Last updated on March 2019

Clinical Intervention in Alcohol Use Disorder


Brief description of study

Long-term abstinence from alcohol is supported by a compensatory mechanism in functional brain connectivity, 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 functional brain connectivity. The overall objective of this proposal is to enhance brain functional connectivity in short-term abstinent alcoholics as a therapeutic intervention that supports abstinence.

Detailed Study Description

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.

Clinical Study Identifier: NCT02168400

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University of Minnesota

Minneapolis, MN United States
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Recruitment Status: Open


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