Alcohol: Effects on Neurobehavioral Functions and the Brain
Marlene Oscar-Berman & Ksenija Marinković
Published online: 15 September 2007
# Springer Science + Business Media, LLC 2007
Abstract Alcoholism results from an interplay between
genetic and environmental factors, and is linked to brain
defects and associated cognitive, emotional, and behavioral
impairments. A confluence of findings from neuroimaging,
physiological, neuropathological, and neuropsychological
studies of alcoholics indicate that the frontal lobes, limbic
system, and cerebellum are particularly vulnerable to
damage and dysfunction. An integrative approach employ-
ing a variety of neuroscientific technologies is essential for
recognizing the interconnectivity of the different functional
systems affected by alcoholism. In that way, relevant
experimental techniques can be applied to assist in
determining the degree to which abstinence and treatment
contribute to the reversal of atrophy and dysfunction.
Alcoholic beverages contain ethanol, a psychoactive drug
with relaxant and euphoric effects, consumed by people
throughout the world. In general, the effects of alcohol
intoxication follow a biphasic time course as the initial
feelings of relaxation and exuberance give way to hangover,
exhaustion, and depression, or vomiting and loss of con-
sciousness in cases of higher doses (Nagoshi and Wilson
1989). Criteria for classifying someone as an alcoholic vary
(Abel et al. 1999; Eckardt et al. 1998), but it is thought that
excessive alcohol use and alcoholism exist along a contin-
uum of alcohol-disorders associated with increased frequen-
cy of a harmful drinking pattern (Helzer et al. 2006).
Risky drinking patterns for men are defined as consuming
more than 14 drinks per week, or more than four drinks in a
than seven drinks per week and three drinks per day (Dawson
et al. 2005). Individuals who abuse alcohol or are alcohol-
dependent are considered to have alcohol use disorder (Grant
et al. 2004). Alcohol abuse, as described by the American
Psychiatric Association (APA 1994),isa psychiatric condition
whereby alcoholic beverages are consumed despite negative
consequences for health, well being, and interpersonal
relationships. Alcohol dependence has additional physiolog-
ical consequences such as increased tolerance for alcohol
consumed, and withdrawal symptoms upon cessation of
drinking. Studies assessing alcoholism-related neurobehavio-
ral decline commonly require their participants to have had a
history of at least 5 years of drinking 21 or more drinks per
week (Eckardt et al. 1998; Oscar-Berman et al. 2004).
However, problem-based criteria, as well as several endophe-
notypes (e.g., metabolic factors, and neuronal or behavioral
disinhibition), should be considered when identifying alcohol
use disorders, not just quantity and frequency of consumption
(Lancaster 1995; NIAAA 1997; Nolen-Hoeksema and Hilt
2006; Wuethrich 2001). Alcohol abuse and alcohol depen-
Neuropsychol Rev (2007) 17:239–257
M. Oscar-Berman (*)
Departments of Anatomy and Neurobiology, Psychiatry,
and Neurology, Boston University School of Medicine,
L-815, 715 Albany Street,
Boston, MA 02118, USA
Psychology Research Service, VA Healthcare System,
Boston, MA, USA
Radiology Department, Harvard Medical School,
Boston, MA, USA
Athinoula A. Martinos Center for Biomedical Imaging,
Massachusetts General Hospital,
Boston, MA, USA
dence are responsible for failure in everyday life roles and
high costs to society for disability and health expenditures
(APA 1994; NIAAA 1997).
Alcoholism has devastating consequences, but not all
alcoholics are equally at risk for brain changes and neuro-
behavioral deficits. Nearly half of the estimated 18 million
people in the USAwho are problem drinkers (NIAAA 1997)
appear to be free of cognitive, sensory, or motor impair-
ments. By contrast, upwards of 2 million alcoholics develop
permanent and debilitating conditions that require lifetime
custodial care (Oscar-Berman and Evert 1997; Rourke and
Løberg 1996). However, most problem drinkers have mild
abstinence (Bartsch et al. 2007; Ende et al. 2005; Fein et al.
Even though structural and functional brain damage is
partially reversible after several weeks of abstinence (Crews
et al. 2005; Nixon 2006; Rosenbloom et al. 2003), the
underlying mechanisms are poorly understood. It is clear,
however, that the locus and extent of brain damage, as well
as the type and degree of impairment, differ across
individuals. Such differences suggest that certain factors
increase the likelihood of developing cognitive, sensory, or
motor impairments with alcohol misuse. Among the
important factors that must be considered are demographic
variables (e.g., age, gender, socioeconomic background,
and education), genetics and family history of alcoholism,
alcohol use patterns (e.g., the age of onset of alcohol
consumption, the type and amount of alcohol consumed,
severity and duration of the dependency, duration of
abstinence, nutritional status during periods of consump-
tion), and the use or abuse of other psychoactive substances
and nicotine (Gazdzinski et al. 2005; Oscar-Berman and
Marinkovic 2003). Additionally, overall physical and
mental health are important factors, because comorbid
medical, neurological, and psychiatric conditions not only
can interact to aggravate alcoholism’s effects on the brain
and behavior, but they also can contribute to further
drinking (Petrakis et al. 2002).
Factors that Contribute to Alcoholism and its Sequelae:
Age, Gender, Health, and Family History
Alcoholism’s effects on the brain and behavior are diverse,
and are moderated or mediated by many factors (Oscar-
Berman and Bowirrat 2005; Parsons 1996). The most
commonly studied variables are age, gender, health, and
Age Normal chronological aging is associated with a
number of physiological changes suggesting increased
sensitivity to alcohol. For example, with declining body
water content, older people who drink alcohol tend to have
increased blood alcohol concentration compared to younger
people (Dufour and Fuller 1995), and aging interferes with
the body’s ability to metabolize alcohol (Kalant et al. 1998).
Neuroanatomical changes seen in aging are similar to those
associated with chronic alcoholism (Courville 1966; Harper
1998; Pfefferbaum et al. 2005; Wilkinson and Carlen
1982). In both, cerebral atrophy is most prominent in the
frontal lobes. Other effects include greater than normal
ventricular enlargement and widening of the cerebral sulci
of alcoholics in relation to increasing age (Pfefferbaum et al.
1997; Sullivan 2000). Given the observed morphological
similarities in the brains of alcoholic and aging nonalcoholic
individuals, researchers sought to characterize parallels in
functional decline associated with alcoholism and aging
(Gansler et al. 2000), and some investigators proposed that
alcoholism is associated with premature aging.
The premature aging hypothesis has been put forth in
two versions (reviewed by Ellis and Oscar-Berman 1989;
Oscar-Berman and Schendan 2000). It was initially formu-
lated as the “accelerated aging” or “cumulative effects”
model, purporting that alcoholism is accompanied by the
precocious onset of neuroanatomical and behavioral
changes typically associated with advancing age. Accord-
ing to this model, alcoholics at all ages are impaired
compared to age-matched controls, becoming cognitively
old before their time. The second version placed the timing
of the changes somewhat differently. The “increased
vulnerability” interpretation suggests that an aging brain is
more vulnerable to the influences of toxic substances,
including ethanol, than is the brain of a younger person.
This version proposes that only older alcoholics (over age
50) are impaired compared with age-matched controls;
younger alcoholics remain cognitively intact.
Taken together, most of the evidence from neuropatho-
logical and neuroimaging investigations supports the
increased vulnerability model of premature aging (Oscar-
Berman and Marinkovic 2003). That is, certain brain
structures show greater reduction in size (or blood flow)
in older alcoholics than in younger alcoholics: the cerebral
cortex (Di Sclafani et al. 1995; Harris et al. 1999;
Pfefferbaum et al. 1997), the corpus callosum (Pfefferbaum
et al. 1996, 2006; Schulte et al. 2005), the hippocampus
(Laakso et al. 2000; Sullivan et al. 1995), and the
cerebellum (Harris et al. 1999; Sullivan et al. 2000).
At the microstructural level, diffusion tensor imaging
(DTI) measures of neuronal fibers in the corpus callosum
have provided supporting evidence for a detrimental
interaction between recent alcoholism history and age. That
is, Pfefferbaum et al. (2006) reported significant negative
relationships with age, not only in the size of the genu and
splenium of the corpus callosum of older alcoholics, but
also in the microstructure of the callosal fibers (i.e.,
240Neuropsychol Rev (2007) 17:239–257
functional anisotropy, a measure of orientational coherence
of neuronal fibers, and bulk mean diffusivity, an index of
the amount of water motility). The neuroanatomical indices
also correlated with neuropsychological and psychomotor
deficits in older alcoholics: Modest abnormalities in the
genu were associated with diminished working memory
scores, and abnormalities of the splenium were associated
with diminished visuospatial ability. Measures of gait and
balance showed nonspecific relationships with global
measures of callosal size and neuronal structure. Although
the only region displaying age–alcohol interactions in
functional anisotropy was the callosal body, bulk mean
diffusivity was affected in more callosal regions by the
interaction of age and alcoholism.
Results of neurobehavioral investigations tend to support
the view that aging increases one’s vulnerability to
alcoholism-related decline (Oscar-Berman and Marinkovic
2003). Significant correlations have been reported between
age and regional MRI and DTI measures and performance
on working memory, visuospatial ability, and gait and
balance (Pfefferbaum et al. 2006), as well as in interhemi-
spheric processing speed (Schulte et al. 2005). The latter
findings provide evidence for the functional ramifications
of an interaction of age and alcoholism in exerting
compounded abnormalities in the functioning of the corpus
callosum. Pfefferbaum and Sullivan (2005) suggested that
decreased orientational coherence of brain white matter in
alcoholism is attributable, at least in part, to the accumu-
lation of intracellular and extracellular fluid in excess of
that occurring in aging, and that the differential influence of
these fluid compartments can vary across brain regions.
Gender In the past decade, there has been an increasing
interest in alcoholism-related gender differences with respect
to possible changes in brain and behavior (Lancaster 1995;
NIAAA 1997; Nolen-Hoeksema and Hilt 2006; Wuethrich
2001). However, the degree to which men and women
differ with respect to these changes remains controversial.
For example, in a recent cross-sectional, population-based
study in which gender differences in cognitive performance
were explored in relation to alcohol consumption (Yonker
et al. 2005), drinking data were collected from men and
women between 35 and 85 years of age, and the participants
were classified into non, light, moderate, and heavy drinking
subgroups. There were clear gender differences in episodic
memory (favoring women) and visuospatial tasks (favoring
men). When these gender differences were examined by
drinking group, visuospatial performance favoring men
disappeared for the moderate to heavy drinking groups, but
higher performance by womenon episodicmemory tasks was
consistent across all levels of alcohol consumption. The
results suggested that moderate alcohol intake may be less
detrimental to women than to men.
