Defining Autism (Martha Herbert, M.D.)

8/7/2019 Defining Autism (Martha Herbert, M.D.)

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Autism:A Brain Disorder?

Or a Disorder thatAffects the Brain?

Martha Herbert, MD, PhDHarvard Medical School

TRANSCEND Research ProgramTGRI – Treatment Guided Research Initiative - ASA

Pediatric Neurology and Center for Morphometric Analysis

Martinos Center for Biomedical ImagingMassachusetts General Hospital

www.marthaherbert.com



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, savantskills, immune impairments, GI distress(50-75%), food allergies (~50+%)

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, savantskills, 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

Autism: A Behaviorally Defined Syndrome

Biology is not part of the definition(and neither is prognosis)



Static model of autism

Inevitable

Fixed

Hardwired

Unchangeable

Genes

Prenatal

Brain

Hopeless



Modular, StaticAutism Model

Gene

Brain

module

Behavior

AUTISM

SocialInteraction

Communi-cation

Behaviors

Brain A Brain B Brain C



Anomalies thatviolate the static model

1. More than genes

2. More than prenatal

3. More than brain

4. Reasons for hope



Inclusive SystemsAutism Model

PERVASIVELY DYSREGULATED

BIOLOGICAL MECHANISMS

SocialInteraction

Communi-cation

Molecularand

Sensory

Signaling

Behaviors

Anatomy

SleepSensorimotor

Epilepsy

Somatic

Gene Environment

Epigenetics

i.

ii.



After much gene hunting, genetics isnot explaining autism

• Genetic studies have not identified genes ofstrong effect

• Genome scans have not replicated each other

• Novel genetic mechanisms suggestenvironmental role– Copy Number Variants (CNV) may be de novo, not

inherited

– Epigenetics—regulation of gene expression (genesthemselves don’t change)

• Can be passed through several generations



0

1

2

3

4

5

6

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

IMGSAC B

Chromosome

MLSscore

Suggestive

Highly significant

Significant

WEAK RESULTS FROM SEVEN GENOME SCANS:

Low levels of significance of most genes

X

“Critical level”

IMGSAC B



The environment is a VARIABLE, nota CONSTANT

• To focus exclusively on genes, we have toassume no meaningful changes in theenvironment

• This is implausible.



Trends in U.S. Chemical Production, 1920–1980

• 85,000 chemicals inthe Federal inventory

• 2,000-3,000 newchemicals introducedeach year

• Pesticide use morethan doubled between1964 and 1982 (USDA)





Body Burden — The Pollution in Newborns

A benchmark investigation of industrial chemicals, pollutantsand pesticides in umbilical cord blood

Envi ron m en ta l Wor k ing Group , Ju ly 1 4 , 2005 10 n ew borns, $10 ,000 / baby fo r s tudy

Chemicals and pollutants detected in

human umbilical cord bloodMercury (Hg) - tested for 1, found 1

Polyaromatic hydrocarbons (PAHs) - tested for 18, found 9

Polybrominated dibenzodioxins and furans (PBDD/ F)- tested for 12, found 7

Perfluorinated chemicals (PFCs) - tested for 12, found 9

Polychlorinated dibenzodioxins and furans (PBCD/ F)- tested for 17, found 11

Organochlorine pesticides (OCs) - tested for 28, found 21

Polybrominated diphenyl ethers (PBDEs) - tested for46, found 32

Polychlorinated Naphthalenes (PCNs) - tested for 70,found 50

Polychlorinated biphenyls (PCBs) - tested for 209,found 147

Of the 287 chemicals

detected in umbilicalcord blood:

• 180 cause cancer inhumans or animals

• 217 are toxic to thebrain and nervoussystem

• 208 cause birthdefects or abnormaldevelopment inanimal tests

http://www.ewg.org/reports/bodyburden2



Status of Developmental Toxicity Testing

for the 2,863 ChemicalsProduced Above 1 million pounds/year

21.4%

0.4%

78.2%

No DataOn DevelopmentalToxicity

20-30 Tested for

Neuro developmentalToxicityAccording to EPAGuidelines

This testing isNOT REQUIRED.

Some DataOn Developmental

Toxicity

In Harm’s Way, www.preventingharm.org

To test these 2,863chemicals incombinations of 3

would require85 BILLION tests.



Texas autism rates,

by school districts

1990-1993 1998-2000

Potential association

between autism rates,environmental mercuryother toxins in Texas

Palmer, et al., Health and Place, 12 (2006) 203–209



All Reporting Facilities, All Chemicals TRI-(1987-2002)Map shows 3,683 of 48,205 facilities reporting nationwide

Total toxicity

Autism rates

Chemicals-TRI(Toxic Release Inventory)

On average, for each 1000 lb of

environmentally releasedmercury, there was a 43%

increase in the rate of specialeducation services and a 61%

increase in the rate of autism.Palmer et al. Health & Place 12 (2006) 203–209



Maternal Residence NearAgricultural Pesticide Applications and

Autism Spectrum Disordersamong Children in the

California Central ValleyEric M. Roberts et al, Env Hlth Perspectives 2007

Risk of exposed mother having child develop

autism increased with the poundage oforganochlorine applied and decreased with

distance from field sites.

