Clinical Intervention in Alcohol Use Disorder

The relapsing nature of alcoholism is a major obstacle to successful treatment. About 60% of
those entering treatment will relapse within one year. To improve treatment outcome, new
interventions targeting the underlying brain biomarkers of relapse vulnerability hold
significant promise in reducing this critical public health problem. Using resting functional
magnetic resonance imaging (fMRI) we have identified brain biomarkers that support long-term
abstinence. Our cross-sectional and longitudinal findings provide evidence that higher
functional connectivity (FC), particularly between nucleus accumbens (NAcc) and prefrontal
cortex (PFC), is a potential brain biomarker that supports abstinence. Long-term abstinent
alcoholics (7 years of abstinence) have higher resting FC between NAcc and PFC when compared
to controls. Short-term abstinent alcoholics (11 weeks of abstinence) have intermediate FC
(lower than long-term abstinent alcoholics and higher than controls) (Camchong et al., 2013b;
2013c). Further, lower FC between NAcc and PFC at 11 weeks of abstinence can be a predictor
of subsequent relapse (with 74% accuracy) (Camchong et al., 2013a). Moreover, in a pilot
longitudinal FC study examining resting FC of NAcc at 5 and 13 weeks of abstinence in
individuals with substance use disorder, we found that FC between NAcc and PFC decreased from
5 to 13 weeks of abstinence in subsequent relapsers, while it increased in subsequent
abstainers (Camchong et al., 2014). Based on the above, we believe that long-term abstinence
is supported by a compensatory mechanism that mediates proper executive function over reward
(mediated by PFC-NAcc FC), a potential brain biomarker that could be an intervention target.
These findings provide a compelling case to explore whether this brain biomarker can be
modulated to enhance patients' ability to remain abstinent. There is a need to investigate
methods that can be used to increase FC between PFC and NAcc.

Cognitive flexibility, the ability to change maladaptive behavior, depends on PFC input to
NAcc (Gruber and O'Donnell, 2009). PFC transmits reward representations to NAcc through
glutamatergic projections that guide goal-directed behavior (Ballard et al., 2011). If PFC
fails to activate when required, a common observation in substance use disorder, target
neurons in the NAcc core do not receive critical information needed to select the appropriate
outcome, causing acquired maladaptive response patterns to persist (e.g. drug consumption)
(Gruber and O'Donnell, 2009). Higher FC between PFC and NAcc may be achieved by stimulating
PFC while subjects perform a task that requires cognitive flexibility, the reversal learning
task.

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique
that can modulate brain connectivity. PFC stimulation may increase input to NAcc to
facilitate proper selection of goal-directed behavior and may also decrease craving in
individuals with substance use disorder (Boggio et al., 2008). We propose a therapeutic
intervention that stimulates PFC to (i) enhance PFC-NAcc FC, (ii) facilitate cognitive
flexibility and (iii) reduce craving to promote abstinence in individuals with alcohol use
disorder. The long term goal is to develop new addiction treatments that support long-term
abstinence. The overall objective of this proposal is to enhance FC between PFC and NAcc as a
therapeutic intervention to enhance cognitive flexibility and reduce craving in addiction.
Central hypotheses: PFC stimulation will (i) enhance FC between NAcc and PFC and (ii) reduce
craving in addiction.

In a single-blind randomized design, 20 abstinent (2 weeks abstinent) individuals with
alcohol use disorder (AUD) recruited from Lodging Plus Program will receive 10 sessions (2
sessions per day for 5 days) of either (i) transcranial direct current stimulation (tDCS) to
PFC or (ii) sham-tDCS. All subjects will perform the reversal learning task during tDCS
intervention (active or sham) to prime the engagement of the NAcc-PFC brain circuit that
mediates cognitive flexibility (D'Cruz et al., 2011). Rest fMRI and craving measures will be
collected before the first and after the last day of tDCS sessions. Monthly follow-up
interviews will be conducted for 6 months after study completion to query relapse status.
Dependent variables will be (i) change in NAcc-PFC FC between 2 and 3 weeks of abstinence,
(ii) change in craving scores between 2 and 3 weeks of abstinence and (iii) relapse status 6
months after study participation. Aim 1: To investigate whether NAcc-PFC FC can be modulated,
we will compare magnitude of change in NAcc-PFC FC between active-tDCS and sham-tDCS groups.
Aim 2: To determine if PFC stimulation has a short-term effect on behavior related to
clinical outcome, we will compare change in craving scores (difference in craving scores
between 2 and 3 weeks of abstinence) between active-tDCS and sham-tDCS groups. Aim 3: To
correlate neuromodulation intervention with long-term clinical outcome, we will record
craving and relapse status during the 6 months following treatment discharge. We will examine
the relationship between change in NAcc-PFC FC between 2 and 3 weeks of abstinence and
subsequent (i) monthly craving scores and (ii) relapse status.

Inclusion Criteria:

- 20 abstinent individuals (18-45 years old; 2 weeks of abstinence) who meet DSM-V
criteria for alcohol use disorder (AUD) will be recruited from the Lodging Plus
Program, part of University of Minnesota Medical Center

- This 21-day program provides a supervised environment to treat alcoholism in which
patients receive random drug/alcohol screenings daily. Lodging Plus has 50 beds and
admits an average of 20 patients per week and 59% of patients admitted have a
diagnosis of alcohol use disorder.

Inclusion criteria:

- ability to provide written consent and comply with study procedures

- meet the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) diagnostic
criteria for AUD. Subjects may have current comorbid drug use, but their primary
substance use disorder diagnosis needs to be based on alcohol use. Subjects must have
the intention to remain in program until the end of the study (3 weeks).

Exclusion Criteria:

- any medical condition or treatment with neurological sequelae (i.e. stroke, tumor,
loss of consciousness of more than 30 min, HIV)

- any contraindications to MRI scanning (i.e., metal implants, pacemakers, etc.)

- DSM-V criteria for mental retardation or axis I psychiatric disorder, subjects may
have a lifetime but not current diagnosis of depression

- primary current substance use disorder diagnosis on any substance other than alcohol,
except for caffeine or nicotine

- clinical evidence for Wernicke-Korsakoff syndrome. Nicotine use will be recorded but
will not be an exclusion criterion