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date: 13 August 2020

Neuroethics: Neuroscience and Society

Abstract and Keywords

This article reviews different points of interest in neuroethics. These are exemplified by the three broad areas of neuroscience research—neuroimaging, neuropharmacology, and neurostimulation—and the major ethical questions with which they are associated. It considers primary research in neuroscience, ethics, and philosophy and identifies some important questions meriting further attention, primarily in the context of healthcare but also beyond, in the broad areas of education, business, and the military. A heavily debated trend, that of the enhancement use of neuropharmaceuticals and neurostimulation devices, is also discussed, especially in relationship to cognitive enhancement and neuroethics. In addition, emerging forms of neurostimulation are considered with respect to effectiveness and ethics.

Keywords: neuroethics, neuroscience, neuroimaging, neuropharmacology, neurostimulation, cognitive enhancement

Acknowledgments

Writing of this article was made possible by a career award from the Fonds de recherche du Québec (ER) and a grant from the Social Sciences and Humanities Research Council (ER and VD). Research for the preparation of this chapter was partly supported by a previous Health Canada contract to review ethical challenges in neuroscience (ER). The authors thank members of the Neuroethics Research Unit for helpful comments and Victoria Saigle for precious editorial assistance.

Introduction

Rapid advances in areas of neuroscience,1 such as neuroimaging, neuropharmacology, and brain stimulation, have generated important ethical questions in the past decade. The potential for these technologies to improve diagnoses and treatment options for conditions like Alzheimer’s disease,1 Parkinson’s disease,2 and severe depression3 are examples of possible clinical applications of neuroscience. Beyond the conventional boundaries of clinical research and healthcare services, neuroscience has generated insights which have been captured in domains like law4–6 and education.7 In response to the ethical questions raised by such advances and applications, the field of neuroethics tackles these issues and stimulates reflection on the clinical, research, and policy implications of neuroscience, as well as its actual and possible consequences.8 Researchers and other stakeholders (e.g., clinicians, regulators, consumers, and patients) are confronted with important ethical questions, partly because these advances involve the brain, which is the most complex (and least understood) biological organ. In addition, a long history of stigma of psychiatric and neurological disorders shapes responses to both the medical and social needs of patients.9

In this article, we review three broad areas of neuroscience research (neuroimaging, neuropharmacology, and neurostimulation) and associated major ethical questions. We consider primary research in neuroscience, ethics, and philosophy to identify questions meriting further attention with a focus on healthcare applications. However, before starting, a brief acknowledgement of the complexity of neuroethics as a field should be made. The intense activities captured by neuroethics have generated multiple perspectives in the literature regarding the identity, boundaries, and focus of neuroethics. These include:8

  • The knowledge-driven perspective first proposed by Adina Roskies10 and expanded by authors like Neil Levy.11 Adina Roskies was one of the first to define the field of neuroethics.10 She argued that neuroethics was different from other areas of biomedical ethics due to “the intimate connection between our brains and our behaviours, as well as the peculiar relationship between our brains and our selves.”10 Roskies also distinguished two parts of neuroethics: the ethics of neuroscience and the neuroscience of ethics. Although she acknowledged that “each of these can be pursued independently to a large extent,” Roskies stated it is “intriguing … to contemplate how progress in each will affect the other.”10 This is the most widely referenced formal definition of the field, though some have criticized the inclusion of “neuroscience of ethics,” as it might be a separate endeavor.12

  • The technology-driven perspective focuses on the ethical challenges generated by new neurotechnologies. Paul Wolpe described neuroethics as a “content field,” that is, a field “defined by the technologies it examines rather than any particular philosophical approach.”13 Wolpe’s definition stressed that “[n]euroethics encompasses both research and clinical applications of neurotechnology, as well as social and policy issues attendant to their use.”13 For Wolpe, the brain is “the seat of personal identity and executive function in the human organism”13 and thus the distinctive nature of the field derives from novel questions generated through the application of neurotechnology. This perspective is perhaps the most widely implicitly and explicitly shared view in the field and it directly relates to the ethics of neuroscience and neurotechnology.

  • The pragmatic or healthcare-driven perspective proposed by Fins and Racine14 focuses on healthcare-related challenges. According to this view, the defining goal of neuroethics is to improve patient care and the understanding of specific populations of psychiatric patients as well as those who are neurologically atypical.14 One of the features of this definition is the consolidation of some of the earlier historical meanings put forward in the 1970s and 1980s focusing on clinical aspects (e.g., Pontius and Cranford) with some of the contemporary views (e.g., Roskies, Wolpe). Another distinct feature of this view is its description of neuroethics as both a scholarly and practical endeavour that attempts to both understand and intervene in healthcare settings, akin to medicine, nursing, and other healthcare professions.8

These perspectives on the field of neuroethics not only capture fundamental interests and potential fault lines, but they are each differently connected to issues related to research ethics, clinical care, and health policy/regulation. The rest of this article describes major areas of ongoing neuroscience research and some of the salient and difficult ethical questions they raise. A wide range of topics have been discussed in neuroethics, as reviewed recently in monographs8, 11, 15 and edited volumes.16–18 We focus on ethical questions related to three specific and salient areas: neuroimaging, neuropharmacology, and neurostimulation.

