New Federal BRAIN Research Discoveries Are Targeted to Improve Clinical Practice

November 17, 2014

Although the early focus of the NIH component of the BRAIN Initiative is on tool development, the examples listed in this article show that these tools will have relevance to practicing clinicians within the lifetime of the Initiative.

On April 2, 2013, President Obama announced a new public-private partnership to develop new tools and technologies that will enable the research community to obtain a dynamic picture of the brain in action. Initially, 3 federal agencies-the Defense Advanced Research Projects Agency (DARPA, $50M), the NIH ($40M), and the National Science Foundation (NSF, $20M)-were charged with initiating new plans for the Brain Research through Advanc-ing Innovative Neurotechnologies (BRAIN) Initiative activities. That list recently grew to include the FDA and the Intelligence Advanced Research Projects Agency (IARPA).1 Those activities complement work supported by the initial private sector partners, the Allen Institute for Brain Science ($60M), the Howard Hughes Medical Institute ($30M), the Salk Institute for Biological Studies ($28M), and the Kavli Foundation ($4M). In most cases, the funding amounts indicate investments made in 2014.

[[{"type":"media","view_mode":"media_crop","fid":"29461","attributes":{"alt":"BRAIN Research Discoveries","class":"media-image media-image-right","id":"media_crop_8139264562274","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"3049","media_crop_rotate":"0","media_crop_scale_h":"168","media_crop_scale_w":"150","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"float: right; width: 161px; height: 180px;","title":" ","typeof":"foaf:Image"}}]]In addition to these investments in the American BRAIN Initiative, there is a significant investment by the European Commission in a related effort-the Human Brain Project.2 That project is focused on developing new modeling and computing technologies to understand the brain. The Japanese have recently announced an initiative that will fund research on the marmoset as well as on tool and technology development.3,4 Other countries seem to be considering their own versions of a BRAIN Initiative.

The ethical issues involved in the research sponsored under these initiatives are significant. The Presidential Commission for the Study of Bioethical Issues has released a report on ethical issues associated with the conduct of neuroscience research.5 The Human Brain Project also has a robust effort in this area.6

The focus of this report is to provide an update on BRAIN Initiative activities and to discuss the relevance of these activities to psychiatry.

The DARPA was the first federal agency to announce new programs related to the BRAIN Initiative. Large awards under their Systems-Based Neurotechnology for Emerging Therapies (SUBNETS) and Restoring Active Memory (RAM) programs have been announced.

In the RAM program, researchers at the University of California, Los Angeles, and the University of Pennsylvania have received awards for developing and testing wireless implantable neuroprosthetic devices aimed at overcoming memory deficits that result from traumatic brain injury or disease.7 The SUBNETS program has also made awards of interest to the psychiatric community. The University of California, San Francisco, and Massachusetts General Hospital have received awards to develop closed-loop therapies that incorporate recording and analysis of brain activity with close to real-time neural stimulation. If successful, the treatments developed through this program might be useful in the treatment of major depression or PTSD.8

More recently announced DARPA programs include the Neuro Function, Activity, Structure, and Technology (Neuro-FAST) program that is aimed at developing new optical methods to obtain information about cell types, neuronal connections, and firing activity in participants who are awake and performing various tasks.9 The Hand Proprioception and Touch Interfaces (HAPTIX) program aims to provide amputees with prosthetic limb systems that feel and function like natural limbs.10

The NSF and the NIH held a series of meetings and workshops before releasing program announcements. The details of the NSF BRAIN Initiative meetings and funding announcements can be found online.11 As a result of those meetings, NSF solicited Early Concept Grants for Exploratory Research (EAGER) and has funded 36 awards.12

Shortly after the President’s announcement in April, the NIH convened a Working Group to the Advisory Committee to the NIH Director to review recent advances in neuroscience, articulate scientific goals for the NIH component of the BRAIN Initiative, and develop a scientific plan for achieving those goals.13,14 Following extensive consultation with the research community, that Working Group released a detailed 12-year plan for the NIH BRAIN Initiative in June 2014 called BRAIN 2025.13

NIH BRAIN Initiative

In response to an interim report released by the Working Group, the NIH announced 6 different BRAIN Initiative requests for applications in December 2013. New funds were appropriated by Congress, and the requests were grouped into 3 distinct areas of science:

• Cells and circuits: transformative approaches for cell-type classification in the brain15; development and validation of novel tools to analyze cell-specific and circuit-specific processes in the brain16

• Large-scale recording: new technologies and novel approaches for large-scale recording and modulation in the nervous system17; optimization of transformative technologies for large-scale recording and modulation in the nervous system18; integrated approaches to understanding circuit function in the nervous system19

• Imaging technology: planning for next-generation human brain imaging20

A satisfying number of applications (not too few, not too many) were received, and 58 awards were made.21

Relevance for clinical practice

Some of the awards that might be of particular interest to practicing psychiatrists follow.

