National Institute of Neurological Disorders and Stroke Update

May 4, 2016 Walter J. Koroshetz, M.D. Director, National Institute of Neurological Disorders and Stroke, NIH 1 Discussion Items

• NINDS Funding Strategy – Basic neuroscience – Science quality – New • initiative • Alzheimer’s Disease Related Dementia program • Mind Your Risks Public Info Campaign • Programs in Chronic Fatigue • Pain research programs • Neuroscience training Public Interest in Brain Research is Growing Trends in Fields of Study of Trainees and Fellows Receiving Ph.D.s

500

450

400 Biochemistry 350 Engineering

300 Health Sciences Immunology Ph.D.s 250 Molecular Biology

200 Neuroscience Physical Sciences

Number of of Number 150 Psychology 100

50

0 1983 1988 1993 1998 2003 2008 2013 Year of Ph.D. 4 2015 NIH Funding of Disease Categories

7

6

5

4

3 illions B 2 $ in 1

0 Cancer Neuroscience Infectious Diseases Cardiovascular

5 NIH Support for Neuroscience NINDS NIMH Extends across Many Institutes NIA NEI NIDA NICHD NIDCD NIGMS NCI NIAAA NHLBI NIDDK OD/RMAP NIEHS NIBIB NIAID NCATS NCCAM NIDCR NIAMS NINR RCDC reporting - ($$$ in billions) NHGRI NIMHD FIC NLM NIH Neuroscience Blueprint: Multiple ICs Working Together to Advance Neuroscience

7 NINDS Supports Research Across a Wide Disease Spectrum Joubert Absence of Septum Pellucidum Blepharospasm Thoracic Outlet Syndrome Brown-Sequard Syndrome Kearns-Sayre Syndrome Tourette Syndrome Acute Disseminated Encephalomyelitis CADASIL Kennedy’s Disease Trigeminal Neuralgia Adie Syndrome Cerebellar degeneration Kuru Transverse Myelitis Agnosia Cerebellar Hypoplasia Landau-Kleffner Syndrome Tuberous Schlerosis Lennox-Gastaut Syndrome Aicardi Syndrome Cerebral Cavernous Malformation Von-Hippel-Lindau Disease Cerebral Palsy Leukodystrophy Wernicke-Korsakoff Syndrome Aicardi-Goutieres Syndrome Charcot-Marie-Tooth Disease LLyme Disease-Neurological Complications West Syndrome AIDS – Neurological Complications Chiari Malformation Menkes Disease William’s Syndrome Alexander Disease Choreo-acanthocytosis Meralgia Paresthetica Wilson Disease Microcephaly Alpers’ Disease CockayneSyndrome Type II Wolman’s Disease Coffin Lowry Syndrome Miller-Fisher Syndrome Alternating Hemiplesia Zellweger Syndrome Complex Regional Pain Syndrome Moebius Syndrome Amyotrophic Lateral Sclerosis (ALS) Corticobasal Degeneration Myasthenia Gravis Anencephaly Cytomegalic Inclusion Disease Narcolepsy Apraxia Dancing eyes-Dancing Feet Syndrome Neuroleptic Malignant Syndrome Dandy-Walker Syndrome Niemann-Pick Disease Arachnoid Cysts Dravet Syndrome Normal Pressure Arachnoiditis Olivopontocerebellar Atrophy Telangiectasia Early Infantile Epileptic Encephalopathy Pantothenate -Associated Neurodegeneration Barth Syndrome Empty Sella Syndrome Parkinson’s Disease Encephalitis Lethargica Paroxysmal Hemicrania Becker’s Myotonia Epilepsy Pick’s Disease Behcet’s Disease Essential Tremor Post polio syndrome Bell’s Palsy Fabry Disease Primary Later Sclerosis Familial Dysautonomia Progressive Hemifacial Atrophy Binswanger’s Disease Farber’s Disease Pseudotumor Cerebri Blepharospasm Friedreich’s Ataxia Rasmussen’s Encephalitis Brown-Sequard Syndrome Frontotemporal Dementia Refsum Disease Gaucher Disease Rett Syndrome CADASIL Gerstmann’s Syndrome Sandhoff Disease Cerebellar degeneration Gerstmann-Straussler-Scheinker Disease Semantic Dementia Cerebellar Hypoplasia Giant Axonal Neuropathy Septo-Optic Dysplasia Glycogen Storage Disease Spinal Muscular Atrophy Bell’s Palsy Guillain-Barre Syndrome Stiff Person Syndrome Binswanger’s Disease HTLV-1 Associated Myelopathy Stroke Huntington’s Disease Sturge-Weber Syndrome Hydranencephaly Subacute Sclerosing Panencephalitis Inclusion Body Myositis Tay-Sachs Disease The National Institute of Neurological Disorders and Stroke (NINDS)

The mission of NINDS is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.

