.

Ziedel, Boston: Wonderful talk … I am aware of research going on in mice where you can anesthetize the mouse and then stimulate certain areas of its brain and the mouse awakens and functions while under deep anesthesia. As soon as you shut off the electrodes, they go back to being asleep. I think there's great promise in deep brain stimulation; the hope is that what is being done with mice can be applied with more precision to specific neuronal types in the thalamus. How did you choose what you stimulated in the first place, and are we improving that capability?

Fins, New York: Right, so this comes out of my colleague Niko Schiff's work and over two decades of animal modeling and looking at the centrality of the thalamus and the activation of the mesocircuit. This is precisely what we described in our 2007 Nature paper—using deep brain stimulation in the minimally conscious state. There it was direct stimulation of the thalamus that led to activation. Zolpidem enters the mesocircuit at a different juncture and inhibits inhibitions which exist in the basal ganglia and takes the brakes off inhibitory impulses allowing for output from the thalamus to the cortex. So, it's part of that same circuit. As I mentioned earlier, Helen Mayberg's work with depression is also informed by a circuit-based approach. There are people who are doing deep brain stimulation without a circuit-based understanding, and I think it needs to be done within the context of a circuit-based understanding.

Billings, Baton Rouge: I have one minor comment. There's a wonderful book by David and Pauline Rabin entitled, To Provide Safe Passage: Humanistic Aspects of Medicine … That's what all of us do every day in our lives. Particularly physicians in their work and lives. David Rabin was an endocrinologist who died of Lou Gehrig's disease. Before his death, he could only communicate by blinking his eyes. The book contains several chapters detailing what his doctors thought people, who were slowly falling apart, really needed. It was what we all do day in and day out with our friends and families and patients. That is, we try to provide “safe passage.” I am sure you are aware of the book; it is a wonderful book … and dovetails with what you've been talking about.