ORIGINAL ARTICLE

Does the Golem Feel Pain? Moral Instincts and Ethical Dilemmas Concerning Suffering and the Brain Marshall Devor, PhD*; Isabelle Rappaport, BA†; Z. Harry Rappaport, MD‡ *Department of Cell & Developmental Biology, Institute of Life Sciences and Center for Research on Pain, The Hebrew University of Jerusalem, Jerusalem,; †3 Lamerhav St., Ramat Hasharon; ‡Department of Neurosurgery, Rabin Medical Center, Petah Tiqva, Israel

& Abstract: Pain has variously been used as a means of punishment, extracting information, or testing commitment, as a tool for education and social control, as a commodity for sacrifice, and as a draw for sport and entertainment. Attitudes concerning these uses have undergone major changes in the modern era. Normative convictions on what is right and wrong are generally attributed to religious tradition or to secular-humanist reasoning. Here, we elaborate the perspective that ethical choices concerning pain have much earlier roots that are based on instincts and brainseated empathetic responses. They are fundamentally a function of brain circuitry shaped by processes of Darwinian evolution. Social convention and other environmental influences, with their idiosyncrasies, are a more recent, everchanging overlay. We close with an example in which details on the neurobiology of pain processing, specifically the question of where in the brain the experience of pain is generated, affect decision making in end-of-life situations. By separating innate biological substrates from culturally imposed attitudes (memes), we may arrive at a more reasoned approach to a morality of pain prevention. &

Address correspondence and reprint requests to: Marshall Devor, PhD, Department of Cell & Developmental Biology, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel. E-mail: [email protected]. Submitted: February 7, 2014; Revision accepted: March 1, 2014 DOI. 10.1111/papr.12207

© 2014 World Institute of Pain, 1530-7085/14/$15.00 Pain Practice, Volume 15, Issue 6, 2015 497–508

Key Words: ethics, mirror system, moral instinct, pain pathways, sociobiology, suffering, terminal sedation, vegetative, end-of-life

INTRODUCTION Just imagine a television advertisement for a big production in Madison Square Garden featuring gladiators fighting to the death or a web invitation to the burning of heretics under the Arc de Triomphe. The events themselves would clearly be unimaginable, and even the announcements would be in poor taste. Yet, these events were once commonplace. As recently as 1827, breaking-on-the-wheel was still lawful in Germany.1 Have human beings become more “humane” since public torture and pain-as-entertainment were routine? After all, it is during our modern “moral times” that some of history’s cruelest events have occurred.2 To cite just a few: the Holocaust; the “killing fields” of Cambodia; and more recently, bombs intentionally placed in trains, taverns, and pizza restaurants. In this article, we briefly consider the sources of current normative convictions on what is right and what is wrong concerning pain and its uses, and what may have wrought the dramatic changes in approach that have occurred over time in enlightened society. The overall perspective is that fundamental ethical predispositions are a function of brain circuitry shaped

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by processes of Darwinian evolution. Implementation of this underlying biological substrate in the form of specific ethical choices, on the other hand, is subject to evolving (nongenetic) social factors that have changed radically in the past 200 to 300 years in much of the world. We shall begin with a review of the sources, religious and secular humanist, of current attitudes with respect to the uses and abuses of pain. How did it come to be that most people today see virtue in the prevention of pain in ourselves and in others, and in the relief of pain when it is present? We shall then present evidence of an earlier biological substratum: innate cerebral modules that influence our reactions to pain and that antedate cultural/environmental influences. These include “mirror neurons” in the brain and empathy in animals and in man at the sight another apparently in pain. Finally, we will consider the location(s) in the brain where the experience of pain plays out and how this can affect ethical decision making, particularly in end-of-life situations. Awareness of the interaction of our in-built ethical biases (“moral instincts”) with emerging social norms can provide a more robust basis for discussions of ethical approaches to current dilemmas related to pain.

pawn in a seemingly puerile challenge by the devil, supposedly aimed at testing his faith. Despite his innocence, Job is made to suffer terrible loss. In the narrative, this is justified by placing God’s actions outside the realm of human comprehension. Job’s pain and suffering is a device used to test his commitment and as a means of imposing authority. Along the same lines, the use of physical punishment is generally sanctioned as an educational tool to shape the behavior of children: “Spare the rod and spoil the child”, or in its Jewish version, “Whoever loves his son, chastise him often that he may be a joy to him when he grows up. Whoever disciplines his son will benefit from him, and boast of him among his intimates” (Ben Sira.30: 1–2.). Beyond these uses, the gratuitous infliction of pain, even in animals, is strictly condemned in both the Torah and in Talmudic sources. The approach is remarkably modern. For example, there are strict guidelines for minimizing pain in the butchering of animals for human consumption. In general, the Old Testament prohibits causing pain or injury for the advancement of personal or public interests. Violations are condemned. But elsewhere in the ancient world, noble limitations on the infliction of pain were by no means universal or even common.

