COSIG CONFERENCE BROCHURE.pdf - Drexel University College ...

Fetal alcohol spectrum disorders for mental health professionals Lockhart 465
susceptible to the same pattern, duration, timing, and
dose of alcohol. Because heavy maternal alcohol
consumption leads to full FAS features in 25±45% of
exposed pregnancies, other factors seem to in¯uence the
outcome of the fetus [2,3]. Constitutional genetic factors,
smoking, other drug use, physical illness and infection,
poor nutrition, trauma, stress, parity, age of the mother,
and having given birth to a child previously with FAS,
are all factors related to the severity of alcohol-related
neurotoxicity in the fetus [2,3].
Alcohol has been shown in numerous human and animal
studies to have potent direct and indirect effects on the
developing brain, with there appearing to be no safe
level of prenatal alcohol exposure [2,3]. Genetic
variability and the degree of the other in¯uences
described above in both the fetus and the mother,
seem to modulate its deleterious effects in certain
individuals in whom the blood alcohol concentration has
been high throughout gestation. Several studies demonstrate
that `binge' drinking (intermittent drinking
leading to high blood levels) is associated with more
severe CNS effects than the continuous consumption of
alcohol throughout pregnancy [13 . ]. The production of
high blood alcohol concentrations intermittently
throughout pregnancy appears to cause the most
extreme cases of prenatal alcohol-related disability in
those susceptible [13 . ].
Central nervous system effects
Alcohol's neurotoxic effects [14,15 . ] have been shown to
cause a disturbance of the normal architecture of the
brain along a continuum in a `dose±response' relationship.
Autopsy ®ndings demonstrate the range of severe
CNS malformations that can be caused by this neurotoxin.
The vulnerability of the CNS to alcohol is related
to: the developmental period during which the exposure
occurs, the dose, and the sensitivity of the brain region to
alcohol's toxic effects. For example is has been shown
that alcohol can trigger massive neurodegeneration
through apoptosis (programmed cell death) during one
of the most vulnerable periods of gestation ± synaptogenesis
(extending from 6 months of gestation to several
years after birth). By blockade of N-methyl, D-aspartate
(NMDA) glutamate receptors and excessive activation of
gamma-butyric acid (GABA), prenatal alcohol exposure
can cause the death of millions of neurons in the rat
forebrain. This can result in reduced brain mass, and in
the case of the human infant, the possibility of later
neuropsychiatric problems among other dif®culties [16].
It is demonstrated in numerous studies that cell types
throughout the CNS, and cell types within the same
structure appear to be differentially sensitive to alcohol's
neurotoxic effects during different times in gestation
[17,18 . ].
Alcohol's effects can also cause less dendritic branching
in the frontal and parietal lobes, causing fewer connections
with neighboring neurons. Studies conducted over
the past two decades [17,19±21] demonstrate alcoholinduced
defects in neuronal migration, reduced number
of neurons in the mature cortex with the same origin,
delay in cortical neurons being generated, and alteration
in the distribution of neurons on a speci®c day. Studies
further suggest that alcohol has an effect on the
`desynchronization' of radial glia (precursor cells) into
astroglia. The results of this desynchronization lead to
late generated neurons unable to complete their migration
to the super®cial cortex; resulting in neurons being
stranded in the deep cortex in certain cases. The impact
of desynchronization may then lead to cortical neurons
having dif®culty establishing normal circuitry, and
therefore dif®culties establishing normal CNS architecture
[19±21]. Adding to these ®ndings, Archibald et al.
[22 . ] found that white matter volumes, especially in the
parietal lobe, are more affected than gray matter
volumes, emphasizing the deleterious effect alcohol
may have on normal myelination in the CNS. The
cortex therefore is particularly sensitive to alcohol,
leading to a thinner cortex, reduced overall mass, fewer
neurons and a reduced number of glia. Other structures
of the brain that appear particularly sensitive to the
direct and indirect effects of alcohol include the corpus
callosum [23 . ], basal ganglia (particularly the caudate)
[24] and cerebellar vermis (lobules I±V)] [25].
In selected studies, dopamine and norepinephrine
[26 .. ], serotonin [27], glutamate [28 . ], gamma-aminobutyric
acid [29 . ] and other neurotransmitter systems have
all been found to be affected as a consequence of early
prenatal alcohol exposure. These neurotransmitter abnormalities
and structural brain changes are of prime
importance in the etiology of speci®c neuropsychiatric
conditions, mental retardation, and other cognitive
disorders.
Positron emission tomography (PET) studies have
demonstrated that even in brains without obvious gross
pathological changes, disturbances in the metabolism of
certain structures are evident (e.g. caudate nucleus)
[29 . ]. This indicates that even when the brain is
displaying no visible changes in its gross architecture,
the damage can be microscopic. These changes that are
not readily obvious can also lead to disturbances in
cognition and behavior. Behavior problems in particular
appear to be the most sensitive indicator of the presence
of prenatal alcohol-related disability [29 . ].
As the next section indicates, when these structural and
neurotransmitter abnormalities are combined, they may
form the neurobiological substrate of such problems as:
altered response inhibition, memory disturbances, and