Pediatrics Grand Rounds 2 May 2014

University of Texas Health Science Center at San Antonio, Texas

1

Autism: Chronic Features and Dynamic Mechanisms

Martha Herbert, PhD, MD TRANSCEND Research Program Pediatric Neurology Martinos Center for Biomedical Imaging Center for Morphometric Analysis Massachusetts General Hospital Harvard Medical School www.TRANSCENDresearch.org www.AutismRevolution.org www.autismWHYandHOW.org

Learning Objectives At the end of this presentation the participant will be able to: 1. Explain how the concept of “allostatic” or “total” load applies to

the autism spectrum 2. List public health measures that could contribute to improving

resilience on the autism spectrum and that could broaden access to appropriate medical care

3. Compare emerging systems biology models of what autism “is” with earlier models focusing mainly on the idea that autism is a lifelong static disorder stamped into the brain by genes

4. Explain how the concepts of neuroplasticity, bandwidth and signal-to-noise ratio may help identify actionable clinical targets in the autism spectrum

5. Describe health justice issues related to developing standards of care that emphasize the potential for plasticity and improvement by addressing actionable issues in autism.\

Changing Concepts and

Findings on Autism Michael Rutter, JADD, 2012

• “New research findings provide major

challenges regarding our understanding of the

concept of autism. ….. It is concluded that,

although there have been major research

advances; there is a need for a

reconceptualization and an avoidance of claims

that go beyond the evidence.”

• In fact, many of the things we have believed

about autism have gone beyond the evidence.

We were doing the best we could. Now we have

a great opportunity to regroup! 4

Many new observations in ASD:

Where might they point?

• It is necessary to think really carefully about

what we think autism “is” and how autism

“works”

• Critical to ask:

– What is “behavior”?

– What generates behavior?

– How can we modulate the processes that

generate behavior?

www.autismWHYandHOW.org 5

From Definition to Model of Autism:

Classic Modular Framework

Gene Brain module Behavior

AUTISM

Social

Interaction

Communi-

cation

Behaviors

Brain A

Brain B

Brain C

(Or neural systems)

6

Assumption: Autism is a “developmental

disorder”

This seems obvious.

But it carries a lot of extra baggage.

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Pediatrics Grand Rounds 2 May 2014

University of Texas Health Science Center at San Antonio, Texas

2

Assumption: Autism is a

“developmental disorder”

What are the IMPLICATIONS of this assumption?

1. It’s all genetic and predetermined

2. The damage is done really early, probably before you

are born

3. The brain is fundamentally and irretrievably

differently structured and “broken”

4. Brain changes are the cause of ALL the problems

5. There is nothing you can do about it

These assumptions are

not supported by evidence.

Emerging science contradicts them. 8

Beyond Genes

• Not a Static Prevalence

• Not Just Genes: Environmental Contributors

• Not Just a Few High-Impact Genes: Hundreds of Mostly

Lower-Impact Genes

• Not Just Inherited Genes: De Novo Mutations (that children

have but their parents don’t – where do they come from??)

• Not Even Mainly Genes: Substantial Environmental

Contribution

• Not Just Mutations: Epigenetics

9

Genome-wide expression studies in

Autism spectrum disorder, Rett

syndrome, and Down syndrome Lintas et al., Neurobiol Dis, 2010

…Our results surprisingly converge upon immune, and not

neurodevelopmental genes, as the most consistently shared abnormality

in genome-wide expression patterns. A dysregulated immune response,

accompanied by enhanced oxidative stress and abnormal mitochondrial

metabolism seemingly represents the common molecular underpinning of

these neurodevelopmental disorders. This conclusion may be important

for the definition of pharmacological therapies able to ameliorate clinical

symptoms across these disorders.

ALSO: genes most upregulated in autism in recent study were

NEUROIMMUNE genes, not neurodevelopmental. –Kong/Kohane, 2012

10

Etiological heterogeneity in autism spectrum

disorders: more than 100 genetic and genomic

disorders and still counting C. Betancur, Brain Res 2011 42-77

• An exhaustive review of the clinical genetics

and research genetics literature

• 103 disease genes and 44 genomic loci

reported in subjects with ASD or autistic

behavior.

• Commonalities with intellectual disability and

epilepsy.

