Alcoholism and the brain: An overview

Abstract

Alcoholism can affect the brain and behavior in a variety of ways, and multiple factors can influence these effects. A person's susceptibility to alcoholism-related brain damage may be associated with his or her age, gender, drinking history, and nutrition, as well as with the vulnerability of specific brain regions. Investigators use a variety of methods to study alcoholism-related brain damage, including examining brains of deceased patients as well as neuroimaging, a technique that enables researchers to test and observe the living brain and to evaluate structural damage in the brain.

Full text

Alcoholism and the Brain:
An Overview
Marlene Oscar
-Berman, Ph.D., and Ksenija Marinkovic, Ph.D.
Alcoholism can affect the brain and behavior in a variety of ways, and multiple factors can
influence these effects. A person’s susceptibility to alcoholism-related brain damage may be
associated with his or her age, gender, drinking history, and nutrition, as well as with the
vulnerability of specific brain regions. Investigators use a variety of methods to study alcoholism-
related brain damage, including examining brains of deceased patients as well as neuroimaging, a
technique that enables researchers to test and observe the living brain and to evaluate structural
damage in the brain.
K
EY WORDS: neurobehavioral theory of AODU (alcohol and other drug use);
alcoholic brain syndrome; brain atrophy; neuropsychological assessment; neurotransmission; risk
factors; comorbidity; disease susceptibility; neuroimaging; treatment factors; survey of research
T
he brain, like most body organs,
ously affects many mental functions
at which the person began drinking, and
is vulnerable to injury from
in addition to memory (e.g., language,
the duration of drinking; the patient’s age,
alcohol consumption. The risk
reasoning, and problem-solving abili-
level of education, gender, genetic back-
of brain damage and related neuro-
ties) (Rourke and Löberg 1996). Most
ground, and family history of alcoholism;
behavioral deficits varies from person
alcoholics with neuropsychological
to person. This article reviews the
impairments show at least some improve-
many factors that influence this risk,
ment in brain structure and functioning
M
ARLENE OSCAR-BERMAN, PH.D., is a
the techniques used to study the effects
within a year of abstinence, but some
professor in the Departments of Anatomy
of alcoholism
1
on the brain and
people take much longer (Bates et al.
and Neurobiology, Psychiatry, and
behavior, and the implications of this
2002; Gansler et al. 2000; Sullivan et
Neurology, Boston University School of
research for treatment.
al. 2000). Unfortunately, little is known
Medicine, and a research career scientist
About half of the nearly 20 million
about the rate and extent to which people
at the U.S. Department of Veterans
alcoholics in the United States seem to
recover specific structural and functional
Affairs Healthcare System, Jamaica
be free of cognitive impairments. In the
processes after they stop drinking. How-
Plain Division, Boston, Massachusetts.
remaining half, however, neuropsycho-
ever,research has helped define the various
logical difficulties can range from mild
factors that influence a person’s risk for
K
SENIJA MARINKOVIC, PH.D., is a
to severe. For example, up to 2 million
experiencing alcoholism-related brain
research scientist at the Athinoula A.
alcoholics develop permanent and debil-
deficits, as the following sections describe.
Martinos Center for Biomedical Imaging,
itating conditions that require lifetime
instructor in the Radiology Department
custodial care (Rourke and Löberg 1996).
at Harvard Medical School, and assistant
Examples of such conditions include
Risk F
actors and Comorbid
in Neuroscience at the Massachusetts
alcohol-induced persisting amnesic dis-
Conditions That Influence
General Hospital, Boston, Massachusetts.
order (also called Wernicke-Korsakoff
Alcohol-Related Brain
syndrome) and dementia, which seri-
Damage
This work was supported by National
Institute on Alcohol Abuse and Alcoholism
1
Alcohol dependence, also known as alcoholism, is charac-
Alcoholism
’s effects on the brain are diverse
grants R37–AA–07112, K05–AA–
terized by a craving for alcohol, possible physical depen-
and are influenced by a wide range of
00219, K01–AA–13402, and by the
dence on alcohol, an inability to control one’s drinking on
variables (Parsons 1996). These include
Medical Research Service of the U.S.
any given occasion, and an increasing tolerance to alco-
hol’s effects (American Psychiatric Association [APA] 1994).
the amount of alcohol consumed, the age
Department of Veterans Affairs.
