Handbook of Clinical Neurology, Vol. 118 (3rd series) Ethical and Legal Issues in Neurology J.L. Bernat and R. Beresford, Editors © 2013 Elsevier B.V. All rights reserved
Chapter 26
The ethics of surgically invasive neuroscience research 1 2
PAUL J. FORD1* AND ABHISHEK DESHPANDE2 Department of Bioethics, Cleveland Clinic, Cleveland, OH, USA
Department of Medicine, Case Western Reserve University, Cleveland, OH, USA
STATEMENT OF THE PROBLEM A clear understanding of various distinctions and definitions is needed to provide a lucid ethical analysis and set of arguments regarding which types of surgically invasive neuroscience research should be permitted and how they can properly be undertaken. Great excitement has been generated by the development and application of invasive neurologic procedures, given the tantalizing possibility of restoration or augmentation of lost function through intervening in the nervous system. With improvements in technologies related to imaging, computer modeling, stereotaxis, implanted electric modulation, and radiofrequency ablation, various invasive interventions have now become more specifically targeted and result in lower levels and rates of morbidity. Deep brain stimulation (DBS) for the treatment of Parkinson’s disease is the most common example of the immediate and dramatic beneficial effects on a person’s motor dysfunction from a technology arising from such research. These almost magic effects quickly capture the attention of those thinking about the ethics of invasive research. While these neurosurgical procedures have a great potential to treat diseases and enhance patients’ quality of life, any rush to undertake invasive neuroscience research should be approached with a cautious ethical analysis that accounts for the breadth of potential research contained in this category. Although therapeutic neurosurgeries may be one paradigm within surgically invasive neuroscience research, the breadth of area encompassed by the topic becomes muddled by the varieties of possible activities that go beyond those research endeavors with direct therapeutic goals. Invasive neuroscience research could have goals focused on determining the biologic, physiologic, or psychologic function of the brain, i.e., a goal related to more
diffuse generalizable knowledge. None of these types of research needs be connected to a therapeutic goal, either immediate or on the horizon, and could be directed towards a variety of tasks, including developing models of human thought for mere interest or even for purposes of manipulation. Although there are a variety of purposes to which research may be focused, invasive neuroscience research projects share common characteristics that spark interest and create unique risks and challenges. A failure to be clear about the varieties of ethical distinctions in invasive neuroscience research will hinder attempts for clear ethical analysis and guidance. A checkered ethical history already exists with respect to invasive neurologic research (Ford and Henderson, 2005). A lack of clear ethical analysis in turn could result in poorly considered or inconsistently applied guidelines and principles. To evaluate this category of research from an ethical perspective, at least four main challenges need to be addressed: 1.
2.
3. 4.
To what extent is “invasiveness” an important moral characteristic in the calculation about permissibility of a research project? Are there special brain-related considerations in the severity of, and uncertainties about, expected sideeffects and risks? Is the use of the targeted research participant populations justified for specific projects? What is the nature of interpretation related to normal functions of persons?
These four domains provide an opportunity to explore and understand how to create an ethical analysis for whether invasive neurosurgical research should move forward and if so, what constraints would have strong ethical justification. In an overarching way, the four
*Correspondence to: Paul J. Ford, Ph.D., Department of Bioethics/JJ60, 9500 Euclid Ave., Cleveland, OH 44195, USA. Tel: þ1-216444-8723, E-mail: [email protected]
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domains of ethical considerations persist through the entire spectrum of research development, beginning with the design choices in initial conceptualizing and engineering process and continuing through human subjects research and the adoption as standards of practice (Kubu and Ford, 2007). At any point in the research endeavor, one may find that potential harms may outweigh potential benefits in terms of large scale values. Although the ethical considerations for invasive neurologic technologies appear similar to those reflected upon in research ethics more generally, there is a distinct set of ethical considerations that call for special attention in this area. In considering these problems we can draw on considerations found in the ethics literature about medical implants, psychiatric pharmaceutical research, and neurologic ethics (Morreim et al., 2006; Bernat, 2009). Although this is not a completely new domain in ethics, invasive neurologic procedures require special attention because of the value placed on preserving cognition as well as questions about alterations in identity and selves. Further, the complex and intricate nature of the nervous system makes it both resilient and fragile. These elements combine to create sets of complicated challenges for the researcher to unravel. Many research participants may be considered particularly vulnerable to undue influence or manipulation given the relationships between the procedures, their function as a person, and the continued power imbalances found in these complicated relationships with researchers and interventional neuroscientists (Ford, 2009). Simply put, although all of the usual concepts of research ethics are relevant, there are added textures to be considered in the current discussion.