Neuroimaging

Neuroscientific research19 has been propelled by the development and refinement of advanced neuroimaging techniques. Although contemporary neuroimaging appears recent, techniques like computed tomography (CT) scans and standard magnetic resonance imaging (MRI) have been developed over the past few decades. Furthermore, techniques like EEG point to a longstanding tradition of neuroscientific research into physiological and cognitive processes. However, neuroscience research accelerated when positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) flourished in the 1980s and the 1990s. Given this development, an increasing number of scientific activities, publications, and research programs based on neuroimaging tools have surfaced internationally. These are considered to bear great potential for the further development of neuroscience and for our understanding of brain function.

It is important to distinguish between structural and functional neuroimaging modalities, given their different uses and related ethical questions. Structural neuroimaging techniques such as MRI and CT have been around for longer than most functional techniques. They are commonly used in clinical medicine to detect structural tissue anomalies such as tumours and lesions.20, 21 Even though the focus of neuroethics has been on information gathered through functional neuroimaging,22 structural neuroimaging raises important questions in its own right which significantly overlap with questions raised by functional neuroimaging.6 Advances in structural imaging have led to a greater ability to quantify neuroanatomical structures (e.g., through enhanced spatial resolution) in living subjects. For example, structural neuroimaging research in Alzheimer’s disease frequently measures the hippocampus to better understand and potentially develop a biomarker for its early development.23, 24 Landmark studies using structural MRI to complement fMRI and genetics are promising to establish more precise risk profiles and neurobiological mechanisms of depression.25 For example, a study examined associations between measurements of brain structure (e.g., limbic regions such as the perigenual cingulate and amygdala), and brain activation patterns in response to fearful stimuli. They found that these associations differed between individuals with either the short or long allele for the serotonin transporter gene, which is believed to be involved in depression. Given the linkage between the genetic profiles, brain structure, and activation, the authors concluded that the “genotype-related alterations in anatomy and function of an amygdala-cingulate feedback circuit critical for emotion regulation implicate a developmental, systems-level mechanism underlying normal emotional reactivity and genetic susceptibility for depression.”25 This line of research may lead to further possibilities in predicting the development of neurological or psychiatric disorders, which clearly ties to important ethical questions in terms of the use of predictive prognostic information.26

Many of the ethical discussions in neuroethics have occurred in connection with the evolution of functional neuroimaging techniques, i.e., techniques which measure the activity of the brain.22, 27 These techniques are often depicted by the media (and occasionally by researchers and clinicians) as providing a “window” into the brain. However, in order to grasp the ethical landscape of these techniques, it is important to understand that all current functional imaging modalities measure brain activity indirectly; they measure surrogate biomarkers of neuronal activity like oxygen consumption (fMRI), glucose consumption or metabolism (PET), electric activity (EEG), or magnetic fields (magnetoencephalography, MEG).28, 29 These biomarkers are presumed to be associated with increased neuronal activity, therefore an increase of these parameters should correlate with an increase of neuronal function. However, it is important to remember the tremendous complexity underlying what can easily be described as simple “neuroimages” showing increased or diminished neuronal activation in specific contexts or tasks. Important caveats in the interpretation and generalization of results obtained through functional neuroimaging include the task-dependency of most paradigms (e.g., brain activity is measured in response to a specific task), the complex statistical processing which allows the distinction of significant from insignificant neuronal activation (based on the computation of hundreds of thousands of “voxels”—measurements of very small brain volumes determined to be activated or not based on statistic thresholds), the evolving but still limited spatial and temporal resolution of imaging modalities, the lack of research paradigm and procedure standardization, the fact that the imaging environment may not reflect real-world task performance (external validity), and the fact that expert performance tends to consume less oxygen and glucose, which increases the tendency for false negatives.28, 30

Keeping these caveats in mind, it is important to also recognize the potentially tremendous power of functional imaging (1) to inform our understanding of diseases, behavior, and personality, and potentially (2) to change practices in the clinical environment. As the brain is involved in regulating and controlling most biological functions and social activities, a better understanding of its function in vivo touches upon a wide set of clinical situations and behaviors. This is well reflected in the breadth of phenomena that has been studied through the lenses of functional neuroimaging. From a clinical standpoint, a wide range of neurological and psychiatric conditions such as depression, schizophrenia, and attention deficit/hyperactivity disorder (ADHD)31 have been investigated with aims including better understanding of neurobiological mechanisms, monitoring the efficacy or effect of treatment and developing better diagnostic tools.

Perhaps most striking is the use of functional neuroimaging, fMRI in particular, to understand more basic (nonclinical) phenomena such as personality, behavior, and decision making. An early trend in fMRI research showed an increasing number of studies dedicated to such “neurosocial” investigations.32 Attempts to apply and discuss the implications of this research have spanned domains such as education (neuroeducation),33, 34 law and criminal justice (neurolaw),5 ethics (neuroethics,10 at least according to some authors), religion (neurotheology),35 and economics (neuroeconomics and neuromarketing).36, 37 A recent set of reports of the Royal Society in the UK has underscored the interest in neuroeducation and called for enhanced public neuroscience literacy to ensure that relevant results are integrated,7 and that hasty and premature uses are prevented. Programs have been developed to integrate new insights about education (e.g., at Johns Hopkins University).38 Attempts to introduce functional neuroimaging in the legal system as a lie-detection device have been examined by American courts in the states of New York and Tennessee. To date, these courts have concluded that there is an insufficient consensus of experts and insufficient evidence to accept the validity of this method.39, 40 Another recent UK report on law and neuroscience from the Royal Society has examined emerging evidence in “neurolaw” and concluded that the current evidence does not support changes to our understanding of liability and responsibility (as brain lesions and abnormalities could potentially be a mitigating factor for legal responsibility).41 Consequently, the potential for fMRI and other imaging modalities to infringe on what has been dubbed “cognitive liberty,” “a fundamental right to think independently” and to control one’s brain activity and access to it42 may be limited or unclear at this point given technological limitations. Some astonishing results from the use of imaging in a clinical setting indicate, however, that crude forms of “mind-reading” could potentially be an important medical tool when communication is extremely limited.

