Life is a journey not a destination

1
Life is a journey not a destination
-fortune cookie from the Peking Duck, Bethesda,
MD 2002
2
Sexual Dimorphism in the Developing Brain
Jay Giedd, MD NAS December, 2005
3
Sex Differences in Child Adolescent Psychiatry

• Nearly all neuropsychiatric disorder of childhood
  onset have different prevalences, ages of onset,
  and symptomatology between boys and girls.
• Might sexually distinct patterns of normal brain
  development may interact with other environmental
  or genetic factors to account for some of these
  clinical differences?

4
(No Transcript)
5
Initial comments
6
Short talk, huh?
7
Oh, you mean they found one?
8
Isnt that a contradiction of terms?
9
What is your next talk on the Loch Ness
Monster?
10
(No Transcript)
11
How the Brain Looks to MRI
12
The Neuron
Dendrites
Axon
Cell body (the cells life support center)
Terminal branches of axon
Neuronal Impulse
Myelin sheath
Donald Bliss, MAPB, Medical Illustration
13
Data Base

• Longitudinal Assessment ( 2 year intervals)
• Imaging
• Genetics
• Neuropsychological / Clinical
• 4000 scans from 2000 subjects
• ½ typically-developing

14
White Matter
White Matter
Male (152 scans from 90 subjects) Female (91
scans from 55 subjects) 95 Confidence Intervals
Age in years
15
4D Growth Maps (Thompson et al., 2000)
16
White Matter vs Gray Matter

• Gray Matter
• Inverted U
• Regionally specific

• White Matter
• Linear increase
• Not different by region

17
Brain Development in Healthy Children
Adolescents Longitudinal and Cross-Sectional
Data (243 Scans from 145 Subjects)
Frontal Gray Matter
18
Neuronal Branching
Dendrites Synapses
Diamond, Hopson, Scheibel, 1998
BIRTH
3 MONTHS OLD
2 YEARS
19
Images by Diane Murphy, PhD, National Institutes
of Health
20
Gray Matter Thickness Ages 4 to 22 years
21
Questions related to changing cortical thickness

• What are the social/judicial/parenting/ personal
  implications of late DLPFC maturation?
• What influences the build up stage?
• Parenting / Medications / Diet / Video games /
  Other
• Does the use it or lose it principle guide the
  adolescent pruning?

• Overproduction/Selective Elimination as a
  construct to understand developmental pathology?

22
The Unique Cerebellum! (among our gross anatomic
measures)

• Least heritable
• Most sexually dimorphic (male gtfemale, surviving
  TCV covariate)
• Latest to reach adult volume

Cerebellar Atlas Schmalmann, Doyon, Toga,
Petricles, Evans (2000)
23
Summary

• Overwhelming more alike than different
• Developmental trajectories more different than
  final destination
• Male brain morphometry more variable
• Effects of environment, sex chromosomes, hormones
  being elucidated
• Differences are between groups does NOT imply
  constraints for individual boys or girls

24
Influences on Brain Development

• Environment/Genetics ? Twin studies
• Sex
• XXY (Klinefelters Syndrome)
• Congenital Adrenal Hyperplasia
• Specific Genes
• Psychopathology
• ADHD
• Bipolar
• Childhood Onset Schizophrenia
• Autism

25
XXY (Klinefelters Syndrome)

• Physical
• Tall
• Sparse body hair
• Small testes
• Infertility
• Psychological
• Speech/Language
• Social
• Executive Dysfunction
• Motor control
• Visuo-spatial

• Most common sex chromosome aneuploidy
• 1/600 live male births
• Nondisjunction during meiosis

26
T- maps of cortical thinning at each surface
vertex in 42 XXY subjects compared to 87 controls

• Key areas
• Temporal lobes, bilaterally
• Frontal, left inferior
• Motor strip, particularly on the left
• Parietal lobe sparing bilaterally

27
Sex Chromosome Dosage Effects

• XO, XYY, XXY, XXYY, XXX, XXXY, XXXXY
• Clinical severity worsens with increasing number
• X gene dosage effects should be related to the
  15 of the X chromosome genes that are not
  inactivated.

