Deep Brain Stimulation for Alzheimer’s Disease: Ethical Challenges for Clinical Research

Abstract

Deep brain stimulation (DBS) is an invasive neuromodulation modality that has shown early promise as a novel treatment of Alzheimer’s disease (AD). Further clinical research is warranted on the basis of positive results from animal and human studies, as well as the inadequacy of existing treatments in reducing the enormous medical and financial costs of untreated AD. Nevertheless, unique ethical challenges require particular attention to elements of subject enrollment and informed consent. Study protocols should specify robust assessment and regular monitoring of subject decision-making capacity to consent to trial participation. Investigators should also assess for and mitigate therapeutic misconception (the phenomenon whereby a research participant conflates the goals of research with those of clinical treatment) and ensure that all prospective trial participants have adequate post-trial access to treatment and DBS device maintenance. In the following discussion, each issue is summarized and followed by recommendations for proper ethical procedure. We conclude by assimilating relevant ethical considerations into a decision-making algorithm designed to aid future clinical investigators of DBS for AD with the task of ethical subject enrollment.

Keywords

Advance directive Alzheimer’s disease deep brain stimulation informed consent research ethics

INTRODUCTION

Deep brain stimulation (DBS) is an invasive neuromodulation modality that shows promise for the treatment of debilitating and treatment-refractory neurologic and psychiatric disorders [1, 2]. With significant advances in neuroscience, surgical procedures, and device technology, DBS has demonstrated effectiveness in the treatment of medication-resistant Parkinson’s disease, essential tremor, dystonia, and obsessive compulsive disorder. Driven by the urgent need for effective disease-modifying therapy and the success of several recent human trials, DBS has now emerged as a possible treatment of Alzheimer’s disease dementia (AD) [3 –6]. At the time of this writing, a search of the U.S. National Institutes of Health online clinical trials database using the terms “deep brain stimulation” and “Alzheimer’s disease” reveals seven studies in various stages of completion [7].

Further clinical trials of DBS for treatment of AD are greatly needed, spurred by promising animal and human data and the recognition that conventional pharmacologic therapies have been inadequate to halt the increasing prevalence, direct and indirect costs of AD [8 –11]. Given the cost of untreated disease in addition to the ineffectiveness of conventional AD treatments, DBS may be cost-effective even as a nascent technology. In fact, Mirsaeedi-Farahani and colleagues showed that DBS, compared to standard treatment, would be cost effective over 5 years with a success rate above 20% [12]. Studies in laboratory animals have shown that DBS applied to structures in the Papez circuit (i.e., fornix, anterior nucleus of the thalamus, entorhinal cortex) can result in neurogenesis in the hippocampus [13 –15]. Available data show early promise with respect to cognitive endpoints in DBS AD trial subjects that are supported by corresponding neurophysiologic and neuroanatomical changes [6 , 16–20]. A primary target for AD DBS stimulation is the nucleus basalis of Meynert (NBM), the rationale including the recognition that cholinergic denervation is integral to AD pathogenesis in addition to promising case studies of DBS for AD and Parkinson’s disease dementia (PDD) [21 –23]. A recently completed phase I trial of bilateral low-frequency DBS of the NBM involved a 4-week sham-control phase followed by an 11-month follow-up open label phase [16]. Four of six subjects were deemed ‘responders’ based on an improved Alzheimer’s disease assessment scale-cognitive subscale (ADAS-Cog) score at 1 year. Additionally, stimulation resulted in a global increase in cortical glucose metabolism on FDG-PET imaging that was most pronounced in the amygdalo-hippocampal and temporal regions [16].

A more recent target for DBS in AD is the fornix, a fiber bundle within the memory circuit of Papez, where axonal degeneration has been associated with AD progression [24, 25]. Laxton et al. tested the hypothesis that DBS applied to the fornix in patients with dementia would restore memory by increasing activity within the circuit of Papez. In this phase I study, 6 patients were enrolled with mild or moderate AD, and all received fornix DBS. At 12-month follow-up, there was a mean increase in the ADAS-Cog of 4.2 points, which compares favorably with historical figures on the natural progression of AD [17].

