Pat Levitt: Neurodevelopmental Disorder Heterogeneity, Brain Development and Plasticity Over the...

Brain Development, Neurodevelopmental Brain Development, Neurodevelopmental Disorder Heterogeneity, and PlasticityDisorder Heterogeneity, and Plasticity

Beit Issie Shapiro International ConferenceJuly 8, 2015

PAT LEVITT, PH.D. SIMMS/MANN CHAIR IN DEVELOPMENTAL NEUROGENETICS

CHILDREN’S HOSPITAL LOS ANGELESWM KECK PROVOST PROFESSOR OF NEUROGENETICS

UNIVERSITY OF SOUTHERN CALIFORNIA

SCIENTIFIC DIRECTOR, NATIONAL SCIENTIFIC COUNCIL FOR THE DEVELOPING CHILDSENIOR FELLOW, CENTER FOR THE DEVELOPING CHILD, HARVARD UNIVERSITY

No Financial Disclosures or Conflicts of Interest No Financial Disclosures or Conflicts of Interest to Declare for this Presentationto Declare for this Presentation

Positive Exposure

What Do These All Have in Common?What Do These All Have in Common?

Occupational TherapySpeech-Language

Physical Therapy

EducationBehavioral Counseling

Spiritual

Positive Psychology

Primary care

Social Communication

Zimmer Children’s Museum @ the Jewish FederationLos Angeles, August, 2013

• Brain Development - the early neurobiological blueprint and the essential role of experience over time in brain-building

• Origins of heterogeneity- individual differences are typical and complex

• The Biology of Change – we’re more ‘plastic’ than you think

Presentation

The Core Story of Development

#1 - Brains are built over time, from the bottom up (skill begets skill)

#2 - Genes and experiences together build brains

#3 - Cognitive, social and emotion development are inextricably intertwined (“SERVE & RETURN”)

#4 – Resilience/Plasticity is not an internal character strength, but rather is built through combined influence of genes and life experiences

#5 - For many functions, the brain’s capacity for change decreases over time (cost-effectiveness factor) - but not all functions are impacted equally

Serve and Return

‘‘Serve and Return’ is a Lifetime Activity that Serve and Return’ is a Lifetime Activity that Continues to Build Skills (more later)Continues to Build Skills (more later)

Common Misconceptions of Development

Children are………..

80% of brain development occurs by………

Bad stuff happens………you just have to be…….

Ready to learn is all about…….




Presentation

Expansion of the Cerebral Cortex – What Makes All of Us Human

Rakic, Nature Reviews Neurosci. 2009

Rakic, Nature Review Neuroscience, 2002 Clinical Neuroscience, 2002

Timing of How Different Brain Areas Develop is not Synchronous – And Selectively Vulnerable

attention EF hearing vision

It’s All Designed to Generate Neuronal Diversity

10 billion neurons – 3 trillion connections (synapses)

Prenatal Development = Circuit Blueprint

Preparing for the World - Sensory Wiring Develops By 3rd Trimester!!

Kostovic et al Neurosci Lett 90:107, 1988

28W NEWBORN 3 YRS

Neural Circuits are Wired in a Neural Circuits are Wired in a Bottom-Up Sequence Bottom-Up Sequence

environment

critical periodsgenes behavior

in utero adulthood

Substance exposureMaternal infectionMalnutritionStressAir PollutionPoverty

What’s Going On in the Brain During These What’s Going On in the Brain During These Periods of Development?Periods of Development?

Courchesne et al, Neuron 56, 2007

Dramatic Growth of Neuronal Architecture - Birth - 2 yrs

(700 synapses formed per second in the early years)

birth 6 years 14 years

Experience Shapes Brain Architecture – Overproduction Followed by Pruning Through Childhood

Jeff Lichtman Lab at Harvard

Hoftman and Lewis, Schiz Bull, 2011

80% of brain development occurs by………

Two Flavors of Synapses (+/-):Formation and Maturation is a LONG Process

700/second

+

-

1M

2M

3-6M

7-9M

>9M

Paus et al Brain Res Bull 54:255, 2001

Early Myelination: Creating Efficiency in Information Flow in the Brain

Through 5th decade

Precursor Myelinating Cells are Targets of Perinatal Complications

What is Occurring Developmentally To What is Occurring Developmentally To Bring Bring EachEach Function Online? Function Online?

Skill Begets Skill For Social, Emotional and Cognitive Functions(‘serve and return’)

(e.g. language)

Werker & Hensch Ann Rev Psychol. 2014

What Does Experience Do?What Does Experience Do?