11

SHANK3, the

Synapse and

Autism

• Altered postsynaptic

density (PSD) proteins

• Smaller PSD

• Fewer dendritic spines

• More dendritic

arborization

• Weaker signaling

• Larger striatum

• Autistic-like behaviors

12

Herbert NEJM 2011 commenting on Peça et al., Nature 2011

Lower dendritic spine density

• Spine density in

striatal medium

spiny neurons

(MSNs) from

Shank3B-/- mice is

lower than that of

wild-type MSNs

Peça et al., Nature 2011

13

WT

KO

Pediatrics Grand Rounds 2 May 2014

University of Texas Health Science Center at San Antonio, Texas

3

Complications

• Well over 100 different genetic disorders involve an autistic

phenotype (Betancur, Brain Res, 2011)

• These in turn comprise a small minority of cases with autism

• The synapse and PSD are highly complex

• Shank3 is expressed not just in brain but in gut and kidney,

is involved in epithelial turnover and mucosal immune

development, and is utilized by some gut pathogens in actin

rearrangement. (Huett et al., Exp Cell Res, 2009)

14

Beyond the Brain

• Not Just Brain Genes: Immune and Metabolic

Genes expressed systemically

• Not Just Local, Modular Brain Disturbances:

Whole Brain Involvement

• Not Just Regional Problems: Brain

Coordination is Widely Challenged

• Not Just Brain Wiring: Active tissue

pathophysiology in the brain (inflammation,

oxidative stress,)

• Not Just the Brain – Whole Body, Whole

System Involvement

15

16

Problems that often precede

the autism diagnosis (plenty of data on this)

• Parents with health problems – Health issues, particularly Metabolic Syndrome (diabesity,

hypertension, etc)

– Exposures (toxins, EMF/radiation, stress) leading to genotoxicity and metabolic dysfunction

• Pregnancy issues – Inadequate nutrition

– Exposures (toxics, medications, EMF, stress, infections, allergens)

• Infancy issues – Infections, antibiotics that injure microbiome

– Allergens, lack of microbiome support

– Insufficiency of various nutrients for handling load of stressors

17

Beyond Neurons

• Not Just Neurons: Glial Cells

• Not Just Brain Cells: Blood flow

• Not Just Brain Cells: maybe even Extracellular Matrix

• How much might the astrocytic dysfunction and swelling

which impairs blood flow, and poor fluid flow in the

extracellular matrix, be hindering synaptic function?

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THE OTHER BRAIN

by Douglas Fields, PhD, NIH scientist

ABOUT GLIAL CELLS

www.theotherbrainbook.com

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Pediatrics Grand Rounds 2 May 2014

University of Texas Health Science Center at San Antonio, Texas

4

Beyond

“Prenatally Programmed Deficit”

• Not Just Deficit: Giftedness and High Intelligence.

• Not Just Prenatal

• Not Necessarily Present at Birth

• Not Just Behavior

20

Circular thinking

in autism data interpretation

We believe autism starts prenatally

We do a study

We only consider interpretations of the data related to

prenatal mechanisms

We pick one of those

mechanisms that fits best with our

data

Ta da – we’ve proved that

autism starts prenatally

21

How to account for these phenomena?

22

Patchy lesions were reported by Stoner et al. widely

distributed in postmortem tissue samples of young people

with ASD (top figures)

We also observed widely distributed increases and

decreases in Cortical Thickness (CT) in brains of children

with autism as compared to the control mean volume

Just because cortical lamination

develops prenatally, that does not

mean that its disruption must

emanate from primary

neurodevelopmental processes.

Stoner et al.,, 2014, NEJM

Herbert et al., paper in preparation

Beyond Hopelessness

• Not a Life Sentence: Evidence of

– Severity that varies, particularly in individuals with autism and

mitochondrial disease

– Transient marked reduction of severity in fever

– Remission and loss of diagnosis (currently being studied at the

NIMH)

From Static to Dynamic Encephalopathy

23

Improvement in core autism behaviors

in setting of fever:

not consistent with “hard-wired” cause

Challenges posed by this study:

• This is not consistent with “static encephalopathy”

• What mechanisms might be consistent with this?