(Odds ratio 6.1)



Environmentally responsivegeneshigh frequency, lowhigh frequency, low penetrancepenetrance modulationmodulation

of vulnerabilityof vulnerability

http://www.niehs.nih.gov/envgenom/egp6.htm

• cell cycle

• cell division

• cell signaling

• cell structure

• DNA repair

• gene expression

• homeostasis

• metabolism

• immune and inflammatory response

• hormone metabolism

• nutrition

• oxidative metabolism and stress• membrane pumps and/or drug resistance

• signal transduction

AUTISM AND ENVIRONMENTAL

GENOMICSHerbert MR, Russo JP, Yang S, Roohi J, Blaxill M, Kahler SG,

McCoy L, Ziegler DA, Hatchwell E

Neurotoxicology, 2006

Brain effects may be downstreamof genetic vulnerabilities or gene-

environment interactions thataffect 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: Much documentation oflarge brains in autism

measures:

head circumference

brain weightbrain volume

• About 20% of young autistic headsare “macrocephalic” (>97th %ile)

• Most are above average in volume

• This is an atypical brain size

distribution.

• It has no precedent in the literature.Herbert, The Neuroscientist, October 2005

Redcay & Courchesne, 2005

•Dementieva, Y.A. (2005)•Deutsch, C. K. (2003)

•Courchesne, E. (2003)•Sparks, Friedman (2002)

•Gillberg, C. (2002)

•Alyward, E. H. (2002)•Courchesne, E. (2001)

•Miles, J. H. (2001)•Fidler, D. J. (2000)

•Fombonne, E. (1999)

•Ghaziuddin, M. (1999)•Bailey, A. (1999)

•Lainhart, J. E. (1997)•Rapin, I. (1996)

•Davidovitch, M. (1996)

•Woodhouse, W. (1996)•Piven, J. (1996)•Piven, J. (1995)

•Bailey, A. (1993)

•Bauman & Kemper (1985)



WhatWhat’’s making autistic brainss making autistic brains

bigger?bigger?

Abnormal brain growth

Disproportionate

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

Herbert M. 2005Herbert M. 2005



0

0.5

1

1.5

2

2.5

Total Brain

Volume

Cerebral

White

Matter

Total

Radiate

WM

Prefrontal

Frontal

Lobe

Parietal

Lobe

Temporal

Lobe

Occipital

Lobe

Autism

SLI

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

that is due to Increased White Matter Volume #66% 89%

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*

Autism-LanguageImpairmentSimilarities:Effect Sizes

as high as 2

Effect Sizes



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

Redcay and Courchesne 2004

Courchesne 2003

Dementieva 2005

Tapering off after the first few years

1.18 1.15 1.13

0.82

0.8

1

1.2

Volume Ratio

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

Courchesne

Courchesne

Autism -

Nosology

Autism -

BU



Brain Connectivity



White Matter: Brain

Connections

Catani et al (2003). Brain



Reliable differences in functional connectivity:

Autism group has lower functional connectivitybut same rank order

Marcel Just

• “Functional connectivity” is ameasure of how well brain

synchronization and coordinationis working.

• Reliably lower functionalconnectivities (degree ofsynchronization) in autism group.

• This is a widespread phenomenonwith local exacerbations.



Multispectral MRI Imaging



Inflammation and Oxidative Stress in Autism:

chronic, ongoing postnatal medical problems,not confined to brain

Neuroglial activation andneuroinflammation in the brain of

patients with autismVargas et al, 2005, Annals of Neurology

A B

DC

• These changes were foundat similar intensities inbrain aged 5-44 years

• Greater intensity ofinflammation in a 3-yearold’s brain

Oxidative stress in brain tissuesfrom autistic patients Increased

concentration of isoprostanesVargas et al, 2005, Annals of Neurology



Astrogliosis Microgliosis

GFAP HLA-Dr

Pardo

Pardo: Astrogliosis in Radiate White Matter

Herbert:

Radiate WhiteMatter Enlargement



GI, Immune and Metabolic problems

• 46-96% of autistic children have GI disease

• constipation, diarrhea, inflammatory bowel disease, abnormalintestinal 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

Mild Moderate Severe

Lymphocytic

infiltration



Immune signs andsymptoms in autism

Onychomycosis

Eczema

Allergic Facies

Protein calorie



Protein-caloriemalnutrition due to

malabsorption:

“Intrinsic static

comorbidity” or treatablemedical condition?

