2

Overview of Gaps, Challenges, and Potential Opportunities

Non-invasive neuromodulation provides the neuroscience community with a unique ability to gain fundamental insight into brain function while at the same time helping patients, Alvaro Pascual-Leone explained. He suggested that, in combination with other therapies and other methods to assess brain function (such as quantitative behavior assessment, electroencephalography [EEG], or brain imaging), noninvasive neuromodulation also may offer the ability to personalize treatment by enabling a better understanding of the specific neural substrates underlying the symptoms of disease, then targeting the specific neurobiological circuits involved. However, along with many participants, he also emphasized the need for more basic research, as well as larger and longer clinical studies with suitable control interventions to better understand the long-term benefits and risks of non-invasive neuromodulation.

Given the way the market is progressing, particularly the rapid growth of non-therapeutic uses of neurostimulation for cognitive and performance enhancement, several participants called for more attention to consumer, DIY, and off-label uses of non-invasive neuromodulation. Ethical, legal, and safety implications of non-medical uses deserve particular scrutiny, they said. Should consumer-targeted devices take hold in the marketplace, they will inevitably have implications for medical device research and innovation, said Hank Greely. Indeed, Jeffrey Nye suggested that these devices could essentially disrupt the regulatory approval of medical devices by further blurring the distinction between medical and non-medical approaches. They could also disrupt clinical trials by making it increasingly difficult to identify treatment-

naïve patients and by making it more difficult to blind patients as to whether they are receiving treatment or placebo.

Throughout the workshop, many participants discussed the research gaps and challenges associated with non-invasive neuromodulation and identified potential opportunities to address them. In addition, policy issues were examined, and workshop participants focused their discussions primarily on challenges and potential opportunities related to ethical, legal and social implications, regulation, reimbursement, and the current business development environment for non-invasive neuromodulation, all of which are further discussed in subsequent chapters. While there are a number of barriers to address, including the need for a greater understanding of the underlying mechanisms and long-term effects of neuromodulatory devices, many participants acknowledged the vast opportunities of such devices and how all sectors (e.g., regulatory, payers, researchers, companies, and society) might contribute to bring this technology forward to clinicians and patients.

RESEARCH GAPS AND CHALLENGES¹

During the workshop presentations and discussions, many participants identified research gaps and challenges associated with noninvasive neuromodulation. The suggestions, listed here and attributed to the individual(s) who made them, are expanded on in succeeding chapters. Their full names and affiliations are listed in Appendix C.

Limited Understanding of the Fundamental Neurobiology of Non-Invasive Neuromodulation

• Knowledge gaps exist regarding basic mechanisms of action of noninvasive brain stimulation, and the neurophysiologic effects of noninvasive neuromodulation on the brain (Lisanby, Pascual-Leone).
• Knowledge gaps exist in the brain circuitry, and neurobiology of core symptoms and disabilities caused by many of the brain diseases being targeted with non-invasive brain stimulation (Lisanby, Pande, Pascual-Leone, and others).

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¹The points in this list were made by the individual(s) to which they are attributed; they are not intended to reflect a consensus among workshop participants.

• Although there are clear anatomical and physiological differences between the brains of children and adults, as well as developmental changes in plasticity, little is known about the effect of non-invasive neuromodulation on the immature brain given that most studies exclude children (Rotenberg).
• A better understanding of why some people do not respond to non-invasive neuromodulation is needed at the neurobiological level (Pascual-Leone and others).
• Genetic and epigenetic factors of individual variability of the effects of non-invasive neuromodulation need to be explored further (Pascual-Leone and others)

The Large Number of Parameters Involved in Non-Invasive Neuromodulation: Challenges for Understanding the Neurobiological Effects

• The efficacy of non-invasive neuromodulation is highly variable, most likely because of both individual differences, patient differences, differences in stimulation characteristics of the various devices, and failure to engage the appropriate neurobiological target (differences in the brain substrates of similar symptoms and disabilities) (Pascual-Leone).
• The large number of coil designs and the various options for placement on the head make it important to systematically evaluate the corresponding electric field distribution of various devices (Lisanby).