Still, enthusiasm for the use of DBS in treating AD should be tempered by prudent ethical deliberation that takes into account the uncertainty of benefit to individual trial subjects and the complex risk-benefit considerations relevant to ensuring robust informed consent. DBS is an FDA-approved treatment for Parkinson’s disease, tremor, dystonia, and was approved in 2009 for humanitarian use in obsessive compulsive disorder [26]. It has yet to receive FDA approval for use in treatment-resistant depression [27], but remains an active area of clinical research. Data gleaned from trials of DBS for each of these indications, as well as clinical trials for AD, may better inform the AD patient of risks inherent to DBS trials.

Adverse events related to DBS fall into two general categories: (1) those occurring as a consequence of surgery and (2) stimulation-related effects. Compared to non-invasive neuromodulation therapies, such as transcranial magnetic stimulation (TMS), DBS is unique in its requirement for neurosurgery and its attendant risks. For DBS in Parkinson’s disease, permanent neurological sequelae result in 4% to 6% of cases [28]. The phase I DBS trial targeting the fornix in AD patient mentioned earlier was well tolerated by a majority of subjects. Adverse effects were noted only at higher stimulation settings and included a sensation of warmth, flushing, sweating, and increases in heart rate and blood pressure. No patients required hospitalization following implantation during 12 months of follow-up [17]. Surgical complications, although relatively uncommon, include hemorrhage and infection. In one open-label trial of DBS for treatment-resistant unipolar and bipolar depression, serious adverse events (SAEs, defined by the study authors as an adverse event “resulting in death, permanent loss of biological function, and/or the need for or prolongation of hospitalization”) occurred in four out of the seventeen enrolled subjects [29]. In each case, SAEs resulted in increased length of hospital stay but there were no deaths or permanent loss of biological function. Device-related infection required explanation in one patient. Other adverse events related to DBS brain stimulation include transient depression, hypomania, anxiety, flushing, sweating, smiling, headache, paresthesia, olfactory hallucinations, and disequilibrium [29 –32]. Any risk/benefit analysis of DBS in AD must be undertaken in the context of available alternative non-invasive interventions. Transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS) are two such modalities that have shown a favorable effect on AD-associated cognitive decline [33]. Adverse effects are mild, with a small number of studies with AD patients reporting painful scalp sensation after rTMS [34], or itching, headache, and dizziness after tDCS stimulation [35]. Other adverse events after tDCS include irritation and a burning sensation [36 –39].

The history of psychosurgical interventions remind us of the abuses and ethical challenges that can occur when the regulatory framework is insufficient to guide their use [32, 40]. In 1977, a national commission on “psychosurgery” made several recommendations for ethical practice including an emphasis on obtaining adequate informed consent and heightened oversight of research trials. While the concept of psychosurgery may be an anachronism, new implantable devices investigated to treat disorders of mood and cognition raise similar issues. Additionally, the awarding of significant research funding from the U.S. Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative and Defense Advanced Research Projects Agency (DARPA) in implanted neurological devices adds urgency to examining the ethical issues raised by the expanding use of these devices [41]. In the future, it may be necessary for society and the research community to explore the implications of a more advanced neuromodulation technology on personal identity. Ethicist Debra Mathews has called for research to assess how DBS and other implantable brain-interfacing devices affect one’s sense of self over time [42]. Such data could then be incorporated into the risk-benefit calculations of various stakeholders (i.e., research subjects, IRBs, policy makers) when deciding if and how to participate.

This review highlights the current ethical challenges we believe are unique to conducting DBS research on individuals with AD. First, such individuals, by definition, have deficits in cognition that may reasonably limit decision-making capacity and thereby compromise informed consent. Furthermore, the nature of DBS as an intervention of last resort increases the risk of therapeutic misconception and demands some provision of post-trial access to care. In the following discussion, each issue is summarized and then followed by suggestions forresolution.