PAIN AND RELIGION Pain for Punishment, Control, and Education

Pain to Extract the Truth

In the biblical narrative of creation, pain as punishment appears early. In the story of Adam and Eve, after eating from the Tree of Knowledge, God punishes Eve with the curse of bearing children: “b’tza’ar”, a word in the original Hebrew that is consistently interpreted as “in pain” or “in sorrow”. Painful retribution for misdeed has been with us ever since. In the mid1800s, general anesthesia was introduced, permitting complex surgery and painless childbirth. This discovery was broadly hailed as “The conquest of pain”. But it was condemned by some Christian clerics as an unholy subversion of God’s mandate that childbirth be painful. Even some physicians supported this position. One was quoted as saying, “Pain is the wise provision of nature, and patients ought to suffer pain while their surgeons are operating: they are the better for it, and recover better.”3 In the well-known biblical story of Job, the role of pain and suffering in the world is viewed differently. Job feels that he has led a blameless life, and in fact, we as insiders in the story know that this is so. He is a

Until fairly recently, legal systems in Europe routinely inflicted pain as part of a mandated attempt to discover truth, albeit following hopelessly misguided logic by today’s standards. In “trial by ordeal,” it was believed that the innocent individual would not succumb to wounds inflicted by the court, while the guilty would. Legally mandated torture had a different aim, which was to extract a confession of guilt, and hence to permit a valid conviction and punishment. Punishment was not the objective of torture, at least not until the “guilty” had confessed. Indeed, judges were formally responsible for the wellbeing of the individual on trial. If the torture ordered by the judge was too intense, and the person on trial died, the judge himself could be charged with murder.4 The Catholic inquisition also used torture to extract confessions of guilt, notably from converted Jews who were suspected of secretly practicing their old religion (Judaizers). For other victims, the aim was not so much to establish guilt as to extract confession of sin, a prerequisite of true contrition and ultimately salvation.4

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Pain as Currency: Paying your Debt and Gaining Favor The live sacrifice of children in the ovens of Moloch was aimed at obtaining benefits for the parents; the price they paid was acknowledged. The pain of the children was not. In the Roman Empire, the infliction of painful death began as a means of political control and proceeded to sport and public entertainment. In Christian eschatology, the transgression of Adam and Eve plays a role far beyond their specific crime and its punishment. It set the stage for Christ’s enduring pain and suffering on the cross so as to redeem mankind from Adam and Eve’s original sin (Romans 5:19).4 By suffering pain, and according to some by inflicting it, a debt is paid. Pain buys redemption. The ennobling features of pain and martyrdom are also part and parcel of other faiths such as Shi’ite Islam,5 Sikhism, the Hindi Thaipusam festival, the Plains Indian “Sundance”,6 body scarification in some African tribal religions, and more., although it is generally shunned in Judaism. Pain proves courage, coming of age, manliness, and devotion to the deity (in men and sometimes also in women) and wins atonement.

SECULAR HUMANIST APPROACHES TO THE ETHICS OF PAIN For the Greater Good One of the first secular authors to deal explicitly with ethical aspects of pain was the infamous Marquis de Sade. He proposed a strange ethic focused on the perpetrator and ignoring the victim. Sade stressed the usefulness of pain in social control as well as its desirability in personal life, codifying all manner of coercion and torture routinely used by the state, the church, and individuals as a means for achieving their ends.7 Beyond utility, the sadist actually draws pleasure from inflicting pain. Then as now, most people viewed sadism as perverse and evil, even if it is not uncommon. This testifies to an underlying predisposition that theories such as de Sade’s must overcome. Jeremy Bentham, a contemporary of Sade, promoted an opposite point of view more in keeping with most people’s moral instincts. “Nature has placed mankind under the governance of two sovereign masters: pain and pleasure. It is for them alone to point out what we ought to do, as well as to determine what we shall do”.8 His philosophy of “Utilitarianism” posited that man is driven by the desire to maximize pleasure and avoid