Vol. 27, No. 2, 2003
125

and neur
opsychiatric risk factors such as
alcohol exposure before birth and gen-
eral health status. Overall physical and
mental health is an important factor
because comorbid medical, neurologi-
cal, and psychiatric conditions can
interact to aggravate alcoholism’s effects
on the brain and behavior. Examples of
common comorbid conditions include:
•Medical conditions such as malnu-
trition and diseases of the liver and
the cardiovascular system
•Neurological conditions such as head
injury, inflammation of the brain
(i.e., encephalopathy), and fetal alcohol
syndrome (or fetal alcohol effects)
•Psychiatric conditions such as depres-
sion, anxiety, post-traumatic stress
disorder, schizophrenia, and the use
of other drugs (Petrakis et al. 2002).
These conditions also can contribute to
further drinking.
Models for Explaining
Alcohol-Related Brain
Damage
S
ome of the previously mentioned factors
that are thought to influence how alco-
holism affects the brain and behavior
have been developed into specific models
or hypotheses to explain the variability
in alcoholism-related brain deficits. The
accompanying table lists the prevailing
models (Oscar-Berman 2000). It should
be noted that the models that focus on
individual characteristics cannot be totally
separated from models that emphasize
affected brain systems because all of
these factors are interrelated. Several of
the models have been evaluated using
specialized tests that enable researchers
to make inferences about the type and
extent of brain abnormalities.
M
odels Based on Characteristics
of Individual Alcoholics
Pr
emature Aging Hypothesis.
A
ccording to this hypothesis, alcoholism
accelerates natural chronological aging,
Hypotheses Proposed to Explain the Consequences of Alcoholism for the Brain
Hypotheses Emphasizing the Personal Characteristics Associated With Vulnerability
Characteristic Hypothesis
Aging Premature aging hypothesis: Alcoholism accelerates aging. Brains of alcoholics
resemble brains of chronologically old nonalcoholics. This may occur at the onset
of problem drinking (“accelerated aging”) or later in life when brains are more
vulnerable (“increased vulnerability” or “cumulative effects”).
Gender Alcoholism affects women more than men. Although women and men metabolize
alcohol differently, it is not yet clear if women’s brains are more vulnerable than
men’s brains to the effects of alcoholism.
Family history Alcoholism runs in families; thus, children of alcoholics face increased risk of
alcoholism and associated brain changes.
Vitamin deficiency Thiamine deficiency can contribute to damage deep within the brain, leading to
severe cognitive deficits.
Hypotheses Emphasizing the Vulnerability of Brain Regions or Systems
Region/System Hypothesis
Entire brain Vulnerable to cerebral atrophy.
Limbic system, thalamus, Vulnerable to alcohol-induced persisting amnesic disorder (also known as
and hypothalamus Wernicke-Korsakoff syndrome).
Frontal lobe systems More vulnerable to the effects of alcoholism than other brain regions/systems.
Right hemisphere More vulnerable to the effects of alcoholism than the left hemisphere.*
Neurotransmitter systems Several neurotransmitter systems are vulnerable to effects of alcoholism.
(e.g., gamma-aminobutyric acid (GABA),
glutamate, dopamine, acetylcholine,
and serotonin systems)
*
hypothesis listed above.
brain scans, and post mortem neuropathology.
The right hemisphere is also believed to be more vulnerable to the effects of normal aging than the left hemisphere, which is taken as support for the premature aging
NOTE: These hypotheses are not mutually exclusive; some are interrelated. Supporting data for these models come from neurobehavioral and electrophysiological studies,
Alcohol Research & Health
126

beginning with the onset of pr
oblem
drinking.
An alternate version suggests that older
patients (age 50 and older) are especially
susceptible to the cumulative effects of
alcoholism, and aging is accelerated only
later in life. The preponderance of scientific
evidence suggests that although alcoholism-
related brain changes may mimic some
of the changes seen in older people,
alcoholism does not cause premature
aging. Rather, the effects of alcoholism
are disproportionately expressed in
older alcoholics (Oscar-Berman 2000).
G
ender.
Although it has been hypothe-
sized that women’s brain functioning
is more vulnerable to alcoholism than
men’s, studies of gender differences
have not consistently found this to be
true (see Wuethrich 2001 for a review),
even though women and men metabo-
lize alcohol differently (i.e., women
achieve higher blood alcohol contents
[BACs] than men after consuming the
same amount of alcohol). However, it
is not known whether this comparison
between men and women holds among
older populations (Oscar-Berman 2000).