Investigators in Belgium, the United States (US), the United Kingdom (UK), and Canada studying neurological conditions like the vegetative state and the minimally conscious state have published a series of studies conducted with PET, fMRI, and EEG showing that in a minority of patients once thought to be unresponsive and unaware, signs of awareness can be detected.43–48 These results have not only shown the ability of neuroimaging to change our understanding of certain neurological conditions, but also point to ways in which neuroimaging could be used to establish rudimentary forms of communication with otherwise unresponsive patients.45, 48 However, the clinical use of these techniques is still debated, especially as the prognosis for these patients remains unchanged even if there are signs of awareness. The results do not clearly lead to interventions alleviating profound disability or severe cognitive and speech impairments.49 Thus, even if crude forms of communication could be established, the implications for the treatment course and communication of patient’s preferences remains unclear. We have identified a number of similar ethical questions in the literature surrounding the evolution of neuroimaging that can be found elsewhere in this chapter (see Table 1).

Some of the technical and methodological limitations we mentioned for the use of fMRI and PET could be addressed by newer techniques (as well as more novel uses of older techniques, the combined use of different imaging modalities, or even hyperscanning techniques, i.e. simultaneous multi-subject imaging during on-line interaction50). Such advances would impact the ethical landscape of neuroimaging by increasing accuracy or making imaging more portable. For example, MEG has a greater time resolution than techniques like PET and MRI and could yield more accurate results if combined with higher spatial resolution techniques like MRI. EEG is a less expensive technology than fMRI and has been used as a substitute for this technique, as it enables a much more clinically friendly bedside examination (EEGs are common in hospitals). Near-infrared spectroscopy (NIRS) is a form of optical imaging that allows the monitoring of oxygen consumption in brain tissue. It relies, in some cases, on inexpensive equipment (in comparison to other very expensive technologies) and wireless technologies.51 This technique is currently limited to the examination of the surface of the brain (or “cortex”) because of the inability of infrared light to penetrate deep tissues. Were a portable form of NIRS developed, it would enable brain imaging to be conducted in more natural settings as well as expand its use to include a much broader range of applications.52 The technological and scientific evolution of imaging modalities, which is very hard to predict, could cause changes that would radically impact the ethical landscape of neuroimaging modalities (e.g., by allowing its use in real-world situations in a wide range of settings such as education, law, and business). A detailed examination of applicable regulations and policies is beyond the scope of this article, but clearly neuroimaging represents an important area of possible ethical and regulatory challenges (see Table 1) in addition to applications in law, military, and business which are beyond the scope of this review.

Neuropharmacology

Arguably the most well-known type of “neurotechnology” is neuropharmacology—a field concerned with the research and development of drugs that act on the nervous system.53 This accounts for a wide range of drugs—some of which are widely prescribed and used54–56—including anesthetics, anticonvulsants, and antidepressants. Accordingly, the challenges evoked by the development and usage of neuropharmaceuticals touch upon a range of issues, which can only be briefly described here. There is a rough distinction between challenges related to the recommended medical usage of prescription drugs and those associated with their off-label and nonmedical use. By the term “recommended medical use,” we refer to the use of a drug in the way specified by the label for which it was approved. In addition, this use is defined as involving drugs that are typically prescribed and taken under the supervision of a medical professional. The term “off-label” designates instances in which a drug is used under medical supervision to treat an identified disorder or neurological condition outside of its original purpose. We reserve the term “cognitive enhancement” for the use of a drug to augment cognitive performance, without the intent to treat an identified disorder and typically without medical supervision (nonmedical uses).

We acknowledge that these terms are broad nets that capture fluctuating and evolving realities. For example, the American Academy of Neurology (AAN) has called for greater medical oversight and supervision regarding the use of drugs for enhancement purposes (see the discussion in the next section),57 therefore blurring the medical/nonmedical dichotomy captured in the earlier definition of cognitive enhancement. Furthermore, some instances of “enhancement” uses may in fact be disguised self-treatment. Accordingly, the phenomenon of cognitive enhancement can be captured following different, even diverging, frameworks.58, 59

Neurocognitive enhancement

“Cognitive enhancement” (CE) has been defined in several ways, and it is worth noting the terminology and assumptions inherent to each perspective. It is commonly understood that CE “includes the use of drugs and other interventions to modify brain processes with the aim of enhancing memory, mood, or attention in people who are not impaired by illness or disorder.”60 Frequently cited CE drugs include stimulants like methylphenidate (used to enhance concentration), acetylcholinesterase inhibitors (used in the treatment of Alzheimer’s to enhance memory), and modafinil (used to enhance wakefulness).61 Although this definition does not mention medical supervision, we will assume (given evidence from public health studies) that current use of drugs as enhancement generally lacks medical supervision even though there have been attempts to establish a firmer role of physicians in prescribing CE.57 However, another, more general definition articulated by proponents of CE states that it is the “amplification or extension of core capacities of the mind through improvement or augmentation of internal or external information processing systems.”62 According to this definition, although chiefly considered within the application of medical treatments, CE can be considered to involve a wider range of technologies (e.g., computer technology, education).61 It is important to make several observations about the definition of CE itself, which is pregnant with important ethical, social, and regulatory challenges.