DEGREES OF INVASIVENESS Although it might at first seem obvious that a least invasive principle of always selecting the least invasive research procedure for accomplishing the research goal should be a primary and controlling first principle, it is much less clear than it appears on the surface. The ethical analysis of invasive neurosurgic research properly hinges more on a least harm principle than on a least invasive principle. The least invasive principle lacks clarity both in defining which kinds of invasiveness matter and whether a more invasive procedure is always more ethically troubling than a less invasive one. The more directly controlling principle is to minimize potential harms while maximizing potential scientific knowledge gain that is worthwhile. At least two definitions of invasiveness are simultaneously at play in this debate. A first understanding of invasive is something that “transgresses” the body
boundaries, usually the skin and bones of a person. (This is an arbitrary definition for the sake of contrasting the distinctions, with any number of competing definitions possible for different purposes.) This includes things that penetrate or are lodged within the body in some ways. A second definition of invasive is more metaphoric in that it transgresses a person’s rights, interests, or personhood. This definition includes things that invade privacy, interfere with daily functioning, or invade one’s sense of self. These two definitions of invasiveness are easily confused, but must be separated for an ethical analysis. Just because something invades the body boundary does not necessarily mean it is more detrimental to a person’s interests than an intervention that does not invade the body boundary but that instead invades a sense of self. Starting from a first principle of protecting research participants’ interests more broadly than simply the body boundary leads to a framing of issues in ways that challenge traditional intuitions. Drawing from clinical practice, psychotherapy, for example, can be destructive to a person when performed poorly. Psychotherapy, while not physically invasive, can be personally invasive. Experts in the field go so far as to ask whether malfunctioned DBS therapy could cause less personal disruption than wrongly conducted psychotherapy (Synofzik and Schlaepfer, 2010)? This same type of question arises in considering whether imaging the brain to read “brain states” can be invasive in a metaphoric sense. When looking at the spectrum of surgically invasive neuroscience research, the degree of physical invasiveness does not serve well as a primary marker of the degree for prohibition or for increased scrutiny necessary to the research. These ideas also become relevant as the rhetoric introduces “minimally” or “non” as modifiers to invasive as a way of avoiding the conversation about morbidity. Researchers, grant reviewers, and institutional review board members particularly need to take note that just because something is described as “minimally” invasive, it does not mean that it is less harmful or risky. In considering the “icepick frontal lobotomy” made famous by Walter Freeman, one would likely think of the procedure as “minimally invasive” but also very destructive to many of the people to whom it was applied (Pressman, 1998; El-Hai, 2005). Describing the procedure as minimally invasive gives the impression that it is also minimally harmful. However, Freeman’s technique was much less precise and probably more “invasive” than Egas Moniz’s original prefrontal leucotomy, developed as a more traditional open surgery (Moniz, 1937). The language of invasiveness carries with it this sense of degree of harm. One important caveat in these considerations of the importance of invading body boundaries is that an
THE ETHICS OF SURGICALLY INVASIVE NEUROSCIENCE RESEARCH ideologic framing of the body as “sacred” could once again move the degree of transgressing or modifying the physical body as a primary ethical principle apart from harm. If the body is sacred and any significant transgression of the body boundary should be rejected, then noninvasive endeavors should always be chosen over invasive ones for research. However, given the ways that contemporary western medical research is permitted to modify bodies, creating a first principle that treats bodies as sacred apart from function and personal values would be inconsistent. Although we should pay attention to the proper respect for research participants, and as an extension the boundaries of themselves, we should reject the primacy of the physical invasions mattering most as a moral imperative (Anderson, 2008). It is instructive to consider the diversity of interventions that could be considered as invasive interventions. The most obvious type would be an open neurosurgical intervention, such as a surgery for tumor removal, to treat refractory epilepsy or to ablate a nerve. A second type would be those interventions requiring a burr hole and a penetration of the brain, such as the implantation of a DBS probe. One step away from this would be intracerebral or intraventricular interventions by means of a catheter. The question then arises whether technologies like gamma knife, ultrasound, transcranial magnetic stimulation, or electroconvulsive therapy are invasive. They are not physically invasive in so far as they do not pierce the skin; however the radiation, sound and magnetic waves, and electricity all penetrate into the brain and can be invasive on a person’s life. These technologies all cause structural or electric changes. A final step away from this would be research involving the injections of biologics into the system such as gene or stem cell therapy. It becomes clear that the mere categorization of interventions by degrees of invasiveness does not clarify the permissibility of research, and as such is not very useful in the ethical debate. In general, the axis of more or less invasive as an ethical analysis is most useful in the second definition of being invasive in a personal sense, rather than the first bodily invasive sense. Programmable brain implants that remain as parts of the body are one such type of invasiveness in terms of a constant modifiable intrusion on a person. Although the idea of a foreign body remaining implanted might raise primary concerns about infection or immunologic responses, the sense of others being able to manipulate brain function so directly may be of greater concern. Robert Heath’s work is instructive with regard to personal invasiveness. His research included a subject who was a psychiatric patient at a county facility and for whom Heath intended to cure homosexuality through
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implantation of electric brain stimulators. The research was both physically and personally invasive, given the implants as well as his hiring a prostitute to be intimate with the subject while being monitored (Moan and Heath, 1972; Baumeister, 2000). In considering this research, the personal invasiveness is important, as well as the underlying assumptions about healthy human persons and the use of a vulnerable subject. It is paradoxical that in this discussion of invasive neuroscience research there is an argument made against “invasiveness” as the distinguishing strong moral component. It would then seem that the reason to lump this group of research together no longer holds. However, this grouping still makes sense for more reasons than the intuition of invasiveness as important to an ethical debate. Given the limited number of disciplines that are authorized to carry out surgically invasive research, the history of past abuses using invasive research, and the significant personal and societal harms from a subset of this research, it is valuable to lump these together for consideration.
SPECIAL CONSIDERATIONS OF SIDEEFFECTS AND HARMS Brain research often raises consternation because of the potential to alter persons significantly in terms of their selves, personalities, and identities. These elements are essential to our understanding of individuality and personal rights. Invasive neuroscience research, particularly involving the brain, puts at risk elements of the person either directly or indirectly. Any brain surgery research is ethically significant by being an elective, nonstandard procedure without proven benefit. Even those considered to be nonablative may in fact have irreversible harms either operatively or from sustained research intervention. For example, although technology like DBS and insertion of cortical grids are considered “reversible” procedures, they have significant risks of hemorrhage during the operation and the microlesions of the brain produced by each technique are irreversible. Further, the long-term changes induced by actual electric stimulation are also unknown. Although these procedures often attempt to restore function to a patient, paradoxically they often carry the risk of producing more dysfunction in ways that seriously alter the person’s self than the actual dysfunction for which they were being studied. For instance, there are paradoxes in pain management where the very intervention to alleviate pain may make the individuals suffer more significant pain. A second important type of risk is related to incidental findings. With increased attention to small differences in neurologic systems, there is less clarity about
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which differences are clinically significant. Even if the research is basic and intended to understand better some cognitive function, it may uncover some type of abnormality or difference in a research subject’s neuroanatomy or function. There is a spectrum of possibilities in the knowledge a researcher has about these differences. Some are known to be normal variations in normal anatomy while others are known to have clinical significance. The more challenging categories are those differences that arise in at least three ways: from a new modality where there are no normal data established; a poorquality testing not intended to have significant sensitivity or specificity related to the finding; or a subtle finding that does not need immediate attention but might have a clinical implication at some point. If clinically relevant findings include psychologic wellbeing as well as preservation of life and motoric function, then the incidental findings become even more challenging in deciding which findings are of clinical significance. In incidental findings, we are left with questions about which categories should be reported. To whom should they be reported, i.e., to a research participant or a healthcare provider? Who bears the burden of the costs of follow-up and the harms produced by falsepositive results? What obligations are there to report incidental findings? An ethics literature has emerged considering how to handle incidental findings in neuroimaging research that apply equally to surgically invasive research with the added twist of being able to identify specific functional anomalies beyond just anatomic ones (Illes et al., 2008; Wolf et al., 2008). The possibility of incidental findings and creating a process to handle them needs to be included in almost every research study of invasive neurosurgical research as a requirement to respect the welfare of research participants. The ethical principles for consideration include benefit to a participant in identifying an abnormality of significance otherwise undetectable, harming a participant by unnecessarily increasing worry or expense, and overextending expertise or research funding for a research complication that lies outside a project’s scope.