pain. The role of society, and hence its moral compass, is to facilitate the achievement of pain-free happiness for the majority of citizens, even if the principle clashes with the well-being of a minority. Interestingly, Bentham was a firm champion of animal rights. He argued that the ability to suffer, which he believed animals have, underlies moral choice with respect to pain, and not the ability to reason. A variant of utilitarianism argued that in the dynamic balance of pain and pleasure it is better to prevent pain than to promote happiness (“Negative utilitarianism”9). A modern bioethical movement, “Abolitionism”, champions the use of biotechnology to avoid pain and increase happiness. It promotes the wider use of mood enhancing drugs such as antidepressants, for example, and deep brain stimulation of pleasure centers.10 The utilitarian emphasis on the avoidance of pain and enhancement of pleasure, weighing right and wrong by the utility of the decision (“the greater good”), resonates widely. But it also sometimes clashes with other deepseated cultural attitudes such as the sanctity of life (regardless of the presence of pain), the work ethic (even if the work is not pleasurable), and the idea that individual rights need to be considered in addition to the common good (even if this may spell pain for some). Utilitarianism also fails to distinguish between action and the withholding of action. This limitation is captured in contemporary philosophy by a series of “trolley dilemmas”.11,12 The original version applies to the obligation to save lives, although within utilitarianism, these dilemmas translate easily to minimizing pain. For example, the trolley driver sees 5 backpackers on the track ahead and realizes that they will surely die a painful death if the trolley continues on down the track. The brakes and bell have failed so he can’t stop or sound a warning. His one option is to turn onto a side-track. But on the side-track there is a single backpacker walking who will surely face the same painful fate if the driver should turn. Strict utilitarianism calls for making the turn, saving the 5 at the cost of the one. In Jewish legal thinking (Halacha), this has been debated. But key decisors, notably Maimonides, insist that the principle, “Thou shalt not murder,” is absolute. The killing of one through a voluntary act is unacceptable, even at cost 5 dying as a result of withholding action. The passive option is taken as the “right” one. The fate of the 5 is “in God’s hands”. The Utilitarian can feel proud that, in aggregate, his decision has minimized suffering. However, he tends to hit a wall of uncertainty when the details of

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the hypothetical are changed. For example, what happens when the requirement is to murder a healthy person to provide transplant organs in order to save the lives of 5 others (or 10)? Killing the one for parts is an active choice, just like killing by turning the trolley. And yet most people instinctively sense a profound difference, accepting the former decision but not the latter. Again, an underlying predisposition appears to be present. The absolutist religious conviction, that withholding action is the ethically correct decision, also becomes strained when the details of the scenario are changed. Does inaction remain right when the number of innocents about to suffer and die increases from 5, to 10, to 100? To dispel any doubt, Halacha remains absolute; no matter how many people might die as a result, one must not murder. In all fairness, however, we should point out that the commandment “Though shalt not murder” refers to murder. It cannot be assumed that the calculus for pain is the same as the calculus for life. We are not aware of clear guidelines in Halacha as to whether it might be acceptable to inflict torture on an innocent bystander if this were to save 5 (or 10, or 100) from certain torture.

CHANGING MORES CONCERNING PAIN Current Attitudes and the Criminalization of Cruelty Attitudes have changed radically since the dawn of the industrial revolution. The 8th Amendment of the United States constitution (passed in 1787) and the British Slavery Amelioration Act (1798) both include a clause against “cruel and unusual punishment”. Cruelty, at least in part, refers to whipping and other practices intended to inflict pain. In 1948, the General Assembly of the United Nations adopted the Universal Declaration of Human Rights in which Article 5 states that: “No one shall be subjected to torture or to cruel, inhuman, or degrading treatment or punishment”. Although there are dissenting voices, current interpretations hold that the infliction of pain must be avoided even in the interrogation of a terrorist who might yield information that could save the lives of many innocents (the “ticking bomb” scenario). Even “soft” torture, such as sleep deprivation or psychological distress, is deemed unacceptable.13 In fact, for many, the modern obligation to circumvent pain goes well beyond questions of punishment and torture. A number of major organizations have recently come out with public calls that access to

treatment for pain, in a medical context, be declared a fundamental human right.14 Set against the norms of earlier generations, including European jurisprudence and medicine, and Christian religion, the change in attitudes over the past 200 to 300 years is astounding. It clearly does not involve genetic evolution, but we contend that it does rest upon an underlying moral instinct that is Darwinian. One might consider it a gene 9 environment interaction. We do not pretend to have a comprehensive explanation of this change, but we note a few contributing factors. Rising Standards of Living Increased (some might say excessive) aversion to the presence of pain is at least in part a consequence of improved standards of living. Life has ceased being cheap. If one no longer has to contend with hunger, then why should one have to suffer back pain? Life has also become less “physical”. We switch on the lights rather than rubbing sticks together to make fire, we buy our food rather than growing it and we use machinery more than muscles. Keeping physically fit has become a leisure-time activity, paid for at the gym. The minimization of physical contact with nature reduces day-today experience with pain and with it, the willingness to tolerate pain. The Ascent of Diversity Trends such as the collapse of colonialism, the ease of long-distance travel, instant communication, international labor markets, and the spread of democracy have resulted in societies far more heterogeneous than ever before. Day-to-day contact with people of different races, religions, and cultural mores makes it more difficult to stigmatize strangers as “other” or even subhuman and hence fit subjects for abuse. It is easier to empathize with others, to feel their pain, when one’s experience ranges beyond the village square. Josef Stalin is quoted as saying, “The death of one man in a tragedy; the death of a million is a statistic”.4 Public Scrutiny The development of the media and mass dissemination of facts, images, and opinion has had the effect of homogenizing ethical perspective across societies. It is harder to sustain ethical positions far from the main-

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stream. The loss of anonymity makes people more accountable for their attitudes and actions.