F
amily History.
F
amily history of alco-
holism has been found to be important
Alcoholism and the Brain: An Overview
because it can influence such things as
tolerance for alcohol and the amount of
consumption needed to feel alcohol’s
effects. Also, studies examining brain
functioning in people with and without
a positive family history of alcoholism
have shown that there are clear differ-
ences between the groups on measures
of brain electrical activity (Porjesz and
Begleiter 1998).
V
itamin Deficiency.
R
esearch on mal-
nutrition, a common consequence of
poor dietary habits in some alcoholics,
indicates that thiamine deficiency (vita-
min B
1
) can contribute to damage deep
within the brain, leading to severe cog-
nitive deficits (Oscar-Berman 2000).
The exact location of the affected parts
of the brain and underlying neuro-
pathological mechanisms are still being
researched (see the next section).
M
odels Based on Vulnerable
Brain Systems
The outer
, convoluted layer of brain
tissue, called the cerebral cortex or the
gray matter, controls most complex men-
tal activities (see figure 1). Just beneath
it are the nerve fibers, called the white
matter, that connect different cortical
regions and link cortical cells with other
structures deep inside the brain (sub-
cortical regions).
Areas of the brain that are especially
vulnerable to alcoholism-related damage
are the cerebral cortex and subcortical
areas such as the limbic system (impor-
tant for feeling and expressing emotions),
the thalamus (important for communi-
cation within the brain), the hypothalamus
(which releases hormones in response to
stress and other stimuli and is involved
in basic behavioral and physiological
functions), and the basal forebrain (the
lower area of the front part of the brain,
involved in learning and memory)
(Oscar-Berman 2000). Another brain
structure that has recently been impli-
cated is the cerebellum (Sullivan 2000),
situated at the base of the brain, which
plays a role in posture and motor coor-
dination and in learning simple tasks.
A
lcohol-Related Brain Atrophy.
A
ccording to one hypothesis, shrinkage
(i.e., atrophy) of the cerebral cortex and
white matter, as well as possible atrophy
of basal forebrain regions, may result
from the neurotoxic effects of alcohol
(Lishman 1990). Furthermore, thiamine
deficiency may result in damage to portions
of the hypothalamus (perhaps because
blood vessels break in that region).
According to this hypothesis, alcoholics
who are susceptible to alcohol toxicity
2
may develop permanent or transient
cognitive deficits associated with brain
shrinkage. Those who are susceptible
to thiamine deficiency will develop a
mild or transient amnesic disorder, with
short-term memory loss as the salient
feature. Patients with dual vulnerability,
those with a combination of alcohol
neurotoxicity and thiamine deficiency,
will have widespread damage to large
regions of the brain, including structures
deep within the brain such as the lim-
bic system. These people will exhibit
severe short-term memory loss and col-
lateral cognitive impairments (Oscar-
Berman 2000).
Fr
ontal Lobe Vulnerability.
Although
alcoholics have diffuse damage in the
2
Some people may have better immunity than others to
alcohol’s toxic effects.
Figure 1 Schematic drawing of the human brain, showing regions vulnerable to
alcoholism-related abnormalities.
Parietal lobe
Cerebral cortex
Frontal
lobe
Hippocampal
regions
Temporal
lobe
Corpus callosum
Thalamus
Occipital
lobe
Cerebellum
Hypothalamus
{
Vol. 27, No. 2, 2003
127

cer
ebral cortex of both hemispheres
of the brain, neuropathological studies
performed on the brains of deceased
patients as well as findings derived from
neuroimaging studies of living brains
point to increased susceptibility of frontal
brain systems to alcoholism-related dam-
age (Moselhy et al. 2001; Oscar-Berman
2000; Sullivan 2000). The frontal lobes
are connected with all other lobes of
the brain (i.e., the parietal, temporal,
and occipital lobes on both halves of
the brain; see figure 1), and they receive
and send fibers to numerous subcortical
structures. Behavioral neuroscientists
have determined that the anterior region
of the frontal lobes (i.e., the prefrontal
cortex) is important for engaging in
ordinary cognitive, emotional, and
interpersonal activities. The prefrontal
cortex is considered the brain’s executive—
that is, it is necessary for planning and
regulating behavior, inhibiting the
occurrence of unnecessary or unwanted
behaviors, and supporting adaptive
“executive control” skills such as goal-
directed behaviors, good judgment,
and problem-solving abilities. Disruptions
of the normal inhibitory functions of
prefrontal networks often have the
interesting effect of releasing previously
inhibited behaviors. As a result, a person
may behave impulsively and inappro-
priately, which may contribute to
excessive drinking.