Note distended abdomen,Note distended abdomen,

skinny arms and legsskinny arms and legs

This will chronicallyThis will chronically•• Deplete nutrientsDeplete nutrients

•• Circulate substances toCirculate substances to

body and brainbody and brain

These can worsen brain andThese can worsen brain andbody metabolic shortfallsbody metabolic shortfalls

until treateduntil treated

Permission Granted to use by mother – copy on file



Krigsman, Thoughtful House, Tx

Pain-based behavior:

pressure on abdomen



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 normalappetite.”

Case 2: “…large and ragged tonsils.”

Case 3: diarrhea and fever following smallpox vaccination …. healthy except for largetonsils and adenoids.

Case 4: vomited a great deal during his first year… feeding formulas were changedfrequently … 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 andmalnutrition 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 andotitis media

Case 11: was given anterior pituitary and thyroid preparations for 18 months

Kanner’s original paper, discussed in Jepson 2007



Brain/NervousSystem

GutImmuneSystem

GUT BRAIN: Vagus afferents; Gut neuropeptides

BRAIN GUT: Endorphins; Neuropeptides

IMMUNE BRAIN: Cytokines; microglia activation

BRAIN IMMUNE: Endorphins; Neuropeptides;Cortisol

GUT IMMUNE: Gut neuropeptides; microbialproducts

IMMUNE GUT: Cytokines; GALT

(Steve Kahler)

Beyond the BrainThe Autism Triad: Brain-Gut-Immune Axis



The “Blood-Brain Barrier” isnot an absolute barrier



Regression, Fluctuation and Improvement:

Beyond “static encephalopathy”

• Variable severity with transient striking improvements and recovery offunction 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

Neurobiological Implications:

NEUROMODULATORS, not just wiring

• 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



MIGHT AUTISM HAVE A

COMPONENT OF TREATABLEENCEPHALOPATHY?

• Would correction of metabolic, immunological orbiochemical contributors to an increasedexcitation/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

ORAccumulation of environmentally-relatedcompromises 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



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*

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*

Catechol-O-Methyltransferase (COMT 1947A→G)Polymorphisms Affecting Methylation and Increased Oxidative Stress

James, AM J Med Genetics, 2006

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*

Combined TCII GG plus COMT GG in the same individual



Proportion of Autistic Children within Normal Range

Before and After Supplementation

Folinic+Betaine

Metabolite Normal Range a Baseline Folinic+Betaine +methylB12Methionine (µmol/L) > 24 1/8 5/8 7/8SAM (nmol/L) > 80 2/8 8/8 8/8SAH (nmol/L) < 23 2/8 7/8 7/8SAM/SAH > 4 1/8 7/8 7/8

Adenosine (µmol/L) < 0.3 4/8 8/8 8/8Homocysteine (µmol/L) >5.5 3/8 8/8 8/8Cysteine (µmol/L) >180 0/8 2/8 7/8GSH (µmol/L) >5.4 0/8 2/8 7/8

GSSG (µmol/L) < 0.33 0/8 2/8 8/8GSH/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

• Genetically determined

• Brain based• Hard-wired

• Treatable but not curable

Newer model

• Environmentally triggered• Genetically influenced

• Both brain and body

• Metabolic abnormalities play bigrole

• Treatable and recovery possible

Is autism a BRAINDISORDER?

OR is itA DISORDER THAT

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 InstituteSacramento

Thur-Fri Nov 2-3

Clinical

Implications ofEnvironmentalToxicology for

Children’sNeurodevelopm

ent in autism



Autism Societyof America

Special Issue ofAdvocate on

Environmentalhealth and

Autism

December 2006www.autism-society.org

A tism En ironment



• Concerning increases in autism as well as allergies, asthma, learningdisabilities and other pediatric conditions, all suggest a contributory role for

environmental factors.

Herbert, Future Neurology, March 2007 v2, no2.

Autism-Environment

CME Executive Summary

• Understanding mechanisms of environmental toxicology has the potential toimprove how we treat affected individuals.

• Research findings support consideration of immune abnormalities, gene-

environment interactions and enhanced vulnerability to toxins and infection inautism.

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

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

• Environmental exposures exact an enormous and preventable economic andsocial impact.



Autism: A Brain Disorderor a Disorder that Affects the Brain?

www.marthaherbert.com



From Modular

Gene

Brain

module

Behavior

AUTISM

SocialInteraction

Communi-cation

Behaviors

Brain A Brain B Brain C

G E i



To Systems

PERVASIVELY DYSREGULATEDBIOLOGICAL MECHANISMS

SocialInteraction

Communi-cation

Molecularand

SensorySignaling

Behaviors

Anatomy

SleepSensorimotor

EpilepsySomatic

Gene Environment

Epigenetics

i.

ii.

T G E i t



To a

Whole-BodyUnderstanding of

AutismPERVASIVELY DYSREGULATED

BIOLOGICAL MECHANISMS

SocialInteraction

Communi-cation

Molecularand

SensorySignaling

Behaviors

Anatomy

SleepSensorimotor

EpilepsySomatic

Gene Environment

Epigenetics

i.

ii.

Documents

Defining Autism (Martha Herbert, M.D.)