• Proposed so far: locus ceruleus, environmental impact on glial gap

junctions, cytokines, membrane lipids, dysfunctional electrophysiological

oscillations

• Additional pertinent citations:

Helt / Fein et al, Neuropsychology Review, 2007; Herbert in Chauhan et al CRC Press late 2009, Mehler & Purpura 2009

Behaviors Associated with Fever in

Children with Autism Spectrum Disorders.

Curran et al, Pediatrics 2007

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Rapid IMPROVEMENT in

brain connectivity suggests

“state” not “trait”

• Functional connectivity, assumed to be a fixed trait, changed rapidly with drug that impacts brain stress level (propranolol)

Effect of Propranolol on

Functional Connectivity in

Autism Spectrum

Disorder—A Pilot Study Narayanan et al. (Beversdorf

lab)

Brain Imaging and Behavior,

2010

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Pediatrics Grand Rounds 2 May 2014

University of Texas Health Science Center at San Antonio, Texas

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Reversal in Mouse Models

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Autism and Dietary Therapy: Case Report and Review of the Literature Martha R. Herbert, PhD, MD1⇑

Julie A. Buckley, MD, FAAP2 1Pediatric Neurology and TRANSCEND Research, Massachusetts General Hospital, Boston, MA, USA 2Pediatric Partners of Ponte Vedra, Ponte Vedra Beach, Florida; Nova Southeastern University, Fort Lauderdale, FL, USA

Martha R. Herbert, PhD, MD, Pediatric Neurology, TRANSCEND Research, Massachusetts General Hospital, Boston, MA 02129, USA. Email: marthaherbertmd@gmail.com

Author Contributions: MRH and JAB contributed equally to this work.

Abstract

We report the history of a child with autism and epilepsy who, after limited response to other interventions following her regression into autism, was placed on a gluten-free, casein-free diet, after which she showed marked improvement in autistic and medical symptoms. Subsequently, following pubertal onset of seizures and after failing to achieve full seizure control pharmacologically she was advanced to a ketogenic diet that was customized to continue the gluten-free, casein-free regimen. On this diet, while still continuing on anticonvulsants, she showed significant improvement in seizure activity. This gluten-free casein-free ketogenic diet used medium-chain triglycerides rather than butter and cream as its primary source of fat. Medium-chain triglycerides are known to be highly ketogenic, and this allowed the use of a lower ratio (1.5:1) leaving more calories available for consumption of vegetables with their associated health benefits. Secondary benefits included resolution of morbid obesity and improvement of cognitive and behavioral features. Over the course of several years following her initial diagnosis, the child’s Childhood Autism Rating Scale score decreased from 49 to 17, representing a change from severe autism to nonautistic, and her intelligence quotient increased 70 points. The initial electroencephalogram after seizure onset showed lengthy 3 Hz spike-wave activity; 14 months after the initiation of the diet the child was essentially seizure free and the electroencephalogram showed only occasional 1-1.5 second spike-wave activity without clinical accompaniments.

OnlineFirst Sage Publications May 13, 2013

The Center for Discovery:

Whole Body SENSITIVE treatment of

neurodevelopmental disabilities based on

Biodynamic Farm

“Wild-type microglia arrest pathology in a

mouse model of Rett syndrome” Derecki et al, Nature, 2012

• Rett features had been attributed to neuronal

dysfunction related to MECP2 mutation

• Astroglial cells now known to contribute

• Now microglia shown to contribute as well: bone

marrow transplant of wild type microglia

– Increased lifespan, normalized breathing, increased

body weight, improved locomotor activity

– Improvement even without direct change to neurons

– Improvements lost when microglial phagocytic

(garbage-collecting) activity inhibited

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Autism: From Static Genetic Brain Defect

to Dynamic Gene- Environment- Modulated

Pathophysiology

Ch.10 on Autism: By Martha Herbert

in Genetic Explanations: Sense and Nonsense Ed. Krimsky S and Gruber J

Contains detailed exposition, with extensive citations, of the argument that autism is a dynamic—not a static—encephalopathy

30

A Middle-Out Approach to Autism:

Multi-Scale, (Patho)Physiology Centered (see Denis Noble THE MUSIC OF LIFE)