In other studies, Sullivan and her colleagues adminis-
tered an extensive battery of neuropsychological tests to
recently detoxified alcoholic men (Sullivan et al. 2000) and
women (Sullivan et al. 2002) compared with nonalcoholic
control men and women. In alcoholic men and women
alike, there were deficits in visuospatial abilities and
balance. The alcoholic men, but not the women, had
deficits in executive functions and gait, and the alcoholic
women, but not the men, had additional impairments in
short-term memory and fluency. In both gender groups,
there was relative preservation of declarative memory and
upper limb mobility. Parsons (1994) reported that although
alcoholic men and women showed impaired performance
on neuropsychological tests relative to same-sex nonalco-
holic control participants, only the alcoholic men differed
from their controls on a measure of visually evoked event-
related brain potentials. Other investigators found that
alcoholic men and women displayed similar electrophysi-
ological abnormalities (Hill and Steinhauer 1993).
Neuroimaging studies that measured gender differences
in alcoholics’ brain functioning have yielded contradictory
evidence, with some studies showing women to be more
susceptible than men to brain impairments, and other
studies showing no such distinction. Using functional
magnetic resonance imaging (fMRI), Tapert et al. (2001)
found decreased activity in parietal and frontal cortex,
particularly in the right hemisphere, in alcohol-dependent
women during performance of a spatial working memory
task. Other studies, however, did not find functional
differences based on gender (Wang et al. 1998), or even
found that alcohol intoxication decreased brain metabolism
in men more than in women as measured with positron
emission tomography (PET; Wang et al. 2003). Using
structural MRI, Kroft et al. (1991) found that the average
ventricular volume in alcoholic women was within the
typical range found in MRI studies of nonalcoholic women
of similar ages. Another MRI study reported that although
age and alcoholism interacted adversely in both sexes,
alcoholic men, but not alcoholic women, had abnormal
cortical white matter and sulcal volumes compared to same
sex healthy comparison groups (Pfefferbaum et al. 2001b).
In contrast, Hommer et al. (2001) reported clear gender
differences in the brain structure of alcoholics. In that study,
alcoholic men and women had smaller volumes of gray and
white matter, as well as greater volumes of sulcal and
ventricular CSF, than nonalcoholic men and women, but
these differences were largest for the women. Comparisons
between alcoholic men and women on the proportion of
intracranial contents occupied by gray matter indicated
smaller size in alcoholic women than in alcoholic men.
Using computerized tomography (CT) scans to measure
brain atrophy, another group found evidence of a similar
degree of brain shrinkage in men and women, despite
Neuropsychol Rev (2007) 17:239–257241
shorter drinking histories in the women (Mann et al. 1992).
MRI-based volumetric measures of the corpus callosum
(Hommer et al. 1996) indicated that alcoholic women had
smaller callosal areas than alcoholic men and nonalcoholic
controls; alcoholic men did not differ from nonalcoholic
control men. Abnormalities in the structure of the corpus
callosum can occur as a consequence of diffuse cortical
damage and subsequent degeneration of cortical axons.
Furthermore, the size of the corpus callosum is notably
reduced with age in alcoholic men (Pfefferbaum et al. 1996).
Pfefferbaum et al. (2002) measured white-matter brain
macrostructure in women alcoholics to determine whether
observed abnormalities interact with age. Although the
alcoholic women did not differ from controls in any brain
measures, greater length of sobriety was associated with more
cortical white matter. Based on the results of a similar study
employing DTI (a technique highly sensitive to microstruc-
ture damage) on separate subject groups, Pfefferbaum and
Sullivan (2002) suggested that alcohol use by women causes
white matter microstructural disruption that is not detectable
with gross measures of white matter mass, and may antedate
Clearly, many questions remain concerning the nature
and extent of gender differences in the effects of alcoholism
on brain and behavior. These potential differences deserve
close scrutiny in the context of other variables such as age,
drinking history, perceived social sanctions for drinking,
impulsivity, genetic risk factors, etc. (Nolen-Hoeksema and
Health Medical conditions concomitant with alcoholism
that are most likely to influence neurobiological and
neurobehavioral functioning include liver disease, cardio-
vascular disease, and malnutrition. Thus, poor liver func-
tion (Stranges et al. 2004a) and hypertension (Stranges et
al. 2004b) have been associated with drinking outside of
meals, and certain arrhythmias have been associated with
binge drinking (Klatsky 2007). Thiamine (vitamin B1)
deficiency, a consequence of poor diet, can contribute to
Alcohol-Induced Persisting Amnestic Disorder (Korsakoff’s
syndrome), a severe disorder characterized by permanent
cognitive and emotional deficits (Oscar-Berman and Evert
1997; Oscar-Berman et al. 2004). Other common neuro-
logical conditions in alcoholics are head injury, encepha-
lopathy, and fetal alcohol syndrome (or fetal alcohol
effects), all of which can have an impact on neuro-
Regarding the influence of mental health factors, a
comprehensive 12-month epidemiological study (Kessler
et al. 2005) showed a prevalence of 44% comorbidity of
alcohol abuse and dependence with externalizing disorders
(e.g., conduct disorder). Other significant correlations with
alcoholism were phobias, generalized anxiety disorders,
and posttraumatic stress disorder. Frequently occurring
comorbid psychiatric conditions also include depression,
schizophrenia, and the use of other drugs, including
nicotine (Durazzo et al. 2006; Petrakis et al. 2002).
Interestingly, a twin study examining risk factors for
common substance abuse and associated psychiatric dis-
orders suggested that the underlying structure of genetic
risk factors is similar for men and women, and genetic
loadings for alcohol dependence are disorder specific
(Kendler et al. 2003). However, the presence of a lifetime
psychiatric diagnosis in mood, anxiety, and externalizing
disorder domains in abstinent long-term alcoholics does not
militate against achieving sustained abstinence, and absti-
nence can be maintained in the presence of a current mood
or anxiety disorder (Di Sclafani et al. 2007).
These various findings emphasize that consideration must
be given to the potential influence of a host of psychiatric and
medical conditions on neurocognitive functioning in studies
to quantify the significance of comorbid conditions, whether
they are secondary or tertiary illnesses, into a single,
predictive variable that measures neurobehavioral or neuro-
biological outcomes in alcoholism. Instead, comorbid con-
ditions deserve independent consideration, in addition to
examining multivariate effects and interactions. Furthermore,
specific psychiatric diagnosis, the use of continuous measures
of psychological abnormalities can yield a more accurate
picture of psychiatric illness co-occurring with alcoholism
(Fein et al. 2007).
Family history Results of twin, family, and adoption
studies have shown that hereditary factors influence
vulnerability to alcoholism (Begleiter and Porjesz 1999;
Dick and Foroud 2003; Schuckit et al. 2004; Whitfield et
al. 2004). Additionally, the pharmacogenomics of alcohol
response is well established, and genetic variants for the
principal enzymes of alcohol metabolism are thought to
influence drinking behavior and protect against alcoholism
(Dickson et al. 2006; Enoch 2003). Convergent evidence
supports the view that vulnerability to alcoholism is likely
to be due to multiple interacting genetic loci of small to
modest effects (Johnson et al. 2006).
In an attempt to clarify the nature of genetic factors in
relation to alcoholism, the National Institute on Alcohol
Abuse and Alcoholism (NIAAA) sponsored a multi-
institutional program: Collaborative Studies on Genetics
of Alcoholism (COGA) in 1989. Since then, COGA
investigators have successfully recruited thousands of
individuals from hundreds of extended families densely
affected by alcoholism (Begleiter and Porjesz 1999; Bierut
et al. 2002). The investigators have collected detailed and
extensive clinical, neuropsychological, electrophysiologi-
242 Neuropsychol Rev (2007) 17:239–257
cal, biochemical, and genetic data. Evidence from these
studies has led to the identification of chromosomal regions
containing genes that influence alcoholism risk and related
phenotypes (Edenberg and Foroud 2006). Subsequently,
single nucleotide polymorphisms (SNPs) have been geno-
typed in positional candidate genes located within the
linked chromosomal regions, and analyzed for association
with these phenotypes. Using this sequential approach,
COGA investigators have reliably detected and identified
associations with specific genes contributing to the risk for
alcoholism (Edenberg and Foroud 2006).
Other studies have revealed an association between certain
dopaminergic gene polymorphisms and a number of reward
dependent behaviors including addictive, compulsive, and
impulsive tendencies (Blum et al. 2000). Alcohol and other
drugs of abuse cause activation and neuronal release of brain
dopamine, which can decrease negative feelings and satisfy
abnormal cravings (Bowirrat and Oscar-Berman 2005). A
deficiency or absence of the D2receptors then predisposes
individuals to a high risk for multiple maladaptive behaviors
(Koob 2003). Other neurotransmitters, e.g. glutamate,
gamma-aminobutyric acid (GABA; Dick et al. 2004),
serotonin (Goldman et al. 1992), and enkephalins (Comings
et al. 1999) also may be important in determining the
rewarding and stimulating effects of ethanol, but dopamine
may be critical for initiating drug use and for reinstating drug
use during protracted abstinence (Bowirrat and Oscar-
Berman 2005; Connor et al. 2002).
As noted by Dick and Foroud (2003), sequencing of the
human genome has facilitated the development of a catalog
of human genes. Based on the findings from this catalog,
researchers can identify candidate genes to determine the
degree to which they are associated with alcoholism. Once
replicable associations are established, the next step will be
to identify the causative genetic variants responsible for the
role of those genes in alcohol dependence. It also will be
important to understand how the relevant genes influence
patterns of alcohol use and metabolism, as well as the
manner in which the genes may contribute to comorbidity
of alcoholism with other psychiatric disorders. Genotype
and environmental risk factors act and interact through
complex pathways to influence alcohol dependence. Find-
ings from COGA studies have exemplified the significance
of careful screening and selection of the research partic-
ipants when considering the influence of factors such as
family history, age, gender, and health variables.