Strategies: • Invest across the full spectrum of basic, translational, and clinical research • Establish a data-driven process to identify unmet scientific opportunities and public health needs within and across neurological diseases • Support research resources and technical advances that catalyze new discoveries • Communicate and collaborate with the public and with others involved in biomedical research • Train a robust and diverse neuroscience research workforce • Adopt a culture of evaluation and continuous improvement across all NINDS programs http://www.ninds.nih.gov/about_ninds/plans/NINDS_strategic_plan.htm NINDS Is Investing Across the Research Spectrum

High Disease- FDA Basic Target Assay Thru- Pre- FDA focused Ph. I Ph. II Ph. III Re- Clinic Research ID Dev. put Clinical IND research view Screen Competing RPG Trends

2010 2011 2012 2013 2014 2015 Competing 699 749 701 702 750 819 Awards

Number of 3,097 3,549 3,588 3,551 4,002 4,007 Applications

Success Rate 22.6% 21.1% 19.5% 19.8% 18.7% 20.5%

Average Cost $405K $392K $378K $378K $396k $379k

Payline 14 14 15 14 14 14 (Percentile)

Data includes complete RPG portfolio of Unsolicited Announcements, RFAs, PAs, PASs NINDS Funding Trends

Competing Dollars Basic // Basic 70 Basic // Disease-related Applied // Translational 60 Applied // Clinical Competing Awards 50 70 40 60 30 50 20

Percentage of Competing $s 40 10

0 30

20

10 Percentage of Competing Awards

0 How Does a Basic Science Grant Applicant Address “Relevance”?

4.2.1 Description: Project Summary and Relevance – The second section of the Description is Relevance. Using no more than two or three sentences, describe the relevance of this research to public health. In this section, be succinct and use plain language that can be understood by a general, lay audience. • Should NIH acknowledge here that high impact basic research is relevant to the public health? The Growing Challenge

• Noted by research community; in multiple publications – Across research areas – Especially in preclinical research Enhancing Reproducibility through Rigor and Transparency

ü Guidance crafters ü Journal editors ü Reviewers ü End users

Nature 2012; 490: 187-191 NINDS Research Program Award (R35)

v Program Goals Ø Provide freedom for investigators to pursue longer range, innovative, or high- risk research Ø Reduce pressure to generate results quickly to renew short-term grants Ø Allow investigators flexibility to follow up on serendipitous findings and explore new areas Ø Reduce amount of time spend writing and administering multiple grant awards

v NINDS Commitment Ø Up to $20 Million to support 20-30 awards. NINDS Mentorship Award • Purpose: To reward outstanding mentorship (of pre- or postdocs), and incentivize good mentorship. • Send a strong message that NINDS (and NIH) values good mentorship • Provide tangible reward for mentorship that will be understood by: Investigators, Chairs, Deans • Provide additional support for excellent mentors doing excellent science so they can train additional trainees AD/ADRD Research Increases at NIH

$991M* $991M* $161M ADRD

$526M $631M $562M $503M $504M $448M $195M $56M $125M $82M $830M AD

$448M $447M $422M $437M $436M $465M

FY2011 FY2012 FY2013 FY2014 FY2015 FY2016 FY2016

Courtesy of Robert Egge *Projected ADRD Summit 2016

• Took place March 29-30, 2016 • Update research recommendations: • Frontotemporal degeneration • Lewy body dementia • Multiple etiology dementias • Vascular contributions to cognitive impairment and dementia • Health disparities • New in 2016: NGO Session • Open to the public • Hosted by NINDS in collaboration with NIA Mind Your Risks A New NINDS Public Education Campaign

• Raise awareness among middle-aged people with hypertension that controlling blood pressure may decrease risk for dementia, as well as stroke, in later life

• Provide scientific evidence for doctors who wish to discuss this topic with their patients

• Campaign launched with PSA placement in Stroke Belt States

• NINDS-led campaign in partnership with Million Hearts®, NHLBI and NIA The BRAIN Initiative®

• A focus on circuits and networks • Measure the fluctuating electrical and chemical patterns within circuits • Understand how all of this helps generate our unique thoughts and actions Where Does Scientific Progress Come From?