Genes Genome

Environment G x E

Systemic Physiology

Gene Expression

Nervous System

Physiology Behavioral Cognitive Medical

Etiology

Pathogenesis & Active, ongoing

(patho) physiology Phenotype

Developmental Time 31

Pediatrics Grand Rounds 2 May 2014

University of Texas Health Science Center at San Antonio, Texas

6

ENVIRONMENTALLY VULNERABLE

PHYSIOLOGY

Current Opinion in Neurology, April, 2010

32

Whole Body Systems Model: Symptoms Emerge from

Problems with Underlying Functions

33

VISIBLE Social

& Behavioral

SYMPTOMS

are OUTPUT

DISTURBANCE OF

CORE

UNDERLYING

BODY FUNCTIONS

are GENERATORS

Ziggarut model: http://www.texasautism.com/

All the parts really influence each other

Body Cell Health Problems

Brain Cell Health Problems

Brain Function Glitches

Slower to Learn Skills

Stress and Overwhelm

Challenging Behaviors

Transduction: Critical Question in Multi-

Scale Biology

• How do processes at one level get

TRANSDUCED into changes at other levels?

• A classical model is sensory transduction

– From light through eyes/brain to vision

– From vibrations through ears/brain to sound

• For autism, from a middle-out perspective, the

core question is:

How do we get from tissue

pathophysiology to altered brain function? 35

Location of white matter enlargement

points to postnatal brain changes

What do we need to

learn about the

brain and about

autism to

understand this? 36

Inflammation and Oxidative Stress in Autism:

chronic, ongoing postnatal medical problems,

not confined to brain

Neuroglial activation and neuroinflammation in the brain of

patients with autism Vargas et al, 2005, Annals of Neurology

A B

D C

• These changes were found

at similar intensities in brain

aged 5-44 years

• Greater intensity of

inflammation in a 3-year

old’s brain

• Could increase in brain size

relate to inflammation?

Hard to test.

Oxidative stress in brain tissues from autistic patients Increased concentration of isoprostanes

Vargas et al, 2005, Annals of Neurology

37

Pediatrics Grand Rounds 2 May 2014

University of Texas Health Science Center at San Antonio, Texas

7

Astrogliosis Microgliosis

GFAP HLA-Dr

Pardo

Pardo: Astrogliosis in Radiate White Matter

Herbert:

Radiate White

Matter Enlargement

Astrogliosis

38 39

Could Connectivity Alterations in

ASD be based in Tissue Issues?

•Water, not fiber

changes in

brain tissue Hendry 2005

•Less white

matter integrity

•Less

restriction of

water flow

•More diffusivity Sundaram 2008

•Lower perfusion in ASD brains (by many PET or SPECT

studies) could impact brain function.

How might this affect brain electrophysiology?

The idea that brain

connectivity abnormalities

arise from metabolic, immune

and vascular disturbances

that affect synaptic function.

Local and long-range connectivity BOTH

reduced in autism

• This does not map onto the anatomy

• It may not be primarily caused by damage to long-range axons (nerve fibers)

• Khan/Kenet, PNAS 2013

40

Air Pollution and

Brain Inflammation Block and Calderon-Gardicuenas, TNS, 2009

Air pollution already linked

to autism

(e.g. Palmer 2006;

Windham 2006; Volk 2011)

41

Inflammation as a final

common pathway

42

GLUTATHIONE PROTECTS CELLS

from environmental stress,

but is often low in ASD (and many other chronic conditions)

• GLUTATHIONE (GSH) is vital for detoxification

• Mops up toxins and free radicals

• The body’s most potent anti-oxidant

• The most abundant antioxidant in the BRAIN

• Reduced Glutathione = GSH (active form)

• Oxidized Glutathione = GSSG (used-up form)

Made in the liver from

three amino acids:

Glutamate + Cysteine +

Glycine

42

LOW GLUTATHIONE

Shungu et al., 2012

Suh, J., W. Walsh, et al. (2008). American

Journal of Biotechnology and Biochemistry

4(2): 105-113,

Glutathione - critical antioxidant and detox chemical - low

levels in brains of depressed patients,

lower in brains in Chronic Fatigue Syndrome –

And low systemically in Autism

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Pediatrics Grand Rounds 2 May 2014

University of Texas Health Science Center at San Antonio, Texas

8

OK GSH/GSSG

GSH/GSSG

TOXICITY

TOXIC THRESHOLD

Toxic Insults Normal Homeostasis

Toxic Insults

Vulnerability with low GSH

S. Jill James

Fragile Homeostasis

(limited reserve)