Acute Effects of Ethanol Ingestion
Studies using acute alcohol challenges contribute toward
understanding dose-and task-related parameters of ethanol’s
effects on the brain. Furthermore, studies of acute alcohol
challenge are valuable in disclosing the types of functions
and the neural circuits that underlie impairments due to
alcohol intoxication. In concert with studies on chronic
alcoholics and populations at risk, studies using acute
alcohol challenge are important since they may help to
parse out the effects of alcohol neurotoxicity, genetic
susceptibility, and environmental factors. The importance
of such evidence derives from its direct applicability to
driving situations, work-related hazards, and other societally-
individual’s blood alcohol concentration (BAC). Low doses
can have a stimulating effect, and higher levels can have
depressanteffects.Inaddition, effects can differ depending on
the time lapsed since ingestion; the same BAC may result in
different effects on the ascending versus descending limbs of
the BAC curve (Pohorecky and Brick 1977). Individuals also
differ in their tolerance to acute intoxication. Even when
people are subjected to the same environmental conditions,
their responses to a given dose of alcohol vary significantly
on metabolic, physiological, subjective, cognitive, motor,
and other measures (Reed 1985). The pharmacokinetics
(time course of absorption, distribution, metabolism, and
excretion of ethanol) varies significantly when alcohol is
administered orally, but much less so when alcohol is given
intravenously (Grant et al. 2000).
Impairments in mental functions such as attention and
vigilance can be detected at BAC levels much lower than
the legal intoxication levels, such as 0.02–0.03% (Koelega
1995). Alcohol intoxication disrupts neurophysiological
indices of stimulus processing in attentional (Grillon et al.
1995; Jääskeläinen et al. 1999; Marinkovic et al. 2001;
Porjesz and Begleiter 1985), semantic, (Marinkovic et al.
2001, 2004), and psychomotor domains (Ridderinkhof et al.
2002). Furthermore, consistent with the evidence obtained
from chronic alcoholics, acute intoxication results in a
disproportionate impairment of executive functions such as
planning, working memory, or complex behavioral control
(Peterson et al. 1990).
Intoxication and behavioral control It is a common belief
that alcohol ingestion leads to aggression and reduced
impulse control, and there is high association of alcohol
intoxication with violent crimes (Murdoch et al. 1990).
Results of laboratory research have shown that alcohol
intoxication increases the likelihood of aggressive behav-
iors (Bushman and Cooper 1990; Hoaken and Stewart
2003). However, there is a dearth of careful studies of the
complex interactions between alcohol intoxication and the
multifaceted construct of aggression. This is due, in part, to
ambiguities in the terminology. For instance, a behavior
labeled as “aggressive” could include combinations of
Neuropsychol Rev (2007) 17:239–257243
impulsivity, disinhibition, social or sexual inappropriate-
ness, impairments in decision-making and executive func-
tions, or some other feature. Itself a complex construct,
impulsivity has been commonly operationalized with tasks
measuring inhibitory control of responses, i.e., go/no-go
tasks, which require subjects to refrain from responding on
some trials. Some evidence suggests that alcohol may have
disinhibitory effects on behavior. Rather low alcohol doses
(peak BAC of ∼0.04%) decrease the latency of arousal to
sexually explicit stimuli (Wilson and Niaura 1984). Alcohol-
induced disinhibition is also reflected in premature motor
preparation based on incomplete stimulus evaluation
(Marinkovic et al. 2000). The disinhibitory effects could
result from the psychomotor stimulant properties of alcohol
(Wise 1988), or may reflect a disruption in the inhibitory
control of behavior subserved by prefrontal regions (Peterson
et al. 1990). Indeed, alcohol decreases inhibitory control
under the conditions of stop-signal imperative stimuli
(Mulvihill et al. 1997) and a demanding vigilance task
(Dougherty et al. 1999), as demonstrated by moderately
intoxicated subjects who are impaired in withholding
responses to inappropriate stimuli.
In a series of studies using a cued go/no-go task, Fillmore
and colleagues have found a dose-related increase in commis-
sion errors and slower response times to the no-go signals that
were falsely preceded by a “go” cue (Fillmore and Weafer
2004; Marczinski et al. 2005; Marczinski and Fillmore
2003). Similarly, alcohol decreases inhibitory control on the
stop-signal task (de Wit et al. 1990; Mulvihill et al. 1997)
and on a continuous performance task (Dougherty et al.
2000). Alcohol-induced disinhibition is reflected in prema-
ture motor preparation based on incomplete stimulus evalu-
ation as measured by event-related potentials (ERPs;
Marinkovic et al. 2000). Furthermore, these disinhibitory
effects of alcohol are correlated with personality traits related
to impulsivity and hyperactivity (Dougherty et al. 2000;
Marinkovic et al. 2000). A cluster of traits termed “antisocial
personality disorder” inclusive of impulsivity, hyperactivity,
and sensation/novelty seeking correlates with the early-onset
alcoholism, increased drinking (Brown et al. 1996; Finn et al.
2000; Mazas et al. 2000), and chronic alcohol use and
dependence (Hesselbrock et al. 1985; Regier et al. 1990) and
may reflect a disruption in the inhibitory control of behavior
subserved by prefrontal regions (Deckel et al. 1996; Peterson
et al. 1990). Recent models of vulnerability to alcoholism
emphasize the importance of executive functions in mediat-
ing, as well as moderating the effects of alcohol (Finn 2002;
According to the DSM-IV (APA 1994), dysregulation of
impulse control is one of the diagnostic criteria for diverse
psychiatric disorders inclusive of substance abuse and
antisocial personality disorder. In a broader sense, the
underlying symptom concerns an inability to resist engag-
ing in activity that one declares to be unwanted or even
harmful. Alcoholics also have decision-making deficits,
including the likelihood of making poor decisions regarding
their alcohol consumption (Fein et al. 2004; 2006a). The
inability to maintain inhibitory control over drinking has
been considered by some researchers to be fundamental to
alcohol abuse (Fillmore and Weafer 2004; Finn et al. 2000;
Jentsch and Taylor 1999; Lyvers 2000). Evidence suggests
that the vulnerability to alcoholism may share a common
genetic component with antisocial personality disorder
which, as a premorbid trait, may predispose individuals to
a spectrum of conduct disorders including alcohol depen-
dence (Begleiter and Porjesz 1999; Bowirrat and Oscar-
Berman 2005; Dick et al. 2004; Heinz et al. 2001; Pihl et al.
1993; Schuckit et al. 2004). Furthermore, alcohol intoxica-
tion affects cognitive evaluation of the situation and impairs
finding the most suitable response strategies. It may result
in disinhibited behaviors, poor-self control, and inability to
desist drinking. Thus, excessive alcohol use impairs the
executive and motivational functions that determine self-
regulation and goal-directed behavior and can, in turn,
result in a further increase in alcohol intake, tolerance, and
dependence. Consequently, impulsivity seems to mediate
alcohol abuse both as a dispositional risk factor and as a
consequence of excessive drinking.
Improvement with abstinence Neurobehavioral functioning
may improve within 3 to 4 weeks of abstinence (Crews et al.
2005; Sullivan 2000), accompanied by at least partial
reversal of brain shrinkage (O’Neill et al. 2001; Pfefferbaum
et al. 1995; Shear et al. 1994) and some recovery of
metabolic functions in the frontal lobes (Johnson-Greene et
al. 1997) and cerebellum (Ende et al. 2005; Martin et al.
1995; Seitz et al. 1999). Frontal lobe blood flow continues to
increase with abstinence, returning to approximately normal
levels within 4 years (Gansler et al. 2000). Relapse to
drinking leads to resumption of shrinkage (Pfefferbaum et al.
1995, 1998), continued declines in metabolism and cognitive
function (Johnson-Greene et al. 1997), and evidence of
neuronal cell damage (Martin et al. 1995). Abstinence up to
7 years resolves many neurocognitive deficits associated
with alcoholism, except for the suggestion of lingering
deficits in spatial processing (Fein et al. 2006b).
Neural Systems Affected and Concomitant
Results of research employing a variety of different
techniques have determined that the brain structures most
vulnerable to the effects of alcoholism are the neocortex
(especially the frontal lobes), the limbic system, and the
244 Neuropsychol Rev (2007) 17:239–257
cerebellum (reviewed by Moselhy et al. 2001; Oscar-
Berman and Hutner 1993; Oscar-Berman and Marinkovic
2003; Sullivan 2003). Each of these brain systems, and the
functions affected by damage to them, is considered in turn.
Figure 1 represents a schematic summary and conceptual
model of the brain regions in which alcoholic and
nonalcoholic groups have been found to differ with regard
to cognition inclusive of working memory, vigilance, and
proactive interference. Although based upon neuroimaging
studies, the regions highlighted in Fig. 1 lack neuroana-
tomical precision, but they reflect the findings reported in
this review, with one exception: We collapsed findings from
the two cerebral hemispheres. In viewing Fig. 1, therefore,it
is important to note that the differences between alcoholic and
nonalcoholic groups are exclusive of brain laterality effects;
these effects are sensitive to stimulus materials (e.g., verbal
versus visuospatial) and task demands (e.g., attention, percep-
tion, motor response, etc.; Oscar-Berman and Schendan 2000;
Oscar-Berman et al. 1997). Thus, because alcoholics com-
monly display a pattern of deficits that includes visuospatial,
attentional, and emotional abnormalities characteristic of
patients with right hemisphere damage, some investigators
have suggested that the right hemisphere may be more
vulnerable to the effects of alcoholism than the left
hemisphere (Ellis and Oscar-Berman 1989; Oscar-Berman
and Bowirrat 2005). As evidence accumulates, it may favor
the view that group differences between the hemispheres may
be greater for the right hemisphere than for the left (Harris
et al. 2007; Makris et al. 2007).
Frontal lobe structure and function Although alcoholism-
related cortical changes have been documented throughout
the brain, many studies consistently have found the frontal
lobes to be more vulnerable to alcohol-related brain damage
than other cerebral regions (Dirksen et al. 2006; Gansler et al.
2000; Gilman et al. 1996; Oscar-Berman et al. 2004;
Pfefferbaum et al. 1997; Ratti et al. 2002). Neuropatholog-
ical studies performed on the brains of deceased patients
have revealed decreased neuron density in the frontal cortex
of alcoholics (Harper and Matsumoto 2005). Harper (1998)
and his collaborators established that 15–23% of cortical
neurons are selectively lost from the frontal association
cortex following chronic alcohol consumption. Structural
MRI studies have shown frontal lobe volume losses in
alcoholic subjects (Pfefferbaum et al. 1997), and frontal
abnormalities in alcoholics also have been identified with
fMRI scans (Tapert et al. 2001), in addition to reduced
regional blood flow measurements (Gansler et al. 2000;
Melgaard et al. 1990), reduced amplitude of ERPs (Chen et
al. 2007), and with measurements of lower glucose
metabolism throughout the brain (including prefrontal
cortex) during alcohol intoxication (Volkow et al. 1995).