The Large Number of Parameters Involved in Non-Invasive Neuromodulation: Challenges for Understanding the Clinical Effects

• Effects on cognition are influenced by many factors, including the intensity of stimulation, where the stimulation is applied and the anatomy of the targeted network, and the cognitive construct of interest (Hamilton).
• Clinical studies in children are particularly challenging because of limits in the number of patients, lack of homogeneity, interactions with other treatments, and limited access to tissue (Rotenberg).
• The ability to determine effectiveness is hindered by varying definitions and treatment parameters in clinical trials (Gaynes).

Additional Study of Long-Term Safety and Efficacy

• Strategies to optimize the efficacy while preserving the safety of non-invasive neuromodulation are in need of further study and development, in particular, the long-term safety and the impact on the developing brain (Farah, Hamilton, Lisanby).
• Home use of these devices could enable more individualized treatment, but requires a better understanding of the effects of more frequent patterns of stimulation and raises concerns about clinical supervision, regulation, and reimbursement (Maiques).

Knowledge Gaps Associated with Depression and Other Therapeutic Uses

• The most well-developed therapeutic use of non-invasive neuromodulation is for the treatment of medication-resistant depression; less is known about the wide variety of other potential therapeutic uses (Hallett, Pascual-Leone, and others).
• Comparative effectiveness studies of non-invasive neuromodulation for treatment-resistant depression concluded that the quality of evidence was low or insufficient for the effect of repetitive transcranial magnetic stimulation (rTMS) on improving functioning or maintaining remission (Gaynes).

Knowledge Gaps Regarding Appropriate Control Conditions and Clinical Trial Designs

• Better design of sham stimulation and control conditions are critical to assess the effects of non-invasive neuromodulation in clinical trials (Hallett, Pascual-Leone, and others).
• Clinical trial design, including adaptive designs and other approaches, is needed to optimize and speed up solid evidence of clinical efficacy (Connor, Tariah).

POTENTIAL RESEARCH OPPORTUNITIES²

During the workshop presentations and discussions, many participants identified potential opportunities to improve the available evidence on non-invasive neuromodulation. These suggestions, listed here and attributed to the individual(s) who made them, are expanded on in succeeding chapters.

Improving Our Understanding of the Fundamental Neurobiology of Non-Invasive Neuromodulation

• Research is needed to better understand whether neural oscillations are an epiphenomenon of brain function or a signal of information processing, and whether abnormalities are associated with psychiatric and neurological conditions (Lisanby, Pascual-Leone).
• Research is needed to better understand the impact of noninvasive brain stimulation on distributed brain networks—the effects of brain stimulation does not remain limited to the directly targeted brain area and, in fact, the behavioral and ultimately therapeutic effects may be mediated by impact on distant brain regions reached via trans-synaptic network effects. Better characterization of such neurobiological effects can help gain fundamental insights on brain function and brain-behavior relations, while enabling improved therapeutic approaches (Fox, Lisanby, Pascual-Leone).
• Research studies and new tools are needed to better understand the functional role of extracellular currents and the interaction between the stimulation and the brain’s electrical activity (Lisanby).
• Research is also needed to focus on the neurophysiological effects when extracellular currents are exogenously applied compared to when they are endogenously generated, as well as the interaction of the two (Lisanby).
• Similarly, there is a need for a better understanding of basic brain circuitry and the effects of different electromagnetic fields

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²The points in this list were made by the individual(s) to which they are attributed; they are not intended to reflect a consensus among workshop participants.

• on those circuits. Without this, we will be in the position of being able to work with only the clinical phenotype (Pande).
• A better understanding of the neurobiological substrate of various symptoms may reveal additional targets of non-invasive neuromodulation (Pascual-Leone).
• Various types of modeling, including realistic head modeling of the induced electric field distribution in the brain, and animal models of the physiological responses to stimulation provide opportunities for better understanding the effects of different types of non-invasive neuromodulation (Lisanby).
  • An international collaboration of scientists, including those from the Food and Drug Administration (FDA), have developed and are making freely available to the scientific community a realistic head model to study the effects of non-invasive neuromodulation on the brain (Iacono et al., 2015).
• More preclinical studies and animal models are needed to assess the long-term effects of non-invasive neuromodulation on adults and children (Farah, Rotenberg).
  • The large number of animals that can be employed in studies enable investigators to test and tweak systematically a range of different stimulation protocols and different doses to determine the optimal parameters to test in clinical studies. In addition, laboratory models enable studies of mechanisms of action at a resolution not available in humans, for example, by assessing regional gene expression, changes in neurotransmitter receptor subtypes, and other molecular consequences of non-invasive neuromodulation (Rotenberg).
• More research is needed to determine dose−effect relationships and appropriate washout periods for different stimulation protocols (Hamilton and others).