44

Recovery may be

difficult

Glutathione and Oxidative Stress as

“Final Common Pathways” • GSH is depleted by thousands of toxins, oxidative stress,

infection, inflammation, EMF and nutrient-poor diet

• Small exposures of any one thing can still add up to a

substantial depletion of antioxidant resilience

• Oxidative stress present in the majority of DSM-IV psychiatric

disorders including: autism, Rett’s, ADHD, schizophrenia,

anxiety, and mood disorders

• “…all these psychiatric disorders might benefit from a change

to a whole-food plant-based diet.” PMID 2330073 • “Glutathione: a novel treatment target in psychiatry” – Trends Pharmacol Sci. 2008 Jul;29(7):346-51

• Lee, D. H., D. R. Jacobs, Jr., et al. (2009). "Hypothesis: a unifying mechanism for nutrition and chemicals as lifelong

modulators of DNA hypomethylation." Environ Health Perspect 117(12): 1799-1802.

45

Brain cells in inflammation:

What is the FUNCTIONAL IMPACT?

Inflammation and Its Discontents: The Role of Cytokines in the Pathophysiology of Major Depression.

Miller et al., BIOL PSYCHIATRY 2009;65:732–741

Could this be creating NOISE that crowds out the brain’s ability to process information?

• Excitatory chemicals created

by activated glial cells

• Normal housekeeping

functions of glial cells get

neglected

• Chronic inflammation is

irritating and promotes

excitotoxicity

• Chronic inflammation can

cause damage

46 47

Major example of functional impact:

Peripheral Inflammation and Neuronal Excitability

Riazi 2010, doi:10.1016/j.eplepsyres.2009.09.004

Autism Electrophysiological Abnormalities

something in everyone, much in some

28 19 18 28 21 21 230

4

8

12

16

20

24

28

1

Total n

Increased alpha

Paroxysmal/epileptiform

Auditory evoked responses

Click AER

FMAER

VEP high amplitudes

Martien & Duffy

Visual Evoked Potential (VEP) amplitude was bigger:

standard deviation was 2.42-8.92 SD

(average 5.4 SD):

Same stimulus elicits larger response

15 of these patients had

no seizure history.

Prediction: Less extreme sensory reactivity

with effective treatment 48

Reduced functional connectivity in

visual evoked potentials in children

with autism spectrum disorder J.R. Isler, K.M. Martien, P.G. Grieve, R.I. Stark, M.R. Herbert

Clinical Neurophysiology 121 (2010) 2035–2043

EEG power and coherence within

and between two homologous

regions of the occipital cortex

were measured during long latency

flash visual evoked potentials.

Measures were compared between

two groups of children (5.5–8.5

years), one with autism spectrum

disorders and the other with typical

development.

49

Pediatrics Grand Rounds 2 May 2014

University of Texas Health Science Center at San Antonio, Texas

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“Inefficiency” in

brain signaling in autism J.R. Isler, K.M. Martien, P.G. Grieve, R.I. Stark, M.R. Herbert

Clinical Neurophysiology 121 (2010) 2035–2043

ASD has more power than controls… but less coherence

POOR SNR – Sound and Fury, signifying nothing 50

EEG of Sensory Responses

• Sensory stimulation can

be overwhelming

Screen Saver: Less Stimulation

Movie: More Stimulation

5-8 years old

9-11 years old

Autistic children fail to

upregulate activity when

stimulus increases

Looks milder in older kids

Martien et al. 2008

Prediction:

Improved connectivity with

effective treatment 51

Lines indicate differences between

ASD and age-matched controls

Metabolite level

correlating with brain

activation

• More NAA in controls than in autism

• Linear correlation of amount of functional activation to amount of NAA

• NAA = N-acetylaspartate

Kleinhans et al, 2007

Brain magnetic resonance spectroscopy summary of

findings in literature to date: Mostly lower density of

metabolites

• Metabolites

– Mostly reduced or no change; few reports of increase

– Most studies done on 1.5T which has poor signal to noise ratio (only 1 of 22 done on 3T) and could miss differences

Shetty, Ratai, Ringer, Herbert, 2009

Dager review chapter 2008 and many papers

Reversibility of reduced NAA after epilepsy

surgery • NAA (marker of neuronal

density or function) reduced on the side opposite of a seizure focus

• After surgical resection of seizure focus, NAA on the other side returns to normal

Pan, 2008 Neurometabolism in Human

Epilepsy

IMPLICATION: The persistent aberrant electrical charges

afflicting the opposite side appear to have taken those cells off

line, but not “taken them out” since they came back online

after the seizure electrical activity stopped.