BIOLOGICAL ROOTS OF ETHICAL CONVICTIONS CONCERNING PAIN

The Need for Responses to Modern Dilemmas

Ethics as Instinct

The pertinence of ethical debate within and outside of the framework of religion took a remarkable leap forward with advances in medicine in the second half of the 20th century. Organ transplantation and technologies that permit prolonged life-support in vegetative patients have raised unprecedented dilemmas that challenge classical ethical assumptions. What constitutes the death of a person?15 When can we remove organs from a donor for transplanting into another? When does new life acquire rights, including protection from pain? In late term therapeutic abortions, for example, the fetus is dismembered in utero, piece by piece, generally without anesthesia or analgesia. This is despite the fact that the fetus shows adaptive avoidance responses to noxious stimuli and other signs, suggesting that it might feel pain.16 Should failure to provide pain relief for the aborted fetus be considered malpractice? Related questions arise at the end of life. Is it acceptable to carry pain relief all the way to the induction of permanent unconsciousness (“terminal sedation”)? Is this so different from stopping life to relieve pain in incurable disease? How do we balance the duration of life against the quality of life? Secular-humanist thinkers, framers of law, as well as defenders of long established religious doctrine have been challenged by these modern dilemmas. “Bioethics” has emerged as a new academic discipline with the mission of dealing with them. But philosophical analysis is more a tool for defining issues than for establishing truths or avoiding conflicting opinions. For example, Peter Singer, one of the foremost proponents of “Preference utilitarianism”, takes the position that the shared/universal human interest in avoiding pain must be extrapolating to other species.17 He argues that as animals are certainly more conscious than newborn infants or vegetative patients, they too have an intrinsic “right” to protection from pain. Widespread acceptance of the virtue of humane treatment of animals notwithstanding, many find it difficult to accept Singer’s challenge to the special sanctity of human life over animal life, and of human pain over pain in animals. Indeed, erosion of the distinction between man and animal in the discussion of ethical conduct strikes many as intrinsically immoral and dangerous: the biological substratum again shining through?

Ethical approaches based on transcendental-religious and secular-humanist traditions are fundamentally divorced from empirical data and evidence-based reasoning. Wilson18,19 was among the first to argue strongly for a biologically based morality anchored in Darwinian ideas.20,21 The proposed evidence base is the comparative study of animal behavior, particularly of social interactions. The idea is that one might be able to identify origins of underlying ethical predispositions in instincts that arise as a direct product of natural selection. This approach, “Sociobiology”18 or “Evolutionary Psychology”,22 sees the primary origin of our shared moral convictions, both religious and secularhumanist, as an evolutionary consequence of the dynamic relation between social cooperation and defection (“cheating”). An illustration is Game Theory’s Prisoner’s Dilemma.23 In this scenario, 2 players can cooperate to mutual benefit or one can selfishly betray the other to his own maximal benefit. But if they both chose betrayal, they both lose. The most profitable long-term approach from the selfish perspective of both individuals is cooperation, and soon enough this comes to be viewed also as the “right”, the virtuous, approach. Human players can use spoken language to negotiate cooperation, including a means of detecting cheating and applying appropriate sanctions. Remarkably, this same outcome can be achieved in animals in a Darwinian framework, without language or high-level cognitive capacity. As the resulting “cooperative instinct” has survival benefits for all players, during the course of evolution it can become stabilized in the genome and hard-wired in the brain. There may be an appearance here of selfless altruism, including playing fair when you can benefit by cheating. But by cooperating with others (particularly with relatives) individuals help themselves. Thus cooperation, and even self-sacrifice, can be an “evolutionarily stable strategy”, one that persists in the population over generations. A cooperation instinct passed down from our collective animal past is only a breath away from an ethical precept. . . “Do unto others as you would have them do unto you”. Here, we need to point out the obvious: even after codification by religious and secular-humanist tradition, innate predispositions that bias toward what is right and