WHAT POPULATIONS ARE WE JUSTIFIED IN STUDYING AND FOR WHICH PURPOSES? The proper population for study depends largely on the research question being asked and the characteristics of the population. Ethical and scientific choices are made at the beginning of research about which population to study to answer which types of questions. Because of the types of risks to persons and selves discussed above, there is considerable worry about whether there should
be a preference to undertake invasive research on healthy volunteers or those with neurologic dysfunction. Although some research questions can only be answered by using an affected population, for those who could get some answers from either there is a very acute dilemma. Do we put at risk those who have the most to lose or the least to lose? Do we enroll subjects who have the least element of coercion present and are in the best position to understand the research or those who may be easily coerced or not as fully able to understand the research? A clear set of ethical reasons needs to be used in justifying the answers to these for specific research populations. Robert Heath selected a disempowered subject who was under the control of a state mental health facility to perform the brain stimulation and homosexuality research. Although Heath attempted to justify his choice by arguing that his subject was someone he could help the most, it was also a person who had the least opportunity to make an informed decision and who also was ostracized by society (see more about the underlying assumption in the next section). The selection of the proper population should be based on voluntariness and relevance to the research and participant goals. Clearly many conditions that surgically invasive researchers want to explore involve people who have a baseline state of abnormal or altered cognition. The problems corrected by functional neurosurgeries have the potential to influence cognition and/or judgment. This situation can become more complicated when the potential risk of the surgery involves loss of cognition and psychologic impairment. While consent can be withdrawn at any time, even after the planning of surgery, it is challenging in cases of functional neurosurgery where the patient is undergoing a craniotomy procedure while awake and wants to withdraw consent during the procedure. It is even more challenging when we take into consideration that most functional neurosurgeries are elective in nature and are performed for medical conditions not considered life-threatening. These examples are anticipatable situations that therefore need to be addressed prospectively in research protocols for invasive neurologic research. One special category of research involves neuroenhancement technologies (see Chapter 27). These technologies raise unique issues of justice and equity. If in human subjects research the strongest justification for use of humans is for populations who are likely to benefit from the research, then risk and burden should accrue to the healthy population who are likely to benefit from the resulting enhancement technologies (Ford, 2006). There is a fine line between adding a small amount of risk in a therapeutic invasive trial for studying enhancement and using a vulnerable population to study enhancement
THE ETHICS OF SURGICALLY INVASIVE NEUROSCIENCE RESEARCH that is unrelated to their condition. In the first case, one could study the physiologic function of an intraoperative technique on a patient who was otherwise having brain tissue resected that would be of little additional risk. The second type would be to study invasively subjects enrolled in unrelated studies that placed the burden significantly on them. As a matter of justice, each approach should be measured against the potential for wrongly exploiting one vulnerable population for the future benefit of a different and less vulnerable population. The use of sham surgery controls remains controversial. The best example is the poorly controlled phase II trials of fetal cell transplantation for Parkinson’s disease that created heated dialogue (Kim et al., 2012). The design of the clinical trial must consider those who can and should be put at risk and the types of acceptable risks to those with no chance of benefit. One type of argument is that a sham surgery trial design keeps the sham arm patients from potential further harm of the research intervention such as exposure to cells that could be harmful. In contemporary studies of DBS for psychiatric and neurologic disorders (e.g., depression, obsessivecompulsive disorder, and minimally conscious state), a double-blind randomized on/off model has been utilized where all participants receive a working implant and a portion of them remain off at the beginning. There is a strong ethical argument for this model given that all subjects have the potential to gain a benefit, if the intervention later is shown to be effective. This design is possible also for devices, but not for procedures that are destructive or that involve implanting a biologic in a one-time surgery. Important from an ethical perspective is to recognize that a “controlled” trial does not necessarily entail a placebo or sham. Often, when the success of uncontrolled phase II trials is not replicated in a controlled phase III trial, there is a call for all future trials to have a sham or placebo arm. However, this claim does not necessarily follow since there are alternative methods for controlled trials that do not involve doing a risky procedure that has no chance of benefitting the participant. Finally, similar to pharmaceuticals that can alter consciousness, many invasive neuroscience procedures may alter a person’s understanding during the process of research. Since informed consent requires information, understanding, appreciation, consent, and authorization – all of which need to be satisfied on a continuous basis – this creates a dilemma if the procedure itself might alter the participants’ perceptions of risk aversion or about their own values and interest. Of course, the information given to the patient or surrogate should be complete and adequate for decision-making, the patient should demonstrate an understanding of the information given, and should voluntarily wish to proceed and freely consent without any form of coercion, and the patient or lawful
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surrogate should authorize the procedure (Moreno et al., 1998; Scarrow and Scarrow, 2002). A prospective agreement about how situations are handled in a fair way should be implemented by researchers. In particular there should be attention paid to having participants identify a person they trust who can then help articulate their consistent goals and values throughout the process. The use of children as research subjects in any of these types of research is challenging because of a lack of normal data, the hesitancy to involve healthy children in invasive research, and the dynamic nature of their developing nervous systems. In order to conduct valid clinical trials, normal values are usually necessary. The plasticity of children’s neurologic system generally makes the use of adult norms inappropriate. Further, there is a desire to protect children’s right to choose later in life about whether to be part of the research. Society and science can benefit from normal values, but society and individuals want to protect normal children from unnecessary harms. Finally, in doing invasive research in children there is a worry that the risks cannot be fully understood and assessed without long-term follow-up given the brain plasticity inherent in this population. This fact not only poses a problem for informed consent but also raises a question about the researcher’s obligation to follow up long term to determine whether even small invasive procedures might have a clinically significant developmental effect. Unfortunately, most research does not receive funding support for studies that last more than 5 years. As we have shown, a number of important ethical considerations must be considered in selecting and undertaking invasive neuroscience research. These considerations relate to the unique risks as well as the types of coercion that may occur.