28
X-linked Androgen Receptor Polymorphism

• Variable number of CAG repeats on Androgen
  Receptor gene (exon 1)
• Length of CAG repeat inversely correlated to its
  receptor function
• longer less transcriptional activity
• Related to variance in sexual dimorphism?
• Preferential inactivation of short form?

29
Testosterone Replacement Therapy

• What is the effect of postnatal testosterone on
  brain morphometry / behavior?
• 6/18 XXY subjects over age 12 had not had TRT
• Pre and post TRT scanning

30
Influences on Brain Development

• Environment/Genetics ? Twin studies
• Sex
• XXY (Klinefelters Syndrome)
• Congenital Adrenal Hyperplasia
• Specific Genes
• Psychopathology
• ADHD
• Bipolar
• Childhood Onset Schizophrenia
• Autism

31
Congenital Adrenal Hyperplasia

• 21 Hydroxylase deficiency leads to high levels
  of androgens in utero
• Male-typical behavior?
• Smaller amygdala in both boys and girls with CAH

32
Other cohorts with anomalous hormone profiles

• Familial Male Precocious Puberty
• Cushings Syndrome
• Androgen Insensitivity Syndrome
• Hormonal Assays

33
Gray Matter Thickness Changes in Childhood Onset
Schizophrenia
34
Part 2 - Influences on Brain Development

• Environment/Genetics ? Twin studies
• Sex
• XXY (Klinefelters Syndrome)
• Congenital Adrenal Hyperplasia
• Specific Genes
• Psychopathology
• ADHD
• Bipolar
• Childhood Onset Schizophrenia
• Autism

35
Part 2 - Influences on Brain Development

• Environment/Genetics ? Twin studies
• Sex
• XXY (Klinefelters Syndrome)
• Congenital Adrenal Hyperplasia
• Specific Genes
• Psychopathology
• ADHD
• Bipolar
• Childhood Onset Schizophrenia
• Autism

36
Influences on Brain Development

• Environment/Genetics ? Twin studies
• Sex
• XXY (Klinefelters Syndrome)
• Congenital Adrenal Hyperplasia
• Specific Genes
• Psychopathology
• ADHD
• Bipolar
• Childhood Onset Schizophrenia
• Autism

37
Does Size Matter?

• NO
• similar abilities within a broad range of sizes

• YES
• computational science
• evolutionary perspective (interspecies
  differences predictive behavioral complexity)

38
Past PrologueForm Function
39
Does Size Matter?

• However
• Modest positive correlation between IQ and total
  cerebral volume
• Possible relationship between hippocampal size
  and memory recall
• From a computational science perspective it seems
  likely that the number of neuronal connections in
  a structure reflects its information processing
  capacity
• From an evolutionary perspective interspecies
  differences in cerebral morphometry are
  predictive of behavioral complexity

40
Why not better brain/behavior correlations?

• The intricacy of various neurochemical systems
  and the diversity of afferent and efferent
  connections to the many distinct nuclei of most
  brain structures make straightforward
  relationships between volumes of a single
  structure and performance on a particular
  cognitive task uncommon.
• Supports the concept of distributed neural
  systems whereby functional attributes are not
  thought to lie so much within a single structure
  as within a network of structures.

41
Does Size Matter?

• However
• Modest positive correlation between IQ and total
  cerebral volume
• Possible relationship between hippocampal size
  and memory recall
• From a computational science perspective it seems
  likely that the number of neuronal connections in
  a structure reflects its information processing
  capacity
• From an evolutionary perspective interspecies
  differences in cerebral morphometry are
  predictive of behavioral complexity

42
Does Size Matter?

• However
• Modest positive correlation between IQ and total
  cerebral volume
• Possible relationship between hippocampal size
  and memory recall
• From a computational science perspective it seems
  likely that the number of neuronal connections in
  a structure reflects its information processing
  capacity
• From an evolutionary perspective interspecies
  differences in cerebral morphometry are
  predictive of behavioral complexity