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Autism:

A Brain Disorder?
Or a Disorder that
Affects the Brain?

Martha Herbert, MD, PhD


Harvard Medical School
TRANSCEND Research Program
TGRI – Treatment Guided Research Initiative - ASA
Pediatric Neurology and Center for Morphometric Analysis
Martinos Center for Biomedical Imaging
Massachusetts General Hospital
www.marthaherbert.com
Autism: A Behaviorally Defined Syndrome

DSM-IV Criteria for Autistic Disorder (299.0)


1. Impaired social interaction
2. Delayed and disordered communication
3. Markedly restricted repertoire of activities and interests
Secondary Features of Autism
Seizures (~30%+), cognitive deficits, sensorimotor abnormalities, savant
skills, immune impairments, GI distress(50-75%), food allergies (~50+%)
Autism: A Behaviorally Defined Syndrome
Biology is not part of the definition
(and neither is prognosis)

DSM-IV Criteria for Autistic Disorder (299.0)


1. Impaired social interaction
2. Delayed and disordered communication
3. Markedly restricted repertoire of activities and interests
Secondary Features of Autism
Seizures (~30%+), cognitive deficits, sensorimotor abnormalities, savant
skills, immune impairments, GI distress(50-75%), food allergies (~50+%)

No biological markers exist to identify autism at this time


Autism is presumably Heterogeneous biologically
But autism is biological
Static model of autism

Genes Inevitable

Prenatal Fixed

Brain Hardwired

Unchangeable
Hopeless
Modular, Static
Autism Model

Gene

Brain Brain A Brain B Brain C


module

Behavior Communi- Social


Behaviors
cation Interaction

AUTISM
Anomalies that
violate the static model

1. More than genes


2. More than prenatal
3. More than brain
4. Reasons for hope
Gene Environment
Inclusive Systems
Autism Model Epigenetics

PERVASIVELY DYSREGULATED
BIOLOGICAL MECHANISMS

Molecular
and
Anatomy
Sensory
Signaling

Sleep
Sensorimotor
ii. Epilepsy
Somatic

Communi-
Social Behaviors
cation
Interaction
i.
After much gene hunting, genetics is
not explaining autism

• Genetic studies have not identified genes of


strong effect
• Genome scans have not replicated each other
• Novel genetic mechanisms suggest
environmental role
– Copy Number Variants (CNV) may be de novo, not
inherited
– Epigenetics—regulation of gene expression (genes
themselves don’t change)
• Can be passed through several generations
WEAK RESULTS FROM SEVEN GENOME SCANS:
Low levels of significance of most genes
6 Highly significant
MLS
score

5
Significant
IMGSAC B

4
IMGSAC B

3 Suggestive

1 “Critical level”

0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 X23 24
Chromosome
The environment is a VARIABLE, not
a CONSTANT

• To focus exclusively on genes, we have to


assume no meaningful changes in the
environment
• This is implausible.
Trends in U.S. Chemical Production, 1920–1980

• Pesticide use more


than doubled between
1964 and 1982 (USDA)
• 85,000 chemicals in
the Federal inventory
• 2,000-3,000 new
chemicals introduced
each year
Body Burden — The Pollution in Newborns
A benchmark investigation of industrial chemicals, pollutants
and pesticides in umbilical cord blood
Environmental Working Group, July 14, 2005
10 newborns, $10,000/baby for study

Chemicals and pollutants detected in


Of the 287 chemicals
human umbilical cord blood
Mercury (Hg) - tested for 1, found 1 detected in umbilical
Polyaromatic hydrocarbons (PAHs) - tested for 18, found 9 cord blood:
Polybrominated dibenzodioxins and furans (PBDD/F)
- tested for 12, found 7
Perfluorinated chemicals (PFCs) - tested for 12, found 9 • 180 cause cancer in
Polychlorinated dibenzodioxins and furans (PBCD/F)
- tested for 17, found 11
humans or animals
Organochlorine pesticides (OCs) - tested for 28, found 21
Polybrominated diphenyl ethers (PBDEs) - tested for • 217 are toxic to the
46, found 32
Polychlorinated Naphthalenes (PCNs) - tested for 70,
brain and nervous
found 50
Polychlorinated biphenyls (PCBs) - tested for 209,
system
found 147
• 208 cause birth
defects or abnormal
development in
animal tests

http://www.ewg.org/reports/bodyburden2
Status of Developmental Toxicity Testing
for the 2,863 Chemicals
Produced Above 1 million pounds/year
Some Data
On Developmental 0.4% 20-30 Tested for
Toxicity Neurodevelopmental
Toxicity
According to EPA
21.4% Guidelines
No Data
On Developmental This testing is
Toxicity NOT REQUIRED.
78.2%
To test these 2,863
chemicals in
combinations of 3
would require
85 BILLION tests.
In Harm’s Way, www.preventingharm.org
Texas autism rates, Potential association
by school districts between autism rates,
environmental mercury
other toxins in Texas
Palmer, et al., Health and Place, 12 (2006) 203–209