There is evidence that the frontal
lobes are particularly vulnerable to
alcoholism-related damage, and the
brain changes in these areas are most
prominent as alcoholics age (Oscar-
Berman 2000; Pfefferbaum et al. 1997;
Sullivan 2000) (see figure 2). Other
studies of frontal lobe function in older
alcoholics have confirmed reports of
a correlation between impaired neuro-
psychological performance (e.g., execu-
tive control skills, as noted above)
and decreased blood flow or metabolism
(energy use) in the frontal lobes, as seen
using neuroimaging techniques (Adams
et al. 1998).
V
ulnerability of the Right Hemisphere.
S
ome investigators have hypothesized
that functions controlled by the brain’s
right hemisphere are more vulnerable
to alcoholism-related damage than those
carried out by the left hemisphere (see
Oscar-Berman and Schendan 2000 for
review). Each hemisphere of the human
brain is important for mediating differ-
ent functions. The left hemisphere has
a dominant role in communication and
in understanding the spoken and written
word. The right hemisphere is mainly
involved in coordinating interactions
with the three-dimensional world (e.g.,
spatial cognition).
Differences between the two cerebral
hemispheres can easily be seen in patients
with damage to one hemisphere but not
the other (from stroke, trauma, or tumor).
Patients with left hemispheric damage
often have problems with language;
patients with right hemispheric damage
often have difficulty with maps, designs,
music, and other nonlinguistic materials,
and they may show emotional apathy.
Alcoholics may seem emotionally
“flat” (i.e., they are less reactive to emo-
tionally charged situations), and may
Figure 2 Brain MRI scans of age-equivalent men with different histories of alcohol use. The image shows clear evidence of
brain shrinkage in the alcoholic compared with the control subject. The graph on the right shows that older alco-
holics have less cortical tissue than younger alcoholics, and that the prefrontal cortex is especially vulnerable to
alcohol’s effects. The location of the temporal, parietal, and occipital regions of the brain can be seen in figure 1.
*Z-score is a mathematical measure that is useful for showing the difference between the recorded value and a “normal” value.
SOURCE: Pfefferbaum et al. 1997.
Control Subjects
Prefrontal
Temporal
1
0
-1
-2
Z-score
Frontal Ant PostAnt Post
Parietal Occipital
Younger Alcoholics (N=33)
Older Alcoholics (N=29)
Alcoholic Control Subject
Lifetime consumption of alcohol was
1866 kg 60 kg
or 625 gallons or 20 gallons
57-year-old men
Cortical Gray Matter Volumes
Alcohol Research & Health
128

hav
e difficulty with the same kinds of
tasks that patients with damage to the
right hemisphere have difficulty with.
New research has shown that alcoholics
are impaired in emotional processing,
such as interpreting nonverbal emotional
cues and recognizing facial expressions
of emotion (Kornreich et al. 2002;
Monnot et al. 2002; Oscar-Berman 2000).
Yet, despite the fact that emotional
functioning can be similar in some alco-
holics and people with right hemi-
sphere damage, research provides only
equivocal support for the hypothesis that
alcoholism affects the functioning of the
right hemisphere more than the left
(Oscar-Berman and Schendan 2000).
Impairments in emotional functioning
that affect alcoholics may reflect abnor-
malities in other brain regions which also
influence emotional processing, such as
the limbic system and the frontal lobes.
Disr
uption of Neurotransmitter
Systems.
B
rain cells (i.e., neurons)
communicate using specific chemicals
called neurotransmitters. Neuronal
communication takes place at the
synapse, where cells make contact.
Specialized synaptic receptors on the
surface of neurons are sensitive to spe-
cific neurotransmitters. Alcohol can
change the activity of neurotransmitters
and cause neurons to respond (excitation)
or to interfere with responding (inhibi-
tion) (Weiss and Porrino 2002), and
different amounts of alcohol can affect
the functioning of different neuro-
transmitters. Over periods of days and
weeks, receptors adjust to chemical and
environmental circumstances, such as the
changes that occur with chronic alcohol
consumption, and imbalances in the
action of neurotransmitters can result in
seizures, sedation, depression, agitation,
and other mood and behavior disorders.