Experience Promotes the Stabilization of Synapses that Experience Promotes the Stabilization of Synapses that Are Used, and Eliminates Those that Are Not Used – Are Used, and Eliminates Those that Are Not Used –

And It Controls the Genes (And It Controls the Genes (EpigeneticsEpigenetics) & Molecules ) & Molecules that Influence Critical Periods of Developmentthat Influence Critical Periods of Development

‘Critical Periods’ Define Typical Optimal Timing of Change

Werker & Hensch Ann Rev Psychol. 2014

50 days50 days 50 days: exposed to early

noise

Source: Chang & Merzenich (2003)

Extreme Early Experiences Can Dramatically Disrupt the Precision of Sensory Information Processing

16 days 50 days 50 days

•Computerized training (CogMed) for working memory• Reasoning and speed training - domain-specific• Aerobic exercise (high dose - 40-70 min daily)• Martial arts (inhibitory control, mindfulness)• Curricula (Tools of the Mind - planning, inhibitory control)

(reviewed in Diamond and Lee, Science 333, 2011)

The Ingredients of Brain Development The Ingredients of Brain Development Combine to Produce SkillsCombine to Produce Skills

Differences Exist in Timing, Skill Level and Differences Exist in Timing, Skill Level and Developmental TrajectoriesDevelopmental Trajectories


• Origins of heterogeneity- individual differences are typical, particularly with complex phenotypes


Presentation

Heterogeneity in Social Behavior

Sociability

Typical Population

Aloof, Introverted

Gregarious, Extroverted

Limited Sociability

Indiscriminate Sociability

Num

ber o

f Ind

ivid

uals

CATS DOGS

Heterogeneity in Learning Translates into a Range Across Later Social Behavior

Reeb-Sutherland et al., PLoS One, 2012

Initiating Joint Attention (12 mo)

46x

Heterogeneity Is Conserved

Knoll and Levitt, unpublished

Mechanisms of Social Behavioral Heterogeneity

Typical Variation

GenesDisorderGenes

What Else Contributes to Heterogeneity

Continuous Phenotype

All People

Num

ber o

f Ind

ivid

uals

Prevalence for 26 medical conditions in children with autism - AGRE

Phenotype % Phenotype % Phenotype %

Endocrine_problems_growth 2.0 Genital_problems 7.8 Gait_abnormalities 25.9

Kidney_urinary_problems 3.5 Ear_abnormalities_structural 8.8 Skin_abnormalities 30.7

Heart_problems 4.8 Abnormal_growth_pattern 10.6 Allergies 42.2

Cerebral_abnormalities 5.0 Respiratory_problems 11.3 Coordination_abnormalities 42.6

Bone_abnormalities 5.5 Movement_Abnormalities 13.8 Gastrointestinal_problems 43.8

Craniofacial_problems 5.5 Teeth_abnormalities 14.6 Sleep_disorder_symptoms 55.5

Hearing_problems 6.3 Vision_problems 15.1 Stereotypies 77.3

Joint_abnormalities 6.7 Seizures 15.4 Sensory_abnormalities 80.6

Eye_abnormalities_structural 7.5 Asthma 16.3

✓

✓

Shared Biological Load Contributes to Clinical Heterogeneity(not parents’ imagination)

e.g. MET

Biological features can identify unique ASD subgroups

Campbell et al., 2006, 2007, 2009

53%

47%

ASD ASD+GID

39%

61%C allele

G allele

MET promoter variant Expression

•Significantly higher T-score on SRS compared to ASD-only

•4.5-fold increase in a lack of expressive language

Autism Res. 5 (2012)

Biomarker Correlate of Subgroup SeverityElevated Marker of Oxidative Stress in Autism-GIDs

Gorrindo et al, PLoS One, 2013



• The Biology of Change – we’re more ‘plastic’ than we had thought

Presentation

Implications of the science.....

Biological Pathways Provide Opportunities to Determine Disorder Pathogenesis and Plasticity

E I

pre-CP critical period (CP) adult

E I

modulating E-I balance

removing structural “brakes”

HDACsLynx1 / 5HTT

PNN /Otx2 NgR/PirB

(Morishita & Hensch, Curr Op Neurobiol 2008)(Bavelier et al, J Neurosci 2010)

E IGAD65

GABAAa1BDNFOtx2DPSA

Molecular Constraints of Brain Plasticity

strengthenGABA

(diazepam)weaken GABA(GAD65 KO)

(Hensch, Nature Reviews Neurosci 2005)

Birth 20 40 60 (days)

Critical period timing is itself plastic

Adult Plasticity – Molecular Targets Make it Possible

• Brain Development - brain-building is complex and full of opportunities

• Origins of heterogeneity- individual variation creates opportunities for building unique strengths

• The Biology of Change – plasticity is the hallmark of opportunity for change (for everyone)

Yes, It’s the Brain

Pixar/Disney-Pixar, via Associated Press

Thank you!

[email protected]/LevittLab

Pat Levitt: Neurodevelopmental Disorder Heterogeneity, Brain Development and Plasticity Over the...

Services

Transcript of Pat Levitt: Neurodevelopmental Disorder Heterogeneity, Brain Development and Plasticity Over the...