Frontal lobe blood flow (Nicolás et al. 1993) and metabolism
(Volkow et al. 1992, 2002) may decrease in alcoholics before
significant shrinkage or major cognitive problems become
detectable (Nicolás et al. 1993; Wang et al. 1993).
The frontal lobes are connected with the other lobes of the
send fibers to numerous subcortical structures as well (Fuster
1997, 2006). The anterior region of the frontal lobes
(prefrontal cortex) plays a kind of executive regulatory role
within the brain (Goldberg 2001; Lichter and Cummings
2001). Executive functions (which depend upon many of our
cognitive abilities, such as attention, perception, memory,
and language) are defined differently by different theorists
and researchers. Most agree, however, that executive
functions are human qualities, including self-awareness, that
allow us to be independent individuals with purpose and
Fig. 1 A schematic summary and conceptual model of the brain
regions in which alcoholic and nonalcoholic groups have been found
to differ with regard to cognitive functioning. The model is based, in
large part, upon fMRI evidence comparing abstinent alcoholic patients
and healthy controls during cognitive probing of spatial and verbal
working memory (Desmond et al. 2003; Pfefferbaum et al. 2001a;
Tapert et al. 2001), vigilance (Tapert et al. 2001), and proactive
interference (De Rosa et al. 2004). Studies using alcohol cue-exposure
and emotional tasks are not included. The figure lacks anatomical
precision in terms of activation extent and laterality differences. Even
though more studies are needed to confirm, refine, and extend these
findings, the observation of decreased BOLD (blood oxygen level
dependent) activation in lateral and medial prefrontal and also parietal
areas in alcoholics seems robust. This evidence is in overall agreement
with studies showing decrease in global cortical metabolism and blood
flow, especially in frontal areas, using PET (Adams et al. 1993; Dao-
Castellana et al. 1998; Volkow et al. 1992; Wang et al. 1993),
perfusion-weighted MRI (Clark et al. 2007a), and SPECT (Gansler et
al. 2000) methodologies. Furthermore, extensive evidence from
structural neuroimaging and neuropathology studies confirms that
the frontal lobes are particularly vulnerable to alcohol-related brain
damage (Harper and Matsumoto 2005; Oscar-Berman and Marinkovic
2003; Sullivan and Pfefferbaum 2005). However, the activation
decrease is not uniform as alcoholics show increased activity
especially in a fronto–parieto–cerebellar network. This system may
be engaged in order to compensate for deficient dorsolateral prefrontal
and parietal contributions and maintain the accuracy of behavioral
performance (Sullivan and Pfefferbaum 2005). More studies are
needed to investigate interactions between structural abnormalities,
behavioral deficits, and functional brain activations as modulated by
cognitively challenging tasks. Alc. Alcohol group; Cont. control group
Neuropsychol Rev (2007) 17:239–257245
foresight about what we will do and how we behave. For
example, executive abilities include judgment, problem
solving, decision-making, planning, and social conduct, and
they allow us to monitor and change behavior flexibly and in
accord with internal goals and contextual demands.
Prefrontal neurobehavioral dysfunction has been fre-
quently observed in alcoholics with and without the dense
amnesia of Korsakoff’s syndrome (Dirksen et al. 2006;
Gansler et al. 2000; Oscar-Berman and Evert 1997; Oscar-
Berman et al. 2004). In two recent studies (Dirksen et al.
2006; Oscar-Berman et al. 2004), weadministeredaseriesof
neuropsychological tasks sensitive to dysfunction of frontal
brain systems to abstinent alcoholics, including groups of
patients with Korsakoff’s syndrome. The Korsakoff patients
were impaired on tests of memory, fluency, cognitive
flexibility, and perseverative responding. Non-Korsakoff
alcoholics showed some frontal system deficits as well, but
these generally were mildcomparedtothe Korsakoff patients.
In non-Korsakoff alcoholics, factors contributing to cognitive
performance were age, duration of abstinence, duration of
alcoholism, and amount of alcohol consumed.
In addition to causing changes in cognitive functions,
damage to frontal brain systems often leads to aberrations
of emotion and personality. This is due in part to the
interactions of frontal brain regions with limbic and
paralimbic centers that are part of a circuitry involved in
processing information about reward and aversion to
produce optimized and balanced behavior that is critical
for normal emotional functioning (LaBar and Cabeza 2006;
Makris et al. 2007).
Emotional changes have direct social and interpersonal
significance(Kornreichetal.2002). Among the abnormalities
are affective processing deficits such as a diminished ability
to recognize facial expressions of emotion (Clark et al.
2007b; Foisy et al. 2005; Howard et al. 2003; Kornreich et al.
2002; Philippot et al. 1999; Townshend and Duka 2003) and
to decipher affective prosody in spoken language (Monnot et
al. 2002). The abnormalities in emotional perception have
been attributed to a combination of underlying factors, e.g.,
visuospatial deficits, abnormal processing of social informa-
tion, poor inhibitory control, and interpersonal stress
(Moselhy et al. 2001; Philippot et al. 1999).
Frontal personality traits have been described in terms of
“disinhibition” and impulsivity, including aggression and a
lack of concern for the consequences of untoward behaviors
(Dougherty et al. 1999; Laakso et al. 2002; Marinkovic et
al. 2000; Raine et al. 2000; Stevens et al. 2003). A deficit in
response inhibition is enhanced when the response to be
suppressed is tied to alcohol-related information (Noel et al.
2007). Disinhibition and antisocial traits are associated with
increased risk for early-onset alcoholism (Mazas et al.
2000), and sensation or novelty seeking is associated with
increased drinking (Finn et al. 2000). Indeed, a cluster of
traits termed “antisocial personality disorder,” inclusive of
hyperactivity and impulsivity, correlates highly with early-
onset alcoholism, increased drinking (Brown et al. 1996;
Finn et al. 2000; Mazas et al. 2000), alcohol-induced motor
disinhibition (Marinkovic et al. 2000), and chronic alcohol
use and dependence (Hesselbrock et al. 1985; Regier et al.
1990). In a recent study that looked for a possible
relationship between impulsivity and alcohol dependence
(Chen et al. 2007), alcoholic subjects with high impulsivity
amplitudes to visual targets. Other investigators have found
that shared neurochemical markers may underlie the com-
monalities between alcohol abuse and traits associated with
antisocial personality disorder (Virkkunen and Linnoila
1993). This may be suggestive of a preexisting neurochem-
ical milieu in certain individuals that is associated with the
impulsive, hyperactive, or aggressive behaviors and which,
in turn, leads to alcoholism. Thus, impulsive behavior may
be a premorbid trait predisposing individuals to a spectrum
of disorders including alcohol dependence (Pihl et al. 1993).
There may be a genetic predisposition to dysfunctional
frontal circuitry in families with a history of alcoholism.
Duringperformance ofaclassic,visualoddball task,high-risk
children of alcoholics showed lower bilateral fMRI activation
in frontoparietal regions than control children of nonalcoholic
parents (Rangaswamy et al. 2004). Further evidence of a
genetic component of frontal lobe dysfunction in alcoholism
was provided by a dynamic contrast MRI study in
nonalcoholic subjects with family history of alcoholism:
Adult children of alcoholics had abnormal patterns of
regional cerebral blood volume changes in inferior prefrontal
regions, as well as greater mood enhancement with an
alprazolam-induced challenge, than subjects without a
familial history of alcoholism (Streeter et al. 1998).
Limbic system structure and function The limbic system
monitors internal homeostasis, mediates memory and learn-
ing, and contributes to emotional feelings and behaviors. The
limbic system also drives important aspects of sexual
behavior, motivation, and feeding behaviors. Primary areas
of the limbic system include the hippocampus, amygdala,
septal nuclei, hypothalamus, and anterior cingulate gyrus. For
the purpose of this review, because numerous studies of
alcoholics have reported abnormalities in the amygdala,
hippocampus, and hypothalamus, the discussion is focused
on those brain regions.
Amygdala The amygdala is a small almond-shaped struc-
ture, deep inside the anteroinferior region of the temporal
lobe. It is a heterogeneous brain area consisting of 13 nuclei
and cortical regions and their subdivisions (Sah et al. 2003),
with connections to prefrontal cortex, the hippocampus, the
septal nuclei, and the medial dorsal nucleus of the thalamus.
246Neuropsychol Rev (2007) 17:239–257
A number of studies have linked the amygdala to the
processing of motivational significance of stimuli and to the
mediation and control of major emotions such as love, fear,
rage, anxiety, and general negative affective states (Aggleton
2000; Amaral et al. 2003; Breiter and Rosen 1999; Everitt et
al. 2003; LeDoux 2003; Pitkänen et al. 2000; Rolls 2000).
The amygdala, being important in identifying danger,
appears fundamental for self-preservation.
Neuroimaging studies have shown that the amygdala
responds to facial expressions of many emotions, especially
those with negative affective qualities such as sadness,
anger, and fear (Blair et al. 1999; Breiter and Rosen 1999;
Wang et al. 2005; Winston et al. 2003), even in the absence
of conscious awareness of their presentation to subjects
(Whalen et al. 1998). Neuroimaging studies have shown
that conditioned responses to both aversive and positive
stimuli are processed and largely mediated by the amygda-
la, having connections to early sensory processing areas as
well as to autonomic centers. (Davis and Whalen 2001).
The amygdala is partially controlled by the brain’s
dopamine system (Delaveau et al. 2005), as an essential part
of the brain-reward circuitry—the same system that responds
to alcohol and produces feelings of pleasure when good
things happen (Koob 2003). In a recent study using fMRI in
our laboratory (Marinkovic et al. 2007), we observed clear
evidence of differences between abstinent long-term alco-
holics and nonalcoholic controls in amygdala activation to
emotional words and emotional facial expressions. Faces with
negative and positive emotional expressions evoked signifi-
cantly stronger bilateral amygdala activity in the controls than
in the alcoholics, whose activations were blunted. A similar
lack of emotional differentiation to facial expressions by
alcoholics also was observed in the hippocampus. The
observation that alcoholics respond to emotionally-valenced
stimuli in an undifferentiated manner is consistent with
clinical evidence of their interpersonal difficulties (Kornreich
et al. 2002), and may contribute to adverse societal
repercussions for alcoholics. Moreover, that both the
amygdala and hippocampus were hyporesponsive is not
surprising, since encoding of emotional memories depends
on the hippocampus in conjunction with the amygdala, as
well as their interaction (LaBar and Cabeza 2006; Phelps
2004; Richardson et al. 2004).