VALUE-RICH INTERPRETATIONS: METRICS FOR SUCCESS AND ASSUMPTIONS Many competing theories of mind and human “goods” exist. The beginning assumptions matter for research in both how it is conducted and to what uses it is put. There are questions about what metrics of success should be used and about who chooses them. How does an investigator interpret the results as efficacious? In procedures causing a change in personality or identity, how are the ends justified? The cure may come at the cost of identities, themselves (Glannon, 2006). Invasive neuromodulation techniques have had this critique leveled squarely at them in a concern that a person’s psychologic identity will be negatively affected. In the Robert Heath experiments, we can clearly see that the societal premise was that homosexuality was an illness in
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need of cure. Heath purported to want to help the subject by changing his sexuality, when some of his suffering was occurring due to the continued promulgation of a social bias. At the beginning of research development, an ethical imperative exists to recognize the underlying conceptual framework that supports the research (and the biases within it) and the potential misuses to which results could be put.
CROSS-CULTURAL VALUES Cross-cultural and international research creates particularly complex sets of ethical issues. Beyond the varying concepts of self, mind, and identity among different cultures, existing disparities between countries or even within a country’s demographics can add another layer to the value assumptions underlying a study. The contrast between traditional Asian and North American views of independence and interdependence of the self provides a common example of important cultural differences that must be taken into account in the ethical analysis (Markus and Kitayama, 1991). A classic bioethics tenet is that, while ethical values are mostly universal, local values and principles should also be considered (Veatch, 1972). One problem with performing research in developing countries is that the resources are scarce, which could lead to specific types of coercion. It is ethically problematic to conduct research on populations who may not be able to afford the resulting technology and who could not benefit from the findings of the research for years thereafter. High ethical hurdles must be overcome in considering invasive research in populations in which the human subjects have no access to necessary long-term follow-up. For example, implanting deep brain stimulators in research subjects who have no postresearch access to programmers, battery replacements, or explanations would be ethically difficult to justify. Further, when considering the set of riskiest invasive research procedures, there should be careful attention to the ways in which a societal structure may deem something pathologic and in need of intervention, while the subject might deem it normal and acceptable. Further, invasive testing using a prison population, whether as further punishment, as treatment for “criminality,” or as a way of receiving leniency requires careful analysis of concepts of justice and coercion. Finally, when research involves populations or investigators from cross-culturally distinct groups, the most stringent concepts of respect for human dignity and value should be the controlling norm. More specifically, research that cannot be done for ethical reasons in one’s own country should not be attempted to be performed in another person’s country simply out of convenience to circumvent ethical
problems or regulatory requirements. Given the foundational ways that certain invasive neurologic research can alter people and be misused, special safeguards should be in place to assure culturally appropriate models of research design and recruitment.
CONCLUDING REMARKS The standard ethical principles and safeguards found in prevailing research ethics should be followed when considering invasive neuroscience research, no matter whether they are physically or metaphorically invasive. The degree of invasiveness is not the controlling factor in the ethical analysis. Rather, a simpler metric of harm is more ethically sound, involving the thoughtful balance of the probability and type of benefit versus the probability and type of harm. The principle of least harm should be applied with careful attention to the types of harms possible through the misuse of the research for ideologic reasons. Neurologic exceptionalism, the belief that there is something special about neurologic interventions, comes into play in the subcategories where risks could substantially and foundationally alter identities and minds. This is the area with the most delicate ethical distinction, particularly when the research is aimed at either developing a quality-of-life intervention or in more basic research aimed primarily at knowledge. Careful attention to the ethical risks we discussed is necessary, with protections put in place to offset research subjects’ vulnerabilities. Additionally, attention needs to be paid to the conceptual challenges in research participants’ understanding of what it would be like to have a significant alteration in cognitive or affective life. Although, in many cases, surgically invasive neuroscience can be justified ethically, the potential harms to larger groups within society need to be addressed by a reasonable interpretation of data and meticulous avoidance of misguided underlying assumptions. These considerations need to be attended to by researchers, funders, and review boards so that proper safeguards are in place from the point of conception of research through the final application of research results.
REFERENCES Anderson J (2008). Neuro-prosthetics, the extended mind and respect for persons with disability. In: M D€ uwell, C Rehmann-Sutter, D Mieth (Eds.), The Contingent Nature of Life. International Library of Ethics, Law and the New Medicine. Springer, Netherlands, pp. 259–272. Baumeister AA (2000). The Tulane Electrical Brain Stimulation Program: a historical case study in medical ethics. J Hist Neurosci 9: 262–278. Bernat JL (2009). Ethical issues in the treatment of severe brain injury: the impact of new technologies. Ann N Y Acad Sci 1157: 117–130.
THE ETHICS OF SURGICALLY INVASIVE NEUROSCIENCE RESEARCH El-Hai J (2005). The lobotomist: A maverick medical genius and his tragic quest to rid the world of mental illness. John Wiley, New Jersey. Ford PJ (2006). Advancing from treatment to enhancement in deep brain stimulation: a question of research ethics. Pluralist 1: 35–44. Ford PJ (2009). Vulnerable brains: research ethics and neurosurgical patients. J Law Med Ethics 37: 73–82. Ford PJ, Henderson J (2005). Neuroethics in the operating room: functional neurosurgical interventions. In: J Illes (Ed.), Neuroethics: Defining the Issues in Theory, Practice and Policy. Oxford University Press, New York, pp. 213–228. Glannon W (2006). Neuroethics. Bioethics 20: 37–52. Illes J, Kirschen MP, Edwards E et al. (2008). Practical approaches to incidental findings in brain imaging research. Neurology 70: 384–390. Kim SY, De Vries R, Holloway RG et al. (2012). Sham surgery controls in Parkinson’s disease clinical trials: views of participants. Mov Disord 27: 1461–1465. Kubu CS, Ford PJ (2007). Ethics in the clinical application of neural implants. Camb Q Healthc Ethics 16: 317. Markus HR, Kitayama S (1991). Culture and the self: implications for cognition, emotion, and motivation. Psychol Rev 98: 224–253.