“New directions in science are launched by new tools much more often than by new concepts. The effect of a concept-driven revolution is to explain old things in new ways. The effect of a tool-driven revolution is to discover new things that have to be explained.”

Freeman Dyson (1997) Imagined Worlds Harvard University Press, Cambridge, MA What’s Next?

1974 2012

Original axial CT image form Siretom CT scanner circa 1975. Physicians were fascinated by the ability to see the brain and ventricles for the first time. The BRAIN Initiative® Brain Research through Advancing Innovative Neurotechnology (BRAIN) Initiative • Tools to measure the fluctuating electrical and chemical patterns within circuits • A focus on circuits and networks • Understand how all of this helps generate our unique thoughts and actions 2014 NIH BRAIN awards • 58 awards, $46 million 2015 NIH BRAIN awards • 67 awards, $38 million • 131 investigators, 8 countries outside the US http://braininitiative.nih.gov/ FY 2016 BRAIN Appropriation (approx.)

IC FY 2014 FY 2015 FY 2016 Δ FY 2016 Total NINDS 12,850,000 25,150,000 27,929,000 $53,079,000 NEI 4,857,000 $4,857,000 NIDCD 1,821,000 $1,821,000 NIMH 12,850,000 25,231,000 27,929,000 $53,160,000 NIA 3,643,000 $3,643,000 NIDA FY16 President’s Budget request: $70M new4,000,000 4,000,000 8,500,000 $12,500,000 FY16 BRAIN appropriation: $85M new NIAAA 2,732,000 $2,732,000 NCCIH 1,214,000 $1,214,000 NIBIB 1,000,000 1,000,000 3,643,000 $4,643,000 NICHD 2,732,000 $2,732,000 Blueprint 10,000,000 19,107,785 To be determined ICO* Add’l $ 5,431,142 10,492,257 To be determined Total $46,131,142 $84,981,042 ~$150,000,000 *ICO – Institutes, Centers, and OD Offices that provided additional $ beyond BRAIN appropriations 25 BRAIN Portfolio by Categories

?

FY2016: Amounts are estimates based on RFA set-aside totals – final allocations will depend on number and quality of applications for each RFA. FY2017: Proposed RFA that have received “concept clearance” from participating NIH Institute/Center Directors and MCWG. We do not yet know the FY17 budget. President’s budget provided $45M increase for NIH. International Partnerships

Goals: • Develop a coordinated program to foster collaborative research in areas of mutual interest within the BRAIN Initiative • Jointly support research projects involving Danish and U.S. scientists; exchange of scientific information. • Funding for projects in Denmark funded by Foundation.

• Similar to partnerships between NIH and research organizations in Canada and Australia Brain Initiative Alliance

Mission Statement: The aim of the BRAIN Initiative Alliance is to coordinate and facilitate communications from its members related to the White House BRAIN Initiative. Short Term Focus: Website that serves as a single point of communication for all BRAIN Initiative-related announcements of funding opportunities and accomplishments

28 Launch of New BRAIN Website

Explore New Features: www.brainintiative.nih.gov BRAIN Initiative: Exciting Advances Beginning to Emerge BRAIN Initiative: Exciting Advances Beginning to Emerge BRAIN Neuroethics

BRAIN Neuroethics Workgroup • A consultative ethics group to work with BRAIN leadership and BRAIN investigators • Co-chaired by Dr. Christine Grady and Hank Greely • Services: • Advise NIH on neuroethics questions important for BRAIN that could be answered through focused empirical research • Draft relevant guidance documents to address critical ethical issues associated with BRAIN research • Consider proposed funding areas for BRAIN projects for questions of ethical risk • Workgroup meeting with BRAIN PIs conducting invasive studies • New joint BRAIN/Blueprint neuroethics project team (Team N) • http://braininitiative.nih.gov/about/newg.htm Update on Concussion Research Two neuropath studies ongoing • Published guidelines for pathologic diagnosis of CTE • Screen of May neuro brain bank for CTE • Found in 30% of those with some history of playing contact sports. 0% in matched non-sports cohort and 0% in female cohort. • Screen of Queen’s Square neuro bio bank • CTE in 12% and history of TBI in 94%, but TBI not sports related, question raised whether TBI related to falls from neuro conditions. • NINDS funded longitudinal study to characterize clinical syndrome of CTE from its appropriated budget. NINDS-funded longitudinal study to characterize clinical syndrome of CTE from its appropriated budget NINDS will form a working group of Council to discuss next highest priority opportunities in concussion research • In concert with NICHD • Jonathan Mink to lead • Will hold a workshop and create research plan • Concept clearance for Council • Discuss research plan with FNIH Chronic Fatigue Syndrome • Affects between 800,000 - 2.5 million in the US • 75% affected are women • Cause unknown but many have distinct onset with flu-like symptoms • Plans for CFS/Myalgic Encephalitis Research • NIH-wide intramural protocol through IRB to begin phenotyping, neuro and immunologic studies • Led by Dr. Avi Nath • Trans-NIH working group developing an extramural research program • Led by Dr. Vicky Whittemore NINDS’s Role in CFS