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what it wrong have only a limited effect on human behaviors. They do not usually provide specific guidance re particular dilemmas. And even when they do, they only provide guidance. All the things that wise men tell us about “weakness of the flesh” and other diversions from the path of righteousness continue to apply. The fact that people do bad things does not mean that there is no bedrock of shared ethical conviction. Moral instincts are of a general nature: predispositions, not reflexes. Empathy In addition to instinctive predispositions to cooperation based on mutual benefit, the biological roots of ethical sentiment appear to have at least one additional element: emotional bias toward others (empathy). Empathic response reflects “resonance” between oneself and others. This response is particularly marked between adults and children, including the children of others, but it also applies among adults. It appears to be a built-in function of the brain of higher mammals, including man.24,25 A possible neurophysiological substrate for empathy is “mirror neurons” and the “mirror system” in primates.26 A mirror neuron is a cortical cell that fires, that is, becomes electrically active, both when an animal acts (eg, by grasping an object) and also when it simply observes another animal (or a human) performing a similar act. It has been proposed that mirror systems contribute by enabling animals to anticipate the actions of others so as to optimize responses. They may also enable children (and perhaps higher primates?) to impute intent and conscious awareness in others (“Theory of Mind”27). Empathy in animals may additionally extend to the realm of emotions and sensations.28,29 For example, there is evidence that a mouse may experience pain, or at least exhibit pain behavior, simply by viewing another (familiar) mouse that is in pain.28 Data based on non-invasive brain scans suggest that a mirror system relevant to pain and suffering also operates in man. For example, when human experimental subjects undergo functional magnetic resonance imaging (fMRI) while observing a loved one suffering in pain, the anterior insular cortex bilaterally, the rostral anterior cingulate cortex (ACC), and other brain areas associated with affect (emotions) “light up”. Some individuals report actually feeling pain, as a sensory experience, when they observe another in pain.30,31 In these subjects, the primary somatosensory cortex also

becomes activated. This empathic “resonance” of the brain likely evolved to promote cohesiveness among kin for mutual protection, as well as to help the individual to avoid painful experiences himself. Consistent with this perspective, empathic neural responses tend to be larger when subjects are confronted with loved ones experiencing pain, or members of their own social or racial group.32,33 Non-invasive brain imaging offers the intriguing possibility of actually visualizing the brain areas where activity correlates with moral choice.34 Extrapolating, an agenda aimed at modifying the activity of these brain areas is possible.35 Does the Golem Feel Pain? Is it possible to distinguish between what is biologically hard wired in our moral personalities and what constitutes cultural overlay? Has the mandate of “the hardware” shaped our modern ethical attitudes in the same sense that we physically resemble our ancestors (hardware), but are taller and live longer by virtue of improved nutrition and hygiene? Is this why gladiatorial sport is no longer conceivable? Novel ethical dilemmas are being created galore with our exponentially increasing scientific abilities. Tackling them might benefit from a better appreciation of the relationship between our underlying human inclinations and more recent sociocultural trends. An example of this line of thought is the hypothetical question of whether it is morally acceptable to inflict pain on an android (an intelligent robot). This issue has been popularized in the widely seen movies, The Blade Runner (1982) by Scott Ridley and Artificial Intelligence: AI (2001) by Steven Spielberg, which feature robots that are virtually indistinguishable from human beings. Causing these androids to suffer leaves the viewer profoundly uncomfortable as a strong empathic response is evoked. On the other hand, intellectually he knows that his empathy may be misplaced. . . the android is in fact nothing more than a machine, a toaster with a human-like outer wrapper. Medieval Jewish jurisprudence deals with the question of whether it is permissible to be cruel to a Golem. The Golem is an apocryphal human-like creation made of clay that is endowed with basic intelligence by supernatural (Kabalistic) means. The argument is made that as long as the Golem does not cause harm to the community, cruelty is not permissible. Interestingly, this position is not based on the presumption that the Golem has the capacity to suffer. Rather, the rationale is that

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cruel behavior to a life-like being might lead to the adoption of cruelty to real human beings.36 A similar line of thinking surrounds the rationale for the ancient (biblical) injunctions against taking eggs from a nest without first shooing away the mother bird, or slaughtering a calf in the presence of its mother. The ethical/ Torah precept does not presuppose anthropomorphic emotional responses in animals as does much of contemporary discourse about animal rights. Rather, it rests on the effect that wanton cruelty to animals is likely to have on man.36 This is clear from the parallel, explicit biblical injunction against cooking a kid in its mother’s milk. In this instance, the mother is not even present.

ETHICAL CONVICTIONS ABOUT PAIN AND THE BRAIN Whether or not the mother bird, or the Golem, is capable of suffering in the same sense as humans remains ambiguous. But humans can suffer. We will now turn to a consideration of how our understanding of specific neural substrates of pain can impact on moral choice. Where is Pain in the Brain? Pain is a sensory and emotional phenomenon experienced by a conscious individual. The central abiding mystery of the brain is the question of how electrical and chemical activity of nerve cells can give rise to conscious experience. No answers are currently in sight. However this question may ultimately be resolved, there has never been much doubt among neuroscientists or neurologists that the neural process that constitutes pain perception, as well as other forms of conscious experience, occurs in the cerebral cortex.37 If the cortex is destroyed, or not yet sufficiently developed (human fetus, lower animals), it is presumed that consciousness must be absent. And if consciousness is absent there can be no pain experience and hence, no ethical issues concerning the unnecessary infliction of pain. The dogma of a cortical seat of pain and consciousness is convenient. First, until recently, the presence of a “flat” EEG (a marker of lost cortical function) was a key criterion for “brain death” and a diagnostic basis for the ethical harvesting of vital organs for transplantation. The logic is that if the individual is already dead, brain dead, then turning off the respirator is not murder.12 (Note that criteria have changed recently and now focus on indicators of irreversible damage to the brainstem.)