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Moan CE, Heath RG (1972). Septal stimulation for the initiation of heterosexual behavior in a homosexual male. J Behav Ther Exp Psychiatry 3: 23–30. Moniz E (1937). Prefrontal leucotomy in the treatment of mental disorders. Am J Psychiatry 93: 1379–1387. Moreno J, Caplan AL, Wolpe PR (1998). Updating protections for human subjects involved in research. JAMA 280: 1951–1958. Morreim H, Mack MJ, Sade RM (2006). Surgical innovation: too risky to remain unregulated? Ann Thorac Surg 82: 1957–1965. Pressman J (1998). Last Resort: Psychosurgery and the Limits of Medicine. Cambridge University Press, Cambridge. Scarrow AM, Scarrow MR (2002). Informed consent for the neurosurgeon. Surg Neurol 57: 63–68. Synofzik M, Schlaepfer TE (2010). Neuromodulation – ECT, rTMS, DBS. In: H Helmschen, N Sartorius (Eds.), Ethics in Psychiatry. European Contributions. Springer, Heidelberg, pp. 299–320. Veatch RM (1972). Medical ethics: professional or universal? Harv Theolog Rev 65: 531–559. Wolf SM, Lawrenz FP, Nelson CA et al. (2008). Managing incidental findings in human subjects research: analysis and recommendations. J Law Med Ethics 36 (211): 219–248.
Chapter 26
The ethics of surgically invasive neuroscience research 1 2
PAUL J. FORD1* AND ABHISHEK DESHPANDE2 Department of Bioethics, Cleveland Clinic, Cleveland, OH, USA
Department of Medicine, Case Western Reserve University, Cleveland, OH, USA
STATEMENT OF THE PROBLEM A clear understanding of various distinctions and definitions is needed to provide a lucid ethical analysis and set of arguments regarding which types of surgically invasive neuroscience research should be permitted and how they can properly be undertaken. Great excitement has been generated by the development and application of invasive neurologic procedures, given the tantalizing possibility of restoration or augmentation of lost function through intervening in the nervous system. With improvements in technologies related to imaging, computer modeling, stereotaxis, implanted electric modulation, and radiofrequency ablation, various invasive interventions have now become more specifically targeted and result in lower levels and rates of morbidity. Deep brain stimulation (DBS) for the treatment of Parkinson’s disease is the most common example of the immediate and dramatic beneficial effects on a person’s motor dysfunction from a technology arising from such research. These almost magic effects quickly capture the attention of those thinking about the ethics of invasive research. While these neurosurgical procedures have a great potential to treat diseases and enhance patients’ quality of life, any rush to undertake invasive neuroscience research should be approached with a cautious ethical analysis that accounts for the breadth of potential research contained in this category. Although therapeutic neurosurgeries may be one paradigm within surgically invasive neuroscience research, the breadth of area encompassed by the topic becomes muddled by the varieties of possible activities that go beyond those research endeavors with direct therapeutic goals. Invasive neuroscience research could have goals focused on determining the biologic, physiologic, or psychologic function of the brain, i.e., a goal related to more
diffuse generalizable knowledge. None of these types of research needs be connected to a therapeutic goal, either immediate or on the horizon, and could be directed towards a variety of tasks, including developing models of human thought for mere interest or even for purposes of manipulation. Although there are a variety of purposes to which research may be focused, invasive neuroscience research projects share common characteristics that spark interest and create unique risks and challenges. A failure to be clear about the varieties of ethical distinctions in invasive neuroscience research will hinder attempts for clear ethical analysis and guidance. A checkered ethical history already exists with respect to invasive neurologic research (Ford and Henderson, 2005). A lack of clear ethical analysis in turn could result in poorly considered or inconsistently applied guidelines and principles. To evaluate this category of research from an ethical perspective, at least four main challenges need to be addressed: 1.
2.
3. 4.
To what extent is “invasiveness” an important moral characteristic in the calculation about permissibility of a research project? Are there special brain-related considerations in the severity of, and uncertainties about, expected sideeffects and risks? Is the use of the targeted research participant populations justified for specific projects? What is the nature of interpretation related to normal functions of persons?
These four domains provide an opportunity to explore and understand how to create an ethical analysis for whether invasive neurosurgical research should move forward and if so, what constraints would have strong ethical justification. In an overarching way, the four
*Correspondence to: Paul J. Ford, Ph.D., Department of Bioethics/JJ60, 9500 Euclid Ave., Cleveland, OH 44195, USA. Tel: þ1-216444-8723, E-mail: [email protected]
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domains of ethical considerations persist through the entire spectrum of research development, beginning with the design choices in initial conceptualizing and engineering process and continuing through human subjects research and the adoption as standards of practice (Kubu and Ford, 2007). At any point in the research endeavor, one may find that potential harms may outweigh potential benefits in terms of large scale values. Although the ethical considerations for invasive neurologic technologies appear similar to those reflected upon in research ethics more generally, there is a distinct set of ethical considerations that call for special attention in this area. In considering these problems we can draw on considerations found in the ethics literature about medical implants, psychiatric pharmaceutical research, and neurologic ethics (Morreim et al., 2006; Bernat, 2009). Although this is not a completely new domain in ethics, invasive neurologic procedures require special attention because of the value placed on preserving cognition as well as questions about alterations in identity and selves. Further, the complex and intricate nature of the nervous system makes it both resilient and fragile. These elements combine to create sets of complicated challenges for the researcher to unravel. Many research participants may be considered particularly vulnerable to undue influence or manipulation given the relationships between the procedures, their function as a person, and the continued power imbalances found in these complicated relationships with researchers and interventional neuroscientists (Ford, 2009). Simply put, although all of the usual concepts of research ethics are relevant, there are added textures to be considered in the current discussion.