Hippocampus As part of the limbic system, the hippocam-
pus is intimately involved in motivation and emotion, and it
also plays a central role in the formation of memories
(Cipolotti and Bird 2006; LaBar and Cabeza 2006). The
hippocampus consists of the complex inter-folded layers of
the dentate gyrus and Ammon’s horn, which are continuous
with the subiculum, which in turn merges with the
parahippocampal gyrus. Although the notion that the
hippocampus may play a role in brain mechanisms
underlying anxiety is not new (Bannerman et al. 2002;
Gray and McNaughton 2000), there is mounting evidence
that the ventral hippocampus is part of a brain system
associated with fear and/or anxiety (Bannerman et al. 2004;
Kjelstrup et al. 2002; McHugh et al. 2004). The anatomy of
the hippocampus is closely associated with subcortical
structures, which contribute to the hypothalamic–pituitary–
adrenal axis (Kjelstrup et al. 2002).
Results of a nonhuman animal study have suggested that
the deleterious effect of ethanol on the survival of newly-
formed neurons in the adult rat hippocampus could result in
impairment of hippocampal-dependent cognitive functions
(Herrera et al. 2003). Neurogenesis is primarily a develop-
mental process that involves the proliferation, migration,
and differentiation into neurons of primordial stem cells of
the central nervous system. Neurogenesis declines until it
ceases in the young adult mammalian brain, with two
exceptions: The olfactory bulb and the hippocampus
produce new neurons throughout adult life. The ethanol-
induced reductions in hippocampal neurogenesis can be
attributed to two general mechanisms: an effect on cell
proliferation or on cell survival. These changes in hippo-
campal structure could be part of the anatomical basis for
cognitive deficits observed in alcoholism.
Structural neuroimaging studies have demonstrated a
reduction of hippocampal volume in alcoholics (Agartz et
al. 1999; Beresford et al. 2006; Kurth et al. 2004; Sullivan
et al. 1995). The loss of hippocampal volume has been
attributed to changes in white matter (Harding et al. 1997),
but the incorporation of newly-formed neurons to the
dentate gyrus could also be affected by alcohol. One MRI
study measured hippocampus volume in late-onset alco-
holics (Type I) and violent, early-onset alcoholics (Type II),
compared to nonalcoholic controls (Laakso et al. 2000).
The right, but not left, hippocampus was significantly
smaller in both alcoholic groups. While there was no
correlation between the hippocampal volumes with age in
the control subjects, there was tendency toward decreased
volumes with aging and also with the duration of
alcoholism in the Type I alcoholics. Hippocampal volume
reduction also was reported in heavy chronically-drinking,
alcohol-dependent subjects compared with nonalcoholic
controls (Beresford et al. 2006), with left hippocampal
volume reduction being slightly greater than on the right. A
study of teens (aged 15–17 years) with alcohol use
disorders found reduced left—but not right—hippocampal
volume compared to healthy age-equivalent controls (Nagel
et al. 2005). The groups were equivalent in right hippo-
campal, intracranial gray and white matter volumes, and
memory performance. The authors suggested that premor-
bid volumetric differences might account for some of the
observed group differences in hippocampal volume. Re-
Neuropsychol Rev (2007) 17:239–257247
duction of hippocampal volume in alcoholics is reversible
after short periods of abstinence (White et al. 2000).
Similarly, hippocampal dependent cognitive functions have
shown reversibility after comparable periods of abstinence
(Bartels et al. 2006).
Hypothalamus The hypothalamus literally means “under the
thalamus.” It is a small structure nestled within the limbic
system directly above the brainstem. The hypothalamus has
connections with many other brain regions, and it is involved
in learning and memory, as well as in regulatory functions
such as eating and drinking, temperature control, hormone
regulation, and emotion. Long-term alcoholism and concom-
to the mammillary bodies of the hypothalamus, and memory
deficits (amnesia) often follow. Although damage to other
regions of the brain in addition to the hypothalamus have also
been implicated (e.g., basal forebrain, hippocampus, fornix,
medial and anterior nuclei of the thalamus), when amnesia
as alcohol-induced persisting amnestic disorder (APA 1994),
or alcoholic Korsakoff’s syndrome (Oscar-Berman and Evert
1997). The specific memory impairments include severe
anterograde amnesia for newly learned information, and
some retrograde amnesia, i.e., loss of memory for events that
happened long ago (prior to the appearance of obvious
Amnesia, especially anterograde amnesia, or memory loss
with Korsakoff’s syndrome are permanently unable to
remember new information for more than a few seconds.
Because new events are forgotten a few seconds after they
occur, virtually nothing new is learned, and patients with
Korsakoff’s syndrome live perpetually in the past. However,
in contrast to patients with alcoholic dementia, who have
generalized cognitive decline (including widespread memory
formed prior to the onset of alcohol-related brain damage.
Although anterograde amnesia is the most obvious
presenting symptom in Korsakoff patients, these individuals
have additional cognitive and emotional impairments
(Clark et al. 2007b; Dirksen et al. 2006). Like patients
with bilateral prefrontal cortical lesions, Korsakoff patients
are abnormally sensitive to distractions (proactive interfer-
ence). This sensitivity may be due to alcoholism-related
prefrontal dysfunction, which impairs the ability to coun-
teract the effects of cognitive interruptions. In addition to
their memory problems and their sensitivity to interference,
Korsakoff patients also tend to repeat unnecessary behav-
iors (perseverative responding), have restricted attention,
retarded perceptual processing abilities, ataxia, and de-
creased sensitivity to reward contingencies (Oscar-Berman
and Evert 1997).
Asa partofa widerarrayofinterrelatedabnormalities,ithas
been shown that the hypothalamic–pituitary–adrenocortical
(HPA) function is hyporeactive in chronic alcoholics (Errico
et al. 2002; Lovallo 2006). Cortisol, in turn, increases
mesencephalic dopaminergic transmission that underlies the
activation of alcohol-induced brain reward circuitry (Bowirrat
and Oscar-Berman 2005; Gianoulakis 1998; Piazza et al.
1996), in which the amygdala plays an essential role (Koob
2003). These additional abnormalities reflect widespread
cerebral atrophy accompanying sustained alcohol abuse. Thus,
consideration should be given to sensory and cognitive
deficits that may be integral to the disease process caused by
Cerebellar structure and function The cerebellum is a brain
structure that coordinates movement of voluntary muscles,
balance, and eye movements, and it also is essential to the
neural circuitry subserving cognition and emotion
(Schmahmann 2000, 1997). The cerebellum contains about
half of the brain’s neurons, but the nerve cells are so small
that the cerebellum accounts for only 10% of the brain’s
total weight. The cerebellum consists mainly of two large,
tightly folded lobes, joined at the middle by the vermis.
Also located anteriorly are the small flocculonodular lobes
(flocculi). The cerebellum connects with the other brain
structures through the cerebellar peduncles, located to the
anterior of the cerebellum. Five different nerve cell types
make up the cerebellum: stellate, basket, Purkinje, Golgi,
and granule cells. The Purkinje cells are the only ones to
send axons out of the cerebellum.
Atrophy of the cerebellum is commonly associated with
alcoholism. White matter volume of the cerebellar vermis is
significantly reduced (Baker et al. 1999; Pentney et al.
2002; Sullivan et al. 2000), and cerebellar vermian atrophy
occurs in 25–40% of all alcoholics. Vermal white matter
volume was reduced in ataxic alcoholics by 42%. It occurs
even more often in people with additional thiamine
deficiency, with 35–50% of those individuals showing
evidence of superior vermian degeneration (Victor 1992).
Gross vermian atrophy is commonly seen post mortem in
alcoholics (Phillips et al. 1987; Sullivan et al. 2003), and it
also has been observed with in vivo neuroimaging techniques
Over the past two decades, careful study has expanded
the purview of the cerebellum to include influence on
functions classically associated with frontal lobe function-
ing (Schmahmann 2000; Sullivan et al. 2003). As noted in
the previous section on frontal lobes, this part of the brain
has executive control functions such as cognitive flexibility,
speed in allocation of attentional resources, shifting ability,
inhibition of perseverative errors, abstractive and planning
skills, and suppression of irrelevant information. Together,
these observations suggest a functional role for frontocer-
248Neuropsychol Rev (2007) 17:239–257
ebellar circuitry (Schmahmann 1997). Further, cerebellar
volume shrinkage in alcoholics has been shown to correlate
with performance on tests of executive function, tradition-
ally attributed to frontal pathology, thus revealing the
importance of disrupted frontocerebellar circuitry in the
constellation of alcoholism-related functional impairments
(Chanraud et al. 2007; Harris et al. 1999; Sullivan 2003;
Sullivan et al. 2003). Additionally, an fMRI study of
alcoholic and nonalcoholic control subjects performing a
verbal working memory task showed that despite comparable
levels of task performance by the two groups, the alcoholic
in the right superior cerebellar and left frontal regions
(Desmond et al. 2003). As Sullivan and her colleagues have
suggested, it may be that increased demands on frontal brain
regions may be incurred to overcome alcoholism-related
impairments, and that the cerebellum provides supplementary
compensation for maintaining information in a compromised
brain system (Desmond et al. 2003; Harris et al. 1999;
Alcoholics with Korsakoff’s syndrome have shown a
significant decrease in Purkinje cell density in the cerebellar
vermis and molecular layer volume (Baker et al. 1999). A
36% reduction in Purkinje cell numbers in the flocculi
suggests disruption of vestibulocerebellar pathways. This is
of particular interest given recent data showing the
importance of cerebellum in the organization of higher
order cerebral functions (Schmahmann 2000).
Right hemisphere structure and function Impairments in
cognitive functioning found to be associated with alcohol-
ism are also prominent in patients with damage to the right
hemisphere (RH) of the brain unrelated to alcoholism. This
similarity led Jones and Parsons (1971) to propose that RH
functions may be more vulnerable than left hemisphere
(LH) functions to the effects of chronic alcoholism. A
variety of studies have found evidence to support this
proposition (Ellis and Oscar-Berman 1989; Oscar-Berman
and Schendan 2000). This evidence comes from findings of
impairments of cognitive functions for which the RH is
generally more specialized than the LH. These include:
greater impairments on performance (nonverbal) tasks than
on verbal tasks of IQ tests (Parsons and Leber 1981);
reduced visual-spatial and perceptual-motor performance
(Bowden and McCarter 1993; Ellis and Oscar-Berman
1989; Parsons 1987); emotional abnormalities (Clark et al.