Second, even when the EEG is not quite flat, or when cortical function is lost but the subcortex is still viable, the patient may be declared permanently vegetative with no chance of recovery. At this point, it may be deemed acceptable to shorten life by withholding life-support technology. We do not propose to debate whether shortening life under these circumstances is or is not acceptable. Some argue that the value of life itself, irrespective of its quality, trumps all other considerations. Rather, we will ask whether cortical death (as opposed to brainstem death) indeed means the absence of pain and the absence of consciousness. Might pain be experienced in the vegetative patient despite the absence of cortical functioning? And if pain is (or might be) present, once a decision to shorten life has been made, is it necessary to use a painless method of ending life? All of these questions revolve around an answer to the question, “Where is pain in the brain?” Consider the following: A vegetative patient with massive cortical injury is presumed to have no conscious experience and no pain sensation. Under certain circumstances, legal authorities may sanction the removal of life-support modalities from such patients. The widely reported late 1990s case of Terry Schiavo is an example. If the patient is being artificially respired, this might mean switching off the respirator; death comes in a matter of minutes. But if, as is often the case, the patient can breathe and regulate blood pressure and chemistry on his own, ending life-support usually means withdrawing a feeding tube. The patient then proceeds to die of starvation and dehydration over a period of weeks. In both cases, death could, of course, have been caused rapidly and painlessly with a lethal injection. But this would be active intervention. Permitting death by being passive, by withholding life-support, is also proscribed as noted above, but in most traditions it is a lesser evil. We comfort ourselves with the thought that we are “simply letting nature take its course”. Presuming that the patient is indeed unconscious and feeling no pain, the difference for the patient between withholding life support and administering a lethal injection is minor, and it avoids the slippery slope of actively causing death. But what if we are wrong about the seat of pain, and severe cortical damage does not preclude suffering? This might be the case, for example, if pain processing can be sustained in subcortical parts of the brain. If so, slow death by starvation might be an extremely unpleasant experience. To condemn a helpless patient, perhaps a loved one, to this end is by no means a trivial choice when the option of a quick and painless

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Brain injury, depending on location and severity, can cause a wide spectrum of disordered consciousness. At one end is deep, irreversible coma with brainstem damage incompatible with recovery. At the other is transient syncope (fainting) or minor concussion, with rapid and full recovery. The part of the spectrum where ethical judgments regarding pain arise is the minimally conscious patient and the patient in a persistent or permanent vegetative state (PVS). Permanence is usually declared after 3 or 6 months, depending on the cause of the brain injury. Both states reflect severe cortical damage, typically due to prolonged oxygen starvation (such as from drowning or cardiac arrest) with largely preserved brainstem function. The main difference between minimal consciousness and PVS is that in the former, unequivocal awareness returns intermittently, at least for short periods of time, and prospects of eventual improvement are realistic. Both states differ from coma. The PVS patient may lack awareness, but he retains sleep-wake cycling including times of eyes-open arousal. “Automatic” responses to external stimuli such as eye blink are present, as are appropriate withdrawal responses to noxious stimuli such as pinch and pinprick. Parenthetically, disordered consciousness does not include the “locked-in” state, in which the individual is paralyzed and unable to communicate, but is otherwise fully awake and aware.

Even such complex “nocifensive” responses as guarding with the arm, facial grimacing, and a painful cry do not necessarily indicate the presence of conscious pain experience. They can still be seen, for example, in (lightly) anesthetized patients who are able-bodied but unconscious, and in decorticate animals.38 The basic problem is that we have no “neural signature” of pain perception; no objective way has yet been found of proving that pain has been experienced, even by recording or imaging brain activity.39 Pain remains inherently a “first-person” experience. The vegetative patient is unable to report verbally on pain experience due to his severe cognitive (including in language) deficit. Like the unborn fetus, he cannot let us know if he is suffering. Despite the ambiguity, conventional reasoning in the neurological community arrives at the conclusion that pain experience is absent, and indeed impossible, in the PVS patient. The logic is as follows. As it is assumed that all conscious perception, including pain, resides in the cortex and in the PVS patient cortical function is absent, it follows that the PVS patient is incapable of feeling pain.37 However, what if the fundamental premise is incorrect? This question will be addressed in the next section. But before going there, does it matter? The PVS patient is clearly severely incapacitated. In addition to having no language ability, virtually no cognitive functions, and severely degraded sensory and motor capacity, he is left with virtually no long-term memory and presumably little if any short-term memory. Even if felt, there is clearly no recollection of pain. Nonetheless, such a patient would presumably experience an ongoing stream of pain, from moment-to-moment, for as long as the noxious stimulus lasts. Under some circumstances, his existence would be nothing but pure pain from out of the blackness. This situation clearly ought to be avoided.