NAA = n-acetylaspartate

Reduced

informational

complexity and

organization

Reduced signal

to noise ratio

Increased chaos

and confusion

Too Much

Excitation

Not

Enough

Inhibition

=

More:

irritability,

hypersensitivity,

overload

ALLOSTATIC LOAD MODEL: Genetic and

Environmental Stressors are contributing to an

ONGOING, CHRONIC DEGRADATION OF BRAIN

AND BODY FUNCTION and increase in ENTROPY Model of autism: Increased ratio of excitation / inhibition in key neural systems

Rubenstein & Merzenich, Genes, Brain and Behavior (2003) 2: 255-267

This excitation/inhibition ratio can be increased by inflammation,

oxidative stress and toxicants, as well as genetic dysfunction

Pediatrics Grand Rounds 2 May 2014

University of Texas Health Science Center at San Antonio, Texas

10

A must-read statement of a systems biology

approach to complex illness:

From ‘omics’ to complex disease:

a systems biology approach to

gene-environment interactions in cancer

By Sarah S Knox: http://www.cancerci.com/content/10/1/11

Looks at cancer as accumulated ALLOSTATIC LOAD

from diet and environment

Advocates a dynamic transdisciplinary systems

biology approach aimed at reversing multiple levels of

dysfunction.

JUST ABOUT EVERYTHING SHE SAYS

APPLIES TO AUTISM

56

Metaphor: Tissue pathophysiology REDUCES BRAIN BANDWIDTH

Lots of Bandwidth:

Good Reception

Poor Bandwidth:

Limited Reception

Better Reception Allows Better Discernment of Differences and More Spontaneous Learning 57

SIGNAL to

NOISE ratio

(SNR) and

BANDWIDTH

Better Reception Allows More Spontaneous Learning

More SIGNAL

Less SIGNAL

Better SNR, Better Bandwidth Worse SNR, Less Bandwidth

More NOISE

Less NOISE

58

“Wild-type microglia arrest pathology in a

mouse model of Rett syndrome” Derecki et al, Nature, 2012

• Rett features had been attributed to neuronal

dysfunction related to MECP2 mutation

• Astroglial cells now known to contribute

• Now microglia shown to contribute as well: bone

marrow transplant of wild type microglia

– Increased lifespan, normalized breathing, increased

body weight, improved locomotor activity

– Improvement even without direct change to neurons

– Improvements lost when microglial phagocytic

(garbage-collecting) activity inhibited

59

Electron microscopy of

therapeutically activated glia turning into

“brain garbage collectors and transporters” CELLS PICK UP CELLULAR DEBRIS, SIDLE OVER TO BLOOD VESSEL, AND DUMP DEBRIS INTO BLOOD VESSEL

They do this after receiving an intensive nutiritional stimulation program

RIGA, S. et al., Ann. N.Y. Acad. Sci. 1067: 383–387 (2006)

RIGA, S. et al., Arch. Gerontol. Geriatr. suppl. 4 (1994) 227-234

60

PROPOSITION / ASSERTION:

We know enough now to

promote health and hunt for and

remove contributors to harm

61

Everyday Epigenetics: From Molecular Intervention

to Public Health and Lifestyle Medicine By Martha R Herbert PhD MD

www.najms.net

July 25, 2013

[N A J Med Sci. 2013;6(3):167-170. DOI: 10.7156/najms.2013.0603167]

Pediatrics Grand Rounds 2 May 2014

University of Texas Health Science Center at San Antonio, Texas

11

Toward the Pathophysiology of

Autistic Regression • Too much allostatic load plus genetic and

environmental weak points.

• Oxidative stress and inflammation

• Cells become hypersensitive and overreactive

• Tipping point is reached.

• Brain glial cells dysfunction and don’t keep up their housekeeping functions.

