Perspectives from the NIMH

Joshua A. Gordon, M.D., Ph.D.

Director

National Institute of Mental HealthApril 26, 2019

Follow me on twitter @NIMHDirector

• NIMH and the Neurodevelopmental Perspective

• Autism: Harnessing Genetics & Developmental Neuroscience

• Approaches to Early Intervention

■ Autism

■ Schizophrenia

• Platforms for Understanding Risk & Resilience Pathways in Development

• Discussion

Agenda

2

• NIMH and the Neurodevelopmental Perspective

• Autism: Harnessing Genetics & Developmental Neuroscience

• Approaches to Early Intervention

■ Autism

■ Schizophrenia

• Platforms for Understanding Risk & Resilience Pathways in Development

• Discussion

Agenda

3

About the NIMH

• The National Institute of Mental Health (NIMH) is the lead federal agency for research on mental illnesses.

• NIMH supports more than 3,000 research grants and contracts at universities and other institutions across the country and overseas.

• NIMH intramural research programs support approximately 600 scientists working on the NIH campuses.

(Neuro)developmental Perspective

5

Early & Differential Onset

Roots in Neurodevelopment

Early insult alters trajectories

Early interventions improve outcomes

Psychiatric Disorders Onset During

Childhood and Adolescence

6 Casey et al. Biol Psychiatry, 2014

• NIMH and the Neurodevelopmental Perspective

• Autism: Harnessing Genetics & Developmental Neuroscience

• Approaches to Early Intervention

■ Autism

■ Schizophrenia

• Platforms for Understanding Risk & Resilience Pathways in Development

• Discussion

Agenda

7

Neurodevelopmental Pathway to Autism

8

• Birth

• 4 years

• Prenatal

• 18-24 months

Brain Development

Genetic and

Environmental Risk

Joseph Tart/EHP; Clouchoux, Brain Structure and Function, 2012; NIH

Early Treatment

Improves

Outcomes

Screening

Exome analysis of 35,584 samples identified 99 ASD-associated

genes

Genetic Risk for ASD

9 Satterstrom … Daly, preprint, 2018

GWAS analysis of over 18,000 ASD cases identifies 2-5 loci from common variants

Grove, Nature Genetics, 2019

KMT2E,

SRPK2

MACROD2LOC1027

23661,

PTBP2

C8orf74,

SOX7KIZ,

XRN2

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Genetic Risk for ASD

Likely Complexity

11

Towards Genome-Scale Neurobiology

Penetrant Risk

Loci

(KDM5b, NRXN1,

CNTNAP2, ARID1B,

dup15q, …)

CONVERGENCECONVERGENCE

human forebrain spheroids (hFS*)

CellularCellular MolecularMolecularAnatomic/

Structural

Anatomic/

StructuralPhysiologyPhysiology

• Composition

• Fate

• Migration

• Identity

• Maturity

• Regulatory

networks

• Dendritic spines

• Synaptic

connectivity

• Intrinsic properties

• Synaptic activity

• Network activity

sc-RNAseq / RNAseqimaging

slice recordings

Bottom

10% PGR

for ASD

Top 10%

PGR for ASD

Network

In Vivo Ephys

and Behavior

In Vivo Ephys

and Behavior

Adapted from Sergiu Pasca and John Hugenard12

13

• Birth

• 4 years

• Prenatal

• 18-24 months

Brain Development

Genetic and

Environmental Risk

Joseph Tart/EHP

Early Treatment

Improves Outcomes

Screening

From risk factors

to mechanisms

Early identification

and early

intervention

Improved therapeutic

approaches

throughout the lifespan

Research Strategy

Neurodevelopmental Pathway to Autism

• NIMH and the Neurodevelopmental Perspective

• Autism: Harnessing Genetics & Developmental Neuroscience

• Approaches to Early Intervention

■ Autism

■ Schizophrenia

• Platforms for Understanding Risk & Resilience Pathways in Development

• Discussion

Agenda

14

Early Trajectories Predict ASD

15

Hazlett, Nature, 2017

Brain Growth Predicts Autism Diagnosis

Children’s Early Visual Behavior Predicts Autism

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Constantino, Nature, 2017

Eye Gaze in Autism

Children’s Early Visual Behavior Predicts Autism

17

Constantino, Nature, 2017

Eye Gaze in Autism

Early Interventions Improve Outcomes

18 Rogers, JAACAP, 2019; Kasari, J Consult Clin Psychol, 2016

• NIMH and the Neurodevelopmental Perspective

• Autism: Harnessing Genetics & Developmental Neuroscience

• Approaches to Early Intervention

■ Autism

■ Schizophrenia

• Platforms for Understanding Risk & Resilience Pathways in Development

• Discussion

Agenda

19

The Problem

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TreatmentEarlier?