A novel approach for cell-type classification and connectivity in the human brain (Dr Nenad Sestan, principal investigator, Yale University; grant number U01MH105972). Dr Sestan and colleagues are going to try to generate a census of all of the cell types in the human, macaque, and mouse prefrontal cortex. They have chosen this brain region because of its importance in many higher cognitive functions as well as its involvement in certain psychiatric and neurological disorders. This team plans to use a novel tissue processing protocol to keep postmortem brains in prolonged hibernation, which should minimize differences between various tissue types in the intact brain. The team plans to develop a comprehensive list of cell types based on the molecular identity of the cells as well as their connectivity. This list will be compared across species, ages, and sexes. If successful, this approach could be extended to the entire human brain in both healthy and disease states.

The in vivo circuit activity measurement as single-cell, subthresh-old resolution (Dr Craig Forest, principal investigator, Georgia Institute of Technology; grant number U01MH106027). In this tool development award, Dr Forest and colleagues are going to try to extend a newly developed tool to measure electrical fluctuations across neuronal cellular membranes. For many years, whole-cell patch clamping has been the gold standard for measuring these fluctuations. Unfortunately, patch clamping is an in vitro technique that requires great skill to perform a small number of experiments on a few cells each day. This is far from what would be needed for large-scale analysis of neuronal communication in cells and circuits in living organisms.

Dr Forest and his collaborator, Dr Ed Boyden at Massachusetts Institute of Technology, have recently developed an “autopatching robot” that algorithmically detects cells through changes in electrode impedance in the brains of living mice. This robot will be adapted to make intracellular recordings from 2 neurons in vivo that are synaptically connected. If successful, this will provide a new powerful tool to allow the detailed analysis and manipulation of cell circuits and subcircuits in living animals.

Imaging brain function in real-world environments and populations with portable MRI (Dr Michael Garwood, principal investigator, University of Minnesota; grant number R24MH105998). Structural and functional MRI continues to be the dominant tool to visualize the living human brain. Invariably, MRI experiments require a large fixed magnet. In most cases, the subject lays down during the imaging experiment. It is possible for the subject to watch movies or other visual input, and it is possible to measure his or her responses to that input by monitoring eye movement or using a finger response. However, this situation is far from a natural environment. The proposed next-generation imaging technology from Dr Garwood and colleagues is a new type of device that is portable and relatively inexpensive. If successful, the technology would make it possible to study the human brain outside the confines of an imaging suite in a research laboratory.

Novel technologies for nontoxic transsynaptic tracing (Dr Ian Wickersham, principal investigator, Massachusetts Institute of Technology; grant number U01MH106018). New genetic tools have made it possible to monitor and perturb specific populations of neurons in a number of ways. These tools would be much more powerful if it was possible to deliver them to the neurons that are involved in a specific circuit. Current ways of targeting neurons in a circuit use a virus that can cross between conecting neurons. Unfortunately, these viruses are toxic within a relatively short time. Dr Wickersham and colleagues will develop a virus-based transsynaptic tracing system that will have greatly reduced or no toxicity. This will allow optical imaging or other methods to monitor activity in the context of behavioral experiments that last for very long periods. Such experiments will significantly improve our understanding of the neuronal circuitry underlying cognitive operations and how that circuitry is altered by mental disorders.

The Multi-Council Working Group

The NIH has created a group of advisors that will act as ongoing external consultants to the BRAIN Initiative project. That group, the Multi-Council Working Group (MCWG), met for the first time in August 2014.22 The purpose of that group is to provide ongoing oversight of the implementation of BRAIN 2025 and to help the NIH update implementation plans as results from the BRAIN Initiative awardees (and others) become available and the initial report becomes outdated. At their first meeting, the MCWG reviewed the pay plans for the awards made from the first 6 program announcements and reviewed proposals for NIH activities in fiscal year 2015, which started on October 1, 2014.22

Application

When the President announced the BRAIN Initiative, he called for a “bold new research effort to revolutionize our understanding of the human mind and uncover ways to treat, prevent, and cure brain disorders such as Alzheimer disease, schizophrenia, autism, epilepsy, and traumatic brain injury.”23 Although the early focus of the NIH component of the BRAIN Initiative is on tool development, the examples listed above show that these tools will have relevance to practicing clinicians within the lifetime of the Initiative.

We anticipate that these new tools will open the pathway to understanding the biological basis for mental disorders. When these new tools are combined with the new approaches fostered by the Research Domain Criteria (RDoC) effort24 and by the new focus on target engagement in NIMH-sponsored clinical trials,25 it is easy to imagine a transformation in the care of those who suffer from mental illness. These new tools will help us understand the brain and will give us a more complete understanding of the biological causes of mental disorders.

Disclosures:

Dr Farber is Director of the Office of Technology Development and Coordination, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services in Bethesda, Md. He reports no conflicts of interest concerning the subject matter of this article.

References:

1. Fact Sheet: Over $300 million in support of the President’s BRAIN Initiative. September 30, 2014. http://www.whitehouse.gov/sites/default/files/
microsites/ostp/brain_fact_sheet_9_30_2014_final.pdf. Accessed October 8, 2014.

