Clinical Intervention in Alcohol Use Disorder
Condition: Alcohol Use Disorder; Eligible to go Into the MRI Scanner; Short-term Abstinence From Alcohol Use (2 Week Abstinent)
MeSH terms: Alcoholism; Alcohol Drinking
Study type: Interventional

Summary: 
      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 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) the investigators have identified brain biomarkers that
      support long-term abstinence. Cross-sectional and longitudinal findings provide evidence that
      higher functional connectivity (FC), particularly between nucleus accumbens (NAcc) and
      dorsolateral prefrontal cortex (DLPFC), is a potential brain biomarker that supports
      abstinence. Long-term abstinent alcoholics (7 years of abstinence) have higher resting FC
      between NAcc and DLPFC 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). Further, lower FC between NAcc and DLPFC at 11 weeks of abstinence can be a
      predictor of subsequent relapse (with 74% accuracy). 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, the investigators found that FC between NAcc and DLPFC decreased from
      5 to 13 weeks of abstinence in subsequent relapsers, while it increased in subsequent
      abstainers. Based on the above, the investigators 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 DLPFC and NAcc.

      Cognitive flexibility, the ability to change maladaptive behavior, depends on DLPFC input to
      NAcc. DLPFC transmits reward representations to NAcc through glutamatergic projections that
      guide goal-directed behavior. If DLPFC 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). Higher FC between DLPFC and NAcc may be achieved
      by stimulating DLPFC 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. DLPFC 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.

      Genetics and treatment response: A source of treatment response variability could stem from
      differences between participants in baseline genetic profiles or epigenetic changes over the
      course of treatment. Genetic polymorphisms, especially in genes important for
      neuroplasticity, may also mediate neuroplastic changes underlying the effects of tDCS, as has
      been demonstrated with gene BDNF. In light of these genetic influences on key tenants of the
      study - i.e. treatment response in alcohol use disorder and psychological effects of tDCS -
      the investigators will collect genetic samples from participants to determine whether genetic
      or epigenetic variations may affect response to the cognitive training and tDCS intervention.
      As the secondary aim, participants will be given the choice in the consent form to opt in or
      out of the genetic sampling procedure.

      In a double-blind randomized design, up to 100 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. 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 ~8 months after study
      participation. Aim 1: To investigate whether NAcc-PFC FC can be modulated, the investigators
      will compare magnitude and durability 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, the investigators 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, the investigators will record craving and relapse status during the ~8 months
      following treatment discharge. The investigators 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. Aim 4: Examine relationship between genetic variants, epigenetic
      changes and treatment outcome (e.g. durability, functional connectivity).
    

Intervention name(s): Transcranial Direct Current Stimulation (tDCS)
Intervention type(s): Device
Intervention description(s): tDCS will be performed with Neuroelectrics Starstim Enobio 20, a non-invasive investigational device that has been labeled as a non-significant risk device by the FDA. This study is regulated by the FDA as an Abbreviated IDE. It has built-in safety mechanisms which allow for immediate cessation of stimulation if the subject becomes uncomfortable. The current will be administered via two electrode sponges for 25 mins with 1-2 milliamperes. These administration protocols are in line with protocols that have outlined safe administration (Nitsche 2007; 2008). No side-effects have been reported with the exception of slight itching under the electrode and occasional occurrence of headache, fatigue, or nausea (Poreisz 2007). Electrodes placement: dorsolateral prefrontal cortex (DLPFC); cathode on left DLPFC, anode on right DLPFC.
Other intervention name(s): Starstim
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Prevention