DEGREES OF INVASIVENESS Although it might at first seem obvious that a least invasive principle of always selecting the least invasive research procedure for accomplishing the research goal should be a primary and controlling first principle, it is much less clear than it appears on the surface. The ethical analysis of invasive neurosurgic research properly hinges more on a least harm principle than on a least invasive principle. The least invasive principle lacks clarity both in defining which kinds of invasiveness matter and whether a more invasive procedure is always more ethically troubling than a less invasive one. The more directly controlling principle is to minimize potential harms while maximizing potential scientific knowledge gain that is worthwhile. At least two definitions of invasiveness are simultaneously at play in this debate. A first understanding of invasive is something that “transgresses” the body
boundaries, usually the skin and bones of a person. (This is an arbitrary definition for the sake of contrasting the distinctions, with any number of competing definitions possible for different purposes.) This includes things that penetrate or are lodged within the body in some ways. A second definition of invasive is more metaphoric in that it transgresses a person’s rights, interests, or personhood. This definition includes things that invade privacy, interfere with daily functioning, or invade one’s sense of self. These two definitions of invasiveness are easily confused, but must be separated for an ethical analysis. Just because something invades the body boundary does not necessarily mean it is more detrimental to a person’s interests than an intervention that does not invade the body boundary but that instead invades a sense of self. Starting from a first principle of protecting research participants’ interests more broadly than simply the body boundary leads to a framing of issues in ways that challenge traditional intuitions. Drawing from clinical practice, psychotherapy, for example, can be destructive to a person when performed poorly. Psychotherapy, while not physically invasive, can be personally invasive. Experts in the field go so far as to ask whether malfunctioned DBS therapy could cause less personal disruption than wrongly conducted psychotherapy (Synofzik and Schlaepfer, 2010)? This same type of question arises in considering whether imaging the brain to read “brain states” can be invasive in a metaphoric sense. When looking at the spectrum of surgically invasive neuroscience research, the degree of physical invasiveness does not serve well as a primary marker of the degree for prohibition or for increased scrutiny necessary to the research. These ideas also become relevant as the rhetoric introduces “minimally” or “non” as modifiers to invasive as a way of avoiding the conversation about morbidity. Researchers, grant reviewers, and institutional review board members particularly need to take note that just because something is described as “minimally” invasive, it does not mean that it is less harmful or risky. In considering the “icepick frontal lobotomy” made famous by Walter Freeman, one would likely think of the procedure as “minimally invasive” but also very destructive to many of the people to whom it was applied (Pressman, 1998; El-Hai, 2005). Describing the procedure as minimally invasive gives the impression that it is also minimally harmful. However, Freeman’s technique was much less precise and probably more “invasive” than Egas Moniz’s original prefrontal leucotomy, developed as a more traditional open surgery (Moniz, 1937). The language of invasiveness carries with it this sense of degree of harm. One important caveat in these considerations of the importance of invading body boundaries is that an
THE ETHICS OF SURGICALLY INVASIVE NEUROSCIENCE RESEARCH ideologic framing of the body as “sacred” could once again move the degree of transgressing or modifying the physical body as a primary ethical principle apart from harm. If the body is sacred and any significant transgression of the body boundary should be rejected, then noninvasive endeavors should always be chosen over invasive ones for research. However, given the ways that contemporary western medical research is permitted to modify bodies, creating a first principle that treats bodies as sacred apart from function and personal values would be inconsistent. Although we should pay attention to the proper respect for research participants, and as an extension the boundaries of themselves, we should reject the primacy of the physical invasions mattering most as a moral imperative (Anderson, 2008). It is instructive to consider the diversity of interventions that could be considered as invasive interventions. The most obvious type would be an open neurosurgical intervention, such as a surgery for tumor removal, to treat refractory epilepsy or to ablate a nerve. A second type would be those interventions requiring a burr hole and a penetration of the brain, such as the implantation of a DBS probe. One step away from this would be intracerebral or intraventricular interventions by means of a catheter. The question then arises whether technologies like gamma knife, ultrasound, transcranial magnetic stimulation, or electroconvulsive therapy are invasive. They are not physically invasive in so far as they do not pierce the skin; however the radiation, sound and magnetic waves, and electricity all penetrate into the brain and can be invasive on a person’s life. These technologies all cause structural or electric changes. A final step away from this would be research involving the injections of biologics into the system such as gene or stem cell therapy. It becomes clear that the mere categorization of interventions by degrees of invasiveness does not clarify the permissibility of research, and as such is not very useful in the ethical debate. In general, the axis of more or less invasive as an ethical analysis is most useful in the second definition of being invasive in a personal sense, rather than the first bodily invasive sense. Programmable brain implants that remain as parts of the body are one such type of invasiveness in terms of a constant modifiable intrusion on a person. Although the idea of a foreign body remaining implanted might raise primary concerns about infection or immunologic responses, the sense of others being able to manipulate brain function so directly may be of greater concern. Robert Heath’s work is instructive with regard to personal invasiveness. His research included a subject who was a psychiatric patient at a county facility and for whom Heath intended to cure homosexuality through
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implantation of electric brain stimulators. The research was both physically and personally invasive, given the implants as well as his hiring a prostitute to be intimate with the subject while being monitored (Moan and Heath, 1972; Baumeister, 2000). In considering this research, the personal invasiveness is important, as well as the underlying assumptions about healthy human persons and the use of a vulnerable subject. It is paradoxical that in this discussion of invasive neuroscience research there is an argument made against “invasiveness” as the distinguishing strong moral component. It would then seem that the reason to lump this group of research together no longer holds. However, this grouping still makes sense for more reasons than the intuition of invasiveness as important to an ethical debate. Given the limited number of disciplines that are authorized to carry out surgically invasive research, the history of past abuses using invasive research, and the significant personal and societal harms from a subset of this research, it is valuable to lump these together for consideration.