• NINDS leads Trans-NIH ME/CFS Working Group – Goals • Advance research on the cause, prevention, diagnosis, pathophysiology and treatment of ME/CFS • Communicate ME/CFS research information with ICs, OD – Activities • Organize Federal Partners meeting (follow-up to 2014 Pathways To Prevention (P2P) Workshop) – Develop disease parameter – Create new knowledge » Diagnostics, Epi studies, Prognostics » Causation- immunologic, neurologic, genomic – Develop outcome measures – Develop and test treatment – Training and education Workshop Goal: Ensure that evidence- based information is available to inform practice and policy, particularly important at this time given the rapidly shifting landscape regarding the recreational and medicinal use of marijuana.

36 National Pain Strategy: A Comprehensive Population Health Level Strategy for Pain 2010 Patient Protection & Affordable Care Act

2011: Relieving Pain in America

Professional Professional Education & Education & TrainingTraining Public Education 2012 Assistant Secretary for Health, HHS Public Education & Population & tasked IPRCC and NIH to address IOM ResearchPopulation Communication Recommendation: “develop a Research Communication Disparities comprehensive, population health-level Service Delivery & Disparities Service Delivery & Reimbursement strategy for pain prevention, treatment, Reimbursement management, education, reimbursement, Care & and research that includes specific goals, PreventionCare & Prevention actions, time frames, and resources.”

Agency clearance February 2016 National Pain Research Strategy pain as a temporal process, beginning with an acute phase that may progress to a chronic maladaptive state

PREVENTION OF ACUTE PAIN & TRANSITION CHRONIC PAIN ACUTE & ACUTE PAIN FROM ACUTE TO & CHRONIC PAIN DISPARITIES CHRONIC PAIN MANAGEMENT CHRONIC PAIN MANAGEMENT

WHAT HAPPENS AND BASIC CLINICAL TO WHOM? SCIENCE SCIENCE

WHY AND HOW DOES UNDERSTAND IT HAPPEN? MECHANISMS

TRANSLATE/ HOW TO MANAGE? TREAT

Completion January 2017 Neuroscience Training: What’s Changed?

• Neuroscience is expanding in multiple directions • Numbers of graduate students increased dramatically • Time to independence increased dramatically • Tools have become more sophisticated, and an increased degree of sophistication is needed for data analysis • New emphasis on attracting scientists from outside biology • New emphasis on rigor in experimental design and statistical analysis • Funding climate became much more competitive during the 12 flat budget years and concern that associated pressures led to decline in career mentoring • Early movement within BRAIN initiative to adapt a more “physics- like” model to engage team science to attack problems • Data platforms and data sharing • Concern that attempts to increase diversity in trainees not translating as well as hoped into diversity in the academic science workforce Trends in Fields of Study of Trainees and Fellows Receiving Ph.D.s

500

450

400 Biochemistry 350 Engineering

300 Health Sciences Immunology Ph.D.s 250 Molecular Biology

200 Neuroscience Physical Sciences

Number of of Number 150 Psychology 100

50

0 1983 1988 1993 1998 2003 2008 2013 40 Year of Ph.D. IOM Neuroscience Forum: Defining the Expertise Needed for a 21st Century Neuroscience Workforce

• Transdisciplinary training. • Training for neuroscientists needs more: – mentoring – experimental and analytical skills – communication and writing skills – lab and office management – ethics in science – fundamental neuroscience knowledge and its history, – teaching and mentoring • Training “in neuroscience” needs: – tracks for those coming from physical and computational backgrounds – team science – tracks for translational science IOM Neuroscience Forum: Defining the Expertise Needed for a 21st Century Neuroscience Workforce

• Experimental and analytical skill development – Statistical reasoning and facility in statistical methods – Reducing bias by training for rigorous experimental design – Demystify neurotechnologies – Data analytic skills • programing, data management platforms, multidimensional cloud computing, data visualization and feature extraction, algorithm development, machine learning and computer modeling Bridging the Gaps NINDS Seeking Knowledge about the Brain . . . Reducing the Burden of Disease