Opinion
EDITORIAL
Age, Alcohol Use, and Brain Function
Yoda Says, “With Age and Alcohol, Confused Is the Force”
George F. Koob, PhD
In a new study by Sullivan et al,1 cortical brain structure was
examined across a 50-year adult age range in 222 individuals
with alcohol dependence and an age-matched control group
of 199 individuals. The au-
thors used atlas-based, quan-
Related article titative magnetic resonance
imaging and criteria for sub-
stance dependence on alcohol based on the DSM-IV, which
likely represents moderate to severe alcohol use disorder (AUD)
in the DSM-5. Regionally selective volume deficits were ob-
served most extensively in the lateral and medial frontal, pa-
rietal, and insular cortices, with additional deficits in tempo-
ral and cingulate regions. These effects remained in participants
without comorbidity of drug dependence or hepatitis C virus
infection, although there was evidence of compounded un-
toward effects of drug dependence and hepatitis C infection
on AUD.
Longitudinal analysis of the AUD group identified inter-
actions between age and alcoholism in precentral and supe-
rior frontal regions beyond the expected age-associated cor-
tical volume decline observed in the control participants.
According to the authors, these findings, examined up to
8 times during intervals of 1 month to 10 years, represent
the largest and longest-studied group to date. Overall, the
authors conclude that the results support the hypothesis
that AUD may accelerate aging and cortical volume deficits
independent of drug dependence and hepatitis C infection
comorbidity.
Interactions between age and alcoholism in cortical vol-
ume declines are highly significant for several reasons. First,
the population of the United States is aging. Currently, 26% of
men and 30% of women in the United States are 55 years or
older,2 compared with 21% men and 24% women 10 years ago.3
Projections suggest that this trend in aging will continue. By
2050, nearly 1 in 5 people in the United States will be 65 or older
compared with 1 in 7 now.4 Second, several recent epidemio-
logic surveys have shown significant increases in alcohol use
and misuse among older individuals.4 For example, recent
years have seen an increase in alcohol use among men and
women4 and an increase in binge drinking among women 60
years and older.4
Perhaps the most compelling finding of the study by
Sullivan et al1 is the prominent alteration of frontal cortex vol-
umes. What we know of the neurobiology of AUD suggests that
the frontal cortex plays a key role in executive function, which
can be defined as “control processes responsible for plan-
ning, assembling, coordinating, sequencing, and monitoring
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other cognitive operations”5(p566) or “a set of cognitive pro-
cesses such as attentional control, planning, reasoning, prob-
lem solving, and monitoring.”6(p755-756) Neuroscientists al-
ready know several salient facts about the development and
function of the frontal cortex. In normal individuals, the con-
nections between the frontal cortex and other brain regions
do not fully develop until a person reaches his or her mid-20s.7
In adults, the volume of the frontal cortex in normal individu-
als continues to decline throughout adulthood (Figure).8 The
frontal cortex controls executive function, and the ventrome-
dial frontal cortex (orbitofrontal cortex) has prominent pro-
jections to the basal ganglia and amygdala, controlling
impulsivity (basal ganglia) and compulsivity (amygdala). This
top-down control is part of the causative mechanism of AUD,
in which a failure to develop such control (as in adolescents)
because of developmental delays, chronic alcohol use, or both,
can unleash alcohol misuse, risk-taking behavior, and self-
medication. This interaction may also occur in the elderly popu-
lation, in which age-associated declines in top-down control
also interact with impairments in top-down control caused by
chronic high-dose alcohol use.
Alcohol use disorder can be conceptualized as a 3-stage
cycle—binge/intoxication, withdrawal/negative affect, and
preoccupation/anticipation—that represents dysregulation in
3 functional domains (incentive salience/habits, negative
emotional states, and executive function, respectively) and is
mediated by 3 major neurocircuitry elements (basal ganglia,
extended amygdala, and prefrontal cortex, respectively;
Figure). Excessive alcohol use in the binge/intoxication stage
can be facilitated by impairments in frontal cortical function
that drive impulsivity and risk-taking behavior. The binge/
intoxication stage engages neural circuits that are involved in
incentive salience. The reinforcing effects of drugs may
engage reward neurotransmitters and associative mecha-
nisms and stimulus-response habits in the basal ganglia,
including the nucleus accumbens shell and core and the dor-
sal striatum. Such excessive alcohol consumption, in turn,
can further drive the allostatic dysregulation of reward/stress
homeostasis that generates the withdrawal/negative affect
stage and contributes to the preoccupation/anticipation
stage.9 The withdrawal/negative affect stage engages neural
circuits that are involved in negative affect, reflecting the loss
of reward function and the activation of aversive brain stress
systems in the extended amygdala. The extended amygdala
is composed of several basal forebrain structures, including
the bed nucleus of the stria terminalis, central nucleus of the
amygdala, and possibly a transition zone in the medial por-
(Reprinted) JAMA Psychiatry Published online March 14, 2018 E1
 Opinion Editorial