ETHICAL CHALLENGES

Ensuring trial subjects possess adequate decision-making capacity

Overview

Decision-making capacity is fundamental to the principle of respect for patient autonomy and a necessary condition of adequate informed consent whether in regard to a complicated hospital procedure or routine outpatient care [43]. Over the past 70 years, the manner in which informed consent is obtained for research and treatment interventions has changed considerably. Although the Nuremberg Code (1946) established decision-making capacity as a necessary component of voluntary consent for research, it was decades later before there was any explicit concern for the process by which decision-making capacity is evaluated.

In the 1980s, psychiatrists Paul Appelbaum and Thomas Grisso created a standard for evaluating decision-making capacity that has legal precedent and continues to have broad support among the ethics and medical communities [44, 45]. Four categories of patient behavior (consistency of choice, understanding, appreciation, logical reasoning) are considered necessary and sufficient criteria for the establishment of decision-making capacity. Understanding and consistency in choice to participate are particularly relevant for a subject being evaluated for inclusion in a clinical trial of AD. Study designs are complex and participation has lengthy implications as DBS devices often remain implanted in the brains of subjects for years after trial completion. Potential DBS for AD research participants are highly likely to lack decision-making capacity at study entry or to lose decision-making capacity at some point during their participation due to several factors. First, AD is, by definition, a progressive disorder impairing cognitive domains essential to decision-making capacity. One study compared capacity to consent for drug treatment between patients with dementia, depression, or schizophrenia using the MacArthur Competency Assessment Tool for Treatment (MacCAT-T), a validated measure of decision-making capacity [46, 47]. Findings revealed a substantial difference between the groups, with the dementia group showing the most impairment overall. More than 50% of the dementia patients were impaired in understanding and reasoning. Other studies have shown that patients with even mild cognitive impairment may have significantly diminished capacity to consent to treatment [48, 49]. Second, patients with late-stage AD are likely to remain a target group for clinical trials of DBS, especially if alternative interventions have proved ineffective. Such research subjects would almost surely lack decision-making capacity to consent to trial participation. Therefore, DBS for AD trials must include a robust mechanism for both detecting loss of decision-making capacity and protecting the interests of incapacitated subjects.

Recommendations

I. Assessing Decision-Making Capacity to Consent to DBS for AD Clinical Trials

Because the stakes for participation are high, we believe it is incumbent upon investigators to ensure that patients know to what they are consenting and are capable of deciding based on a rational weighing of relevant information as it pertains to their values and preferences. The importance of establishing formal processes to assess potential subjects’ capacity to consent to such research was highlighted in the 2007 consensus statement of the U.S. National Institutes of Health (NIH) and Dana Farber Foundation conference on the Scientific and Ethical Issues involved in the use of DBS for Disorders of Mood, Behavior and Thought [50]. Furthermore, the Alzheimer’s Association consensus recommendations for obtaining informed consent on cognitively impaired adults stipulates that all research participants be evaluated for decision-making capacity using the Appelbaum and Grisso criteria [51]. For clinical trials involving more than minimal risk to subjects, IRBs may consider mandating the use of validated decision-making capacity assessment measures, such as the MacCAT-CR. The MacCAT-CR is a structured interview that incorporates information specific to Appelbaum and Grisso’s four decision-making capacity domains, and generates performance scores for each that have been shown to have high inter-rater reliability[52, 53].

Further, individual hospitals and medical centers should establish clear policies, practices, and training regimens related to assessing capacity. Use of an auxiliary “consenter,” as originally recommended by the 1977 Commission on psychosurgery, would also help to ensure clear and accurate understanding by patients/subjects. An auxiliary consenter would not be someone directly affiliated with the study but would meet with each patient to determine the person’s knowledge about study procedures, risks and benefits, treatment device, and study follow-up. Only after this determination of understanding is obtained would informed consent proceed.

