Brantford, Ontario. FETAL ALCOHOL SPECTRUM DISORDER SYMPOSIUM

FETAL ALCOHOL SPECTRUM DISORDER SYMPOSIUM
SEEING THE OTHER PERSPECTIVE
DA DWA DA DEHS NYE>S
SEPTEMBER 9, 2014
Barry Stanley. www.barrystanleyfasd.com. Docstoc bstanley31

When you're up to your neck in alligators, sometimes
you forget that your mission is to drain the swamp.
barry stanley www.barrystanleyfasd.com docstoc bstanley 31

Historical view of prenatal alcohol and FASD
Aristotle - 384-322 B.C.
Diogenes - cir. 400 B.C.
Plutarch- 45-125 A.D.
Behold, thou shalt conceive and bear
a son: And now, drink no wine or
strong drink.
Judges 13:7
Navajo tradition, women who drink
crazy water when bearing a child,
will give birth to a child crazy in
body and mind.
barry stanley www.barrystanleyfasd.com docstoc bstanley31

19th century - 21 references to the
effect of PAE
1726- British College of Physicians report to Parliament.
‘a cause of weak, feeble and distempered children.
1834- British House of Commons Commission.
‘starved, shriveled and imperfect look’
1899- British scientist, Sir Francis
Galton. ‘children born to alcoholic mothers were- defective-neurotic.”
1899-Dr. W.C.Sullivan. First scientific study- 120 chronic alcoholic
women prisoners-had healthy babies if pregnancy was carried while
incarcerated, compared to crippling or lethal birth defects when out
of jail.

20th Century
Paul Lemoine - French pediatrican. Published 1968
Jaqueline Rouquette – France. Thesis. Published 1957
The Lancet . Saturday 9 June 1973
PATTERNS OF MALFORMATION IN OFFSPRING OF CHRONIC ALCOHOLIC MOTHERS
Kenneth L. Jones, David W. Smith, Christy N. Ulleland, Ann Pytkowicz Streissguth

21st Century
EPIGENETICS
The factor of the mother drinking in a pregnancy
NO LONGER STANDS ALONE

Opposition and reduced awareness to
the consequences of prenatal alcohol
- Reaction to prohibition
-Focusing [distracting] on aboriginal populations
- Recognition of women’s rights together with society’s
ambivalent attitude to alcohol
- Post WW11 affluence
- Development of the DSM [from 1952]- symptom based
- Influence of the alcohol industry barry stanley www.barrystanleyfasd.com docstoc bstanley 31

Nomenclature-1996
{Institute of Medicine, Washington, D.C. U.S.A.}
F.A.S- Fetal Alcohol Syndrome.
with and without confirmed maternal alcohol exposure.
Partial F.A.S. with confirmed maternal alcohol exposure.
A.R.B.D.- Alcohol Related Birth Defects.
with confirmed maternal alcohol exposure.
A.R.N.D.- Alcohol Related Neurodevelopment Disorder
with confirmed maternal alcohol exposure.
F.A.E.- Fetal Alcohol Effects. No longer used.
F.A.S.D.- Fetal Alcohol Spectrum Disorder – includes all the above

FAS – Only the tip of the iceberg
- Fetal alcohol syndrome
- F.A.E.
-A.R.N.D.
-Alcohol Related
Neurodevelopmental Disorder.
barry stanley www.barrystanleyfasd. docstoc bstanley31

FASD 1996
ARND - 63%
FAS – 37%

FASD 2014
FAS – 10%
ARND – 90%
PUBMED 2014
- 4,343 results for
publications on “Fetal Alcohol
Syndrome”
- 3,661 results for
publications on “Fetal Alcohol
Spectrum Disorder”

1996 Report – University of Washington,
Seattle , U.S.A.
Ann P. Streissguth et.al
Understanding the Occurrence of Secondary
Disabilities in Clients with Fetal Alcohol Syndrome
[FAS] and Fetal Alcohol Effects [FAE]

Primary Disabilities
-- “are inherent in FASD individuals and are a consequence of the neurological damage
and impaired neurological function” {Washington Report. 1996}
affecting
- Cognition and Learning
- Memory – all types
- Information processing – speed, receiving and conveying
- Attention
- Perseveration
- Adaptive and Executive Functioning
- Modulation
-Sensory systems
- Psychiatric Conditions

