Alcoholics exhibit a number of neurocognitive deficits ranging from
impaired memory capacity to limited abstract thinking, some of which result
from the direct adverse effect of alcohol on the brain. It appears, however,
that some cognitive deficits reflect the pres ence of an underlying liver disease.
The neurocogni tive deficiencies that occur with liver disease reveal the link
between liver dysfunction and impaired brain function.
The central nervous system (CNS) can be adversely affected by a damaged liver.
Evidence suggests that impaired liver function, resulting from alcohol abuse
as well as other causes, can produce subtle but measurable cognitive deficits
(Tarter et al. 1984a). It is well established that chronic alcohol consumption
in animals has a direct toxic effect on the brain (Freund 1985). This effect,
however, does not appear to explain the spectrum of cognitive deficits that
commonly are observed in alcoholics.
The liver is the primary site of alcohol metabolism and can be severely affected
by chronic alcohol use. Positioned beneath the diaphragm in the abdominal
cavity, this organ acts as a detoxification center by removing toxic substances
(i.e., byproducts of metabolism and drugs) from the blood. Although some alcoholics
exhibit no evidence of liver damage or dysfunction, alcohol abuse can produce
this wide spectrum of liver injury:
- Fatty liver--a benign and reversible condition that causes mild pathological
damage, yet no clinical dysfunction.
- Alcoholic hepatitis--a more serious condition that causes increasing destruction
of hepatic (liver) tissue and produces varying degrees of liver dysfunction.
- Alcoholic cirrhosis--an advanced form of hepatic degeneration, characterized
by diffuse scarring of the liver. If an individual abstains from alcohol
consumption, the liver can function normally, without apparent injury. Alcoholic
cirrhosis is only one type of cirrhosis. Cirrhosis can develop in nonalcoholic
individuals who have liver damage due to a nutritional deficiency or to
viral or bacterial infections.
- Alcohol hepatitis plus cirrhosis--a serious condition that can produce
severe injury (abnormal pathology) and severe dysfunction (impaired function).
When the liver becomes diseased, its ability to metabolize, digest, and detoxify
can become impaired. Impaired liver function contributes to the disruption
of proper functioning of other systems that depend, in part, upon normal liver
activity, leading to kidney failure, changes in blood chemistry and blood
clotting, gastrointestinal bleeding, and brain disorders.
Primary hepatic encephalopathy, a brain dysfunction associated with both
alcoholic hepatitis and cirrhosis, is caused by a metabolic liver disorder.
The condition is marked by both altered intellectual function and emotion,
as well as disturbed psychomotor and behavioral regulation (for a more comprehensive
review, see Jones and Gammal 1988). The specific biochemical mechanisms of
hepatic encephalopathy are extremely complex. Moreover, our understanding
of the link between liver dysfunction and brain function is far from complete.
Results of our studies, as well as findings reported by others, indicate
that the neurocognitive deficits (e.g., motor speed, abstraction) observed
in alcoholic and nonalcoholic patients with cirrhosis have a similar pattern
and severity (Tarter et al. 1988). These findings suggest that cirrhosis,
more than alcoholism, per se, may be one of the most important factors underlying
neurocognitive deficits commonly observed in alcoholic populations. Some of
these cognitive deficits, however, cannot be attributed to hepatic encephalopathy:
Alcoholic individuals with cirrhosis do not perform as well as nonalcoholic
individuals with cirrhosis on several cognitive tests (e.g., memory) (Arria
et al. in submission a). A more comprehensive battery of assessment tests
than those administered currently may reveal that, in addition to diminished
memory capacity, other higher order brain functions (e.g., abstract thought,
learning) also may be impaired.
In alcoholic individuals, there is a correlation between certain biochemical
measures of liver injury and function and performance on cognitive tests (Tarter
et al. 1986). In addition, a recent study in our laboratory demonstrated that,
with the exception of memory capacity, most alcoholics return to normal cognitive
and psychomotor functioning following liver transplantation (Arria et al.
in submission b). These provocative findings illustrate that hepatic encephalopathy
may be a major determinant of the neuropsychological disturbances found in
alcoholics.