2. Human Brain Project. https://www.humanbrain project.eu. Accessed October 8, 2014.

3. Global Discovery Project. http://www.lifescience.mext.go.jp/files/pdf/n1332_07.pdf [in Japanese]. Accessed October 8, 2014.

4. Okano H, Mitra P. Brain-mapping projects using the common marmoset. Neurosci Res. 2014 Sep 27; [Epub ahead of print].

5. Presidential Commission for the Study of Bioethical Issues. Gray matters: integrative approaches for neuroscience, ethics, and society. http://bioethics.gov/node/3543. Accessed October 8, 2014.

6. Rose N. The Human Brain Project: social and ethical challenges. Neuron. 2014;82:1212-1215.

7. DARPA. Restoring Active Memory (RAM). http://www.darpa.mil/Our_Work/BTO/Programs/Restoring_Active_Memory_RAM.aspx. Accessed October 8, 2014.

8. DARPA. Systems-Based Neurotechnology for Emerging Therapies (SUBNETS). http://www.darpa.mil/Our_Work/BTO/Programs/Systems-Based_
Neurotechnology_for_Emerging_Therapies_SUBNETS.aspx. Accessed October 8, 2014.

9. DARPA. Neuro Function, Activity, Structure, and Technology (Neuro-FAST). http://www.darpa.mil/Our_Work/BTO/Programs/Neuro_Function_Activity_Structure_and_Technology_NeuroFAST.aspx. Accessed October 8, 2014.

10. DARPA. By restoring sense of touch to amputees, Haptix seeks to overcome physical and psychological effects of upper limb loss. April 24, 2014. http://www.darpa.mil/NewsEvents/Releases/2014/04/24.aspx. Accessed October 8, 2014.

11. National Science Foundation. Understanding the brain. http://www.nsf.gov/news/special_reports/brain. Accessed October 8, 2014.

12. National Science Foundation. NSF awards $10.8 million in early concept grants for brain research. http://www.nsf.gov/news/news_summ.jsp?cntn_id=132371. Accessed October 8, 2014.

13. National Institutes of Health. Brain Research through Advancing Innovative Neurotechnologies (BRAIN). http://www.nih.gov/science/brain. Accessed October 8, 2014.

14. Insel TR, Landis SC, Collins FS. Research priorities: the NIH BRAIN Initiative. Science. 2013;340:
687-688.

15. Department of Health and Human Services. BRAIN Initiative: transformative approaches for cell-type classification in the brain (U01). RFA-MH14-215. http://grants.nih.gov/grants/guide/rfa-files/RFA-MH-14-215.html. Accessed October 8, 2014.

16. Department of Health and Human Services. BRAIN Initiative: development and validation of novel tools to analyze cell-specific and circuit-specific processes in the brain (U01). RFA-MH-14-216. http://grants.nih.gov/grants/guide/rfa-files/RFA-MH-14216.html. Accessed October 8, 2014.

17. Department of Health and Human Services. BRAIN Initiative: new technologies and novel approaches for large-scale recording and modulation in the nervous system (U01). RFA-NS-14-007. http://grants.nih.gov/grants/guide/rfa-files/RFA-NS-14007.html. Accessed October 8, 2014.

18. Department of Health and Human Services. BRAIN Initiative: optimization of transformative technologies for large-scale recording and modulation in the nervous system (U01). RFA-NS-14-008. http://grants.nih.gov/grants/guide/rfa-files/RFA-NS-14008.html. Accessed October 8, 2014.

19. Department of Health and Human Services. BRAIN Initiative: integrated approaches to understanding circuit function in the nervous system (U01). RFA-NS-14-009. http://grants.nih.gov/grants/guide/rfa-files/RFA-NS-14-009.html. Accessed October 8, 2014.

20. Department of Health and Human Services. BRAIN Initiative: planning for next generation human brain imaging (R24). RFA-MH-14-217. http://grants.nih.gov/grants/guide/rfa-files/RFA-MH-14-217.html. Accessed October 8, 2014.

21. National Institutes of Health. NIH BRAIN Awards. http://www.braininitiative.nih.gov/nih-brain-awards.htm. Accessed October 8, 2014.

22. National Institutes of Health. BRAIN MultiCouncil Working Group Meeting. August 2014. http://videocast.nih.gov/summary.asp?Live=14589&bhcp=1. Accessed October 8, 2014.

23. The White House. BRAIN Initiative. http://www.whitehouse.gov/share/brain-initiative. Accessed October 8, 2014.

24. Insel TR. The NIMH Research Domain Criteria (RDoC) Project: precision medicine for psychiatry. Am J Psychiatry. 2014;171:395-397.

25. National Institute of Mental Health. NIMH policy for submission of applications containing clinical trials. February 25, 2014. http://grants.nih.gov/grants/guide/notice-files/NOT-MH-14-007.html. Accessed October 8, 2014.