Using Non-Invasive Neuromodulation for Diagnosis and Research

• Because stimulating a part of the brain can evoke a measurable response, neurostimulation coupled with electrophysiologic recording techniques may provide biomarkers for disease states that could be modulated by non-invasive neuromodulation, or even serve as stand-alone biomarkers (Rotenberg).

Developing a Taxonomy or Classification Scheme for Non-Invasive Neuromodulation

• The lack of a consensus taxonomy or classification scheme for non-invasive neuromodulation technologies, in combination with sometimes unclear specification of clinical and performance standards for different devices makes it difficult for clinicians to extract relevant information from the literature about safety, efficacy, risks, etc. that are unique to a form of device or are generalizable across all device types within a category (Demitrack and others; see Box 2-1).

Optimizing the Therapeutic and Non-Therapeutic Uses of Non-Invasive Neuromodulation Through an Improved Understanding of Clinical Effects, Safety, and Efficacy

• The field of non-invasive neuromodulation, and stimulation in combination with pharmacotherapy, would benefit from an experimental medicine approach where various parameters, dosing, duration, intensity, etc., are tested against a variety of constructs (e.g., cognitive constructs) and electrophysiological recording techniques (Insel and others).
• The tools of cognitive neuroscience, including neuroimaging and neurophysiologic approaches, could be used to guide the development of safer and more effective non-invasive neuromodulation strategies in heterogeneous populations (Pascual-Leone).

• Pre-registration of studies and/or the establishment of a repository for null results (a “file drawer” repository) might improve information on both safety and efficacy by reducing the problem of publication bias, which is most pronounced with underpowered studies. Given the likely small effect sizes for enhancement uses, supporting well-designed larger scale studies would also improve assessment of efficacy (Farah).
• Adaptive and other innovative trial designs may be useful for clinical trials of non-invasive neurostimulatory devices and for combination trials (Connor).
• Combining non-invasive neuromodulation with pharmacotherapy, cognitive therapy, or behavioral approaches could provide novel and more efficacious interventions (Hallett, Pascual-Leone).
• There is a need to know more both about the neurobiological characteristics that differentiate between those who do and do not respond to neurostimulation, and the synergies among different therapies (Pascual-Leone).
• Animal studies could enable investigators to examine the effects of combining pharmacologic agents with non-invasive neuromodulation, both to design combination trials where neuromodulation and pharmacotherapy are complementary, and to avoid drugs that may interfere with a desired neuromodulation effect (Rotenberg).
• Realizing the potential for home use of neuromodulatory devices under clinical supervision will require more research on the effects of more frequent patterns of stimulation as well as attention to regulatory and reimbursement issues (Maiques).
• There is a need for comparative effectiveness studies to provide efficacy information for decision-making on the part of payers, providers and patients. With the availability of this type of information, improvements would follow in the consistency of clinical decision making and reimbursement policies (Robinson-Beale).
• Non-invasive neuromodulation combined with monitoring of brain activity using technology such as EEG could enable individualized approaches to treatment (Maiques).

Improving Understanding of the Use of Non-Invasive Neuromodulation for the Enhancement of Brain Function and Performance

• Performance enhancement applications have the potential to be used by a wide range of individuals, from the very elite to the severely disabled and from school children to pilots; and aside from important ethical issues, questions that need to be addressed include where they would use these devices and under what kinds of supervision and training (D. Edwards).
• Much more work is needed to demonstrate the mechanisms underlying enhancement, the reproducibility and long-term effects of these approaches, and the potential of combining neurostimulatory approaches to cognitive and performance enhancement with exercise training and cognitive training (Cohen Kadosh, D. Edwards).

POLICY ISSUES AND POTENTIAL OPPORTUNITIES³

During the workshop presentations and discussions, many participants identified issues and potential opportunities related to ethical, legal, and social issues; the regulation of non-invasive neuromodulation devices; reimbursement for treatment using these devices; the business environment in which these devices are being developed; and education/awareness about these devices among clinicians, the general public, and others. These suggestions, listed here and attributed to the individual(s) who made them, are expanded on in succeeding chapters.