PORTAL SYSTEMIC ENCEPHALOPATHY
Portal systemic encephalopathy (PSE), the most common form of hepatic encephalopathy,
is a cerebral complication of cirrhosis that causes disruption of consciousness,
emotional regulation, and mental efficiency and, in its advanced stages, hepatic
coma (Zieve 1979). Clinicians observe major biochemical aberrations, which
arise from impaired liver function, in tandem with PSE (e.g., elevated levels
of ammonia and glutamine, diminished glucose and oxygen consumption). It is
important to note that although PSE is associated with these biochemical changes,
no single biochemical factor appears to be responsible for the many symptoms
related to PSE in humans. In addition, the biochemical disturbances detailed
below may not be present in all individuals; their expression depends on the
intrahepatic and extrahepatic factors within each person. Researchers believe,
however, that PSE is a consequence of the inability of the liver to perform
its normal metabolic detoxification function.
In a healthy individual, the liver serves as a detoxification center that
breaks down toxins, particularly such nitrogen-containing substances as ammonia,
so that they may be excreted into either bile or urine. Ammonia is a toxin
that is a normal byproduct of protein digestion; it is carried to the liver,
via the portal vein, where the liver selectively can remove the toxin from
the circulating blood. In a cirrhotic liver, however, blood flow often is
shunted around rather than through the organ. In addition, an intrinsic reduction
in liver cell function occurs with cirrhosis. Thus, toxins that can impede
proper brain function remain in the plasma.
Individuals with PSE often are found to have increased levels of ammonia
and the amino acid glutamine in the blood, brain, spinal fluid, and muscles
as a consequence of the impaired liver function. Glutamine is the major transport
protein for ammonia. Normally, ammonia is transported via the blood from peripheral
tissues to the liver where it is changed to urea. Because ammonia is neurotoxic,
it must be converted by the body into a nontoxic compound to be transported
through the blood. In many tissues, ammonia is combined enzymatically with
glutamate to yield glutamine. Ammonia toxicity may be a significant determinant
in the development of PSE. Glutamine transports ammonia from peripheral tissues
to the liver, acting as a neutral nontoxic compound that can pass readily
through cell membranes.
Decreased brain glucose and oxygen consumption are associated with PSE. Oxygen
is vital for sustaining normal brain functions. Glucose, stored in the liver
as glycogen, supplies the primary source of energy for work performed by cells.
The liver is involved in regulating and maintaining blood glucose concentrations;
as energy requirements increase in the body, glycogen is broken down and released
as glucose. This process is disrupted in the cirrhotic liver: Decreased glucose
metabolism results in a decreased availability of glucose to the brain. Thus,
decreased glucose and oxygen consumption by the brain can result in diminished
systemic energy. Although clinicians often do not understand fully the correlation
between these biochemical abnormalities and PSE, these observed changes may
be responsible for the fatigue that often is reported by patients with PSE.
Increased short-chain fatty acid levels have been observed in the blood and
may appear in the brain of patients with PSE. These fatty acids result from
the incomplete metabolism of fatty substances in the intestine and interfere
with the conversion of ammonia to urea in the liver. Researchers have found
that short-chain fatty acids potentiate the neurotoxicity of ammonia in animals
(Zieve 1979). In addition, they appear to act as an anesthetic in the brain.
Individuals with PSE have altered plasma amino acid ratios resulting from
increases in aromatic amino acids and decreases in branched-chain amino acid
levels. These amino acids, which differ in structure, are important for brain
metabolism. Alcohol and its metabolites may directly affect amino acid metabolism;
alcohol-induced liver injury and nutritional imbalances contribute to abnormal
plasma amino acid composition. Increased levels of aromatic amino acids and
decreased levels of branched-chain amino acids favor the production of "false"
neurotransmitters (i.e., octopamine) and are associated with diminished levels
of "true" neurotransmitters (i.e., GABA, dopamine) in the brain and the blood
of PSE individuals. (A neurotransmitter is a chemical messenger released by
a brain cell to excite or inhibit adjacent brain cells.) "False" neurotransmitters
displace "true" neurotransmitters at brain receptors, possibly accounting
for ineffective neurotransmission.
Increased mercaptan levels have been noted in patients with PSE. Mercaptans
are a class of substances that result from the metabolism of the amino acid
methionine. Although the link between elevated mercaptan levels and PSE development
is unclear, researchers have determined that mercaptans are highly neurotoxic
and can induce hepatic coma: Mercaptan levels increase in the brain because
the injured liver cannot detoxify these substances. In addition, their toxicity
is enhanced in the presence of elevated ammonia levels that occur with cirrhosis.
It also is thought that increased GABA (gamma-aminobutyric acid), the major
inhibitory neurotransmitter in the brain, also may play a key role in the
expression of hepatic encephalopathy. Jones and Skolnick (1990) have reviewed
extensively the neurochemical aberrations that may be involved in the development
of hepatic encephalopathy.