Primary Disabilities show as –
or interpreted as -
• Stupid
• Not caring
• Selfish
• Attention seeking
• Impulsive
• Confabulation / Lying
• Not interested
• Lazy-Learning disabilities at
school
• Not learning from experience
• Poor hygiene.
• Difficulty with relationships.
• Violent
• Boundary issues.
• Lonely.
• Poor judgment.
-Difficulty communicating
- Concrete thinking - taking everything literally
- Problems planning and organizing
- Easily lead
- Difficulty abstractions, humor, sarcasm
- Difficulty relating cause and effect,
anticipating consequences
- Difficulty appreciating others’ points of view
- Difficulty expressing remorse or taking
responsibility
- Frustration

Secondary Disabilities
“Individuals with FAS/FAE have a range of secondary disabilities –
disabilities that the individual is not born with, and which could be
ameliorated with appropriate interventions.” {Washington Report 1996}
Dependant living > 85%
Problems with employment > 94%
Streissuguth et.al.

Understanding the Occurrence of Secondary Disabilities in
Clients with Fetal Alcohol Syndrome [FAS] and Fetal Alcohol
Effects [FAE]. Final Report, 1996. University of Washington,
Seattle, U.S.A.

Myth - FAS is the most severe/worst form of FASD
The terms “severe / worst” need to be qualified.
Truth –
- Only approximately 27% of those with FAS will have an I.Q.
below 70 – often protected, with fewer secondary disabilities.
- 9% of those with ARND will have an I.Q. below 70.
-

Adaptive Functioning
• SIB-R “- an individual’s ability to effectively meet
social and community expectations for
establishing personal independence, maintaining
physical needs, conforming to social norms, and
sustaining interpersonal relationships”
• Vineland “- the performance of the daily activities
required for personal and social sufficiency”

All those individuals exposed to prenatal alcohol [FASD], FAS
and ARND will have permanent inadequate adaptive
functioning.
Children who have not been exposed to prenatal alcohol may
also have inadequate adaptive functioning, that is not
permanent.

Developmental
stages of 18
year old
FASD child!
Jodee Kulp www.Betterendings.org

ALCOHOL
-use – 12,000 Years
-Records negative effects –individual and
society.
Rare references to effects
of PAE – 4,000 years, until
the last 300 years
Generations – approx.
600 - 12,000 years
200 – 4,000 years

ALCOHOL – 2014
Reflects the historical perspective
Research on alcohol and alcohol related issues
-cost – millions annually.
- all related to the developed brain.
- negligibly less on PAE exposure.
- the role of PAE still largely ignored by the alcohol research community,
the medical profession and governments.
Pubmed - 2014
-778,348 results for publications on “alcohol”
- 75,348 results for publications on “alcoholism”
- 3,696 results for publications on “Prenatal Alcohol Exposure”
- 4,343 results for publications on “Fetal Alcohol Syndrome”
- 3,661 results for publications on “Fetal Alcohol Spectrum Disorder”

barry stanley www.barrystanley.com docstoc bstanley31
-ca. 4000 B.C. - Clay tablets from Mesopotamia discuss how to use alcohol to dilute medicine
-460-379 B.C. - Hippocrates states that the brain is involved with sensation and is the seat of
intelligence
-335 B.C. - Aristotle writes about sleep; believes heart is seat of mental process
-1543 - Andreas Vesalius discusses the pineal gland and draws the corpus striatum
-1564 - Giulio Cesare Aranzi coins the term hippocampus
-1587 - Guilio Cesare Aranzi describes ventricles and hippocampus. He also demonstrates that
the retina has a reversed image
-1760 - Arne-Charles Lorry demonstrates that damage to the cerebellum affects motor
coordination
-1673 - Joseph DuVerney uses experimental ablation technique in pigeons
-1792 - Giovanni Valentino Mattia Fabbroni suggests that nerve action involves both chemical
and physical factors
-1838 - Theordor Schwann describes the myelin-forming cell in the peripheral nervous system
-1960 - Oleh Hornykiewicz shows that brain dopamine is lower than normal in Parkinson's
The Brain and the development of Neurology

Phrenology
19th, 20th, 21st Centuries

19th – 20th Century
Phineas Gage 1848

20th, 21st Centuries
Investigative Tools
- Clinical observation of brain
injury/disease
-Animal – brain injury/disease
- Brain waves
- Electrical activity
- Neuroimaging
- Scans
- Functional Neuroimaging
- Brain stimulation
-Histology
- Biochemical
Concepts of Brain Function
- Discrete areas
- Hubs
- Generalized
- Complex system

“Specialization alone, however, cannot fully account for most aspects of
brain function. Mounting evidence suggests that integrative processes
and dynamic interactions across multiple distributed regions and
systems underpin cognitive processes as diverse as visual recognition ,
language, cognitive control,
Emotion, and social cognition”—
-- “Abnormal anatomical connectivity and functioning of hub regions has
been hypothesized to relate to behavioral and cognitive impairment in
several neurological and psychiatric brain disorders.”
[ Network hubs in the human brain. Trends in Cognitive Sciences. 2013 ]
Conectomes, Hubs, Nodes and Axes

Connectomes, Hubs, Nodes and Axes
Examples
 Hypothalamic – Pituitary – Adrenal Axis
stress- related autonomic and behavioral reactivity.
 Prefrontal Cortex, Hippocampus and Amygdala
Executive functioning, adaptive functioning and stuck-
in-set perseveration.