Figure. Conceptual Framework for the Neurobiological Basis of Substance Use Disorder Vulnerability

A Neural circuits involved in the B Neural circuits involved in the C Neural circuits involved in the
binge/intoxication stage of AUD withdrawal/negative affect preoccupation/anticipation
stage of AUD stage of AUD
Basal Basal Basal
ganglia ganglia ganglia

Prefrontal Prefrontal Prefrontal

cortex cortex cortex

Extended Extended Extended

amygdala amygdala amygdala

D Top-down prefrontal cortex control

100
Frontal Cortex Function, % of Maximum

80

60

40

20

0
Fetus Child Adolescent Young Adult Middle Age Senior
0-12 y 13-18 y 19-25 y 26-54 y ≥55 y
Stage of Life

A-C, Neural circuits involved in the 3-stage cycle of AUD. D, A hypothetical presentation of top-down prefrontal cortex control across the life course.
AUD, alcohol use disorder.

tion (or shell) of the nucleus accumbens. The preoccupation/ tracted withdrawal associated the withdrawal/negative affect
anticipation (craving) stage engages neural circuits that are and preoccupation/anticipation stages, generating a second
involved in executive function, including the processing of motivational drive from negative reinforcement (ie, self-
cues and contexts that trigger craving, along with compro- medication). Therefore, excessive alcohol consumption con-
mised executive control that depends on dysregulated activ- tributes to the aging process, and aging itself may contribute
ity of the prefrontal cortex and other cortical and allocortical to the AUD process by generating a 2-way pathophysiological
areas. The 3 stages feed into each other, intensify, and ulti- interaction. In short, excessive drinking in the elderly popu-
mately lead to the pathological state known as AUD. lation may tap into misdirected attempts at self-regulation in
Frontal cortical deficits that are associated with aging which an individual takes the drug to fix the problem that the
would be hypothesized to also result in impulsivity and com- drug caused.
pulsivity, presumably contributing to even further dysregu- The study by Sullivan et al1 provides compelling evi-
lation of basic motivational systems. The hypothesis is that the dence that alcohol misuse during later adulthood could con-
top-down prefrontal cortex control to reduce impulsivity and fer a greater risk of deficits in frontal lobe function beyond the
compulsivity is underdeveloped in adolescence and compro- deficits that typically occur with aging. Given the rapidly grow-
mised in aging, thus opening the possibility of greater vulner- ing aging population the United States, it is critical that we im-
ability to AUD early and late in life. Particularly with alcohol, prove and implement strategies to address alcohol misuse
the negative emotional states associated with aging may con- among older drinkers. As Yoda might say, “Protect their brains,
verge with the negative emotional states of acute and pro- we must.”

ARTICLE INFORMATION Corresponding Author: George F. Koob, PhD,
Author Affiliation: National Institute on Alcohol National Institute on Alcohol Abuse and Alcoholism,
Abuse and Alcoholism, National Institutes of 5635 Fishers Ln, Ste 2000, Room 2001, Rockville,
Health, Rockville, Maryland. MD 20852 (george.koob@nih.gov).
Published Online: March 14, 2018.
doi:10.1001/jamapsychiatry.2018.0009
Conflict of Interest Disclosures: None reported.
Additional Contributions: I thank Michael Arends,
BS, The Scripps Research Institute, for assistance
with manuscript preparation and Aaron White, PhD,
National Institute on Alcohol Abuse and Alcoholism,

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for advice on an early draft of this article. They
received no compensation for these contributions.
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Editorial Opinion
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