The term “cognitive enhancement” suggests that the use of these drugs would result in “enhancements” (also assumed by the public and in much of the academic literature). However, not unlike a drug undergoing clinical trials cannot properly be called a “treatment” or “therapy” before its effectiveness has been proven, it is important to keep in mind that current evidence is quite contradictory with respect to the possible enhancement effects of neuropharmaceuticals. Therefore, the label “cognitive enhancement” may be misleading. Many of the so-called CE drugs have not been tested in the same way or with the same rigor as they were for their original purposes. Recent reviews have, in fact, highlighted limited evidence supporting claims of enhancement.63–67 In addition, there is perhaps unsuspected complexity in understanding or defining what constitutes CE for an individual (given that the effect is contingent on expectations for greater performance) or for an external body (e.g., regulatory review body) trying to assess such a claim. Since the use of CE would by definition not be in response to a clear pathology, lesion, or identified behavioral or psychiatric problem, the measures used to evaluate significant effects of enhancement would likely be complex. Current studies have examined the enhancement effects of neuropharmaceuticals (and other technologies like TMS,68 DBS,69, 70 and tDCS71, 72) on specific tasks conducted in a controlled laboratory environment, but critics have pointed out that these tasks do not fully capture the effect of the technology on the more general capacity underlying the tasks (e.g., memory, creativity) and would need to be examined in the context of a real-world performance.73 Furthermore, the term “enhancement” has positive resonance that may understate possible risks and short-term and long-term side effects. This lack of information combined with limited long-term data on drug safety, as well as patterns of nonmedical drug use, could augment risks for individuals undertaking CE.74

Definitions of CE usually lack clarity, as the term refers to a range of practices and assumptions that overlap with other concepts and is often defined differently by diverse communities.59 For example, several public health and epidemiological studies describe the use of CE drugs as the “non-medical use of prescription drugs,” “drug misuse,” or even “drug abuse.”75 Clearly, some of the optimistic assumptions about CE (often reflected in interdisciplinary bioethics literature as well as in neuroscientific and clinical journals) are not captured in such terminology.59 Separately, the notion “cognitive enhancement” is unspecific because the most common definition underscores its use in healthy individuals, although the term also has a long history of use in Alzheimer’s research76 and in research on schizophrenia.77 In these disciplines, cognitive enhancement refers to possible therapeutic interventions to improve memory or cognitive function of patients. Hence, CE can designate very different interventions and, unfortunately, recent papers have combined both therapeutic and nontherapeutic uses under the same umbrella term. This obfuscates the ethical discussion (because interventions to restore people to healthy functionality are typically less ethically fraught than interventions to raise selected people above others in better-than-healthy functionality). It also obscures, to some extent, the specific scientific questions underlying both contexts of application.78 Other notions than cognitive enhancement are also used to capture the concept of nonmedical use of drugs to augment performance. For example, “lifestyle use”79 of drugs partially captures the fact that some instances of drug use do not correspond to a medical situation or a medical need in the traditional sense of the term, but instead to requests for greater performance or lifestyle modulation. The usage of “CE” in the literature may also obscure a longer history of nonmedical use of drugs to enhance performance. For example, in a recent paper, a group of Australian authors has argued that the current enthusiasm for enhancement use of methylphenidate and modafinil may fall within a cycle of enthusiasm and subsequent social backlash, as was historically the case with illicit drugs (e.g., cocaine and amphetamines).80

Obviously, a more nuanced definition of CE is warranted even if the delineation is practical and not definitive. Improvements of cognitive function or “performance augmentations,” for which there is no sufficient evidence, should be dissociated from “performance maintenance” effects. “Performance maintenance” refers to the prolongation of normal levels of functioning and the reduction of effects of fatigue and sleep deprivation, which also raise important ethical issues.81

These considerations about definitions and related topics (like the level of evidence for efficacy and concerns about safety for novel uses of drugs) carry important implications for regulatory and ethical issues. Indeed, the different perspectives and understandings of what CE refers to may magnify or diminish the resemblance between this and other phenomena related to drug use, thereby prompting regulatory responses in different directions in spite of common grounds. A few considerations stand out, with respect to general health policy/regulation and their relevance to the health of broader society:

  • Approval mechanisms/oversight of enhancement use of prescription drugs: Would the examination and eventual approval of drugs for CE indications entail changes to current regulatory processes? Would a claim to enhance cognition be captured by existing regulatory approval mechanisms? Furthermore, what would be the different challenges for approval of a completely novel drug used solely for CE versus an already approved medical drug that can also be used for CE?