20th, 21st Centuries
An accurate description of the human brain – the most complex
terrestrial system known - Barry Stanley
“A possible definition of a complex system. Acknowledged features of a complex system are the
following: -- the system is composed of a large number of elements; -- the elements are often of
different types and have an essential internal structure; -- the elements are related by nonlinear
interactions, often of several different types; -- the system experiences inputs at several
scales. But I argue that the main hallmark of complex systems is circular causality, namely, the
presence of feedbacks of (macroscopic) collective properties and emergent features on the
behavior of (microscopic) elements. Elements collectively modify the surroundings, which in turn
exerts constraints on them and endow them with different possible states or behaviors. In
complex systems, knowing the features and behavior of the single components in isolation is not
sufficient to predict the behavior of the system as a whole”.
Annick Lesne
Multiscale modeling of living systems and their regulation.Proceedings of the Ist Conference CoMMISCo’10 on Mathematics and Computer
Modelling of Complex Systems. Institut de recherché pour developpement, Bundy, France. 2010: p13

SOME OF THE REGIONS OF THE BRAIN
AFFECTED BY PRENATAL ALCOHOL EXPOSURE

barry stanley. www.barrystanleyfasd.com. docstoc bstanley31
Gross Anatomy

Brain Size and Cortical Thickness
and the Glial Cell
0ur Brain consists of neurons and glial cells. Neurons
constitue about half the volume of the CNS and glial
cells make up the rest. Glial cells provide support and
protection for neurons. They are thus known as the
"supporting cells" of the nervous system. The four
main functions of glial cells are: to surround neurons
and hold them in place, to supply nutrients and oxygen
to neurons, to insulate one neuron from another, and to
destroy and remove the carcasses of dead neurons
(clean up). The three types of CNS supporting cells are
Astrocytes, Oligodendrocytes, and Microglia. The
supporting cells of the PNS are known as Schwann Cells.

Corpus Callosum
Callosal Disconnection Syndrome
stanley www.barrystanleyfasd.com docstoc bstanley31

Amygdalae

Thalamus

Hypothalamus

Hippocampus

Prefrontal Cortex

Cerebellum

Basal Ganglia

Cell Structure, Function and
Neurotransmitters
-some of the effects of PAE

Neurotrophic Factors and Adult Neurogenesis
Proteins that control the development, survival and function of nerve
cells [ neurons ]
They trigger the development of neurons from progenitor cells
Neuronal progenitors persist in the adult brain, but die. Neurotrophic
factors might be used to develop those cells for repair of damaged
nerve cells.
www.barrystanleyfasd.com docstoc bstanley31

Neurotransmitters, Neuromodulator Systems and Hormones
- Dysregulation of Insulin Growth Factors
- NMDA glutamate receptors > synaptic plasticity and memory systems
-GABA [a,b,c] gamma-aminobutyric acid > C.N.S. inhibitory [and excitatory during development]
neurotransmitter > cell membrane function
-- Reduced Choline Acetyltransferase > decreased acetylcholine > Hippocampus > memory –
Neuromodulator > platicity, arousal, reward, sensory perceptions and
sustained attention.
Hydroxylase > mood, appetite, sleep, memory, learning
- Decreased Dopamine receptor function > reward learning, reward seeking. Decreased levels of Dopamine
in the Prefrontal Cortex, Ventral Tegmental Area
- Hypothalamic-Pituitary Axis > differing activation > stress responsiveness. Male/Female differential stress
responsiveness > protective role of estrogens.
-Inhibition of Serotonin synthesis and expression of serotonin precursor, tryptophan