2007b; Oscar-Berman et al. 1990); atypical laterality
patterns on dichotic listening tests (Drake et al. 1990), but
only for the male alcoholics); impaired performance for
nonverbal stimuli on visual search tasks (Bertera and
Parsons 1978); and limited attentional resources (Evert
and Oscar-Berman 2001; Smith and Oscar-Berman 1992).
It is important to note, however, that while many studies
have found evidence to support the “right hemisphere
hypothesis” of alcoholism-related cognitive decline, others
have not found such support (Cermak et al. 1989; Mungas
et al. 1994).
Based on the many findings that suggest RH functional
decline associated with alcoholism, one might expect to
find neuropathological and neuroradiological evidence
indicating greater morphological and physiological changes
in the RH than in the LH. However, this level of analysis
has been marked by inconsistent findings. In a post mortem
study of the brains of alcoholics, no differences were
identified between the right and left hemispheres (Harper et
al. 1985). Several studies using CT imaging in living
alcoholics also have not found significant differences in
brain morphology between the two hemispheres (Lee et al.
1979; Wilkinson and Carlen 1980). In two CT studies that
did find evidence of hemispheric differences in alcoholics,
changes were more marked in the LH than in the RH
(Gebhardt et al. 1984; Golden et al. 1981). By contrast, an
MRI study by Makris et al. (2007) demonstrated that
abstinent alcoholic subjects had volumetric deficits in the
RH of the brain’s extended reward and oversight system
(EROS). This system includes dorsolateral prefrontal,
orbitofrontal, and anterior cingulate cortices, the anterior
insula, hippocampus, amygdala, nucleus accumbens, and
ventral diencephalon. This circuitry processes information
about reward and aversion and is fundamental for the
determination of goals optimizing normal emotional func-
tioning and its malfunction. The regions having the most
pronounced RH deficits were dorsolateral prefrontal cortex,
anterior insula, and nucleus accumbens (Makris et al.
2007). In a companion study (Harris et al. 2007) we used
DTI to assess functional anisotropy (a measure of white
matter integrity), in the brains of abstinent alcoholics
compared to matched controls. We found that alcoholics
had diminished functional anisotropy in the right frontal
lobe in superior longitudinal fascicles II and III, orbito-
frontal cortex white matter, and cingulum bundle, but not in
corresponding left hemisphere regions. These right frontal
and cingulum white-matter regional functional anisotropy
measures provided 97–100% correct group discrimination
Findings with respect to hemispheric differences in
alcoholics with the use of functional brain imaging studies
also have shown inconsistent results. There have been
reports that cerebral blood flow of the RH is more affected
than the LH (Berglund 1981). Other studies have found
either no difference in cerebral blood flow and glucose
metabolism between the halves of the brain (Adams et al.
1993; Gilman et al. 1990; Nicolás et al. 1993; Samson et al.
1986; Wang et al. 1993), or increased hypometabolism in
the LH (Erbas et al. 1992). To complicate matters, Volkow
et al. (1992) found that the right frontal cortex showed
Neuropsychol Rev (2007) 17:239–257249
greater hypometabolism than the left, and the left parietal
cortex showed greater hypometabolism than the right.
Perhaps the most consistent evidence of greater RH
dysfunction has come from studies utilizing electrophysio-
logical measures, although this observation has to be
tempered by the poor spatial resolution of ERPs. In one
study, ERP abnormalities in alcoholics were particularly
evident in the right frontal area (Porjesz and Begleiter
1982). In addition, the alcoholics did not show normal
asymmetrical ERP responses (i.e., the finding that RH
amplitudes are normally greater than LH amplitudes; see
also Zhang et al. 1997). Similarly, Kostandov et al. (1982)
found abnormally long latencies and small amplitudes of
the P300 component of the ERP in the RH of the
alcoholics, whereas LH measures did not differ between
the alcoholic and control groups.
Implications for Treatment and Recovery
Clinicians must consider a variety of treatment methods to
promote cessation of drinking, maintenance of sobriety, and
recovery of impaired functioning. In a comprehensive
review of the pharmacogenomics of alcohol response and
addiction, Enoch (2003) noted that treatment is complicated
by the comorbidity of alcoholism with other disorders (e.g.,
anxiety, depression, antisocial personality disorder, smok-
ing, and other addictions). Furthermore, specific environ-
mental contexts such as stress and alcohol-related stimuli,
can stimulate craving for alcohol. Of interest, Sinha and
colleagues (Fox et al. 2007; Sinha and Li 2007) have
evaluated the separate contributions of stress and alcohol
cues to alcohol craving, anxiety, and bodily responses in
recently detoxified alcoholic individuals. The researchers
reported that although there is overlap in brain circuits for
processing stress and alcohol cues, each produced a
dissociable psychobiological state involving subjective
emotional, cardiovascular, and cortisol responses. That is,
stress-induced alcohol craving was related to increased
systolic and diastolic blood pressure, as well as sadness,
anger, and anxiety ratings, but alcohol cue-induced craving
was associated with increased salivary cortisol, as well as
anxiety and fear ratings. Thus, co-occurring conditions
having disparate underlying psychobiological underpin-
nings need to be considered when planning rehabilitation
and treatment strategies.
First-line therapeutic targets for alcoholism are neuro-
transmitter pathway genes implicated in alcohol use. Of
particular interest are the reward pathways (serotonin,
dopamine, GABA, glutamate, and beta endorphin) and the
behavioral stress response system (corticotrophin-releasing
factor and neuropeptide Y). Common functional poly-
morphisms in these genes are likely to be predictive
(although each with small effect) of individualized phar-
macological responses. As we have noted earlier, genetic
studies, including case-control association studies and
genome wide linkage studies, have identified associations
between alcoholism and common functional polymor-
phisms in several candidate genes. Meanwhile, the current
pharmacological therapies are only modestly effective in
preventing relapse and dependence in alcoholics (Doggrell
2006; Kranzler and Van Kirk 2001; Mann 2004), prompting
more research. Additionally, treating co-occurring disorders
remains a challenge, and the use of creative approaches that
would encompass individualized psychosocial support, as
well as a combination of treatments, might be the most
effective way to address this problem.
Because alcoholism is associated with diverse changes to
the brain and behavior, treatment professionals might find it
most helpful to use a combination of neuropsychological
observations and structural and functional brain imaging
results in developing predictors of abstinence versus
relapse, with the purpose of tailoring treatment methods to
each individual patient. For example, the development of
effective medications for controlling alcoholism relies upon
knowledge about the neuroanatomical origins of neuro-
transmitters involved in craving, intoxication, and addic-
tion. 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 biochem-
ical changes in patients across time as a result of
abstinence, therapeutic interventions, withdrawal, or re-
lapse. 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 structure and function (Bartsch et al. 2007;
Ende et al. 2005; Fein and Chang 2006; Gansler et al. 2000;
O’Neill et al. 2001). Thus, through the combined efforts of
scientists and clinicians, important strides already have
been made in the diagnosis, prevention, and treatment of
alcoholism, and hopefully there will be continued advances
in the future.
Alcoholics are a diverse group. They experience different
subsets of symptoms, and the disease has different origins
and modulating influences for different people. Therefore,
250 Neuropsychol Rev (2007) 17:239–257
to understand the effects of alcoholism, it is important to
consider the influence of a wide range of variables on a
particular behavior or set of behaviors. The underpinnings
of alcohol-induced brain defects are multivariate; to date,
the available literature does not support the assertion that
any one variable can consistently and completely account
for these impairments. Instead, the identification of the
most salient variables is a primary focus of current research.
In the search for answers, we recommend an integrative
approach that recognizes the interconnectivity of the
different functional systems to account for the heterogene-
ity of outcome variables associated with alcoholism-related
impairments and recovery of functions. It is helpful to use
as many kinds of tools as possible, keeping in mind that
specific deficits can be observed only with certain methods,
with rigorous paradigms, and with particular groups of
people with distinct risk factors. Such confluence of
information can provide evidence linking structural dam-
age, functional alterations, and the specific behavioral and
neuropsychological effects of alcoholism. These measures
also can determine the degree to which abstinence and
treatment result in the reversal of atrophy and dysfunction.
US Department of Health and Human Services, NIAAA (R01-
AA07112, K05-AA00219, and K01-AA13402), the Medical Research
Service of the US Department of Veterans Affairs, and the Alcoholic
Beverage Medical Research Foundation.
The writing of this paper was supported by the
Abel, E. L., Kruger, M. L., & Friedl, J. (1999). How do physicians
define “light,” “moderate,” and “heavy” drinking? Alcoholism:
Clinical and Experimental Research, 22(5), 979–984.
Adams, K. M., Gilman, S., Koeppe, R. A., Kluin, K. J., Brunberg, J. A.,
Dede, D., et al. (1993). Neuropsychological deficits are correlated
with frontal hypometabolism in positron emission tomography
studies of older alcoholic patients. Alcoholism: Clinical and
Experimental Research, 17(2), 205–210.
Agartz, I., Momenam, R., Rawlings, R. R., Kerich, M. J., & Hommer,
D. W. (1999). Hippocampal volume in patients with alcohol
dependence. Archives of General Psychiatry, 56(4), 356–363.
J. P. Aggleton (Ed.) (2000). The amygdala: A functional analysis (2nd
ed.). Oxford: Oxford University Press.
Amaral, D. G., Bauman, M. D., Capitanio, J. P., Lavenex, P., Mason,
W. A., Mauldin-Jourdain, M. L., et al. (2003). The amygdala: Is
it an essential component of the neural network for social
cognition? Neuropsychologia, 41(4), 517–522.
APA (1994). Diagnostic and statistical manual of mental disorders
(DSM-IV). Washington, DC: American Psychiatric Association.
Baker, K. G., Harding, A. J., Halliday, G. M., Kril, J. J., & Harper, C. G.
(1999). Neuronal loss in functional zones of the cerebellum of
chronic alcoholics with and without Wernicke’s encephalopathy.
Neuroscience, 19(2), 429–438.
Bannerman, D. M., Grubb, M., Deacon, R. M. J., Yee, B. K., Feldon, J.,
& Rawlins, J. N. P. (2002). Ventral hippocampal lesions affect
anxiety but not spatial learning. Behavioural Brain Research, 139,
Bannerman, D. M., Rawlins, J. N., McHugh, S. B., Deacon, R. M.,
Yee, B. K., Bast, T., et al. (2004). Regional dissociations within
the hippocampus-memory and anxiety. Neuroscience and Bio-
behavioral Reviews, 28(3), 273–283.
& Krampe, H. (2006). Recovery of hippocampus-related functions
in chronic alcoholics during monitored long-term abstinence.
Alcohol and Alcoholism.