  • Professional responsibility and self-regulation: Some professional bodies like the AAN57 and the British Medical Association (BMA)82 have responded to the medical and ethical questions raised by the phenomenon of CE. The BMA’s report takes the form of a discussion, while the AAN has delivered specific guidance on how to respond to “requests from adult patients for neuroenhancements” and more recently for pediatric neuroenhancement through its Ethics, Law and Humanities Committee.57, 83 There are certainly strengths to self-regulation as exhibited by the AAN, but at the same time a range of ethical issues may not necessarily be handled adequately by self-regulation alone. For example, the AAN’s position on adult neuroenhancement states that, “[t]he prescription of medications for neuroenhancement is 1) not ethically obligatory, 2) not ethically prohibited, and therefore, 3) ethically permissible.”57 This position has been criticized for not capturing the potentially problematic social84 and public health85, 86 consequences of CE, including the differential ability to pay and access cognitive enhancers as well as the professional counseling recommended by the AAN. If CE falls under the purview of physicians as recommended by the AAN, questions could surface about the role of physicians. Physicians are usually considered to be providers of services intended to improve health, though there are exceptions (e.g., cosmetic surgery). Two surveys including Canadian and American physicians have suggested physicians have mixed opinions on the ethical acceptability of prescribing CE (or becoming engaged in doing so)87, 88 while a Swedish survey found that physicians are critical toward CE.89

  • Resource allocation and use of healthcare resources: A chief concern at the core of (public) healthcare systems is accessibility and the use of resources in a way that ensures equitable access to healthcare resources and services. In Canada, for example, the Canada Health Law Act states that, “the primary objective of Canadian health care policy is to protect, promote and restore the physical and mental well-being of residents of Canada and to facilitate reasonable access to health services without financial or other barriers.”90 Likewise, the Canadian Medical Association code of ethics calls to “[r]ecognize the responsibility of physicians to promote equitable access to health care resources” and also to “[u]se health care resources prudently.”91 Furthermore, Quebec’s Commission de l’éthique de la science et la technologie (CEST) has specifically identified that cognitive enhancers could have an impact on the integrity of healthcare care as viewed by Canadian federal and provincial authorities74; the use not only of drugs but also of healthcare personnel to engage in CE could be a significant issue in the context of countries with public healthcare systems. A broader understanding of the acceptability of physicians to respond to nonmedical needs or to use federal and provincial healthcare funds to respond to requests for CE brings important questions to light in matters of resource allocation and health priorities.

  • Epidemiological data on prevalence, motivation, and rationale: In the international context, evidence is scarce about the actual prevalence of CE use and of the rationale or motivations for doing so. For example, prevalence of the nonmedical use of prescription stimulants for CE could range from 3.7 to 11% or from 5 to 35% in college students.59 Likely because early studies pointed to the student population’s use of prescription stimulants, several American public health studies have reported prevalence rates and started to examine issues, such as the underlying motivations. In spite of the usefulness of this research, many questions persist, such as the external validity of studies conducted on specific campuses (given that the reported prevalence rates vary considerably between studies and campuses) and the understandable lack of methodological uniformity between studies.92, 93 For example, one German study suggested a modest 1% prevalence rate,94 while another95 reported 4.56% as lifetime prevalence rate among university students.

  • Public understanding and health literacy: Research has identified important challenges in the way that CE has been depicted in the media and discussed in the public domain. For example, drugs like methylphenidate have been described as “smart drugs,” “study aids,” “smart pills,” and the like.75 This is not restricted to media descriptions of CE, but is also found in interdisciplinary bioethics and medical literature.75 Information surrounding the risks of such practices is also lacking in the media.75, 96 Therefore, the question of health literacy and the public’s understanding of the effects, risks, and ethical questions related to CE is an important challenge with ethical and regulatory implications. Related to the type and level of information available to the public is the question if and how public dialogue on this topic should be increased. Public debate may appear justified with respect to the need to examine a wide range of claims and opinions concerning CE. However, public debate could also promote existing debatable assumptions about CE.

  • Funding of research in this area: Currently, funding for CE research appears to have been generated through general research funding mechanisms. In the US, the Defense Advanced Research Projects Agency of the Department of Defense (DARPA) has had an “augmented cognition” program, which funded research dealing with a range of enhancement technologies.97 Several researchers have argued for further funding for CE research61, 78, 98 while others have been critical and recommended that public funding should actually be prevented.99 The development of programs to fund CE research would likely call for further reflection (as well as the rationale for any moratorium or restriction to research). At the same time, the status quo also involves a decision to allow research to continue to unfold as it has so far.100

  • Commercial aspects, black markets, availability: Reported CE uses point to a variety of underground and potentially illegal practices, such as the black market selling of prescription drugs, prescription drug sharing, and possibly access through online sales with limited control for prescriptions.101 These aspects merit further attention and have clear regulatory implications. Black markets for prescription drugs are a well-known problem,102 likely needing some attention in the context of CE.

Other ethical challenges with less clear regulatory implications have also been associated with CE, especially since enhancers could be used in a variety of contexts (e.g., work, warfare, education) and for myriad purposes involving diverse cognitive functions (e.g., memory, intelligence, concentration).103 These concerns, which may have less clear but nevertheless significant implications for health policy and regulation, can only be reviewed in a cursory fashion. One concern raised by CE is the prospect of overmedicalization and the use of medical science and technology in ways that run counter to “human nature.” Such concerns have been at the center of a report by the US President’s Council on Bioethics104 and have been heavily criticized in scientific circles.105 Other related considerations highlight the value of making an effort to accomplish things and concerns about whether efforts would be trumped through the consumption of enhancement drugs. In this case, one view is that learning to overcome challenges and obstacles (e.g., lack of concentration, memory) is not nurtured in ways that more conventional means and efforts provide. In its stronger forms, the worry is that human agency would be removed or substituted through an increased reliance on technological means.11 Related to this concern is how different international populations would regulate CE use or how existing regulations in different countries would allow the consideration of worker’s rights and individual rights and freedoms. There are concerns that practices could evolve in ways that contradict international declarations (e.g., implicit or explicit pressures to use cognitive enhancers in opposition to worker’s rights). Finally, through the expansion of neuropharmacological research and possible uses of pharmacology, other concerns have been raised about the dual use of neuroscience research generally and of neuropharmacology in particular.106, 107

In this section, we have identified and discussed some key challenges raised by neuropharmacology with a focus on CE. Table 2 captures some trends and areas carrying forth ethical and regulatory questions on this subject.