Hypothalamic-Pituitary-Adrenal Axis

PRENATAL – Existing or Occurring Before Birth
Phenotype - The observable physical or biochemical
characteristics of an organism, as determined by both genetics
and environment
Diagnosis – The identification of the nature of a disease or injury
by history, examination and laboratory data.
D.N.A. – Double helix molecule
Chromosomes , 46 – Storage units for DNA.
Genes – Distinct portions of DNA. Determine biological characteristics.
Genotype – The genetic makeup of an organism or a group of organisms.
GENETICS – The study of heredity and the variation of inherited
characteristics.
EPIGENETICS – The study of changes in gene function [expression]
That do not involve changes in DNA sequence.
STEM CELL – develop into specialized cells or replenish some specialized
cells- can replicate [ reproduce] indefinitiely.
PROGINATOR CELL - more specialized- can only replicate a few times.
Nucleic Acids – DNA and RNA
Nucleotides – are what the Nucleic Acids are formed from.
DEFINITIONS

DNA Structure The long, stringy DNA that
makes up genes is spooled within
chromosomes inside the nucleus of a cell.
(Note that a gene would actually be a much
longer stretch of DNA than what is shown
here.) DNA consists of two long, twisted
chains made up of nucleotides. Each
nucleotide contains one base, one
phosphate molecule and the sugar
molecule deoxyribose. The bases in DNA
nucleotides are adenine, thymine, cytosine
and guanine.
Genetics – D.N.A.

Genetics – R.N.A.
Ribonucleic acid [RNA] is a ubiquitous family of large biological
Molecules that perform multiple vital roles in the coding, decoding,
Regulation, and expression of genes. Together with DNA, RNA
Comprises the nucleic acids, which along with proteins, constitute
Three major macromolecules essential for all known forms of life.

Estimations of the number of Human
Genes
1964 – 6,700,000
1990 – 100,000
1993 - 80,000
1994 - 64,000
1996 - 50,000
2004 – 20,000
2009 - 18,877
Pertea and Salzberg
Genome Biology 2010,
SOME OF US HAVE MORE GENES THAN
OTHERS
- BUT MORE IS NOT NECESSARILY BETTER.

How can so few genes determine our
diverse biological characteristics?
>>> Epigenetics
> By small modifications that cause big changes in how the gene works
> Called - changes in gene expression

EPIGENETICS
EPIGENETICS
EPIGENETIC
SEPIGENETICS
EPIGENETICS
EPIGENETICS
E P I G E N E T I C S
1996
2014
The Explosion of
Epigentics

Genetics and Epigenetics
There are numerous types of epigenetic modifications on
both DNA and nucleosomes, including methylation and
acetylation, which could affect gene regulation and
expression. Alcohol exposure at crucial developmental stages
could result in alterations of the epigenetic marks, thus
altering the expression of key genes resulting in physiological
and/or behavioral changes not only in the exposed individuals
but also in their offspring.
Alcohol Metabolism and Epigenetic Effects on Tissue Injury
National Institutes of Health [NIH]
National Institute on Alcohol Abuse and Alcoholism

Increasing awareness of the Consequences of
Prenatal Alcohol Exposure
• BEFORE our understanding of Epigenetics
• > Clinical presentation and Psychological Assessments
• > Gross anatomy and imaging.
• > Female consumption > FASD [FAS, pFAS, ARND]
• Now with our understanding of Epigenetics
• > Micro-anatomy and advanced imaging.
• > Cellular level studies – animal models
• > Genetics and Epigenetics
• > Female and Male alcohol consumption,
• present and previous generations.

Methylation, Acetylation - leading to
glial and astrocyte cell dysfunction > impaired neuron migration
 impaired development of neurotransmitter receptors
 impaired glucose uptake and transport
impaired IGF receptor function
 suppression of antioxidants -accumulation of free radicles
 impaired cell membrane function > calcium ion exchange
 abnormal protein formation > ubiquitous effects on brain function
 reduced proliferation of neural progenitor cells
 abnormalities of endocrine function and neuroendocrine regulation
 impaired immune function and stress response > deficiencies in number
and function of white blood cells
 cell death > impaired apoptosis and necrosis
barry stanley www.barrystaleyfasd.com docstoc bstanley 31

EPIGENETICS, MENTAL ILLNESS, FASD
Pubmed
Epigenetics and Menal Illness – 73 results
Epigenetics and Psychiatry – 1,160 results
-depression – 649
-adhd – 44 results
- schizophrenia – 808 results
Epigenetics and FAS – 268 results
Epigenetics and Alcohol Related Neourodevelopmental
Disorder – 15 results
Epigenetics and FASD – 56 results