Ethical, Legal, and Social Issues

Challenges

• Non-physical harms, such as effects on a person’s sense of “self,” may result from non-invasive neuromodulation (Parens).

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³The points in this list were made by the individual(s) to which they are attributed; they are not intended to reflect a consensus among workshop participants.

• The fuzzy line between treatment and enhancement follows from unclear definitions of what is normal (Parens).
• The use of non-invasive neuromodulation is expanding, despite incomplete understanding of safety and efficacy (Farah and others).
• The effects of non-invasive neuromodulation on cognition, attention, memory, learning, visuomotor perception, and other neuropsychological functions have led to a growth industry in non-therapeutic enhancement tools, although the possible negative consequences of these technologies are not completely understood (Cohen Kadosh, D. Edwards, Fox).
• Ethical concerns are raised by the use of neuromodulation on people unable to consent for themselves, for example parents choosing non-invasive neuromodulation to treat or enhance their child’s capacities or behavior, and by the involuntary or coercive use of non-invasive neuromodulation, such as the offer of neuromodulation to criminal offenders in exchange for a better sentence (Chandler).
• The DIY movement raises questions about the responsibility of researchers to educate the public (Maslen).

Potential Opportunities

• Concerns about physical and non-physical harms demand a cross-disciplinary conversation among clinicians, epidemiologists, health psychologists and sociologists, welfare economists, philosophers, and many others (Parens).
• A better understanding of the safety and efficacy of non-invasive neuromodulation is needed to make decisions about whether it is appropriate to put neurostimulatory devices in the hands of clinicians, patients, and consumers. To enable adequately powered studies, Farah advocated for the introduction of social structures, ranging from preregistration registries to funding along with education of consumers, and she suggested coming together as a community to articulate a research agenda to accomplish this (Farah).
• As these technologies become more normalized, they may become part of the cultural wallpaper, the “new normal,” but this should not stop the community from considering whether limits should be in place to prevent harmful use (Chandler).

Regulation

Challenges

• Different regulatory paths for neuromodulatory devices in the United States and Europe have resulted in different availability of these devices around the world (Marjenin, Tariah).
• The complex regulatory pathway for non-invasive neuromodulatory devices presents unique challenges for device developers (Marjenin, Tariah).
• The regulatory requirements for non-invasive neuromodulatory devices will vary depending on the perceived level of risk, with non-therapeutic neuromodulatory devices facing less stringent regulatory requirements (Marjenin, Tariah).
• Many transcranial magnetic stimulation (TMS) studies use sham controls, but because TMS is intrinsically multisensory, blinding the patient and therapist is difficult (Pascual-Leone).
• Important and challenging aspects of clinical trials for neuromodulatory devices include the choice of control or comparison condition, determination of dose−effect relationships, and patient heterogeneity (Hamilton, Lisanby).

Potential Opportunities

• Regulatory policies for medical devices in the European Union (EU) should be extended to brain stimulation devices for enhancement. The goal of this proposal is to promote safe use of the devices; however, Maslen acknowledged it would have no effect on DIY uses. (Maslen)
• International harmonization of regulatory policies, though difficult to implement, could expedite regulatory approvals (Hallett).
• Novel clinical trial designs may be needed because clinical trial methods developed in the pharmaceutical sphere may not be appropriate for device-based treatments (Demitrack).
• For sponsors seeking regulatory approval of devices in the United States, the FDA has encouraged the use of new tools, including innovative clinical trial designs, adaptive trials, and modeling and simulation (Connor).

• Preclinical approaches and collaborations with the FDA could be useful to better understand how the various technologies affect the brain (Reppas).
• Regulators from both the United States and Europe encourage sponsors to consult with them early in the development process about the development of their medical device, including clinical trial design issues (Marjenin, Tariah).
• Data submitted to one regulatory agency may possibly be leveraged in a subsequent submission to another agency. This will require developers to consult with regulators to determine which data will be accepted (Marjenin, Tariah).