SPECIAL CONSIDERATIONS OF SIDEEFFECTS AND HARMS Brain research often raises consternation because of the potential to alter persons significantly in terms of their selves, personalities, and identities. These elements are essential to our understanding of individuality and personal rights. Invasive neuroscience research, particularly involving the brain, puts at risk elements of the person either directly or indirectly. Any brain surgery research is ethically significant by being an elective, nonstandard procedure without proven benefit. Even those considered to be nonablative may in fact have irreversible harms either operatively or from sustained research intervention. For example, although technology like DBS and insertion of cortical grids are considered “reversible” procedures, they have significant risks of hemorrhage during the operation and the microlesions of the brain produced by each technique are irreversible. Further, the long-term changes induced by actual electric stimulation are also unknown. Although these procedures often attempt to restore function to a patient, paradoxically they often carry the risk of producing more dysfunction in ways that seriously alter the person’s self than the actual dysfunction for which they were being studied. For instance, there are paradoxes in pain management where the very intervention to alleviate pain may make the individuals suffer more significant pain. A second important type of risk is related to incidental findings. With increased attention to small differences in neurologic systems, there is less clarity about
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which differences are clinically significant. Even if the research is basic and intended to understand better some cognitive function, it may uncover some type of abnormality or difference in a research subject’s neuroanatomy or function. There is a spectrum of possibilities in the knowledge a researcher has about these differences. Some are known to be normal variations in normal anatomy while others are known to have clinical significance. The more challenging categories are those differences that arise in at least three ways: from a new modality where there are no normal data established; a poorquality testing not intended to have significant sensitivity or specificity related to the finding; or a subtle finding that does not need immediate attention but might have a clinical implication at some point. If clinically relevant findings include psychologic wellbeing as well as preservation of life and motoric function, then the incidental findings become even more challenging in deciding which findings are of clinical significance. In incidental findings, we are left with questions about which categories should be reported. To whom should they be reported, i.e., to a research participant or a healthcare provider? Who bears the burden of the costs of follow-up and the harms produced by falsepositive results? What obligations are there to report incidental findings? An ethics literature has emerged considering how to handle incidental findings in neuroimaging research that apply equally to surgically invasive research with the added twist of being able to identify specific functional anomalies beyond just anatomic ones (Illes et al., 2008; Wolf et al., 2008). The possibility of incidental findings and creating a process to handle them needs to be included in almost every research study of invasive neurosurgical research as a requirement to respect the welfare of research participants. The ethical principles for consideration include benefit to a participant in identifying an abnormality of significance otherwise undetectable, harming a participant by unnecessarily increasing worry or expense, and overextending expertise or research funding for a research complication that lies outside a project’s scope.
WHAT POPULATIONS ARE WE JUSTIFIED IN STUDYING AND FOR WHICH PURPOSES? The proper population for study depends largely on the research question being asked and the characteristics of the population. Ethical and scientific choices are made at the beginning of research about which population to study to answer which types of questions. Because of the types of risks to persons and selves discussed above, there is considerable worry about whether there should
be a preference to undertake invasive research on healthy volunteers or those with neurologic dysfunction. Although some research questions can only be answered by using an affected population, for those who could get some answers from either there is a very acute dilemma. Do we put at risk those who have the most to lose or the least to lose? Do we enroll subjects who have the least element of coercion present and are in the best position to understand the research or those who may be easily coerced or not as fully able to understand the research? A clear set of ethical reasons needs to be used in justifying the answers to these for specific research populations. Robert Heath selected a disempowered subject who was under the control of a state mental health facility to perform the brain stimulation and homosexuality research. Although Heath attempted to justify his choice by arguing that his subject was someone he could help the most, it was also a person who had the least opportunity to make an informed decision and who also was ostracized by society (see more about the underlying assumption in the next section). The selection of the proper population should be based on voluntariness and relevance to the research and participant goals. Clearly many conditions that surgically invasive researchers want to explore involve people who have a baseline state of abnormal or altered cognition. The problems corrected by functional neurosurgeries have the potential to influence cognition and/or judgment. This situation can become more complicated when the potential risk of the surgery involves loss of cognition and psychologic impairment. While consent can be withdrawn at any time, even after the planning of surgery, it is challenging in cases of functional neurosurgery where the patient is undergoing a craniotomy procedure while awake and wants to withdraw consent during the procedure. It is even more challenging when we take into consideration that most functional neurosurgeries are elective in nature and are performed for medical conditions not considered life-threatening. These examples are anticipatable situations that therefore need to be addressed prospectively in research protocols for invasive neurologic research. One special category of research involves neuroenhancement technologies (see Chapter 27). These technologies raise unique issues of justice and equity. If in human subjects research the strongest justification for use of humans is for populations who are likely to benefit from the research, then risk and burden should accrue to the healthy population who are likely to benefit from the resulting enhancement technologies (Ford, 2006). There is a fine line between adding a small amount of risk in a therapeutic invasive trial for studying enhancement and using a vulnerable population to study enhancement
THE ETHICS OF SURGICALLY INVASIVE NEUROSCIENCE RESEARCH that is unrelated to their condition. In the first case, one could study the physiologic function of an intraoperative technique on a patient who was otherwise having brain tissue resected that would be of little additional risk. The second type would be to study invasively subjects enrolled in unrelated studies that placed the burden significantly on them. As a matter of justice, each approach should be measured against the potential for wrongly exploiting one vulnerable population for the future benefit of a different and less vulnerable population. The use of sham surgery controls remains controversial. The best example is the poorly controlled phase II trials of fetal cell transplantation for Parkinson’s disease that created heated dialogue (Kim et al., 2012). The design of the clinical trial must consider those who can and should be put at risk and the types of acceptable risks to those with no chance of benefit. One type of argument is that a sham surgery trial design keeps the sham arm patients from potential further harm of the research intervention such as exposure to cells that could be harmful. In contemporary studies of DBS for psychiatric and neurologic disorders (e.g., depression, obsessivecompulsive disorder, and minimally conscious state), a double-blind randomized on/off model has been utilized where all participants receive a working implant and a portion of them remain off at the beginning. There is a strong ethical argument for this model given that all subjects have the potential to gain a benefit, if the intervention later is shown to be effective. This design is possible also for devices, but not for procedures that are destructive or that involve implanting a biologic in a one-time surgery. Important from an ethical perspective is to recognize that a “controlled” trial does not necessarily entail a placebo or sham. Often, when the success of uncontrolled phase II trials is not replicated in a controlled phase III trial, there is a call for all future trials to have a sham or placebo arm. However, this claim does not necessarily follow since there are alternative methods for controlled trials that do not involve doing a risky procedure that has no chance of benefitting the participant. Finally, similar to pharmaceuticals that can alter consciousness, many invasive neuroscience procedures may alter a person’s understanding during the process of research. Since informed consent requires information, understanding, appreciation, consent, and authorization – all of which need to be satisfied on a continuous basis – this creates a dilemma if the procedure itself might alter the participants’ perceptions of risk aversion or about their own values and interest. Of course, the information given to the patient or surrogate should be complete and adequate for decision-making, the patient should demonstrate an understanding of the information given, and should voluntarily wish to proceed and freely consent without any form of coercion, and the patient or lawful