CLINICAL MANIFESTATIONS OF PSE
Traditionally, PSE has been graded into four distinct stages based upon clinical
characteristics, as summarized in table 1. A grade of zero is given if no overt abnormality is present.
Despite the apparent absence of clinical signs or symptoms of encephalopathy,
however, subtle cerebral dysfunction that can be detected by neuropsychological
tests often is present in individuals (Rikkers et al. 1978). The label of
"subclinical" or "latent" hepatic encephalopathy can be assigned to these
individuals based on the presence of neurocognitive impairments (e.g., decreased
memory capacity, impaired psychomotor function) measured by neuropsychological
tests. This group probably comprises the largest percentage of patients with
hepatic encephalopathy.
The severity of encephalopathy can progress rapidly through the various stages
summarized in table 1. This progression can occur as
the result of medical deterioration, gastrointestinal bleeding, dietary overload
of animal protein, a confounding infection, or changes in electrolyte balance.
(Electrolytes are elements such as sodium or potassium that convey an electrical
impulse when in solution.) In addition to its acute manifestations, the encephalopathy
can exist in a chronic and a low-grade form. Typically, individuals do not
progress to stage 2 (moderate) severity without health care professionals
noting the existence of a problem. However, it can be difficult to determine
the stage of an individual's disease. Repeated episodes of acute encephalopathy
can superimpose on a chronic low-grade liver disorder. Hence, it is not uncommon
for an alcoholic with low-grade encephalopathy to lapse suddenly into an acute
hepatic encephalopathy or coma as a result of a change in medical status or
external stress (e.g., hypothermia).
Much of our knowledge about the natural history and clinical presentation
of hepatic encephalopathy is based upon studies of alcoholics because these
individuals comprise the largest population of persons with liver disease.
Only recently have researchers attempted to elucidate the type and severity
of cerebral dysfunction in alcoholic as well as in nonalcoholic individuals
with liver disease. These efforts have been conducted to determine the specific
contributions of alcoholism and liver disease to cerebral disturbances that
frequently are reported in alcoholics with cirrhosis. Prior investigations
of hepatic encephalopathy conducted by hepatologists have focused almost exclusively
on alcoholics whose drinking history has confounded the results about the
source of the encephalopathy. Conversely, studies of alcoholics conducted
by neuroscientists have almost ignored the potential impact of advanced chronic
liver disease on CNS integrity. Thus, neuroscientists and medical researchers
need to integrate their expertise and knowledge to evaluate the specific contributions
of liver disease and alcohol abuse, per se, on brain disturbances observed
in alcoholics with cirrhosis.
COGNITIVE DEFICITS ASSOCIATED WITH ALCOHOLISM
The majority of alcoholics in treatment exhibit a variety of cognitive impairments
(Parsons et al. 1987). Neuropsychological tests reveal deficits in visuospatial
capacity, learning and memory, psychomotor efficiency, and abstracting ability.
These processes are critical for everyday functioning.
For example, impaired visuospatial capacity prevents a person from organizing
and analyzing elements of his or her visual field, thereby limiting the execution
of the appropriate motor responses. In effect, this impairment can affect
an individual's ability to drive a car or operate machinery. A deficiency
in the capacity to learn and store information for subsequent recall is disruptive
in all aspects of everyday life. Impaired psychomotor efficiency requiring
eye-hand coordination and control of fine motor movements can increase chances
of accidental injury. Reduced abstracting ability, such as the capacity to
form concepts, solve problems, and think flexibly, could compromise psychosocial
adjustment severely.
As society becomes technologically more complex, more subtle neurologic disturbances
may impede everyday adjustment. With this in mind, it is important to note
that almost 75 percent of alcoholic individuals commonly express some form
of cognitive impairment, although the prevalence varies from sample to sample
of alcoholic individuals (Goldstein and Shelly 1980).
The neurologic deficits found in alcoholics can result from such factors
as head trauma or malnutrition. Neuropsychological deficits normally are not
evident among alcoholic individuals who are medically intact and have no history
of head trauma (Grant et al. 1984). These findings suggest that disease status
concomitant to the alcoholism influences the manifestation of cerebral disturbance.
Such disease status often is the result of nutritional deficiency and liver
disease.