The major excitatory neurotransmitter
in the human brain is the amino acid
glutamate. Small amounts of alcohol
have been shown to interfere with glu-
tamate action. This interference could
affect several brain functions, including
memory, and it may account for the
short-lived condition referred to as
“alcoholic blackout.” Chronic alcohol
consumption increases glutamate
receptor sites in the hippocampus, an
Alcoholism and the Brain: An Overview
area in the limbic system that is crucial
to memory and often involved in epilep-
tic seizures. During alcohol withdrawal,
glutamate receptors that have adapted
to the long-term presence of alcohol
may become overactive, and this over-
activity has been repeatedly linked to
neuronal death, which is manifested by
conditions such as stroke and seizures.
Deficiencies of thiamine caused by
malnutrition may contribute to this
potentially destructive overactivity
(Crews 2000).
Gamma-aminobutyric acid (GABA)
is the major inhibitory neurotransmitter.
Available evidence suggests that alcohol
3
initially potentiates GABA’s effects (i.e.,
it increases inhibition, and often the
brain becomes mildly sedated). However,
over time, prolonged, excessive alcohol
consumption reduces the number of
GABA receptors. When the person stops
drinking, decreased inhibition combined
with a deficiency of GABA receptors
may contribute to overexcitation through-
out the brain. This in turn can con-
tribute to withdrawal seizures within a
day or two. It should be noted that the
balance between the inhibitory action
of GABA and the excitatory action of
glutamate is a major determinant of the
level of activity in certain regions of the
brain; the effects of GABA and gluta-
mate on withdrawal and brain function
are probably interactive (see Valenzuela
1997 for review).
Alcohol directly stimulates release of
the neurotransmitter serotonin, which
is important in emotional expression,
and of the endorphins, natural substances
related to opioids, which may contribute
to the “high” of intoxication and the
craving to drink. Alcohol also leads to
increases in the release of dopamine (DA),
a neurotransmitter that plays a role in
motivation and in the rewarding effects
of alcohol (Weiss and Porrino 2002).
Changes in other neurotransmitters such
as acetylcholine have been less consis-
tently defined. Future research should
help to clarify the importance of many
neurochemical effects of alcohol con-
sumption. Furthermore, areas amenable
to pharmacological treatment could be
3
The amount of alcohol needed to cause this effect
depends on the person.
identified by studying regionally specific
brain neurochemistry in vivo using
neuroimaging methods such as positron
emission tomography (PET) and single
photon emission computerized tomog-
raphy (SPECT) (described below).
New information from neuroimag-
ing studies could link cellular changes
directly to brain consequences observed
clinically. In the absence of a cure for
alcoholism, a detailed understanding of
the actions of alcohol on nerve cells may
help in designing effective therapies.
T
echniques for Studying
Alcohol-Related Brain
Damage
R
esearchers use multiple methods to
understand the etiologies and mecha-
nisms of brain damage across subgroups
of alcoholics. Behavioral neuroscience
offers excellent techniques for sensi-
tively assessing distinct cognitive and
emotional functions—for example, the
measures of brain laterality (e.g., spatial
cognition) and frontal system integrity
(e.g., executive control skills) mentioned
earlier. Followup post mortem examina-
tions of brains of well-studied alcoholic
patients offer clues about the locus and
extent of pathology and about neuro-
transmitter abnormalities. Neuroimaging
techniques provide a window on the
active brain and a glimpse at regions with
structural damage.
Behavioral N
euroscience
B
ehavioral neuroscience studies the
relationship between the brain and its
functions—for example, how the brain
controls executive functions and spatial
cognition in healthy people, and how
diseases like alcoholism can alter the
normal course of events. This is accom-
plished by using specialized tests designed
expressly to measure the functions of
interest. Among the tests used by scientists
to determine the effects of alcoholism
on executive functions controlled by
the frontal lobes are those that measure
problem-solving abilities, reasoning,
and the ability to inhibit responses that
are irrelevant or inappropriate (Moselhy
et al. 2001; Oscar-Berman 2000). Tests
Vol. 27, No. 2, 2003
129

to measur
e spatial cognition controlled
by the right hemisphere include those
that measure skills important for recog-
nizing faces, as well as those that rely on
skills required for reading maps and
negotiating two- and three-dimensional
space (visuospatial tasks) (Oscar-Berman
and Schendan 2000). With the advent
of sophisticated neuroimaging techniques
(described below), scientists can even
observe the brain while people perform
many tasks sensitive to the workings of
certain areas of the brain.
