In his lecture, Prof. Pat Levitt describes the great heterogeneity of the brain, which makes people different from each other and is a significant challenge to treating people with disabilities.
Pat Levitt: Neurodevelopmental Disorder Heterogeneity, Brain Development and Plasticity Over the Lifespan
1.
2. Brain Development, NeurodevelopmentalBrain Development, Neurodevelopmental
Disorder Heterogeneity, and PlasticityDisorder Heterogeneity, and Plasticity
Beit Issie Shapiro International Conference
July 8, 2015
PAT LEVITT, PH.D.
SIMMS/MANN CHAIR IN DEVELOPMENTAL NEUROGENETICS
CHILDREN’S HOSPITAL LOS ANGELES
WM KECK PROVOST PROFESSOR OF NEUROGENETICS
UNIVERSITY OF SOUTHERN CALIFORNIA
SCIENTIFIC DIRECTOR, NATIONAL SCIENTIFIC COUNCIL FOR THE DEVELOPING CHILD
SENIOR FELLOW, CENTER FOR THE DEVELOPING CHILD, HARVARD UNIVERSITY
3. No Financial Disclosures or Conflicts of InterestNo Financial Disclosures or Conflicts of Interest
to Declare for this Presentationto Declare for this Presentation
4. Positive Exposure
What Do These All Have in Common?What Do These All Have in Common?
Occupational Therapy
Speech-Language
Physical Therapy
Education
Behavioral Counseling
Spiritual
Positive Psychology
Primary care
Social Communication
6. • 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
7. 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
9. ‘‘Serve and Return’ is a Lifetime Activity thatServe and Return’ is a Lifetime Activity that
Continues to Build Skills (more later)Continues to Build Skills (more later)
10. 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…….
11. • 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
12. Expansion of the Cerebral Cortex –
What Makes All of Us Human
Rakic, Nature Reviews Neurosci. 2009
13. 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
14. It’s All Designed to Generate Neuronal Diversity
10 billion neurons – 3 trillion connections (synapses)
16. Preparing for the World - Sensory Wiring Develops By
3rd
Trimester!!
Kostovic et al Neurosci Lett 90:107, 1988
28W NEWBORN 3 YRS
17. Neural Circuits are Wired in aNeural Circuits are Wired in a
Bottom-Up SequenceBottom-Up Sequence
environment
critical periodsgenes behavior
in utero adulthood
Substance exposure
Maternal infection
Malnutrition
Stress
Air Pollution
Poverty
18. What’s Going On in the Brain During TheseWhat’s Going On in the Brain During These
Periods of Development?Periods of Development?
19. Courchesne et al, Neuron 56, 2007
Dramatic Growth of Neuronal Architecture - Birth - 2 yrs
(700 synapses formed per second in the early years)
20. birth 6 years 14 years
Experience Shapes Brain Architecture – Overproduction
Followed by Pruning Through Childhood
22. 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
+
-
23. 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
24. What is Occurring Developmentally ToWhat is Occurring Developmentally To
BringBring EachEach Function Online?Function Online?
25. Skill Begets Skill For Social, Emotional and Cognitive Functions
(‘serve and return’)
(e.g. language)
Werker & Hensch Ann Rev Psychol. 2014
28. Experience Promotes the Stabilization of Synapses thatExperience 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
30. 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
31. •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)
32. The Ingredients of Brain DevelopmentThe Ingredients of Brain Development
Combine to Produce SkillsCombine to Produce Skills
Differences Exist in Timing, Skill Level andDifferences Exist in Timing, Skill Level and
Developmental TrajectoriesDevelopmental Trajectories
33. • Brain Development - the early neurobiological blueprint and the
essential role of experience over time in brain-building
• Origins of heterogeneity- individual differences are typical,
particularly with complex phenotypes
• The Biology of Change – we’re more ‘plastic’ than you think
Presentation
34. Heterogeneity in Social Behavior
Sociability
Typical Population
Aloof,
Introverted
Gregarious,
Extroverted
Limited
Sociability
Indiscriminate
Sociability
NumberofIndividuals
CATS DOGS
35. Heterogeneity in Learning Translates into a Range Across Later
Social Behavior
Reeb-Sutherland et al., PLoS One, 2012
Initiating Joint Attention (12 mo)
46x
41. 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
42.
43.
44. •Significantly higher T-score on SRS compared to ASD-only
•4.5-fold increase in a lack of expressive language
Autism Res. 5 (2012)
45. Biomarker Correlate of Subgroup Severity
Elevated Marker of Oxidative Stress in Autism-GIDs
Gorrindo et al, PLoS One, 2013
46. • 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 we had thought
Presentation
49. E I
pre-CP critical period (CP) adult
E I
modulating E-I balance
removing structural “brakes”
HDACs
Lynx1 / 5HTT
PNN /Otx2
NgR/PirB
(Morishita & Hensch, Curr Op Neurobiol 2008)
(Bavelier et al, J Neurosci 2010)
E I
GAD65
GABAAa1
BDNF
Otx2
DPSA
Molecular Constraints of Brain Plasticity
52. • 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
The implications of the science of early child development are far-reaching, so I’ll touch on just a few. These implications are drawn not from single studies, but from decades of research that have led to widely accepted, broad principles that we can apply to policy and practice.