Bartsch, A. J., Homola, G., Biller, A., Smith, S. M., Weijers, H. G.,
Wiesbeck, G. A., et al. (2007). Manifestations of early brain
recovery associated with abstinence from alcoholism. Brain, 130,
Begleiter, H., & Porjesz, B. (1999). What is inherited in the
predisposition toward alcoholism? A proposed model. Alcohol-
ism: Clinical and Experimental Research, 23(7), 1125–1135.
Beresford, T. P., Arciniegas, D. B., Alfers, J., Clapp, L., Martin, B.,
Du, Y., et al. (2006). Hippocampus volume loss due to chronic
heavy drinking. Alcoholism: Clinical and Experimental Re-
search, 30(11), 1866–1870.
Berglund, M. (1981). Cerebral blood flow in chronic alcoholics.
Alcoholism: Clinical and Experimental Research, 5, 295–303.
Bertera, J. H., & Parsons, O. A. (1978). Impaired visual search in
alcoholics. Alcoholism: Clinical and Experimental Research, 2(1),
Bierut, L. J., Saccone, N. L., Rice, J. P., Goate, A., Foroud, T.,
Edenberg, H., et al. (2002). Defining alcohol-related phenotypes
in humans. The collaborative study on the genetics of alcoholism.
Alcohol Research and Health, 26(3), 208–213.
Blair, R. J. R., Morris, J. S., Frith, C. D., Perrettand, D. I., & Dolan, R. J.
(1999). Dissociable neural responses to facial expressions of
sadness and anger. Brain, 122, 883–893.
Blum, K., Braverman, E. R., Holder, J. M., Lubar, J. F., Monastra, V. J.,
Miller, D., et al. (2000). Reward deficiency syndrome: A biogenetic
model for the diagnosis and treatment of impulsive, addictive,
and compulsive behaviors. Journal of Psychoactive Drugs, 32
(Suppl i–iv), 1–112.
Bowden, S. C., & McCarter, R. J. (1993). Spatial memory in alcohol-
dependent subjects: Using a push-button maze to test the
principle of equiavailability. Brain and Cognition, 22(1), 51–62.
Bowirrat, A., & Oscar-Berman, M. (2005). Relationship between
dopaminergic neurotransmission, alcoholism, and Reward Defi-
ciency syndrome. American Journal of Medical Genetics. Part B,
Neuropsychiatric Genetics, 132B(1), 29–37.
Breiter, H. C., & Rosen, B. R. (1999). Functional magnetic resonance
imaging of brain reward circuitry in the human. In J. F. McGinty
(Ed.), Advancing from the ventral striatum to the extended
amygdala (Vol. 877, pp. 523–547). New York: New York
Academy of Sciences.
Brown, S. A., Gleghorn, A., Schuckit, M. A., Myers, M. G., & Mott,
M. A. (1996). Conduct disorder among adolescent alcohol and
drug abusers. Journal of Studies on Alcohol, 57(3), 314–324.
Bushman, B. J., & Cooper, H. M. (1990). Effects of alcohol on human
aggression: An integrative research review. Psychological Bulletin,
Cermak, L. S., Verfaellie, M., Letourneau, L., Blackford, S., Weiss, S.,
& Numan, B. (1989). Verbal and nonverbal right hemisphere
processing by chronic alcoholics. Alcoholism: Clinical and
Experimental Research, 13(5), 611–616.
Chanraud, S., Martelli, C., Delain, F., Kostogianni, N., Douaud, G.,
Aubin, H. J., et al. (2007). Brain morphometry and cognitive
performance in detoxified alcohol-dependents with preserved psy-
chosocial functioning. Neuropsychopharmacology, 32(2), 429–438.
Chen, A. C., Porjesz, B., Rangaswamy, M., Kamarajan, C., Tang, Y.,
Jones, K. A., et al. (2007). Reduced frontal lobe activity in
subjects with high impulsivity and alcoholism. Alcoholism:
Clinical and Experimental Research, 31(1), 156–165.
Neuropsychol Rev (2007) 17:239–257251
Cipolotti, L., & Bird, C. M. (2006). Amnesia and the hippocampus.
Current Opinion in Neurology, 19(6), 593–598.
Clark, C. P., Brown, G. G., Eyler, L. T., Drummond, S. P., Braun, D. R.,
& Tapert, S. F. (2007a). Decreased perfusion in young alcohol-
dependent women as compared with age-matched controls.
American Journal of Drug and Alcohol Abuse, 33(1), 13–19.
Clark, U. S., Oscar-Berman, M., Shagrin, B., & Pencina, M. (2007b).
Alcoholism and judgments of affective stimuli. Neuropsychology,
Comings, D. E., Dietz, G., Johnson, J. P., & MacMurray, J. P. (1999).
Association of the enkephalinase gene with low amplitude P300
waves. Neuroreport, 10(11), 2283–2285.
Connor, J. P., Young, R. M., Lawford, B. R., Ritchie, T. L., & Noble,
E. P. (2002). D(2) dopamine receptor (DRD2) polymorphism is
associated with severity of alcohol dependence. European
Psychiatry, 17(1), 17–23.
Courville, C. B. (1966). Effects of alcohol on the nervous system of
man. Los Angeles: San Lucas Press.
Crews, F. T., Buckley, T., Dodd, P. R., Ende, G., Foley, N., Harper, C.,
et al. (2005). Alcoholic neurobiology: Changes in dependence
and recovery. Alcoholism: Clinical and Experimental Research,
Dao-Castellana, M. H., Samson, Y., Legault, F., Martinot, J. L., Aubin,
normal chronic alcoholic subjects: Metabolic and neuropsycholog-
ical findings. Psychological Medicine, 28(5), 1039–1048.
Davis, M., & Whalen, P. J. (2001). The amygdala: Vigilance and
emotion. Molecular Psychiatry, 6, 13–34.
Dawson, D. A., Grant, B. F., Stinson, F. S., & Zhou, Y. (2005).
Effectiveness of the derived Alcohol Use Disorders Identification
Test (AUDIT-C) in screening for alcohol use disorders and risk
drinking in the US general population. Alcoholism: Clinical and
Experimental Research, 29(5), 844–854.
De Rosa, E., Desmond, J. E., Anderson, A. K., Pfefferbaum, A., &
Sullivan, E. V. (2004). The human basal forebrain integrates the
old and the new. Neuron, 41(5), 825–837.
de Wit, H., Metz, J., Wagner, N., & Cooper, M. (1990). Behavioral
and subjective effects of ethanol: Relationship to cerebral
metabolism using PET. Alcoholism: Clinical and Experimental
Research, 14(3), 482–489.
Deckel, A. W., Hesselbrock, V., & Bauer, L. (1996). Antisocial
personality disorder, childhood delinquency, and frontal brain
functioning: EEG and neuropsychological findings. Journal of
Clinical Psychology, 52(6), 639–650.
(2005). Effect of levodopa on healthy volunteers’ facial emotion
perception: An FMRI study. Clinical Neuropharmacology, 28(6),
Desmond, J. E., Chen, S. H., DeRosa, E., Pryor, M. R., Pfefferbaum, A.,
& Sullivan, E. V. (2003). Increased frontocerebellar activation
in alcoholics during verbal working memory: An fMRI study.
Neuroimage, 19(4), 1510–1520.
Di Sclafani, V., Ezekiel, F., Meyerhoff, D. J., MacKay, S., Dillon, W. P.,
Weiner, M. W., et al. (1995). Brain atrophy and cognitive function
in older abstinent alcoholic men. Alcoholism: Clinical and
Experimental Research, 19(5), 1121–1126.
Di Sclafani, V., Finn, P., & Fein, G. (2007). Psychiatric comorbidity in
long-term abstinent alcoholic individuals. Alcoholism: Clinical
and Experimental Research, 31(5), 795–803.
Dick, D. M., Edenberg, H. J., Xuei, X., Goate, A., Kuperman, S.,
Schuckit, M., et al. (2004). Association of GABRG3 with alcohol
dependence. Alcoholism: Clinical and Experimental Research, 28
Dick, D. M., & Foroud, T. (2003). Candidate genes for alcohol
dependence: A review of genetic evidence from human studies.
Alcoholism: Clinical and Experimental Research, 27(5), 868–879.
Dickson, P. A., James, M. R., Heath, A. C., Montgomery, G. W.,
Martin, N. G., Whitfield, J. B., et al. (2006). Effects of variation
at the ALDH2 locus on alcohol metabolism, sensitivity, con-
sumption, and dependence in Europeans. Alcoholism: Clinical
and Experimental Research, 30(7), 1093–1100.
Dirksen, C. L., Howard, J. A., Cronin-Golomb, A., & Oscar-Berman, M.
(2006). Patterns of prefrontal dysfunction in alcoholics with
or without Korsakoff’s syndrome, patients with Parkinson’s
disease, and patients with rupture and repair of the anterior
communicating artery. Neuropsychiatric Disease and Treatment,
Doggrell, S. A. (2006). Which treatment for alcohol dependence:
Naltrexone, acamprosate and/or behavioural intervention? Expert
Opinion on Pharmacotherapy, 7(15), 2169–2173.
Dougherty, D. M., Marsh, D. M., Moeller, F. G., Chokshi, R. V., &
Rosen, V. C. (2000). Effects of moderate and high doses of alcohol
on attention, impulsivity, discriminability, and response bias in
immediate and delayed memory task performance. Alcoholism:
Clinical and Experimental Research, 24(11), 1702–1711.
Dougherty, D. M., Moeller, F. G., Steinberg, J. L., Marsh, D. M., Hines,
S. E., & Bjork, J. M. (1999). Alcohol increases commission error
rates for a continuous performance test. Alcoholism: Clinical and
Experimental Research, 23(8), 1342–1351.
Drake, A. I., Hannay, H. J., & Gam, J. (1990). Effects of chronic
alcoholism on hemispheric functioning: An examination of
gender differences for cognitive and dichotic listening tasks.
Journal of Clinical and Experimental Neuropsychology, 12(5),
Dufour, M., & Fuller, R. K. (1995). Alcohol in the elderly. Annual
Review of Medicine, 46, 123–132.
Durazzo, T. C., Rothlind, J. C., Gazdzinski, S., Banys, P., &
Meyerhoff, D. J. (2006). A comparison of neurocognitive
function in nonsmoking and chronically smoking short-term
abstinent alcoholics. Alcoholism, 39(1), 1–11.
Eckardt, M. J., File, S. E., Gessa, G. L., Grant, K. A., Guerri, C.,
Foffman, P. L., et al. (1998). Effects of moderate alcohol
consumption on the central nervous system. Alcoholism: Clinical
and Experimental Research, 22, 998–1040.