Neurostimulation

“Neurostimulation” captures a relatively diverse set of invasive and non-invasive techniques and has a more or less recent history. These include deep brain stimulation (DBS), vagus nerve stimulation (VNS), repetitive transcranial magnetic stimulation (rTMS), and transcranial direct current stimulation (tDCS).108 Only a cursory overview is offered in the following section, with a focus on the most widely discussed invasive technique, DBS, and the newest among non-invasive techniques, tDCS.

Deep Brain Stimulation (DBS)

DBS typically involves the implantation of one or several electrodes in the thalamus, the pallidum, or the subthalamic nucleus regions (regions deep in the brain).109 The implanted electrodes are connected through very small wires (“leads”) to a device called a pulse generator, which is surgically implanted in the upper chest. Although developed in different precursor forms and previously applied in more rudimentary ways, DBS is a leading neurostimulation technique and has reinvigorated interest in this area for movement disorders and beyond.110 For several years, DBS has been investigated internationally to treat neuropsychiatric disorders and other neurological disorders,111 including severe refractory cases of major depressive disorder,112 addiction,113, 114 Tourette’s syndrome,115, 116 and Alzheimer’s disease.117 DBS was approved by the United States Food and Drug Administration (FDA) in 1997 for the treatment of essential tremor and refractory Parkinson’s disease.111 In 2007, there were reports of over 35,000 patients worldwide who had received DBS,118 while more recent figures indicate 80,000 patients have been treated using this technique.119 In contrast to ablative neurosurgery, DBS is considered to have a lower risk because of its reversibility and limited resulting tissue damage.120 Nonetheless, DBS can lead to some irreversible short-term (e.g., haemorrhage) and long-term effects (e.g., reshaping synaptic connectivity).121 DBS is used widely in the treatment of neurological disorders like Parkinson’s and essential tremors even though some aspects regarding the care of DBS patients are still unclear or under investigation (e.g., quality of life, psychosocial aspects). The development of DBS applications for neuropsychiatric disorders, like severe depression and obsessive-compulsive disorder (OCD), have important social and ethical ramifications.108 A humanitarian device exemption has been granted by the FDA for those with OCD.122

Some potential applications of DBS have been discovered through unforeseen circumstances. For example, researchers in Germany trying to treat a generalized anxiety disorder by stimulating the nucleus accumbens found no positive result, but they observed the alleviation of an alcohol dependency in their patient.113, 114 Though this suggests a possible new area of treatment, it raises ethical questions related to patient selection criteria.123 A Canadian team trying to treat obesity in a patient by dampening the feeling of hunger through stimulation of the fornix actually reported a memory enhancement effect in the patient,70 which led to a subsequent phase 1 trial of DBS in Alzheimer’s disease.117 Cocaine124 and nicotine addiction125 have also been identified as amenable to DBS trial, raising substantial research ethics and health policy questions.126

DBS has garnered attention from ethicists and some regulatory circles. Several important ethical questions have been raised surrounding the use and evolution of DBS in both neurological (approved uses) and in neuropsychiatric conditions (investigational uses). These include informed consent, screening procedures, follow-up care and support, resource allocation, and the impact on the identity of the patient.111 Some of these questions are not straightforward, but rather concern ethically salient aspects of DBS, that is, aspects of DBS which present intertwined scientific, clinical, and ethical questions. Other issues involve the capacity of healthcare systems to bear and reimburse the costs of devices and procedures (which can amount to tens of thousands of dollars).127–129 The following are some of the major issues which have been identified in the literature:111

  • Patient selection criteria and screening procedures: The selection of appropriate candidates for DBS is important for both clinical and ethical reasons. Patients and research subjects need to be offered an option based on a favorable risk-benefit ratio and sound ethical principles. The patients most apt to benefit must have the capacity to tolerate the surgical procedure and manage its postoperative implications.130 Comprehensive assessment programs131 and neuropsychological testing have been developed to select candidates.132–135 To support fair and sound screening and selection processes, many have suggested the use of an interdisciplinary approach to review candidates for surgery.136

  • Informed consent: Consent for DBS is complicated by the fact that conditions like Parkinson’s disease or Alzheimer’s disease may involve disrupted cognitive function or mood, including the capacity for memory and reasoning.137 However, a neurological or psychiatric diagnosis should not rule out the capacity for patients to express their healthcare preferences and to participate in decision making.137, 138 The patient or their proxy should be properly informed about the surgical complications, permanent neurologic sequels, and hardware failures that could result.111 DBS has typically been offered as a last-recourse procedure after other means have been exhausted, but this could change in the future if DBS is shown to have a strong preventive value. Currently, the fact that DBS is reserved for instances in which there are no other options is of ethical concern, as this potentially exacerbates the vulnerability of candidates.139, 140

  • Justice and resource allocation: The costs of current medical treatments for conditions like Parkinson’s disease are high. DBS could become a cost-effective procedure when direct and indirect costs are taken into consideration,128, 129, 141, 142 although methodological issues will necessitate that further attention be paid to this issue.143 The impact of using DBS as a treatment option for different conditions (e.g., severe depression, OCD) on costs and resource allocation is an even more complicated question which merits investigation given the different regimes involved for reimbursement of drugs versus medical devices.144, 145