Pain, Consciousness, and the Vegetative Patient

Is Pain Indeed a Cortical Function?

Patients in a vegetative state are severely disabled in all higher cerebral functions, sensory, motor, emotional, and cognitive. However, functions controlled by the subcortical forebrain, the brainstem, and the spinal cord may remain. This includes relatively complex sensorymotor tasks such as visually tracking a moving object and the generation of facial expressions of pleasure and displeasure. What about pain? The spinal flexor (withdrawal) reflex remains, but this proves little about pain perception. Pinprick-evoked leg withdrawal also occurs in paraplegics who report no awareness of the stimulus.

Beyond the dogma that all conscious perception resides in the cortex and hence pain perception also must reside there, there are specific lines of evidence that support this conclusion. First and foremost, results of noninvasive functional brain imaging in humans show excitations in many areas of cortex (as well as the subcortex) during pain-provoking stimulation of the skin and internal organs.40 Together, these areas are called the “pain matrix”. Microelectrode recordings in animals confirm that cortical neurons are indeed activated by such stimuli. Some of the cortical areas

lethal injection is present. Avoiding it may well be adequate justification for taking full responsibility for what we are actually doing, ending life. In this section, we will consider more closely the dogma that conscious perception, and hence pain, is a function of the cerebral cortex. Disorders of Consciousness

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activated have been associated with pain for many years (eg, primary somatosensory cortex, S1). Others, however, including the areas with the most robust activations have previously been associated with emotions, not sensation (eg, the ACC). Interestingly, the strength of cortical activations in the ACC correlates more reliably with the unpleasantness felt by the subject during the stimulation than with stimulus intensity. The two can be dissociated using a variety of experimental manipulations such as deceitful suggestion that a powerful pain reliever (a placebo) has been administered or the use of hypnotic suggestion. These manipulations reduce the amount of suffering reported by the subjects and also the excitations seen in brain scans, even though the noxious stimulus is unchanged.41 Such observations are in line with the dogma that the cortex is the brain’s pain analyzer. Others, however, suggest otherwise. The most important is that direct electrical stimulation of the cortex, including in areas that show activation during painful stimuli, almost never evokes a report of pain in awake patients.42,43 The same is true of transcranial magnetic stimulation. The failure to evoke pain contrasts with results of stimulating cortical areas associated with vision, hearing, smell, and (non-painful) touch. In each of these modalities, direct cortical stimulation readily arouses the corresponding percept, light flashes, sounds, smells, and touch. Recent reports of pain apparently evoked in epileptic patients in whom depth electrodes were used to directly stimulate the posterior insular (and adjacent S2) cortex are a potential exception.44,45,47 The conclusion that this area represents the long-sought “primary pain cortex (P1)”, however, needs to be regarded with caution. Pain-like responses occurred in only a small minority of the patients stimulated, and the observations are inconsistent with those of others46 (also personal communication from Berger MS (UCSF; 2/2009), quoted with permission: “I’ve operated on more than 175 insular tumors, and although I have not mapped all of them, I can tell you that even when patients are awake I have never seen pain being evoked by stimulating, touching or even resecting the posterior insula”). Likewise, the conclusion does not mesh with the rarity of pain during insular seizures and with the fact that destruction of the posterior insula typically has little effect on pain sensation.47–49 The reports44,45 await additional replication. It may be argued that the reason cortical structures from which pain sensation can be reliably evoked have defied discovery is that they are relatively inaccessible to surface stimulation and have therefore not been ade-

quately tested thus far. This may be true for electrical stimulation of the ACC and the insular cortex. However, in epilepsy, cortical discharge is frequently widespread and includes, indeed often favors, these buried limbic cortical areas. Nonetheless, it is very rare for epilepsy to include auras that are painful.48 A related explanation is that unlike the other senses, multiple cortical areas must be activated simultaneously to evoke a sensation of pain. Again, if this were so, then epileptic seizures should be painful. Note that in contrast to cortical stimulation, pain is readily evoked by focal (microelectrode) stimulation in certain non-cortical areas such as the thalamus and brainstem.50,51 Functional activations are also seen in subcortical areas not conventionally associated with pain.40 These include the cerebellum and corpus striatum, structures classically associated with movement. Another retort sometimes given to the question of why cortical stimulation is so rarely painful is that pain is more complex than other senses. Specifically, to generate the raw feel of pain, unlike vision, hearing, smell, and touch, requires precisely orchestrated patterns of activation at multiple locations in the cortex. This condition is not met by Penfield-type stimulation experiments,42,43 nor in natural epileptic seizures, and hence they do not generate a pain percept. A priori, the claim that pain is more complex than vision is counterintuitive. If anything, it seems a more primitive sense. Still, can we be sure that it is untrue? We argue that if pain sensation indeed cannot occur without highly precise, complex and necessarily fragile orchestration of brain activity in the cortical pain matrix, then disruption of the matrix by cortical lesions ought to completely eliminate the ability of natural noxious stimuli to evoke the experience of pain. Patients with cortical lesions should be “blind” to pain. In fact, lesions in pain matrix areas are very common, and they do not produce analgesia. On the contrary, cortical injury is often followed by chronic neuropathic poststroke pain.52 In contrast, lesions in the cortical areas that subserve the other senses do cause corresponding sensory deficits. Interestingly, patients with lesions in the right parietal cortex sometimes show “sensory hemi-neglect”, denying that a contralateral body part (left arm or leg) belongs to them. However, even in such cases, noxious stimulation of the denied limb evokes normal wincing, autonomic responses, withdrawal, and pain report. Pain is clearly experienced. What is not acknowledged is that the source of the pain lies within the individual’s