Reimbursement

Challenges

• Reimbursement for TMS has grown considerably in recent years as devices become more widely accepted by the clinical community, and both patients and clinicians are requesting reimbursement for appropriate clinical care (Demitrack, Maiques, Robinson-Beale).
• Health plans individually determine whether treatment will be reimbursed based on multiple types of data, research–randomized control trial, population-based, comparative effective (often incomplete or conflicting in this arena), comparative efficiencies and cost considerations, and the existence of practice guidelines. These data needs are frequently not available nor included in research protocols. This leads to significant inconsistency in provider application within practice and variation in medical policies and reimbursement decisions (Robinson-Beale).
• The lack of practice guidelines is a barrier to reimbursement. Without such guidelines, decisions may be based on the opinions of independent practitioners who may or may not have experience with a technology. This includes decisions about the coverage of maintenance therapy (Robinson-Beale).
• Inconsistent reimbursement decisions may limit patient access to treatment and business development (Hailey, Reppas).

• Regulatory and reimbursement pathways in different countries complicate the approval process for companies developing noninvasive neuromodulatory devices (Marjenin, Tariah).

Potential Opportunities

• Practice guidelines from professional societies would assist health plans in making appropriate reimbursement decisions and improve the consistency of reimbursement practices (Jaffe, Robinson-Beale).
• There is also a need for comparative effectiveness studies to help determine the relative value of new technologies in comparison to standards and the indications for application (Robinson-Beale).
• When practice guidelines are missing or not explicit enough to clarify practice application to create necessary medical policy, insurance companies would need to include in the technology review process expert or seasoned clinicians who have treated patients using the new technology in providing input into medical policy (Robinson-Beale).
• Organized registries could help capture additional data needed to further inform applications of technologies (e.g., unresponsive subpopulations, longer-term effects, adverse reactions, etc.) on the use of devices after marketing approval has been granted (Morales, Robinson-Beale).
• Standard criteria for reimbursement could help enable universal coverage and access (Morales).

Business Environment

Challenges

• Interest in non-invasive neuromodulatory devices is high among both clinicians and industry. However, growth of the industry is hampered by a number of factors, including low awareness of the technology among the broader practitioner base, lack of direct to consumer education, a limited understanding of the mechanism of the effect of these technologies, a lack of funding from federal grant sources, and sometimes unclear regulatory pathways to approval (Demitrack, Maiques, Pande, and others).

• Development of neuromodulatory devices has been largely the province of small companies with limited resources (who may be interested in selling the devices to larger companies). Small companies may lack sufficient resources to undertake the complicated and lengthy processes required for regulatory and reimbursement approval (Maiques).
• Despite excitement in the field, investors have shied away from medical device companies because of unproven business models for some technologies, lack of regulatory predictability, challenges obtaining reimbursement, and the long development time frame for investors to see a return on their investment (Jaffe).

Potential Opportunities

• Funding sources for large-scale innovative research demanded by clinicians and patients are limited, while such large, time-consuming and often expensive studies are needed in order to clarify the most effective methods of dosing and appropriate short- and longer-term treatment regimens (Demitrack).
• There could be tremendous opportunities for operational synergies between device and pharmaceutical companies in the development of innovative therapies. Potential synergies could include the use of common sales and marketing forces that call on psychiatrists or other clinicians, combined regulatory departments, etc. However, many challenges from a business and regulatory perspective will need to be addressed (Nye).
• Education/awareness efforts (as described below) may help enhance the business environment for device manufacturers and investors (Demitrack).

Education/Awareness

Challenge

• Clinicians and the public have a low awareness and understanding of neuromodulation. Although the brain is responsive to both chemical and electrical stimulation, clinical practice has been dominated by a largely pharmaceutical or

• neurochemically-based understanding of the treatment of disease (Demitrack).

Potential Opportunities

• Professional societies should take a more active role in establishing practice standards and addressing the needs of practicing clinicians who utilize these technologies (Demitrack).
• Providers need improved education and training about the risks and benefits of TMS, as well as efforts to raise awareness among the public (Morales).
• Cross-disciplinary discussions among clinicians, epidemiologists, health psychologists and sociologists, and others are needed to address concerns about the non-physical as well as physical harms that may result from non-invasive neuromodulation (Parens).
• Scientists may need to take more responsibility for educating the public about their work to avoid misinterpretation and misuse of technologies (Maslen and others).