1990-1993 1998-2000
On average, for each 1000 lb of
Autism rates environmentally released
mercury, there was a 43%
increase in the rate of special
education services and a 61%
increase in the rate of autism.
Palmer et al. Health & Place 12 (2006) 203–209

All Reporting Facilities, All Chemicals TRI-(1987-2002)


Map shows 3,683 of 48,205 facilities reporting nationwide

Chemicals-TRI Total toxicity


(Toxic Release Inventory)
Maternal Residence Near
Agricultural Pesticide Applications and
Autism Spectrum Disorders
among Children in the
California Central Valley
Eric M. Roberts et al, Env Hlth Perspectives 2007

Risk of exposed mother having child develop


autism increased with the poundage of
organochlorine applied and decreased with
distance from field sites.
(Odds ratio 6.1)
• cell cycle
• cell division
• cell signaling
Environmentally responsive •

cell structure
DNA repair

genes •

gene expression
homeostasis
high frequency, low penetrance modulation • metabolism
• immune and inflammatory response
of vulnerability • hormone metabolism
http://www.niehs.nih.gov/envgenom/egp6.htm • nutrition
• oxidative metabolism and stress
• membrane pumps and/or drug resistance
• signal transduction

AUTISM AND ENVIRONMENTAL


GENOMICS
Herbert MR, Russo JP, Yang S, Roohi J, Blaxill M, Kahler SG,
McCoy L, Ziegler DA, Hatchwell E

Neurotoxicology, 2006

Brain effects may be downstream


of genetic vulnerabilities or gene-
environment interactions that
affect other organs
or the whole system
Brain and Body show
Chronic, Ongoing Medical Illness

Much is not specific to autism


Overlap with other conditions is common
A systems challenge: •Dementieva, Y.A. (2005)
Much documentation of •Deutsch, C. K. (2003)
•Courchesne, E. (2003)
large brains in autism •Sparks, Friedman (2002)
measures: •Gillberg, C. (2002)
head circumference
brain weight
•Alyward, E. H. (2002)
brain volume •Courchesne, E. (2001)
•Miles, J. H. (2001)
•Fidler, D. J. (2000)
•Fombonne, E. (1999)
• About 20% of young autistic heads •Ghaziuddin, M. (1999)
are “macrocephalic” (>97th %ile) •Bailey, A. (1999)
•Lainhart, J. E. (1997)
• Most are above average in volume •Rapin, I. (1996)
• This is an atypical brain size •Davidovitch, M. (1996)
•Woodhouse, W. (1996)
distribution.
•Piven, J. (1996)
• It has no precedent in the literature. •Piven, J. (1995)
Herbert, The Neuroscientist, October 2005 •Bailey, A. (1993)
Redcay & Courchesne, 2005 •Bauman & Kemper (1985)
What’s making autistic brains
bigger?

Abnormal brain growth

Disproportionate
increase of white matter
(e.g. frontal lobe)

Herbert M. 2005
2.5

Autism-Language 2
Effect Sizes

Impairment Autism
1.5
Similarities: SLI

1
Effect Sizes
as high as 2 0.5

0
Total Brain Cerebral Total Frontal Parietal Temporal Occipital
Volume White Radiate Prefrontal Lobe Lobe Lobe Lobe
Matter WM

MORPHOMETRY FINDINGS Autism SLI


Total Brain Volume Increase 6.4% 3.7%*
Cerebral White Matter Increase 14.8%* 11.9%*
White matter volume as % of Total Brain Volume # 30.3% 30.5%
% of the Increase in Total Brain Volume
66% 89%
that is due to Increased White Matter Volume #
Radiate White Matter Increase
Total 24.4%* 14.8%*
Prefrontal 36.1%* 25.7%*
Frontal 27.3%* 15.9%*
Parietal 19.7%* 3.3%
Temporal 24.9%* 20.6%*
Occipital 22.8%* 21.8%*
Aggregate Rightward Cortical Asymmetries ## 21% Increase* 15% increase*
Major overlaps between autism and
specific language impairment
• Anatomy
– Large brains
– Increase in radiate white matter
– Asymmetry shifts
• (increased rightward cortical in higher order association areas)
• Function
– Abnormal sensory processing
• Auditory; rapid temporal processing
• Physiology
– Question of immune system contribution

• Research shows these disorders are similar


• Clinical measures for these similarities are not available
TIMING OF POSTNATAL ATYPICAL BRAIN GROWTH:
EARLY RAPID GROWTH

Dementieva 2005

Courchesne 2003

Tapering off after the first


few years

1.2
Volume Ratio

1.18 1.15 1.13


Courchesne
1
Courchesne Autism - Autism -
Nosology BU 0.82

0.8
2-3 yo 7-11 yo 7-13 yo 12-16 yo

Redcay and Courchesne 2004


Brain Connectivity
White Matter: Brain
Connections

Catani et al (2003). Brain


Reliable differences in functional connectivity:
Autism group has lower functional connectivity
but same rank order
• “Functional connectivity” is a
measure of how well brain
synchronization and coordination
is working.
• Reliably lower functional
connectivities (degree of
synchronization) in autism group.
• This is a widespread phenomenon
with local exacerbations.