Early/Personalized Intervention

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• Recovery After an Initial Schizophrenia Episode (RAISE) initiative

Client

Medication/ Primary Care

Psychotherapy

Family Education and

Support

Supported Employment

and Education

Case Management

21

Kane, et al., Am. J. Psychiatry, 2016 22

Participants with shorter duration of untreated psychosis had greater

improvement in quality of life and psychopathology over 2 years

Early Intervention

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VT12

AK

Early Intervention Programs, 2008

August 2008 – 12 clinics

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DE

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RI

VT

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88 8

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AK

Early Intervention Programs, 2018

August 2018 – 265 clinics

1-4

HI

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The Problem

25

Etiology Plasticity Treatment

?• Improve outcomes

• Alter progression

• “Recovery”

What’s New: Getting Earlier

26

Genetics Risk Prediction

Parsing Heterogeneity

27Insel & Cuthbert, Science 2015

Patterns of Resting State Connectivity

Drysdale…Liston, Nature Medicine, 20172828

Clustering Patients Based on Connectivity

Drysdale…Liston, Nature Medicine, 20172929

Subtypes Differ in Responsivity to Prefrontal Cortex

Repetitive Transcranial Magnetic Stimulation

Drysdale…Liston, Nature Medicine, 20173030

• NIMH and the Neurodevelopmental Perspective

• Autism: Harnessing Genetics & Developmental Neuroscience

• Approaches to Early Intervention

■ Autism

■ Schizophrenia

• Platforms for Understanding Risk & Resilience Pathways in Development

• Discussion

Agenda

31

• Map the neural pathways that underlie human brain function

• Deciphering the brain’s complex wiring system

■ Mapping the connectomes in over 1,000 healthy adults

■ Optimizing MRI technology for imaging brain structure

Human Connectome Project (HCP)

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• Baby Connectome:

■ Ages 0-5 years; 500 participants; cross-sectional and longitudinal

• Development Connectome:

■ Ages 5-21 years; 1350 participants; cross-sectional and longitudinal

• Young Adult Connectome (initial HCP)

■ Ages 22-35; 1200 participants, twin pairs, siblings

• Aging Connectome:

■ Ages 36 – 100; 1200 participants

Lifespan Connectome

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Adolescent Brain Cognitive Development

(ABCD) Study

34

• Multisite, longitudinal study of children from ages 9-10 through early adulthood

• Examines how childhood experiences (e.g., sports, videogames, social media, unhealth sleep patterns, etc.) affect brain, social, emotional, and cognitive development and other outcomes

Adolescent Brain Cognitive Development

(ABCD) Study

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• Almost 12,000 youth ages 9 -10 enrolled to date

• Baseline data now available through NIMH Data Archive data tool

■ Data Exploration and Analysis Portal for online analyses

■ Data analysis, statistical models, and tools available online

HEALthy Brain and Child Development

(HBCD) Study

Large multi-site longitudinal study to examine brain, cognitive, behavioral, social, and emotional development beginning prenatally and extending through childhood (9-10).

• Oversample for prenatal opioid exposure

• Fall 2018: Expert Panels

• R34 Planning Grant Announcements – RFA-DA-19-029; RFA-DA-19-036

oPublished – December 21, 2018

oApplication deadline – March 25, 2019

oReview – July 2019

oEarliest start date – September 2019

• NIMH and the Neurodevelopmental Perspective

• Autism: Harnessing Genetics & Developmental Neuroscience

• Approaches to Early Intervention

■ Autism

■ Schizophrenia

• Platforms for Understanding Risk & Resilience Pathways in Development

• Discussion

Agenda

37

38

NIMH’s Mission

www.nimh.nih.gov

Research = Hope

Understanding ASD Risk: Genes + Environment

Gaugler, Nature Genetics, 2014

Searching for

Unaccounted Risks

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