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(altered) body schema. The observations just reviewed are inconsistent with the dogma that pain experience is a consequence of neural activity in the cortex. As such, they demand that one seriously consider the possibility that the neural computations that generate pain experience play out sub-cortically. We do not doubt the evidence noted above that information about pain reaches the cortex. But we propose that the resulting cortical activations serve functional roles other than conscious pain experience. Examples are learning or the planning of future response strategies. The same logic applies to activations in motor areas such as the cerebellum. Cerebellar damage causes severe motor deficits, but it is not known to cause analgesia or to obtund consciousness. Despite the prominent cerebellar activations, few would propose that the cerebellum contributes to the conscious experience of pain. The much simpler explanation is that information about noxious events is employed in the generation of complex movement programs. The elegance of your tennis swing, for example, is very likely to be affected, and not for the better, if as you running to intercept the ball you step hard on a nail. Ethical Consequences of Pain Residing Subcortically Moving beyond dogma, let us entertain the possibility that pain experience can emerge from neural activity in subcortical brain structures. An immediate consequence is that the PVS patient may indeed feel pain. Moreover, as he can experience pain, it follows that he has conscious experience. True, with severe cortical damage, his mental life is severely impoverished. But the “he” (or “she”) inside is still present, locked perhaps for years in mute blackness, always in the present tense, but with the ability to suffer. We will not explore the question of whether a changed perspective on the conscious status of PVS patients should revise current standards for shortening life. But it clearly does affect decisions about how the process ought to be carried out. If it is decided to end the individual’s life, it is surely cruel to add to his circumstances the several days or weeks of additional pain, or at least dysphoria, associated with death by dehydration and starvation. If the decision has been made to take action that will hasten death, should we not abandon the fiction that we are only letting nature take its course and take active steps to insure that death comes quickly and painlessly? If not by lethal injection, at a minimum

shouldn’t the patient be rendered unconscious by terminal sedation?

PERSPECTIVE In the fairly recent past “life” was understood as a supernatural quality breathed into the temporal body by the grace of an all-powerful deity. Today most biologists understand it as a complex set of biochemical reactions, textbook stuff. We have already crossed the threshold of creating simple life from chemicals off the shelf.53 The revolution in the biology of life empowers the belief that other frontiers formerly in the realm of the spirit may also succumb ultimately to scientific understanding. We have taken the position that just as “life” is now understood as biology with no ghosts hidden in the machine, so too perception, ethical convictions, and even consciousness itself will ultimately be understood in terms of evolutionary processes and networks of neurons in the brain. The reduction of “life” to the strictly scientific is viewed by many as an assault on human dignity. Others, ourselves included, see the beauty of DNA replication and the choreography of bio-molecular machinery as the ultimate inspiration, the very face of God. Likewise, we see no inherent assault on human dignity in the belief, or when it comes, the knowledge, that conscious experience and all that goes with it is also a consequence of the operation of biological machinery. Neither perspective is a fault-line between scientists and humanists, or necessarily a divide from believers. Finally, we grant that the prospect for deciphering the circuitry of ethical conviction during the course of our lifetimes seems remote at best, and likewise, the appearance of conscious machines that feel pain. The widely held idea of mind as a disembodied spirit only temporarily resident in the brain is not yet under serious assault in the laboratory. Meanwhile, ongoing research on brain function can provide food for thought on ethical dilemmas related to conscious experience and pain. Awareness of our genetic predispositions may allow us to view environmentally and culturally derived attitudes toward ethical behavior with a more critical eye. Ultimately, ethics involves a choice between different values. Improved knowledge can lead to better choices.

ACKNOWLEDGEMENTS We thank Arthur Cohen, Otniel Dror, Tamar Makin, and Danuta Mendelson for their helpful comments on

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the manuscript. The first author’s research on pain is supported by the Israel Science Foundation (ISF) and the Hebrew University Center for Research on Pain.

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