Marcel Just
Multispectral MRI Imaging
Inflammation and Oxidative Stress in Autism:
chronic, ongoing postnatal medical problems,
not confined to brain
Neuroglial activation and Oxidative stress in brain tissues
neuroinflammation in the brain of from autistic patients Increased
patients with autism concentration of isoprostanes
Vargas et al, 2005, Annals of Neurology
Vargas et al, 2005, Annals of Neurology

A B
• These changes were found
at similar intensities in
brain aged 5-44 years
• Greater intensity of
inflammation in a 3-year
C D old’s brain
Pardo: Astrogliosis in Radiate White Matter

Astrogliosis Microgliosis

GFAP HLA-Dr

Herbert:
Radiate White
Matter Enlargement

Pardo
GI, Immune and Metabolic problems
• 46-96% of autistic children have GI disease
• constipation, diarrhea, inflammatory bowel disease, abnormal
intestinal organisms
• 30-70% have immune abnormalities
• Allergy, recurrent infections, eczema, anti-self antibodies
• Many have methylation and/or mitochondrial problems

Example: Ileo-colonic lymphonodular hyperplasia Lymphocytic


Mild Moderate Severe infiltration
Immune signs and
symptoms in autism

Eczema

Allergic Facies Onychomycosis


Protein-calorie
malnutrition due to
malabsorption:

“Intrinsic static
comorbidity” or treatable
medical condition?
Note distended abdomen,
skinny arms and legs
This will chronically
• Deplete nutrients
• Circulate substances to
body and brain
These can worsen brain and
body metabolic shortfalls
until treated

Permission Granted to use by mother – copy on file


Pain-based behavior:
pressure on abdomen

Krigsman, Thoughtful House, Tx


Multi-system from the start?
Kanner 1943 on body symptoms
Case 1: “Eating has always been a problem …..” for him. He has never shown a normal
appetite.”
Case 2: “…large and ragged tonsils.”
Case 3: diarrhea and fever following smallpox vaccination …. healthy except for large
tonsils and adenoids.
Case 4: vomited a great deal during his first year… feeding formulas were changed
frequently … tonsils were removed…
Case 5: nursed very poorly … quit taking any kind of nourishment at three months… tube-
fed five times daily up to one year of age…At camp she slid into avitaminosis and
malnutrition but offered almost no verbal complaints.”
Case 7: vomited all food from birth through the third month….
Case 8: feeding formula caused …concern. … colds, bronchitis, streptococcus infection,
impetigo…
Case 9: none of the usual children’s diseases.” [? Overactive immune system?]
Case 10: frequent hospitalizations because the feeding problem … repeated colds and
otitis media
Case 11: was given anterior pituitary and thyroid preparations for 18 months
Kanner’s original paper, discussed in Jepson 2007
Beyond the Brain
The Autism Triad: Brain-Gut-Immune Axis

Brain/Nervous GUT BRAIN: Vagus afferents; Gut neuropeptides


System BRAIN GUT: Endorphins; Neuropeptides

IMMUNE BRAIN: Cytokines; microglia activation


BRAIN IMMUNE: Endorphins; Neuropeptides;
Cortisol

IMMUNE GUT: Cytokines; GALT


Immune GUT IMMUNE: Gut neuropeptides; microbial
Gut
System products

(Steve Kahler)
The “Blood-Brain Barrier” is
not an absolute barrier
Regression, Fluctuation and Improvement:
Beyond “static encephalopathy”

• Variable severity with transient striking improvements and recovery of


function in some cases
– Transient improvement w fever (Zimmerman A Pediatrics in press)
– Spikes in function in stress or emotional situations
– Transient improvement on antibiotics (Sandler, Finegold, Bolte, JCN 2000)
– Improvement on allergy medications
– Variability in function related to food, allergen and toxic exposures

• Treatment-responsiveness
– Stable improvement can follow treatment
– Published reports of loss of diagnosis (Fein D –Sutera, Kelley JADD ’06,’07)
– Recovery documentation studies in process

Neurobiological Implications:
NEUROMODULATORS, not just wiring
MIGHT AUTISM HAVE A
COMPONENT OF TREATABLE
ENCEPHALOPATHY?
• Would correction of metabolic, immunological or
biochemical contributors to an increased
excitation/inhibition ratio improve level of
functioning?
• Clinical trials are underway and more are
needed.
Postnatal regression to autism

Is this the unfolding of a genetic program


OR
Accumulation of environmentally-related
compromises that reach a tipping point
and cause a systems parameter change
into what we call autism?