Nutritional Deficiency
Nutritional deficiency--resulting from dietary insufficiency (as an individual
substitutes the calories from alcohol for calories from regular meals) or
from concomitant liver disease--can compound the effects of alcohol on the
brain. Vitamin B deficiencies are common in alcoholic patients. Chronic vitamin
B-1 deficiency, for example, can precipitate a Wernicke's encephalopathy,
which typically progresses to the chronic, irreversible Korsakoff's (amnestic)
syndrome, characterized by an inability to remember recent events or to learn
new information (see the article by Berman, pp. 120-129). Other vitamin B
deficiencies also are common in alcoholics and are associated with neurologic
disturbance (e.g., peripheral neuropathies and ocular motor palsies) (Roe
1979).
Although deficiencies of the fat-soluble vitamins A and E occur in alcoholics
(Leo and Lieber 1982; Bjorneboe et al. 1988), the clinical significance of
these vitamin deficiencies has not received much research attention. Vitamin
A deficiency is a primary cause of nightblindness, yet there are few data
on the prevalence of nightblindness in alcoholics (McClain et al. 1979). Vitamin
E deficiency is associated with a neurologic syndrome characterized by lack
of muscle coordination known as gait ataxia, neuromuscular weakness, and motor
incoordination in individuals with cholestatic liver disease (characterized
by diminished bile flow) (Sokol et al. 1983). A recent study has reported
an association between vitamin E deficiency and neuropsychological deficits
in patients with nonalcoholic cirrhosis (Arria et al. in press). These data
suggest that the role of vitamin E deficiency in neuropsychological deficits
among alcoholics with and without cirrhosis should be determined.
Liver-Brain Interactions
Chronic liver disease is, perhaps, the most common medical consequence of
alcoholism and, in its advanced stage, cirrhosis ranks among the top 10 causes
of death. Seventy percent of all liver disease may be associated with alcoholism.
Because liver disease often is an irreversible condition that is prevalent
in nonabstinent alcoholics, it is important to determine the effects of liver
disease on brain integrity. Liver disease is the second major pathological
factor that influences neurological status in alcoholics.
Several forms of nonalcoholic liver disease can influence neurological status.
For example, hepatitis B infection can result in chronic liver injury; 10
percent of the individuals infected with this virus will develop cirrhosis.
Similarly, primary biliary cirrhosis (PBC), a possible form of autoimmune
liver disease (a condition in which the immune system attacks the body's tissues)
that typically affects postmenopausal women, can be progressive and, at times,
fatal. Researchers have compared the neuropsychological test performance of
nonalcoholic and alcoholic patients with cirrhosis to determine which deficits
are related to the cirrhosis, per se, and which may result solely from alcohol
abuse. The studies mentioned below employ these research strategies.
Alcoholics and nonalcoholics with biopsyconfirmed cirrhosis perform similarly
on neuropsychological tests (Rehnstrom et al. 1977; Tarter et al. 1988). Specifically,
tests reveal that impairments in visuospatial and psychomotor capacity are
pronounced in both alcoholic and nonalcoholic individuals with cirrhosis.
These two groups also display deficits in nonverbal intelligence, abstracting
capacity, learning, and memory (Tarter et al. 1984b). Using a battery of approximately
two dozen neuropsychological tests, Tarter and colleagues (1988) recently
found that alcoholics and nonalcoholics with biopsy-proven cirrhosis performed
comparably. It should be noted, however, that some of the neurocognitive deficiencies
(e.g., memory deficits) in alcoholics were not observed in nonalcoholics.
These findings suggest that alcoholism has an additional impact on such cognitive
processes as memory. Nonetheless, most neuropsychological tests do not discriminate
cirrhotic alcoholic individuals from cirrhotic nonalcoholic individuals, suggesting
that advanced liver disease and its various sequelae contribute substantially
to the neurocognitive disturbances found in chronic alcoholics.
Rikkers and colleagues (1978) administered a battery of neuropsychological
tests to a group of nonalcoholic patients with subclinical hepatic encephalopathy.
The tests revealed impaired visuospatial ability in the subjects, but did
not detect impaired learning and memory capacity. These results suggest that
latent hepatic encephalopathy may not produce global intellectual impairments.
In an effort to investigate the mediating role of hepatic disease on memory
impairments in alcoholic individuals, we studied the following four groups
of subjects: (1) normal healthy controls; (2) alcohol abusers without liver
disease; (3) nonalcoholic cirrhotics; and (4) alcoholics with cirrhosis (Arria
et al. in submission a). Although differences were observed between normal,
healthy controls and each of the disease groups, the performances of the cirrhotic
groups were similar. However, alcoholics with cirrhosis performed significantly
worse than did the other three groups on a challenging test of short-term
memory. In this study, alcoholics without cirrhosis had impaired memory capacity
when compared with normal controls. These findings support the hypothesis
that alcohol neurotoxicity and liver disease conjointly contribute to the
memory deficits observed in alcoholics.