  • Transfer of knowledge and public understanding: Two important considerations have been identified with respect to the impact of (inadequate) knowledge transfer and public understanding.111 First, several authors have stressed the expertise and comprehensive aspects of the care needed to handle the DBS procedure properly, screen candidates, and monitor outcomes.146 Second, research has also shown how public understanding about DBS may be seriously hindered by overly optimistic and selective news coverage.147, 148

  • Personality change: The effect of DBS on cognitive function is still unclear and widely debated.111 In Parkinson’s disease, reported cognitive decline as a result of DBS may be due to the disease progression,149–152 though this has also been contradicted in other studies.153–156 The impact of DBS on depression in Parkinson’s is also debated. For example, rates of depression after undergoing DBS vary from single digit to low double digits149, 150, 153 and could be affected by a history of depression.150, 157 Other psychiatric complications such as anxiety153,149 and hypomania as well as impulse control disorder149,157 have been discussed and refuted by other studies, which have shown either improvement in mood and alleviation of anxiety153 or no change at all.158 The incidence of suicide following DBS has also been a source of heated discussion with wide-ranging conclusions.159, 160 The overall consequences of DBS for patients and their quality of life are uncertain, and there have been reports of psychosocial maladjustment (e.g., work and marital complications) following treatment.161, 162 The global effects of DBS is an area where limited evidence and information is currently available, although the results of some preliminary trials suggest DBS’ mechanism of action could possibly elicit rapid changes in patients.3

Social and ethical challenges of recent forms of neurostimulation

We have reviewed important and better-documented challenges related to DBS, a widely used form of neurostimulation. Previous reviews have identified a range of ethical and regulatory challenges,163, 164 but emerging forms of neurostimulation and related technologies could generate further concerns.165 Other neurostimulation techniques include the non-invasive TMS,72 motor cortex stimulation (MCS),166 and magnetic seizure therapy.108 Brain-machine or brain-computer interfaces, which attempt to establish communication with paralyzed patients or to reinstitute motor function, sometimes involve implanted components like electrodes and are considered related to neurostimulation.167

However, the technique that promises to have the greatest impact in the future is transcranial direct current stimulation (tDCS). tDCS is a non-invasive, neuromodulatory technique that uses low-intensity direct current to stimulate cortical areas in order to facilitate or inhibit spontaneous neuronal activity. It is primarily used as an investigative and therapeutic tool in the context of chronic pain, depression, and for neurorehabilitation following a stroke.168, 169 Recently, tDCS has generated excitement in both the lay public and academia, as it has been described as a “portable, painless, inexpensive and safe” therapeutic device with cognitive enhancement (CE) properties.72, 170 The ability of tDCS to induce transient improvement in cognitive performance is well-established.71, 171–173 Despite its potential benefits, tDCS does not escape important ethical and social challenges that are associated with all CE techniques81 and, indeed, its unique characteristics might cause additional problems. Unlike stimulant drugs, which follow a posology with predictable effects, tDCS is a device that can be easily built at home (via readily available internet do-it-yourself manuals) and used repeatedly on different cortical locations and in various modalities.168 Furthermore, the regulatory environment surrounding tDCS is less clear than for stimulant drugs. For example, some manufacturers of tDCS devices (see, e.g., www.foc.us) specifically use this lack of regulation to promote its use for CE: they claim that the device offers no medical benefits and thus does not fall under the jurisdiction of regulatory agencies such as the FDA for medical devices.

Although the investigative use of tDCS appears safe and effective from a strictly scientific standpoint (e.g., in controlled laboratory settings), use without supervision might cause serious adverse effects such as temporary respiratory paralysis.174 In addition, due to the one-sided, overly enthusiastic portrayal of tDCS in the media, the risks and ethical challenges of its use for enhancement are likely to be poorly understood by the general public. An analysis of media content on tDCS has shown that the use of tDCS as an enhancement has bolstered the attention given to this technique. tDCS, although available since 1965, was remarkably ignored by the academic community until 2006, when the number of academic and print media articles on tDCS started increasing. As much as 42% of print media reports focus on tDCS for enhancement purposes and neglect to report any negative side effects.175 Additionally, the academic articles bolster enthusiasm because potentially detrimental effects are not measured and hence not reported, even though tDCS enhances certain cognitive functions while inhibiting others.176 Due to the fact that changes can be prolonged and that the exact mechanisms of tDCS action are currently poorly understood, this raises important ethical concerns, particularly if tDCS is used on populations with developing brains (e.g., children, adolescents).

The apparent effectiveness, reusability, and affordability of tDCS suggest a potential high penetration rate of this technology and a tremendous impact in both the clinical context and competitive social milieus (business, education, military, etc.). In spite of the dynamic emergence and extension of neurostimulation and its related challenges, there are few empirical studies identifying and characterizing the ethical and social landscape of both current and emerging practices. Unlike the case of stimulant drugs,177–180 regulation for tDCS is not clear and there have been no official government policies. This issue merits attention from the academic community and policymakers, particularly given the rapid evolution of neuromodulation techniques. Although the promises and perils of tDCS are still unclear72, 168, 169, the available data suggests that: (1) print media has enthusiastically reported that tDCS could be used to enhance cognitive function to the general public; (2) tDCS is readily available as a service, product, or even a homemade device, and (3) there is currently a regulatory gap, as policymakers are slow in responding to new social challenges created by knowledge transfer from neuroscience and neurology.175

Several challenges remain unclear or poorly defined, although gaps have been identified in the international regulation of DBS and other stimulation techniques.163, 164, 168, 169, 181–183 Table 3 captures some of the trends and salient questions with respect to ethical and regulatory aspects of neurostimulation techniques.