N
europathology
R
esearchers have gained important
insights into the anatomical effects
of long-term alcohol use from studying
the brains of deceased alcoholic patients.
These studies have documented
alcoholism-related atrophy throughout
the brain and particularly in the frontal
lobes (Harper 1998). Post mortem
studies will continue to help researchers
understand the basic mechanisms of
alcohol-induced brain damage and
regionally specific effects of alcohol
at the cellular level.
N
euroimaging
R
emarkable developments in neuroimag-
ing techniques have made it possible to
study anatomical, functional, and bio-
chemical changes in the brain that are
caused by chronic alcohol use. Because
of their precision and versatility, these
techniques are invaluable for studying
the extent and the dynamics of brain
damage induced by heavy drinking.
Because a patient’s brain can be scanned
on repeated occasions, clinicians and
researchers are able to track a person’s
improvement with abstinence and
deterioration with continued abuse.
Furthermore, brain changes can be
correlated with neuropsychological
and behavioral measures taken at the
same time. Brain imaging can aid in
identifying factors unique to the
individual which affect that person’s
susceptibility to the effects of heavy
drinking and risk for developing depen-
dence, as well as factors that contribute
to treatment efficacy.
I
maging of Brain Structure.
W
ith
neuroimaging techniques such as com-
puterized tomography (CT) and mag-
netic resonance imaging (MRI), which
allow brain structures to be viewed
inside the skull, researchers can study
brain anatomy in living patients. CT
scans rely on x-ray beams passing
through different types of tissue in the
body at different angles. Pictures of the
“inner structure” of the brain are based
on computerized reconstruction of the
paths and relative strength of the x-ray
beams. CT scans of alcoholics have
revealed diffuse atrophy of brain tissue,
with the frontal lobes showing the ear-
liest and most extensive shrinkage
(Cala and Mastaglia 1981).
MRI techniques have greatly influ-
enced the field of brain imaging because
they allow noninvasive measurement
of both the anatomy (using structural
MRI) and the functioning (using func-
tional magnetic resonance imaging
[fMRI], described below) of the brain
with great precision. Structural MRI
scans are based on the observation that
the protons derived from hydrogen
atoms, which are richly represented in
the body because of its high water con-
tent, can be aligned by a magnetic field
like small compass needles. When pulses
are emitted at a particular frequency,
the protons briefly switch their alignment
and “relax” back into their original state
at slightly different times in different
types of tissue. The signals they emit are
detected by the scanner and converted
into highly precise images of the tissue.
MRI methods have confirmed and
extended findings from post mortem
and CT scan studies—namely, that
chronic use of alcohol results in brain
shrinkage. This shrinkage is most marked
in the frontal regions and especially in
older alcoholics (Oscar-Berman 2000;
Pfefferbaum et al. 1997; Sullivan 2000).
Other brain regions, including portions
of the limbic system and the cerebel-
lum, also are vulnerable to shrinkage.
I
maging of Brain Function: Hemo-
dynamic Methods.
H
emodynamic
methods create images by tracking
changes in blood flow, blood volume,
blood oxygenation, and energy metab-
olism that occur in the brain in response
to neural activity. PET and SPECT are
used to map increased energy consump-
tion by the specific brain regions that are
engaged as a patient performs a task.
One example of this mapping involves
glucose, the main energy source for the
brain. When a dose of a radioactively
labeled glucose (a form of glucose that
is absorbed normally but cannot be
fully metabolized, thus remaining
“trapped” in a cell) is injected into the
bloodstream of a patient performing a
memory task, those brain areas that
accumulate more glucose will be impli-
cated in memory functions. Indeed,
PET and SPECT studies have confirmed
and extended earlier findings that the
prefrontal regions are particularly sus-
ceptible to decreased metabolism in alco-
holic patients (Berglund 1981; Gilman
et al. 1990). It is important to keep in
mind, however, that frontal brain sys-
tems are connected to other regions of
the brain, and frontal abnormalities may
therefore reflect pathology elsewhere
(Moselhy et al. 2001).