The cerebral cortex is the thin layer of neural tissue that encases the brain, and which is responsible for intelligent behavior, cognition, and perception. Although the cortex In mammals, the cortex consists of six major layers. The cells in these layers are synaptically connected with each other and with other subcortical structures in a way that adds significant complexity to the simple six layered description commonly used to introduce the structure. Each of these layers consists of a highly diverse group of neurons and glia. At the most basic level, neurons can be divided into two general class: excitatory and inhibitory. It has been estimated that excitatory neurons account for 70-80% of neurons in the cortex, while inhibitory interneurons make up the remainder.
The issues we are talking about are not just about children, but about broader societal issues.
Also, this is not about “other people’s children” -- what happens to other people’s children affects all of society.
As you can see, during childhood and adolescence these neural connections are reduced through experience (which is necessary; even if our entire hereditary makeup were devoted . . . ).
This helps to ensure that the neural connections that are most useful to the developing mind are retained. “Use it or lose it.”
But this is a double-edged sword. On the one hand, positive, healthy, growth-promoting experiences help to develop brains that are efficient and sophisticated (language, sight, movement in gravity). But for some young children, their developing brains are incorporating experiences that are abusive or profoundly neglectful, and these alter the brain’s processing sometimes for life (Seth Pollock’s work on sensitivity to anger expressions). These influences begin early, even prenatally.
As you can see, during childhood and adolescence these neural connections are reduced through experience (which is necessary; even if our entire hereditary makeup were devoted . . . ).
This helps to ensure that the neural connections that are most useful to the developing mind are retained. “Use it or lose it.”
But this is a double-edged sword. On the one hand, positive, healthy, growth-promoting experiences help to develop brains that are efficient and sophisticated (language, sight, movement in gravity). But for some young children, their developing brains are incorporating experiences that are abusive or profoundly neglectful, and these alter the brain’s processing sometimes for life (Seth Pollock’s work on sensitivity to anger expressions). These influences begin early, even prenatally.
We know that early experience influences brain architecture and function for a lifetime. Our ability to detect different frequency sounds, which is essential for language development, occurs gradually over time. In the rat, at postnatal day 16, mostly higher frequency sounds are detected in the neocortex, the region of the brain that processes complex information. By postnatal day 50, which is like a teenage rat—in the middle, with normal hearing experience—all frequencies are represented and the region of the cortex is finely tuned. Exposing the animals for a few weeks of mostly one frequency tone (right panel) results in an auditory map that never matures, and in fact, the animals have the high frequency over-represented. They will be unable to decipher lower frequency sounds for the rest of their life, because the early experience of hearing that one tone was sufficient to tune the architecture and connections forever.
The implications of the science of early child development are far-reaching, so I’ll touch on just a few. These implications are drawn not from single studies, but from decades of research that have led to widely accepted, broad principles that we can apply to policy and practice.
Limitations of this slide: Doesn’t clearly acknowledge the impact of differences in anxiety, cognition, personality measures (OCEAN: openness, conscientiousness, extraversion, agreeableness, neuroticism), attachment, neglect, etc….. Perhaps there’s a way to transition to the topic of using factor analysis to examine the relations between complex constructs on a population level.
----- Meeting Notes (1/3/14 13:23) -----
- highly social, frequent and complex
Positivity – Composite score of smiling, laughter, latency to smile (reverse-scored), and positive vocalizations across puppets and peek-a-boo tasks
----- Meeting Notes (1/3/14 13:23) -----
- heterogenity apparent from young ages
Partner strain unfamiliar C57Bl/6J; 4.3 fold variation in social approach across the BXDs.
While the genes that cause variation in typical social behavior may or may not be causal for neurodevelopmental disorders, we hypothesize that the developmental and neural circuit foundation that they establish will influence an individual’s response to disorder-associated environmental and genetic perturbations.
----- Meeting Notes (1/3/14 13:23) -----
Despite the high heritability of many aspects of social behvaior the genetic and neural circuit mechanims...
Limitations of this slide: Doesn’t clearly acknowledge the impact of differences in anxiety, cognition, personality measures (OCEAN: openness, conscientiousness, extraversion, agreeableness, neuroticism), attachment, neglect, etc….. Perhaps there’s a way to transition to the topic of using factor analysis to examine the relations between complex constructs on a population level.
----- Meeting Notes (1/3/14 13:23) -----
- highly social, frequent and complex
Range 2% (endocrine problems) to 81% (sensory abnormalities)
The implications of the science of early child development are far-reaching, so I’ll touch on just a few. These implications are drawn not from single studies, but from decades of research that have led to widely accepted, broad principles that we can apply to policy and practice.
From left: Anger, Disgust, Joy, Fear and Sadness.
The implications of the science of early child development are far-reaching, so I’ll touch on just a few. These implications are drawn not from single studies, but from decades of research that have led to widely accepted, broad principles that we can apply to policy and practice.