AD subjects with demonstrated decision-making capacity at study entry remain at high risk for losing decision-making capacity at one or multiple time points throughout the trial. DBS for AD IRB protocols must therefore specify how reassessment of decision-making capacity will occur during the study trial and actions taken when enrolled participants are found to lose decision-making capacity prior to study completion [51, 54].

II. Protections for Subjects Deemed to Lack decision-making capacity

Under federal regulations for the protection of research participants, known as the Common Rule, research involving vulnerable subjects require additional safeguards [55]. While these regulations do not specify how IRBs and researchers might implement such safeguards, an evolving scholarship in the area has defined the relevant considerations [51 , 56].

The Alzheimer’s Disease Association Consensus Recommendations on obtaining research consent for cognitively impaired adults specify three conditions necessary to justify research on participants who lack decision-making capacity [51].

First, IRBs must decide if the proposed clinical trial offers a reasonable chance of personal health benefits to subjects. If not, then the ethics principle of Nonmaleficence dictates that such studies must involve no more than minimal risk. The Common Rule defines Minimal risk as a research protocol in which “the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests” [55]. By this definition, trials involving DBS for AD would involve significantly more than minimal risk. An exception to this general rule is made if “the condition causing cognitive impairment is the object of study, so that the research could not otherwise be carried out without the involvement of individuals unable to consent, and the individual has given a research advance directive that authorizes a proxy to provide consent for enrollment in research of this kind” [51].

Second, out of respect for subject autonomy, clinical trials enrolling individuals who lack decision-making capacity must solicit consent from an appropriate surrogate decision maker who is capable of employing substituted judgment when rendering his or her decision on behalf of the prospective research participant. Substituted judgment is a standard for decision-making on behalf of another that asks the question of the surrogate, “How would he/she have decided in this instance if possessed with sufficient decision-making capacity?” The surrogate is thus expected to be someone in close relationship with the subject and aware of the subject’s relevant values and preferences. However, there are several instances in which surrogate decision making (SDM) is either inadequate or undesirable. First, a significant minority of subjects may not wish to defer a decision to participate in research to a surrogate [57]. Additionally, studies have shown that surrogate decision makers often cannot accurately infer patient preferences [58, 59]. Moreover, in many jurisdictions, SDM is limited to providing research consent for studies involving no more than minimal risk when there is no expected personal health benefit to participation [51, 60]. Lastly, individuals with mild cognitive impairment with intact decision-making capacity but without readily available surrogates should not be universally excluded from prospective participation in AD research [60]. Advance research directives have been proposed as a mechanism for dealing with these challenges by allowing competent individuals to prospectively consent to future participation in research in the event they lose decision-making capacity to consent [54 , 60].

Third, respect for persons dictates that researchers must seek participant assent and exclude individuals expressing dissent when absence of decision-making capacity precludes formal consent [51]. The concept of Assent grew out of regulations for research with children and is defined by the Common Rule as “a child’s affirmative agreement to participate in research” [55]. Assent is now also sought for adults with cognitive impairment, and we believe IRBs should define standards for assessing and documenting assent or dissent in studies of DBS for AD.

Therapeutic Misconception

Overview

Patients with probable AD, desperate for relief and without effective alternatives, are likely to consider interventions such as DBS a last resort for treatment. Such desperation could so alter a person’s perspective that they view the primary goal of the study to be the provision of personal health benefits rather than generalizable knowledge about the efficacy of DBS (primary goals of research). This phenomenon, whereby a patient conflates the goals of research with those of clinical treatment, is termed therapeutic misconception. Left unchecked, it is likely to distort patients’ understanding of the risks and benefits of DBS.

In one widely cited study in which end-stage oncology patients were offered participation in a phase I medication trial, 75% of respondents reported that their chance of benefit was at least 50%, a figure the authors note is “10 times greater than the chance of benefit usually resulting from phase I trials” [61]. For the desperately ill, for whom enrollment in a research trial often represents a last chance for cure, decisions about enrollment are often made on the basis of hope or trust rather than a careful consideration of risks and benefits [61].