Edenberg, H. J., & Foroud, T. (2006). The genetics of alcoholism:
Identifying specific genes through family studies. Addiction
Biology, 11(3–4), 386–396.
Ellis, R. J., & Oscar-Berman, M. (1989). Alcoholism, aging, and
functional cerebral asymmetries. Psychological Bulletin, 106,
et al. (2005). Monitoringthe effects ofchronic alcohol consumption
and abstinence on brain metabolism: A longitudinal proton
magnetic resonance spectroscopy study. Biological Psychiatry, 58
Enoch, M. A. (2003). Pharmacogenomics of alcohol response and
addiction.American Journal of Pharmacogenomics, 3(4), 217–232.
Erbas, B., Bekdik, C., Erbengi, G., Enunlu, T., Aytac, S., Kumbasar, H.,
et al. (1992). Regional cerebral blood flow changes in chronic
alcoholism using Tc-99m HMPAO SPECT. Comparison with CT
parameters. Clinical Nuclear Medicine, 17(2), 123–127.
Errico, A. L., King, A. C., Lovallo, W. R., & Parsons, O. A. (2002).
Cortisol dysregulation and cognitive impairment in abstinent
male alcoholics. Alcoholism: Clinical and Experimental Re-
search, 26(8), 1198–1204.
Everitt, B. J., Cardinal, R. N., Parkinson, J. A., & Robbins, T. W.
(2003). Appetitive behavior: Impact of amygdala-dependent
mechanisms of emotional learning. Annals of the New York
Academy of Science, 985, 233–250.
Evert, D. L., & Oscar-Berman, M. (2001). Selective attentional
processing and the right hemisphere: Effects of aging and
alcoholism. Neuropsychology, 15(4), 452–461.
252 Neuropsychol Rev (2007) 17:239–257
Fein, G., & Chang, M. (2006). Visual P300s in long-term abstinent Download full-text
chronic alcoholics. Alcoholism: Clinical and Experimental
Research, 30(12), 2000–2007.
Fein, G., Di Sclafani, V., Finn, P., & Scheiner, D. L. (2007). Sub-
diagnostic psychiatric comorbidity in alcoholics. Drug and
Alcohol Dependence, 87(2–3), 139–145.
Fein, G., Klein, L., & Finn, P. (2004). Impairment on a simulated
gambling task in long-term abstinent alcoholics. Alcoholism:
Clinical and Experimental Research, 28(10), 1487–1491.
Fein, G., McGillivray, S., & Finn, P. (2006). Normal performance on a
simulated gambling task in treatment-naive alcohol-dependent
individuals. Alcoholism: Clinical and Experimental Research, 30
Fein, G., Torres, J., Price, L. J., & Di Sclafani, V. (2006). Cognitive
performance in long-term abstinent alcoholic individuals. Alco-
holism: Clinical and Experimental Research, 30(9), 1538–1544.
Fillmore, M. T., & Weafer, J. (2004). Alcohol impairment of behavior
in men and women. Addiction, 99(10), 1237–1246.
cognitive-motivational theory of personality vulnerability to alco-
holism. Cognitive Neuroscience Reviews 1(3), 183–205.
Finn, P. R., Sharkansky, E. J., Brandt, K. M., & Turcotte, N. (2000). The
effects of familial risk, personality, and expectancies on alcohol use
and abuse. Journal of Abnormal Psychology, 109(1), 122–133.
Foisy, M. L., Philippot, P., Verbanck, P., Pelc, I., van der Straten, G.,
& Kornreich, C. (2005). Emotional facial expression decoding
impairment in persons dependent on multiple substances: Impact
of a history of alcohol dependence. Journal of Studies on
Alcohol, 66(5), 673–681.
Fox, H. C., Bergquist, K. L., Hong, K. I., & Sinha, R. (2007). Stress-
induced and alcohol cue-induced craving in recently abstinent
alcohol-dependent individuals. Alcoholism: Clinical and Exper-
imental Research, 31(3), 395–403.
Fuster, J. M. (1997). The prefrontal cortex (3rd ed.). New York:
Fuster, J. M. (2006). The cognit: A network model of cortical
representation. International Journal of Psychophysiology, 60(2),
Gansler, D. A., Harris, G. J., Oscar-Berman, M., Streeter, C., Lewis,
R. F., Ahmed, I., et al. (2000). Hypoperfusion of inferior frontal
brain regions in abstinent alcoholics: A pilot SPECT study.
Journal of Studies on Alcohol, 61(1), 32–37.
Gazdzinski, S., Durazzo, T. C., Studholme, C., Song, E., Banys, P., &
Meyerhoff, D. J. (2005). Quantitative brain MRI in alcohol
dependence: Preliminary evidence for effects of concurrent
chronic cigarette smoking on regional brain volumes. Alcohol-
ism: Clinical and Experimental Research, 29(8), 1484–1495.
Gebhardt, C. A., Naeser, M. A., & Butters, N. (1984). Computerized
measures of CT scans of alcoholics: Thalamic region related to
memory. Alcohol, 1(2), 133–140.
Giancola, P. R. (2004). Executive functioning and alcohol-related
aggression. Journal of Abnormal Psychology 113(4), 541–555.
Gianoulakis, C. (1998). Alcohol-seeking behavior: The roles of the
hypothalamic–pituitary–adrenal axis and the endogenous opioid
system. Alcohol Health and Research World, 22(3), 202–210.
Gilman, S., Adams, K. M., Johnsongreene, D., Koeppe, R. A., Junck, L.,
Kluin, K. J., etal. (1996). Effectsof disulfiramonpositronemission
tomography and neuropsychological studies in severe chronic
alcoholism. Alcoholism: Clinical and Experimental Research, 20
Gilman, S., Adams, K., Koeppe, R. A., Berent, S., Kluin, K. J.,
Modell, J. G., et al. (1990). Cerebellar and frontal hypometab-
olism in alcoholic cerebellar degeneration studied with positron
emission tomography. Annals of Neurology, 28(6), 775–785.
Goldberg, E. (2001). The executive brain: Frontal lobes and the
civilized mind. New York: Oxford University Press.
Golden, C. J., Graber, B., Blose, I., Berg, R., Coffman, J., & Bloch, S.
(1981). Difference in brain densities between chronic alcoholic
and normal control patients. Science, 211(4481), 508–510.
Goldman, D., Dean, M., Brown, G. L., Bolos, A. M., Tokola, R.,
Virkkunen, M., et al. (1992). D2 dopamine receptor genotype and
cerebrospinal fluid homovanillic acid, 5-hydroxyindoleacetic acid
and3-methoxy-4-hydroxyphenylglycol inalcoholics inFinland and
theUnitedStates.Acta Psychiatrica Scandinavica, 86(5), 351–357.
Grant, S. A., Millar, K., & Kenny, G. N. (2000). Blood alcohol
concentration and psychomotor effects. British Journal of
Anaesthesiology, 85(3), 401–406.
Grant, B. F., Stinson, F. S., Dawson, D. A., Chou, S. P., Dufour, M. C.,
Compton, W., et al. (2004). Prevalence and co-occurrence of
Results from the national epidemiologic survey on alcohol and
related conditions. Archives of General Psychiatry, 61, 807–816.
Gray, J. A., & McNaughton, N. (2000). The neuropsychology of
anxiety: An enquiry into the functions of the septo-hippocampal
system (2nd ed.). Oxford, England: Oxford University Press.
Grillon, C., Sinha, R., & O’Malley, S. S. (1995). Effects of ethanol on
the processing of low probability stimuli: An ERP study.
Psychopharmacology (Berlin), 119(4), 455–465.
Harding, A. J., Wong, A., Svoboda, M., Kril, J. J., & Halliday, G. M.
(1997). Chronic alcohol consumption does not cause hippocam-
pal neuron loss in humans. Hippocampus, 7(10), 78–87.
Harper, C. G. (1998). The neuropathology of alcohol-specific brain
damage, or does alcohol damage the brain? Journal of Neuropa-
thology and Experimental Neurology, 57(2), 101–110.
Harper, C. G., Kril, J. J., & Holloway, R. L. (1985). Brain shrinkage in
chronic alcoholics: A pathological study. British Medical
Journal, 290(6467), 501–504.
Harper, C. G., & Matsumoto, I. (2005). Ethanol and brain damage.
Current Opinion in Pharmacology, 5, 73–78.
Harris, G. J., Jaffin, S. K., Hodge, S. M., Kennedy, D., Caviness, V.
S., Marinkovic, K., et al. (2007). Right frontal white matter and
cingulum diffusion tensor imaging deficits in alcoholism.
Biological Psychiatry (submitted).
Harris, G. J., Oscar-Berman, M., Gansler, D. A., Streeter, C., Lewis,
R. F., Ahmed, I., et al. (1999). Hypoperfusion of cerebellum and
aging effects on cerebral cortex blood flow in abstinent
alcoholics: A SPECT study. Alcoholism: Clinical and Experi-
mental Research, 23(7), 1219–1227.
Heinz, A., Mann, K., Weinberger, D. R., & Goldman, D. (2001).
Serotonergic dysfunction, negative mood states, and response to
alcohol. Alcoholism: Clinical and Experimental Research, 25(4),
& Guth, S. E. (2006). Should DSM-V include dimensional
diagnostic criteria for alcohol use disorders? Alcoholism: Clinical
and Experimental Research, 30(2), 303–310.
Herrera, D. G., Yague, A. G., Johnsen-Soriano, S., Bosch-Morell, F.,
Collado-Morente, L., Muriach, M., et al. (2003). Selective
impairment of hippocampal neurogenesis by chronic alcoholism:
Protective effects of an antioxidant. Proceedings of the National
Academy of Sciences, 100(13), 7919–7924.
Hesselbrock, V. M., Hesselbrock, M. N., & Stabenau, J. R. (1985).
Alcoholism in men patients subtyped by family history and
antisocial personality. Journal of Studies on Alcohol, 46(1), 59–64.
Hill, S. Y., & Steinhauer, S. R. (1993). Event-related potentials in
women at risk for alcoholism. Alcohol, 10, 349–354.
Hoaken, P. N., & Stewart, S. H. (2003). Drugs of abuse and the
elicitation of human aggressive behavior. Addictive Behaviors, 28
Hommer, D. W., Momenan, R., Kaiser, E., & Rawlings, R. R. (2001).
Evidence for a gender-related effect of alcoholism on brain
volumes. American Journal of Psychiatry, 158(2), 198–204.
Neuropsychol Rev (2007) 17:239–257253