What research program would help decide this?


Polymorphisms in the Methionine Cycle Pathway
Transcobalamin II (TCII 776 66C→G)

TCII 776 GG Frequency Odds Ratio 95% C.I.


Control Individuals (203): 16.0%
Autistic Children (360): 25.8% 1.8 1.02,2.82*

Polymorphisms Affecting Methylation and Increased Oxidative Stress


Catechol-O-Methyltransferase (COMT 1947A→G)
COMT 1947GG:
(low activity variant) Frequency Odds Ratio 95% C.I.

Control Individuals (205): 16.3%


Autistic Children (360): 26% 2.34 1.06,2.85*

Combined TCII GG plus COMT GG in the same individual

TCII GG/COMT GG Frequency Odds Ratio 95% C.I.


Control Individuals (203): 2.5%
Autistic Children (360): 9.7% 7.0 2.32,21.2*
James, AM J Med Genetics, 2006
Proportion of Autistic Children within Normal Range
Before and After Supplementation

Folinic+Betaine
Metabolite Normal Range a Baseline Folinic+Betaine +methylB12
Methionine (µmol/L) > 24 1/8 5/8 7/8
SAM (nmol/L) > 80 2/8 8/8 8/8
SAH (nmol/L) < 23 2/8 7/8 7/8
SAM/SAH >4 1/8 7/8 7/8
Adenosine (µmol/L) < 0.3 4/8 8/8 8/8
Homocysteine (µmol/L) >5.5 3/8 8/8 8/8
Cysteine (µmol/L) >180 0/8 2/8 7/8
GSH (µmol/L) >5.4 0/8 2/8 7/8
GSSG (µmol/L) < 0.33 0/8 2/8 8/8
GSH/GSSG > 16 0/8 3/8 8/8
______________________________________________________________________
______
a Range estimated to include 90% of control children
James 2004
Before and After Treatment

IQ “60”
IQ 150
The emergence of a
new autism model

Older model Newer model

• Genetically determined • Environmentally triggered


• Genetically influenced
• Both brain and body
• Brain based
• Metabolic abnormalities play big
• Hard-wired role
• Treatable and recovery possible
• Treatable but not curable

OR is it
Is autism a BRAIN
A DISORDER THAT
DISORDER?
AFFECTS THE BRAIN?
THE BRAIN IS WET!
and it’s attached to the
body!!!
It’s not just a computer.

AND, the brain can


GET PHYSICALLY ILL!

AND, physical illness can be TREATED!


MIND Institute
Sacramento
Thur-Fri Nov 2-3

Clinical
Implications of
Environmental
Toxicology for
Children’s
Neurodevelopm
ent in autism
Autism Society
of America

Special Issue of
Advocate on
Environmental
health and
Autism

December 2006
www.autism-society.org
Autism-Environment
CME Executive Summary
• Concerning increases in autism as well as allergies, asthma, learning
disabilities and other pediatric conditions, all suggest a contributory role for
environmental factors.
• Understanding mechanisms of environmental toxicology has the potential to
improve how we treat affected individuals.

• Research findings support consideration of immune abnormalities, gene-


environment interactions and enhanced vulnerability to toxins and infection in
autism.

• Autism can be reframed as a medical condition with features that affect the
whole body including the brain.

• Low dose, chronic and combined exposures can have significant impact on
neurodevelopment and children's health.

• Environmental exposures exact an enormous and preventable economic and


social impact.
Herbert, Future Neurology, March 2007 v2, no2.
Autism: A Brain Disorder
or a Disorder that Affects the Brain?
www.marthaherbert.com
From Modular

Gene

Brain Brain A Brain B Brain C


module

Behavior Communi- Social


Behaviors
cation Interaction

AUTISM
Gene Environment
To Systems
Epigenetics

PERVASIVELY DYSREGULATED
BIOLOGICAL MECHANISMS

Molecular
and
Anatomy
Sensory
Signaling

Sleep
Sensorimotor
ii. Epilepsy
Somatic

Communi-
Social Behaviors
cation
Interaction
i.
To a Gene Environment

Whole-Body Epigenetics
Understanding of
Autism
PERVASIVELY DYSREGULATED
BIOLOGICAL MECHANISMS

Molecular
and
Anatomy
Sensory
Signaling

Sleep
Sensorimotor
ii. Epilepsy
Somatic

Communi-
Social Behaviors
cation
Interaction
i.

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