Patients with AD and their families may feel a similar desperation when considering DBS. For example, a subject consenting to a sham-control trial of DBS for AD may falsely believe the investigators will choose to place her in a particular treatment arm based on the severity of her illness, ignoring the fact of randomization. The same patient may also strongly believe that restoration of her memory impairment is likely to occur following device implantation. Erroneous assumptions such as these can lead to an underestimation of the risks of participation relative to potential benefits. One study of DBS for treatment-resistant depression involving 31 people found that a majority (64.5%) held erroneous beliefs about the likelihood of personal benefit from the study [62].

Recommendations

Despite the ubiquity of therapeutic misconception in clinical trials and its potential to compromise informed consent, there have been no published studies investigating possible interventions for prevention [63, 64]. Moreover, the lack of a consistent definition of therapeutic misconception hampered attempts at measuring its prevalence in different contexts or in testing interventions to reduce it [65]. In particular, researchers and study participants frequently disagree about the extent to which individual therapeutic benefit may be counted as a study purpose [65]. The development of several new consensus definitions of therapeutic misconception is a promising step forward. Henderson et al. convened a workshop of researchers in medicine, sociology, philosophy, anthropology, law, and bioethics, for the purpose of developing a shared understanding of the phenomenon [65]. The resulting definition reflects the group consensus regarding the fundamental purpose of clinical research while recognizing that therapeutic benefit may accrue to individual participants as an important secondary purpose: “Therapeutic Misconception exists when individuals do not understand that the defining purpose of clinical research is to produce generalizable knowledge, regardless of whether the subjects enrolled in the trial may potentially benefit from the intervention under study or from other aspects of the clinical trial” [65]. More recently, Appelbaum and colleagues developed a 10-item therapeutic misconception scale by surveying 220 research subjects across four academic medical centers in the United States. Beliefs associated with therapeutic misconception were assessed via a 28-item Likert questionnaire that was validated against a semi-structured interview, and data was subjected to factor analysis [66]. The final scale includes statements that suggest mistaken beliefs in one or more of three dimensions: “the degree of individualization of treatment, likely benefit from a study, and the overall purpose of the study” [66]. With a consistent definition of therapeutic misconception, studies examining the effectiveness of interventions should proceed. During the consent process, providing information about study methods, risks, and the use of placebo or sham treatments may not be enough to undermine the belief in direct personal benefit. Rather, it may be necessary to directly inform patients during study consent that “scientific goals will have priority over therapeutic goals” [67]. It has also been suggested that research subjects should understand both how and why clinical research and treatment differ [63]. Another intervention that may prove efficacious in reducing therapeutic misconception is the provision of a “cooling off” period, in which subjects are given adequate time to evaluate their options after learning all the relevant information [61, 68].

Post-Trial Access to Treatment

Overview

At the conclusion of a clinical research trial investigating the use of DBS for AD, should subjects who clearly benefit from the intervention be provided continued treatment? If so, who is responsible for payment and providing the clinical care necessary for such treatment? These questions lie at the crux of the ethical debate over post-trial access to treatment (hereafter referred to as Post-Trial Access), and are particularly salient in the case of DBS due to its high cost, long duration of treatment, and use of implanted hardware that may remain in a patient’s body for years after the initial research trial ends.