Even though using low doses of
radioactive substances that decay quickly
minimizes the risks of radiation expo-
sure, newer and safer methods have
emerged, such as MRI methods. MRI
is noninvasive, involves no radioactive
risks, and provides both anatomical
and functional information with high
precision. The fMRI method is sensi-
tive to metabolic changes in the parts
of the brain that are activated during
a particular task. A local increase in
metabolic rate results in an increased
delivery of blood and increased oxy-
genation of the region participating in
a task. The blood oxygenation level–
dependent (BOLD) effect is the basis
of the fMRI signal. Like PET and
SPECT, fMRI permits observing the
brain “in action,” as a person performs
cognitive tasks or experiences emotions.
In addition to obtaining structural
and functional information about the
brain, MRI methodology has been
used for other specialized investigations
of the effects of alcohol on the brain.
For example, structural MRI can clearly
delineate gray matter from white matter
but cannot detect damage to individual
nerve fibers forming the white matter.
By tracking the diffusion of water mol-
Alcohol Research & Health
130

ecules along neur
onal fibers, an MRI
technique known as diffusion tensor
imaging (DTI) can provide information
about orientations and integrity of nerve
pathways, confirming earlier findings from
post mortem studies which suggested that
heavy drinking disrupts the microstruc-
ture of nerve fibers. Moreover, the find-
ings correlate with behavioral tests of
attention and memory (Pfefferbaum
et al. 2000). These nerve pathways are
critically important because thoughts and
goal-oriented behavior depend on the
concerted activity of many brain areas.
Another type of MRI application,
magnetic resonance spectroscopy imag-
ing (MRSI), provides information
about the neurochemistry of the living
brain. MRSI can evaluate neuronal
health and degeneration and can detect
the presence and distribution of alcohol,
certain metabolites, and neurotransmitters.
I
maging of Brain Function: Electro-
magnetic Methods.
In
spite of their
excellent spatial resolution—that is,
the ability to show precisely where the
activation changes are occurring in the
brain—hemodynamic methods such as
PET, SPECT, and fMRI have limita-
tions in showing the time sequence of
these changes. Activation maps can reveal
brain areas involved in a particular task,
but they cannot show exactly when these
areas made their respective contributions.
This is because they measure hemodynamic
changes (blood flow and oxygenation),
indicating the neuronal activation only
indirectly and with a lag of more than a
second. Yet, it is important to under-
stand the order and timing of thoughts,
feelings, and behaviors, as well as the
contributions of different brain areas.
The only methods capable of online
detection of the electrical currents in
neuronal activity are electromagnetic
methods such electroencephalography
(EEG), event-related brain potentials
(ERP),
4
and magnetoencephalography
4
The ERP method is considered derived from electroen-
cephalography.
Alcoholism and the Brain: An Overview
(MEG). EEG reflects electrical activity
measured by small electrodes attached
to the scalp. Event-related potentials are
obtained by averaging EEG voltage
changes that are time-locked to the pre-
sentation of a stimulus such as a tone,
image, or word. MEG uses sensors in a
machine that resembles a large hair dryer
to measure magnetic fields generated
by brain electrical activity. These tech-
niques are harmless and give us insight
into the dynamic moment-to-moment
changes in electrical activity of the brain.
They show when the critical changes
are occurring, but their spatial resolu-
tion is ambiguous and limited.
ERP and MEG have confirmed that
alcohol exerts deleterious effects on
multiple levels of the nervous system.
These effects include impairment of the
lower-level brain stem functions result-
ing in behavioral symptoms such as
dizziness, involuntary eye movement
(i.e., nystagmus), and insecure gait,
as well as impairment of higher order
functioning such as problem solving,
memory, and emotion. ERP and MEG
are remarkably sensitive to many alcohol-
related phenomena and can detect
changes in the brain that are associated
with alcoholism, withdrawal, and absti-
nence. That is, these methods show dif-
ferent activity patterns between healthy
and alcohol-dependent individuals,
those in withdrawal, and those with a
positive family history of alcoholism.
As shown in figure 3, when brain elec-
trical activity is measured in response
to target stimuli (which require the
subject to respond in some way) and
nontarget stimuli (to be ignored by the
subject), the brains of alcoholics are less
responsive than the brains of nonalco-
holic control subjects. Some of the ERP
abnormalities observed in alcoholics do
not change with abstinence, and simi-
lar abnormalities have been reported in
patients who do not drink but come
from families with a history of alcoholism.