A recent study (Arria et al. in submission b) showed that liver transplantation
in alcoholics resulted in a substantial recovery from neurocognitive deficits.
This finding lends support to the hypothesis that the cognitive deficits exhibited
by abstinent alcoholics may have a metabolic basis linked to a low-grade chronic
hepatic encephalopathy. The implantation of a functionally normal liver reversed
psychomotor, visuospatial, and perceptual speed deficits; however, memory
capacity did not improve. Investigations of nonalcoholics with various types
of liver disease before and after their liver transplantation also revealed
almost complete neurocognitive recovery (Tarter et al. 1984a; Tarter et al.
in press).
Several groups of investigators have documented an association between certain
biochemical measures of liver injury and cognitive processes. Gilberstadt
and colleagues (1980) observed that the Wechsler Adult Intelligence Scale
(WAIS) Performance IQ and tests of psychomotor speed and visuospatial capacity
correlated with serum albumin level in alcoholics with cirrhosis. (Serum albumin
level is an index of the liver's capacity of protein synthesis and reflects
the extent of disease.) The correlations between the biochemical and cognitive
variables ranged between-0.47 and -0.64 for the Trailmaking (which measures
attentional and psychomotor speed), Digit Symbol, and Block Design tests (which
measure visuospatial capacities) and Performance IQ scores (which measure
abstraction and conceptual abilities). The biochemical variables accounted
for 22 to 41 percent of the observed variance on the cognitive test performance.
The correlation between fasting blood ammonia level (an indicator of the severity
of encephalopathy) and cognitive variables was less significant with the WAIS
Block Design Test (r = 0.34) and Performance IQ score (r = 0.35).
Other investigators have confirmed the associations between neuropsychological
test performance and functional parameters of the liver. Using the Cattell
Culture Fair Test (an IQ test), Schomerus and colleagues (1981) found that
nonverbal IQ correlated significantly with serum albumin level and inversely
with the gamma globulin level, which indicates the severity of the disease.
Performance on the Benton Visual Retention Test also correlated significantly
with the serum bilirubin and prothrombin time. (These biochemical measures
reflect the status of the liver's excretory and synthetic capacities, respectively).
Furthermore, prothrombin time correlated with the WAIS Block Design score,
the Trailmaking Test, and Motor Steadiness scores (which measures hand tremors).
Hepatic injury variables account for 23 to 56 percent of the cognitive test
score variance (Tarter et al 1984b). No systematic association was, however,
observed between specific cognitive variables and specific hepatic disease
variables; these findings underscore the complexity of the relationship between
liver function and brain function.
Moss and colleagues (in submission) recently found that aspects of liver
disease may be associated differentially with certain specific types of cognitive
impairments in a heterogeneous sample of liver disease patients (e.g., alcoholic
and nonalcoholic individuals). Additionally, Irwin and associates (1989) showed
that gamma glutamyl transferase (GGT), a measure of the production of liver
enzymes, correlated with performance on neuropsychological tests that measure
attention, visuospatial sequencing, and visual search. Although the correlations
were significant, they accounted for less than 10 percent of the overall variance.
Nonetheless, the association between hepatic injury parameters and cognitive
performance in alcoholics underscores the important role of liver dysfunction
in the cognitive deficits observed in alcoholism.
Although the results that demonstrate an association between biochemical
variables and neurocognitive status are intriguing, they should be considered
with caution. First, it should be emphasized that no single laboratory index
of liver injury or dysfunction is associated consistently with cognitive impairment.
Second, no evidence implicates a specific neurotoxin, particularly ammonia
or other nitrogenous compounds, as the sole or even major cause of alcoholic
encephalopathy. Third, the magnitude of test score variance explained by the
correlations indicates that the neurocognitive deficits undoubtedly have a
complex multifactorial etiology; although specific laboratory measures of
hepatic disturbance may correlate with individual test performance, they may
reveal little more than the general severity of liver disease. Other elements,
including both factors within and outside the liver, must be considered for
a more comprehensive understanding of liver-brain relations. Given these limitations,
however, the emerging evidence suggests that liver disease is a major contributing
factor to the underlying neurocognitive deficits exhibited by cirrhotic alcoholics.
