The Brain Initiative—Implications for a Revolutionary Change in Clinical Medicine via Neuromodulation Technology

Introduction – The BRAIN Initiative

Launched in April , the White House Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative is a “bold new research effort to revolutionize our understanding of the human mind and uncover new ways to treat, prevent, and cure brain disorders like Alzheimer’s, schizophrenia, autism, epilepsy, and traumatic brain injury ( )” (see Fig. 5.1 ). The BRAIN Initiative includes participation from numerous companies, research universities, foundations, and philanthropic organizations ( ). The BRAIN Initiative grew out of the Obama Administration’s “GRAND Challenges” program to forward ambitious but achievable goals that require advances in science and technology ( ). The driving motivation for the BRAIN Initiative is to accelerate the development of new technologies enabling researchers to produce dynamic pictures of the brain showing how individual brain cells and complex neural circuits interact with unprecedented spatial and temporal resolution ( ). By developing new technology to better understand the brain, the expectation is that the concomitant improvement in fundamental understanding will ultimately revolutionize therapies for brain disorders.

Mental and neurologic disorders and diseases are estimated to already cost the United States $1.5 trillion per year ( ), and in 2016, the 21st Century Cures Act was signed into law to establish legislative commitment to funding this essential research. The 21st Century Cures Act provided the National Institutes of Health (NIH) with $4.8 billion for the Precision Medicine Initiative, a program established for genetics of disease research, Former Vice President Biden’s “Cancer Moonshot” cancer research program, and the BRAIN Initiative, as part of the NIH Strategic Plan ( ).

The goals of the BRAIN Initiative are particularly germane to the development of next-generation noninvasive and implantable devices to stimulate and record from the human nervous system as a therapy. These devices make up a rapidly growing area of medical device technology, often known as neuroprosthetic, neuromodulation, bioelectronic medicine, or electroceutical devices, but for the purposes of this book, these devices will be called “neuromodulation devices.” In 2014, LifeScienceAlley estimated there to be more than 1000 active clinical trials in neuromodulation, with more than 1300 different therapeutic indications being pursued preclinically ( ).

Neuromodulation therapies have already demonstrated remarkable efficacy in subsets of patients who are refractory to existing drug options in applications such as chronic pain, hypertension, epilepsy, and Parkinson disease. However, there is only limited understanding of their underlying physiologic mechanisms of action (MOAs). Through the development of new technology to improve our understanding of neuromodulation therapies – and a fundamental commitment to sharing of data and experimental best-practices across government, industry, academia, and philanthropic institutions – there is remarkable potential for economic benefit and therapeutic growth in this sector.

History

The initial seed for the BRAIN Initiative began at a special symposium facilitated by the Kavli Foundation in 2011. This symposium included 27 preeminent neuroscientists and nanoscientists. It was titled, “Opportunities at the Interface of Neuroscience and Nanoscience,” and it was at this meeting that the idea of creating a brain activity map was introduced. The proposed goal for a brain activity map was to simultaneously record every action potential from every neuron within a circuit and, ultimately, within the whole brain ( ). Although it was recognized that the technology to accomplish this feat did not yet exist, it was posited that, with recent advances in optogenetic stimulation, optical recordings, and miniaturized implantable transducers, simultaneously recording and precisely manipulating single-neuron function in the brain would be achievable in the not-too-distant future. The impetus provided by this initial meeting led to a series of additional brain activity map symposia and workshops, also facilitated by the Kavli Foundation, and eventually led to a brain activity map white paper that was submitted to the White House Office of Science and Technology Policy. This white paper became the initial template for what would become the White House BRAIN Initiative ( ).

The direct inspiration for the Kavli efforts was the previously successful Human Genome Project (HGP), an international collaborative research project with the goal of providing a complete map and understanding of the human genome. According to an independent analysis performed by Battelle Memorial Institute in Columbus, OH, the $3.8 billion investment in the HGP led to $796 billion in economic impact by 2011 ( ). In the early stages of the HGP, gene sequencing technology was too costly and slow to sequence the estimated 3 billion base pairs that compose it. Strategic investment in new technologies that did not exist before the onset of the HGP was required to reach the aggressive milestones laid out in the initial proposal. Moreover, the ambitious work to be accomplished required coordinated research efforts and minimally restricted data sharing between federal agencies, foundations, academic institutes, and industry at an international scale ( Table 5.1 ).

Although the brain activity map proposal provided the initial framework that formed the foundation of the BRAIN Initiative ( ), each institution participating in the BRAIN Initiative conducted their own planning effort and outlined their own goals, consistent with their own unique missions. Consequently, the overarching goals of the BRAIN efforts have changed from an explicitly stated goal of measuring all of the action potential from all neurons in the human brain simultaneously, to a general commitment to “accelerate the development and application of new technologies that will enable researchers to produce dynamic pictures of the brain that show how individual brain cells and complex neural circuits interact at the speed of thought” ( ). A list of current participating institutions follows ( ); however, this list is expected to expand significantly over the life of the BRAIN Initiative:

Initial Government Contributors

Some of the initial government contributors to the BRAIN Initiative were the National Institutes of Health (NIH), the Defense Advanced Research Projects Agency (DARPA), and the National Science Foundation (NSF). Combined, these organizations proposed investments of $110 million for fiscal year 2014. These government organizations were interested in the development of novel devices, technologies, and applications that could improve, enhance, or advance current understanding and treatment of neurologic function.