Most of the literature addressing these questions focuses on clinical drug trials, but nevertheless examine reasons for providing or withholding Post-Trial Access that can be applied to the use of DBS. A recent review of the literature found 75 peer-reviewed publications that take a position on the matter of Post-Trial Access for investigational drug trials [69]. Reasons used to justify providing or withholding Post-Trial Access fall into four general categories: (1) moral (justice and roles/relationships between stakeholders), (2) practical, (3) legal, and (4) interests/incentives considerations [69]. Only one study concluded that there is no obligation to provide Post-Trial Access to research subjects [70]. The majority of studies (60%) conclude that there is sometimes an obligation to provide Post-Trial Access, when the strength of compelling reasons to provide access outweighs those reasons to withhold. In the case of DBS studied as an intervention for severe treatment-resistant psychiatric and neurologic illness, we believe the relevant moral and legal reasons, as well as stakeholder interests weigh in favor of providing Post-Trial Access to subjects shown to benefit from the trial intervention. Moral reasons to provide Post-Trial Access acknowledge the last-resort nature of DBS and the lack of effective alternative treatments available to study participants. The medical ethics principle, Non-maleficence, or “do no harm,” is embodied in the Federal Common Rule, and requires clinical research to minimize harm relative to potential study benefits [71]. We believe denying a patient access to the only intervention known to alleviate her suffering is tantamount to violating this sacrosanct principle. Furthermore, as long as device hardware remains implanted in the brains of former study subjects, device maintenance and regular consultation with clinical specialists is required to avoid abandoning patients. Legal guidance, until recently, has been scant or nonexistent. However, in 2000, the World Medical Association revised the landmark Declaration of Helsinki, first published in 1964 and which remains an international source of guidance for the ethical conduct of clinical research. One addition to the 2000 revision is particularly relevant to the provision of Post-Trial Access in DBS: “At the conclusion of the study, every patient entered into the study should be assured of access to the best proven prophylactic, diagnostic, and therapeutic methods identified by the study” [72].

Finally, taking into account the incentives or interests of stakeholders further strengthens the arguments for providing Post-Trial Access to DBS and related treatment for patients shown to derive benefit. The trial sponsor has a primary interest in maximizing profit through the successful adoption of the study intervention. Without the trust and participation of patients suffering from the psychiatric condition the intervention is designed to treat, research and clinical development of DBS would come to a halt. We believe an important way for sponsors to create trust is by providing Post-Trial Access to former study subjects who show meaningful clinical improvements in health and disease burden with the use of DBS. Former research subjects have an interest in continuing to receive beneficial treatment when no adequate treatment alternatives exist, at a cost that is not prohibitive. Researchers have an interest in generating meaningful data. The provision of Post-Trial Access that allows for the collection of longitudinal data on effectiveness and safety would improve the quality of clinical post-trial DBS data. In 2013, St. Jude Medical, a manufacturer of DBS hardware, discontinued a large study of DBS for depression due to lackluster results. Nevertheless, Helen Mayberg, an Emory University psychiatrist and DBS pioneer, has continued an independent trial of the St. Jude device because her data shows benefit to a subset of participants [73]. She also noted that insurance will cover part of the medical costs related to the device as long as the trial remains open [41]. Lastly, governments have an interest in the health of its citizens and in protecting the interests of those most vulnerable.

Recommendations

Once we accept the position that Post-Trial Access should be provided to former study subjects who benefit from DBS, the challenge is to assign responsibility for treatment. To date, several hundred patients have undergone DBS as part of psychiatric research trials, and for most, post-trial access will be prohibitively expensive without some form of third party payment. In our correspondence with a prominent neurosurgeon conducing DBS for AD research, we learned that the sponsoring medical center often picks up the tab for the costs of post-trial office visits and device programming when a patient’s health insurance refuses coverage. In fact, grant reviewers may condition research funding on a commitment by the applicants’ host institution to provide necessary DBS maintenance after the trial’s conclusion. We believe that no individual stakeholder should be burdened with sole responsibility for the costs of DBS and necessary ancillary treatment (i.e., DBS battery replacement, DBS device technical support and maintenance, neurosurgery consultations, DBS programming, psychopharmacology, psychotherapy, etc.). Patients, together with sponsors, investigators, health care systems, insurance, governments, and non-profit organizations must partner to share responsibility and negotiate continued access arrangements prior to study enrollment. An example of a successful collaboration in this model is the HIV Netherlands, Australia, Thailand Research Collaboration (HIV-NAT) co-payment and sliding scale drug fund program [74]. A partnership between the Thai Red Cross AIDS research Center in Thailand, the National Centre in HIV Epidemiology and Clinical Research in Sydney, and the International Antiviral Therapy Evaluation Centre in Amsterdam, HIV-NAT sponsored clinical trials of anti-retroviral medications in Thailand and provided funding for several years of post-trial access to study medications [74]. Similar creative funding solutions will be necessary to provide Post-Trial Access for subjects in effective DBS trials.