EPIGENETICS and FASD

Preconception - paternal, 9 weeks exposure
and maternal - 10 weeks exposure
Preimplantation – fertilized egg > implantation
> first two weeks of pregnancy - > placenta > growth
retardation
Gastrulation – 3rd to 8th week of pregnancy > most
sensitive – stem cells > cellular differentiation – birth
defects.
transient exposure to alcohol during the pre-implantation and early gastrulation periods of development may have permanently altered gene
expression patterns in basic cell-signaling pathways involved in limbic/ neuroendocrine development, resulting in reprogramming of the hypothalamic-
pituitary-adrenal (HPA) axis and stress- related autonomic and behavioral reactivity in these infants. On/off switch effect

Epigenetic Adaptation and Evolution
– fetal susceptibility and protection
second and third trimesters –
separate from early embryogenesis
Adaption increases fetus survival but may lead to adult disease – through the
epigenetic regulation of gene expression – rheostat effect, rather than off/on
switch effect.
Fetal insults – anoxia, nutritional > maternal or utero-placental insufficiency
> Adult metabolic disorders, cardiovascular disease, insulin resistance and obesity.
 Sickle Cell Anaemia.

EPEGENETICS > FASD > COMORBIDITY
- Attention, Mood and Personality Disorders
- Addictions
- Cancer
-Infectious Diseases
Prenatal Alcohol Exposure
- IGNORED

CORRELATION – CAUSE AND EFFECT
Because there is a correlation it can not be
assumed that there is a cause and effect.
But, there cannot be cause and effect without
correlation.
Where there is a strong, significant correlation
relating to the health of individuals and society
the medical profession has a moral and ethical
duty to investigate possible cause and effect.

FOLIC ACID AND SPINA BIFIDA
1970s- 1980s Correlation – Spina Bifida was related to
Folic Acid deficiency in the mothers.
1991 – Cause and Effect confirmed - Publication of the
results from the Medical Research Council Vitamin
Study [U.K.]
1992, 14 months later the Centers of Disease Control
and Prevention [U.S.A.] recommended Folic Acid to
reduce incidence of Spina Bifida

MENTAL ILLNESS AND PAE/FASD
Streissuguth et.al 1996

FAS @ Street Level. Conference. Toronto, 2003.
The Incidence and Prevalence of Fetal Alcohol
Syndrome and Alcohol-Related Neurodevelopmental
Disorder – Implications for Mental Health Workers.
“So what are the implications for mental health workers.?
The diagnosis of FAS/ARND should be considered for those
clients who have a history of secondary disabilities.
Especially those diagnosed with chronic mental health
problems.”

• Review of Canadian and American Journals of
Psychiatry
C.J.P- Feb.1996 – Oct.2006
Only one article on FASD
= 0.O8 per cent of all articles published
A.J.P.- Jan.1996 – Sep.2007
Only one article on FASD [ 3 – 2014]
= 0.03 per cent of all articles published

PSYCHIATRIC ASSESSMENT (Calgary Consultation practice)
O’Malley , 2001 ( CDC), O’Malley 2007
57 Patients, 3 to 32 Years
40 Males, 17 Female
AXIS I
ADHD 58%,
Mood Disorder 44%
Personality Change: Labile/Aggressive 36%
AXIS II
Avoidant Personality 14%
Dependent Personality 13%
Passive/ aggressive personality 9%
Schizoid Personality 8%

Parallel Tracks
The Brain of Mental Illness The Brain of Fasd
Psychiatry and PAE/FASD are on parallel tracks. The psychiatric train is a closed train.
Those on the PAE/FASD train are reaching out but are not seen or heard.

Correlations between Prenatal Alcohol
Exposure and Mental Illnesses
Those parts of the brain known to be affected in
attention, mood and personality disorders are also
know to be affected in FASD
The functions of these parts of the brain correlate
with the disturbed behaviors of mental illness and
those afflicted with fasd.

> The brain is a complex system
PAE creates a complex chaotic system
Manipulation of a complex system by a simple
system leads to unintended consequences
The more complex the system is the greater the
unintended consequences
barry stanley www.barrystanley.com docstoc bstanley 31

Epigenetics explains the many puzzling and contradictory observations about FASD.
The brain dysfunctions of PAE are only part of the disease effect of PAE
The factor of the mother drinking in a pregnancy no longer stands alone.
The term “prenatal” for any given pregnancy has to include alcohol exposure from
both parents, including previous generations.
 The nomenclature of FASD needs to be changed to reflect our understanding of
epigenetics without diminishing acknowledgment and treatment of FASD, as occurs at
present.
 Disorders of mood and personality need to be redefined in the context of
environmental factors that cause changes in gene expression- alcohol being a major
factor.
Society needs to be aware that the manipulation of gene expression will result in
harmful unintended consequences
CONCLUSIONS

Brantford, Ontario. FETAL ALCOHOL SPECTRUM DISORDER SYMPOSIUM

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