Conclusion

This article first drew attention to aspects of neuroscience itself and reviewed different perspectives on neuroethics. Three areas of neuroscience and neurotechnology and their respective ethical challenges were reviewed: neuroimaging, neuropharmacology and neurostimulation. As a general observation, it may be noted that ethical concerns have been raised about the use of neuroscience and technology and their applications in society at large. Attempts to apply insights and tools of neuroscientific research (such as neuroimaging) have spanned domains such as education, law and criminal justice, religion, politics, and economics. However, the most debated trend is the enhancement use of neuropharmaceuticals and neurostimulation devices. “Cognitive enhancement” is a somewhat loaded term that describes how some novel or already approved and available drugs or devices could be repurposed as enhancers of cognition in healthy individuals. The demand for such drugs and devices is unclear and there is poor evidence about their prevalence of use. By no means does this imply that the practice is non-existent, but because it challenges commonly used categories, there is scarce relevant epidemiological data that captures the use and purpose underlying enhancement use of drugs and devices, or the application of regulatory approval systems to deal with claims of benefits. Therefore, much of the discussion concerning enhancement technologies is currently open-ended.

Table 1: Ethical and regulatory concerns related to the increased use of neuroimaging techniques

  • The use of structural and functional neuroimaging for diagnostic purposes in the identification of neurological and psychiatric disorders (including pre-symptomatic diagnoses and the assessment of an individual’s susceptibility/vulnerability).

  • The validity of prognoses obtained through the use of functional neuroimaging techniques and its use as a clinical tool (e.g., to monitor disease progression or the effectiveness of different treatments).

  • The possible impact of structural or functional imaging on decisions regarding withdrawal of life support in cases of severe brain injury (e.g., in vegetative patients, patients with severe brain injury, and in early neonates) or pregnancy termination.

  • How the risks of undergoing MRI and other neuroimaging techniques is assessed in existing guidelines (e.g., Canadian guidelines on MRI184) and the congruence between these guidelines and those of other countries.185–188 These concerns include instances in which each technique is used separately as well as the potential for the techniques to be combined.

  • The ability of professional organizations and clinicians to monitor and self-regulate in this evolving scientific field.

  • The ability for conventional research ethics to capture and respond to evolving uses of neuroimaging, including its risks and benefits within multifaceted research paradigms (such as those combining the approaches of the social and biomedical sciences).189, 190

  • The extent to which the public and other stakeholders understand the differences and similarities between ethical questions raised by neuroimaging and genetics in areas like diagnosis and prognosis.

  • The use of imaging markers as surrogate biomarkers of a drug/intervention’s clinical efficacy or its use as a way of characterizing a disease (e.g., amyloid detection by PET scan in Alzheimer’s disease).191

  • The use of neuroimaging to classify mental states clinically (e.g., vegetative or minimally conscious patients) or in disciplines such as in marketing, economics, law, surveillance, and psychology.

  • The emerging clinical use of functional neuroimaging (e.g., new billing codes for the pre-surgical mapping of language and motor function prior to surgery) and the ability of research to generate the need for an examination of new clinical uses.

  • The surveillance of the private sector’s use of imaging modalities given its impact on wait list management,192 and other multifaceted challenges193 including its trend towards whole-body imaging.104, 105

  • The surveillance of nonmedical, for-profit uses of neuroimaging given signs of deficient public understanding of imaging modalities148, 194 and the related risks of misuse,195 which has led some countries to ban neuroimaging for these purposes.196

Table 2: Ethical and regulatory concerns arising from the use of neuropharmacology

  • The regulatory and professional frameworks surrounding off-label uses of neuropharmaceuticals.

  • The limited knowledge surrounding the long-term use of these drugs for both their directed and off-label purposes.

  • The evolving use of pharmaceuticals outside mainstream medicine to obtain a desired lifestyle or level of performance.

  • How to conduct research aiming to study the nonmedical, so-called “enhancement properties” of new or already-in-use prescription drugs.

Table 3: Ethical and regulatory concerns surrounding neurostimulation

  • The current clinical and regulatory systems in place for dealing with ethical aspects of surgical innovation (e.g., research ethics boards (REBs), regulation and assessment of medical devices) and their ability to deal with ethical concerns related to novel uses of devices.

  • The ability of current programs to adequately inform the public about the adverse effects of neurostimulation devices.164

  • The investigation and surveillance of psychosocial side effects of neurostimulation as well as tracking patient-reported outcome measures of trials.197

  • The impact of a broader usage of neurostimulation techniques (e.g., in psychiatry) on healthcare costs and consistency of services offered.144, 145

  • The examination of the need for investigational trials of neurostimulation in psychiatric patients as an added safeguard.198

  • The adequacy of current approval regulations to capture the implications and consequences of active implants and stimulation devices.164

  • The level of health literacy surrounding neurostimulation techniques and the need for their better public understanding as identified by misunderstandings disseminated in the media about the therapeutic, enhancement, and investigational uses of neurostimulation techniques.147

  • The conditions for research and clinical use of neurostimulation techniques in the pediatric context.199

  • The requirement for regulatory programs to ensure consistency in patient selection, surgical expertise, and patient follow-up.

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