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surrogate should authorize the procedure (Moreno et al., 1998; Scarrow and Scarrow, 2002). A prospective agreement about how situations are handled in a fair way should be implemented by researchers. In particular there should be attention paid to having participants identify a person they trust who can then help articulate their consistent goals and values throughout the process. The use of children as research subjects in any of these types of research is challenging because of a lack of normal data, the hesitancy to involve healthy children in invasive research, and the dynamic nature of their developing nervous systems. In order to conduct valid clinical trials, normal values are usually necessary. The plasticity of children’s neurologic system generally makes the use of adult norms inappropriate. Further, there is a desire to protect children’s right to choose later in life about whether to be part of the research. Society and science can benefit from normal values, but society and individuals want to protect normal children from unnecessary harms. Finally, in doing invasive research in children there is a worry that the risks cannot be fully understood and assessed without long-term follow-up given the brain plasticity inherent in this population. This fact not only poses a problem for informed consent but also raises a question about the researcher’s obligation to follow up long term to determine whether even small invasive procedures might have a clinically significant developmental effect. Unfortunately, most research does not receive funding support for studies that last more than 5 years. As we have shown, a number of important ethical considerations must be considered in selecting and undertaking invasive neuroscience research. These considerations relate to the unique risks as well as the types of coercion that may occur.
VALUE-RICH INTERPRETATIONS: METRICS FOR SUCCESS AND ASSUMPTIONS Many competing theories of mind and human “goods” exist. The beginning assumptions matter for research in both how it is conducted and to what uses it is put. There are questions about what metrics of success should be used and about who chooses them. How does an investigator interpret the results as efficacious? In procedures causing a change in personality or identity, how are the ends justified? The cure may come at the cost of identities, themselves (Glannon, 2006). Invasive neuromodulation techniques have had this critique leveled squarely at them in a concern that a person’s psychologic identity will be negatively affected. In the Robert Heath experiments, we can clearly see that the societal premise was that homosexuality was an illness in
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need of cure. Heath purported to want to help the subject by changing his sexuality, when some of his suffering was occurring due to the continued promulgation of a social bias. At the beginning of research development, an ethical imperative exists to recognize the underlying conceptual framework that supports the research (and the biases within it) and the potential misuses to which results could be put.
CROSS-CULTURAL VALUES Cross-cultural and international research creates particularly complex sets of ethical issues. Beyond the varying concepts of self, mind, and identity among different cultures, existing disparities between countries or even within a country’s demographics can add another layer to the value assumptions underlying a study. The contrast between traditional Asian and North American views of independence and interdependence of the self provides a common example of important cultural differences that must be taken into account in the ethical analysis (Markus and Kitayama, 1991). A classic bioethics tenet is that, while ethical values are mostly universal, local values and principles should also be considered (Veatch, 1972). One problem with performing research in developing countries is that the resources are scarce, which could lead to specific types of coercion. It is ethically problematic to conduct research on populations who may not be able to afford the resulting technology and who could not benefit from the findings of the research for years thereafter. High ethical hurdles must be overcome in considering invasive research in populations in which the human subjects have no access to necessary long-term follow-up. For example, implanting deep brain stimulators in research subjects who have no postresearch access to programmers, battery replacements, or explanations would be ethically difficult to justify. Further, when considering the set of riskiest invasive research procedures, there should be careful attention to the ways in which a societal structure may deem something pathologic and in need of intervention, while the subject might deem it normal and acceptable. Further, invasive testing using a prison population, whether as further punishment, as treatment for “criminality,” or as a way of receiving leniency requires careful analysis of concepts of justice and coercion. Finally, when research involves populations or investigators from cross-culturally distinct groups, the most stringent concepts of respect for human dignity and value should be the controlling norm. More specifically, research that cannot be done for ethical reasons in one’s own country should not be attempted to be performed in another person’s country simply out of convenience to circumvent ethical
problems or regulatory requirements. Given the foundational ways that certain invasive neurologic research can alter people and be misused, special safeguards should be in place to assure culturally appropriate models of research design and recruitment.
CONCLUDING REMARKS The standard ethical principles and safeguards found in prevailing research ethics should be followed when considering invasive neuroscience research, no matter whether they are physically or metaphorically invasive. The degree of invasiveness is not the controlling factor in the ethical analysis. Rather, a simpler metric of harm is more ethically sound, involving the thoughtful balance of the probability and type of benefit versus the probability and type of harm. The principle of least harm should be applied with careful attention to the types of harms possible through the misuse of the research for ideologic reasons. Neurologic exceptionalism, the belief that there is something special about neurologic interventions, comes into play in the subcategories where risks could substantially and foundationally alter identities and minds. This is the area with the most delicate ethical distinction, particularly when the research is aimed at either developing a quality-of-life intervention or in more basic research aimed primarily at knowledge. Careful attention to the ethical risks we discussed is necessary, with protections put in place to offset research subjects’ vulnerabilities. Additionally, attention needs to be paid to the conceptual challenges in research participants’ understanding of what it would be like to have a significant alteration in cognitive or affective life. Although, in many cases, surgically invasive neuroscience can be justified ethically, the potential harms to larger groups within society need to be addressed by a reasonable interpretation of data and meticulous avoidance of misguided underlying assumptions. These considerations need to be attended to by researchers, funders, and review boards so that proper safeguards are in place from the point of conception of research through the final application of research results.
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