In summary, it appears that many of the cognitive deficits found in alcoholics
reflect an underlying coexistent hepatic encephalopathy. This conclusion is
advanced based upon studies comparing cirrhotic alcoholics and nonalcoholics,
groups of alcoholics with varying degrees of liver injury, alcoholics before
and after liver transplantation, and the association between biochemical measures
of liver function and injury to neurocognitive test performance. While the
neurocognitive deficits found in alcoholics are not presumed to be entirely
caused by underlying liver disease, the importance of cirrhosis as a critical
factor increasingly is becoming recognized. The importance of this observation
should not be underestimated.
Specifically, the emerging findings suggest that the effective treatment
of alcoholic liver disease should improve cognitive functioning. The ramifications
for psychosocial rehabilitation of alcoholics are obvious inasmuch as neurocognitive
capacity, as mentioned earlier, has a major influence on everyday functioning.
FUTURE RESEARCH
One important goal of future research is to determine the type and severity
of the cognitive deficits that are associated with milder forms of liver disease.
It is reasonable to speculate that individuals in the early stages of alcoholic
liver disease (i.e., fatty liver, alcoholic hepatitis) may well have less
severe but nonetheless detectable cognitive impairments as a result of the
combined effects of alcohol abuse and liver dysfunction. However, virtually
no systematic research has been conducted on this population.
In addition, the multifactorial basis of the encephalopathy in alcoholics
needs to be explored further. For instance, we have found recently that a
vitamin E deficiency is quite prevalent in alcoholic cirrhotics (Arria et
al. in submission c) and is associated with neuropsychological test performance
deficits. Hence, hepatic and nutritional variables should be investigated
conjointly. Furthermore, it is noteworthy that a vitamin E deficiency also
is commonly associated with a vitamin A deficiency; this latter disorder may
underlie the presence of nightblindness. Importantly, and as yet not investigated,
it may be that nightblindness (as a result of vitamin A deficiency), coupled
with deficits in reaction time and attentional capacity, may place an alcoholic
individual at greater risk for motor vehicle crashes even while sober, compared
to nonalcoholics. The major conclusion from the research conducted to date
is that the presence of liver disease not only has significant biomedical
consequences and health service delivery implications, but also may have important
ramifications for psychosocial adjustment and rehabilitation.
table 1 Progression of Neuropsychiatric Disturbance
Associated with Acute Episode of Portal-Systemic Encephalopathy
Part I
Clinical Features O (Normal) 1 (Mild)
Consciousness No detectable No clear impairment
change
Activation Normal Inversion of sleep
pattern and/or
insomnia/hypersomnia
Behavior Normal Personal ty change:
fatigue
Affect Normal Irritability;
euphoria or
depression
Cognition Normal Attention deficit.
concentration
difficulties
Neurological Normal Tremor;
Response incoordination
Part II
Severity Grade of Encephalopathy
Clinical Features 2 (Moderate) 3 (Severe) 4 (Coma)
Consciousness Mild disorientation Confusion/
stupor
Activation Inversion of sleep Somnolence
pattern and/or
insomia/hypersomia
Behavior Lethargy: disinhi- Bizarreness,
bition, in dispersonalization,
appropriateness paronoia
Affect Anxiety, anger Range
Cognition Impaired time Amnesia
sense
Neurological Ataxia; asterixis; Dilation of
Response slurred speech, pupils;
hyperactive hyperactive
reflexes reflexes;
rigidity;
nystagmus
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By AMELIA M. ARRIA, RALPH E. TARTER, PH.D., AND DAVID H. VAN THIEL,
M.D. AMELIA M. ARRIA is an NIAAA Predoctoral Fellow in alcohol epidemiology,
Graduate School of Public Health, University of Pittsburgh, and is a research
associate, Department of Psychiatry, University of Pittsburgh School of Medicine,
Pittsburgh, Pennsylvania RALPH E. TARTER, PH.D., is professor of psychiatry
and neurology, University of Pittsburgh School of Medicine, and director of
the Center for Education and Drug Abuse Research (CEDAR), Department of Psychiatry,
University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania DAVID
H. VAN THIEL, M.D., is professor of medicine, surgery, and psychiatry, Department
of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Dr. Van Thiel serves currently as the president of the Research Society on Alcoholism.Alcohol Health & Research World is published by National
Inst on Alcohol Abuse and Alcoholism and is not copyrighted.
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