• Brain energy production gets less efficient.

• Brain networks get weaker

• Weaker brain networks produce weaker interactions with world

• This produces behaviors we call “autistic.”

Spelled out in more detail in Chapter 5 of

THE AUTISM REVOLUTION (Herbert 2012) 62

BRAIN CHANGES IN INFANTS

DEVELOPING AUTISM

• From higher to lower “FA”

• Decrease in fiber organization relative to

controls

• This DEVELOPS over time

• It is probably DOWNSTREAM of the

metabolic, cellular pileup of problems

• See blog critique of Wolff paper: Why

aren’t we there yet? Valuable but

incomplete brain imaging data in infants • In www.autismWHYandHOW.org

Wolff et al., 2012 63

What we CAN do, but don’t

The Diabetes Prevention Program (DPP) clinical trial and its 10-year outcomes study (DPPOS), both sponsored by the National Institutes of Health (NIH), showed that certain interventions could prevent or substantially delay the onset of type 2 diabetes both safely and cost-effectively.1,2 Yet diabetes prevention is not widely practiced in the United States, and the disease's staggering human and financial costs continue to grow.

What are the consequences of poor lifestyle

choices?

• Physiological dysfunction

– Mitochondrial and metabolic

dysfunction

– Oxidative stress

– Inflammation and immune

dysfunction

• Chronic Illness

• Brain dysfunction

• Greater risk of life-

threatening illness and early

death

ABUNDANTLY

DOCUMENTED IN AUTISM

Autism IS a chronic illness

Autism involves brain

issues

Evidence for this is starting

to accumulate

Large scale systems failure in healthcare

system

• Lifestyle intervention can prevent conversion into diabetes

by 58% compared to the drug metformin (31%)

• CMS (Ctr for Medicare and Medicaid services) lacks statutory

authority to reimburse nontraditional care providers, such as

lifestyle coaches.

• Therefore we spend $750 BILLION dollars a year on diabetes

treatment instead of prevention.

DoD Funded Study:

A MULTI-SYSTEM ASSESSMENT OF

INFANTS AT HIGH RISK FOR AUTISM Initiating PI: Martha Herbert

Partnering PI: Margaret Bauman

• Longitudinal Multisystem assessment

– Metabolism, Immune, Toxics, Endocrine

– Brain (EEG), Autonomics

– Medical Comorbidities

– Developmental/Behavioral Phenotyping

• HYPOTHESIS: Autism emerges from a cascade of insults

to physiological integrity culminating in a shift in the level

of available brain function

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12

Infant EEG

Photos used with permission 68

Sources detailing these arguments

69

• GENETIC EXPLANATIONS: Sense and Nonsense S Krimsky and J Gruber, Eds: "Autism: From Static Genetic Brain Defect to Dynamic Gene-

Environment-Modulated Pathophysiology," Chapter 10, on autism, by Martha Herbert

• THE AUTISM REVOLUTION:

Whole-Body Strategies for Making Life All It Can Be

Random House/Harvard Health Publications 2012 by Martha Herbert with Karen Weintraub

• For more technical detail on pathophysiology: “Autism and EMF? Plausibility of a

Pathophysiological Link” in Pathophysiology, 2013, PMIDs 24095003 & 24113318

• “Everyday Epigenetics: From Molecular Intervention to Public Health and Lifestyle Medicine”,

2013, http://najms.net/v06i03p167a/ or www.marthaherbert.org/publications

• Further papers: www.marthaherbert.org or http://connects.catalyst.harvard.edu/Profiles/display/Person/47629

• Blogs listed on www.AutismRevolution.org

• Overview of multiple synergistic viewpoints on autism: www.autismWHYandHOW.org

Autism: WHY and HOW ?

www.autismWHYandHOW.org

• A website reviewing multiple viewpoints and their intersections

• A literature repository

• A framework for reflective discourse

70

TRANSCEND Research Program

www.transcendresearch.org

transcend@partners.org

Integrative multimodal measurement platform

Optimization of measures that can detect change

In development, in regression, in improvement

MRI MEG

EEG NIRS

Biological Function

MRI MEG

EEG NIRS

Biological Function

MRI MEG

EEG NIRS

Biological Function

MRI MEG

EEG NIRS

Biological Function

71