Initial Private Sector Partners

Initial private contributors, including the Allen Institute for Brain Science, the Howard Hughes Medical Institute, and the Kavli Foundation, invested a combined $122 million in the first year of the BRAIN Initiative. These investments came from both existing and new campaigns and were aimed at developing neural activity maps, imaging technology, and an effort to increase collaborations across different areas of neuroscience. These private sector contributors offered groundbreaking models of scientific discovery from which the BRAIN Initiative adopted many of its core principles. For example, the Allen Institute maintains a “commitment to an open science model within its research institutes,” while the Kavli Foundation and its noted philanthropist founder, Fred Kavli, have invested in the development of research institutes worldwide ( ). Similarly, the Howard Hughes Medical Institute has focused investments on investigator development and the support of innovative scientific pioneers ( ). Combined, these partners provided a model of support for cutting-edge research and information dissemination.

NIH Planning Efforts

Given that the NIH was funding several billion dollars in neuroscience research each year, NIH planning efforts were focused on soliciting input from diverse experts, both in and out of the NIH-funded neuroscience community. The goal was to better understand how a planned, highly coordinated, and sustained effort, leveraging a comparatively much smaller additional amount of funding, could be used to address gaps overlooked by traditional investigator-initiated funding mechanisms. NIH Director Francis Collins—who had previously served as the head of the Human Genome Project—organized an Advisory Committee to the Director to inform the initial planning of the NIH BRAIN efforts. This consisted of leading neuroscientists, engineers, clinicians, and industry partners. The Advisory Committee to the Director, in conjunction with the Office of the Director, convened several workshops to solicit and synthesize input from the wider community over the course of the first year, covering diverse topics such as molecular approaches to understanding the brain, large-scale recording techniques, structural biology, computational theory, data science, and human neuroscience. These deliberations were distilled into the BRAIN 2025 Report, which outlined the long-term scientific plan to serve as the guide for the NIH BRAIN Initiative ( ).

The BRAIN 2025 Report called for a sustained federal commitment of $4.5 billion over 12 years. The NIH also identified a group of external advisors, known as the BRAIN Multi-Council Working Group, which convenes several times a year to advise the NIH Program Staff on how to best implement the recommendations in the BRAIN 2025 Report in light of emerging opportunities ( Fig. 5.2 ).

BRAIN Initiative Programs for Neuromodulation Therapies

The programs under the White House BRAIN Initiative include efforts that are both directly and indirectly intended to affect neuromodulation therapies, either by improving our fundamental understanding of the functional neural circuitry of the brain or by developing new tools that could be used to directly observe and optimize the effects of neuromodulation therapies in real-time. For example, the initial NIH BRAIN 2025 Report highlighted seven “high-priority” areas that have now been implemented as funding programs. These areas are.

• 1.

  Discovering diversity to identify and provide experimental access to the different brain cell types for determining their roles in health and disease,

• 2.

  Building maps at multiple scales to generate circuit diagrams that vary in resolution from synapses to the whole brain,

• 3.

  Imaging the brain in action to produce a dynamic picture of the functioning brain by developing and applying improved methods for large-scale monitoring of neural activity,

• 4.

  Demonstrating causality to link brain activity to behavior with precise interventional tools that change neural circuit dynamics,

• 5.

  Identifying fundamental principles to produce conceptual foundations for understanding the biological basis of mental processes through development of new theoretical and data analysis tools,

• 6.

  Advancing human neuroscience to develop innovative technologies to understand the human brain, treat its disorders, create and support integrated human brain research networks, and

• 7.

  Moving from BRAIN Initiative to the brain to integrate new technological and conceptual approaches produced in goals 1 through 6 to discover how dynamic patterns of neural activity are transformed into cognition, emotion, perception, and action in health and disease.

This list of priorities provides a useful framework to describe efforts from other institutions, which can generally be categorized under these seven priorities. BRAIN Initiative Programs, which were developed to directly address, at least in part, issues pertaining to neuromodulation therapies, are described next. This effort leverages and involves experts spanning 10 of the 27 institutes and centers at the NIH. Each of these contributors brings mission relevance to and expertise on the disorders and pathologies being addressed by the BRAIN Initiative.

NIH BRAIN Programs for Neuromodulation Therapies

The goal of the NIH BRAIN Programs for Neuromodulation is to incentivize work on key gaps that could be catalytic but that do not fare well in traditional NIH grant review. Traditional NIH reviewers place significant emphasis on innovation without incorporating any project-related risks, discourage serial dependency of tasks, and require rigorous experimental design with detailed power analyses to justify the number of subjects. This overwhelming focus on innovation, unwillingness to accept risky project elements, and avoidance of serial dependency of tasks may disadvantage studies characterizing fundamental mechanisms of stimulation, combining multiple pre-existing stimulation modalities to enhance effect, or testing engineering refinements in the clinic necessary to move from a single proof-of-concept demonstration to a practical therapy with a clear business case for industry investment. A list of currently-active NIH funding announcements can be found at https://www.braininitiative.nih.gov/funding/index.htm .

NIH Programs to Support Noninvasive Neuromodulation Strategies

Recently, the NIH has released several new Requests for Application (RFAs) as a part of the BRAIN Initiative Program that encourage investigators to focus on noninvasive neuromodulation devices and techniques. Noninvasive devices “do not require surgery and do not penetrate the brain parenchyma” ( ). Innovative applications of noninvasive neuromodulation devices have the potential to elucidate alternative treatments to neurologic and psychiatric disorders, which may provide additional therapeutic options that do not carry the same risks as invasive therapies. In particular, the following two programs aim to go beyond incremental advances in order to thoroughly explore the relationship between noninvasive neuromodulation and the affected neural circuitry.

Invasive Neuromodulation Strategies