CONCLUSION: WHO IS AN APPROPRIATE RESEARCH SUBJECT FOR TRIALS OF DBS IN AD?

Taking into account the aforementioned analysis of ethical challenges inherent to research involving individuals with cognitive dysfunction (i.e., impaired or expected future loss of decision-making capacity, therapeutic misconception, and need for adequate post-trial access), we created a flowchart to guide subject enrollment in studies of DBS for AD (Fig. 1).

For prospective research subjects, the first task for investigators and IRB reviewers is to ensure adequate post-trial access to care (hereafter referred to as Post-Trial Access), including DBS maintenance. Policy leaders in the Center for Medicare and Medicaid Services, institutional review boards, ethicists, governments, and the research community need to jointly devise viable systems of payment for device maintenance and post-trial clinical care that acknowledges the financial burden placed on all stakeholders. Prospective DBS study participants must be informed of the specific services provided vis-à-vis Post-Trial Access as well as the mechanism to claim Post-TrialAccess.

The second step necessary for ethical subject recruitment is the formal assessment of decision-making capacity. Based on the anticipated study health risks, IRBs should specify the type of assessment and documentation required (i.e., MacCAT-CR or other guiding questions to assess the four functional criteria of decision-making capacity). A well-defined effort to assess for the presence of and mitigate therapeutic misconception should be undertaken in subjects demonstrating adequate decision-making capacity. While empirical research is needed to define effective interventions for assessment and reduction of therapeutic misconception, at a minimum, DBS study investigators should inform prospective subjects how the central goals of the study to which they are consenting differ from that of treatment. The remaining steps in study enrollment for this group are determined by the severity of cognitive dysfunction under study. If mild cognitive impairment or mild AD is the intended DBS intervention group, the time between enrollment and intervention will be short and therefore any decrement in decision-making capacity likely to be relatively small. As in any other clinical trial recruiting subjects with intact decision-making capacity, participation will be authorized via informed consent. However, given the very real risk for loss of decision-making capacity during the intervention and follow-up, we recommend the prospective assignment of a SDM along with the creation of an advance research directive. In the event of loss of decision-making capacity, the advance research directive would provide general guidance for continued research participation, while allowing the SDM to monitor for unforeseen developments and to authorize study withdrawal if he or she perceives such action to be in the subject’s best interests (e.g., verbal or non-verbal expressions suggesting dissent or changes in study protocol) [60]. If moderate to severe AD is the target of DBS intervention, traditional informed consent is not the appropriate mechanism for subject enrollment due to the high likelihood of decision-making capacity loss at the time of study intervention. Instead, investigators should assist prospective subjects in creating an Advance Research Directive guiding authorization for study participation, taking into account reasonable contingencies, the role of a SDM if assigned, changes to study protocol, or the subject’s clinical status. Additionally, an independent oversight committee should be established to provide continuous monitoring to ensure subject participation remains fully consistent with their Advance Research Directive.

For prospective subjects lacking decision-making capacity at enrollment, only those having a relevant Advance Research Directive should be considered for participation, consistent with ethical guidelines covering research of greater than minimal risk not likely to provide direct health benefit to participants[51 , 55].

DBS is one of the few promising new areas of treatment research for patients with AD. It is critical to maintaining the public trust and respecting vulnerable participants that such research proceeds under conditions of robust subject protections and ethical oversight.

Footnotes

ACKNOWLEDGMENTS

The authors thank Casey Halpern, MD, of the Stanford University Department of Neurosurgery, for his feedback regarding an earlier version of this paper.

Authors’ disclosures available online ().

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