The possibility that such abnormalities
may be genetic markers for the predis-
position for alcoholism is under inten-
sive scrutiny in studies combining genetic
and electromagnetic measures in people
with or without a family history of
alcoholism (Porjesz and Begleiter 1998).
0 100 200 300 400 500 0 100 200 300 400 500
Control Subjects
AB
Time (mS)
Response to target stimuli
Response to nontarget stimuli
Time (mS)
Alcoholics
Voltage (mV)
Voltage (mV)
Figure 3 Brain electrical activity measured as event-related potentials (ERPs) in
response to target stimuli (which require the subject to respond in some
way) and nontarget stimuli (to be ignored by the subject). The brains of
alcoholics are less responsive than the brains of nonalcoholic control
subjects. The heights of the peaks are measured in terms of the strength
of the electrical signal (volts) recorded from the scalp over time (in thou-
sandths of a second, or mS).
SOURCE: Porjesz and Begleiter 1995.
Vol. 27, No. 2, 2003
131

Implica
tions for Treatment
B
ecause alcoholism is associated with
diverse changes to the brain and behav-
ior, clinicians must consider a variety of
treatment methods to promote cessation
of drinking and recovery of impaired
functioning. With an optimal combina-
tion of neuropsychological observations
and structural and functional brain
imaging results, treatment professionals
may be able to develop a number of
predictors of abstinence and relapse
outcomes, with the purpose of tailoring
treatment methods to each individual
patient. Neuroimaging methods have
already provided significant insight into
the nature of brain damage caused by
heavy alcohol use, and the integration
of results from different methods of
neuroimaging will spur further advances
in the diagnosis and treatment of
alcoholism-related damage. Clinicians
also can use brain imaging techniques to
monitor the course of treatment because
these techniques can reveal structural,
functional, and biochemical changes in
living patients across time as a result of
abstinence, therapeutic interventions,
withdrawal, or relapse. For example,
functional imaging studies might be used
to evaluate the effectiveness of drugs
such as naltrexone on withdrawal-induced
craving. (Naltrexone is an anticraving
medicine that suppresses GABA activity.)
Additionally, neuroimaging research
already has shown that abstinence of less
than a month can result in an increase
in cerebral metabolism, particularly in
the frontal lobes, and that continued
abstinence can lead to at least partial
reversal in loss of brain tissue (Sullivan
2000). Neuroimaging indicators also can
be useful in prognosis, permitting identi-
fication and timely treatment of patients
at high risk for relapse.
Summary
Alcoholics ar
e not all alike; they experi-
ence different subsets of symptoms, and
the disease has different origins for dif-
ferent people. Therefore, to understand
the effects of alcoholism, it is important
to consider the influence of a wide range
of variables. Researchers have not yet
found conclusive evidence for the idea
that any one variable can consistently
and completely account for the brain
deficits found in alcoholics. The most
plausible conclusion is that neurobe-
havioral deficits in some alcoholics result
from the combination of prolonged
ingestion of alcohol, which impairs the
way the brain normally works, and
individual vulnerability to some forms
of brain damage. Characterizing what
makes alcoholics “vulnerable” remains
the subject of active research.
In the search for answers, it is neces-
sary to use as many kinds of tools as
possible, keeping in mind that specific
deficits may be observed only with cer-
tain methods, specific paradigms, and
particular types of people with distinct
risk factors. Neuroscience provides sen-
sitive techniques for assessing changes
in mental abilities and observing brain
structure and function over time. When
techniques are combined, it will be pos-
sible to identify the pattern, timing, and
distribution of the brain regions and
behaviors most affected by alcohol use
and abuse. Electromagnetic methods
(ERP and MEG) specify the timing of
alcohol-induced abnormalities, but the
underlying neural substrate (i.e., the
anatomical distribution of the participating
brain areas) cannot be unequivocally
evaluated based on these methods alone.
Conversely, the hemodynamic methods
(fMRI, PET, and SPECT) have good
spatial resolution but offer little infor-
mation about the sequence of events.
Drawing on the respective advantages of
these complementary methods, an inte-
grated multimodal approach can reveal
where in the brain the critical changes are
occurring, as well as the timing and
sequence in which they happen (Dale
and Halgren 2001). Such confluence of
information can provide evidence linking
structural damage, functional alterations,
and the specific behavioral and neuropsy-
chological effects of alcoholism. These
measures also can determine the degree to
which abstinence and treatment result in
the reversal of atrophy and dysfunction.
■
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