Longitudinal Assessment of Functional Connectivity in Treatment Engaged Cocaine Users
Condition: Cocaine Dependence; Substance Use Disorders
MeSH terms: Substance-Related Disorders; Cocaine-Related Disorders
Study type: Observational

Summary: 
      High-relapse rates to addiction are likely due to motivational (limbic) and cognitive
      (executive) factors. The purpose of this proposal is to determine the relationship between
      functional connectivity in executive control regions (namely the dorsolateral prefrontal
      cortex) and both proximal and extended outcomes in treatment seeking cocaine and opiate
      users. This longitudinal neuroimaging study will assess the integrity of executive and limbic
      circuits 4 timepoints before and after a 28-day intensive outpatient treatment program.
      Controls will also be recruited as a comparison group. The fundamental neuroscience knowledge
      gained from this proposal will be used to develop new evidence-based brain stimulation
      treatment strategies to enhance the integrity of these circuits and subsequent outcomes in
      traditional treatment programs.

      The purpose of this study is not only to look at the integrity of these circuits in
      individuals entering treatment but also to see how these circuits change after treatment and
      if this can be used to predict outcomes. From the larger societal perspective this research
      may help us determine which individuals are likely going to benefit the most from treatment
      and perhaps those that are at a greater risk for relapse.
    

Detailed description: 
      Chronic cocaine use is among the most difficult substance-use disorders to treat. High
      relapse rates are likely due to a combination of factors that involve limbic and executive
      circuits in the brain, including vulnerability to salient cues and loss of cognitive control
      . This may be due to elevated functional activity within limbic neural circuitry, in the
      presence of a salient cue or to attenuated activity in executive control circuitry, which is
      impaired in users and is likely required to resist the limbic drive to use cocaine among
      individuals trying to remain abstinent.

      Although predicting cocaine relapse after traditional outpatient treatment programs has
      largely focused on behavioral metrics, emerging literature suggests that neurofunctional
      activity may be a more robust predictor of relapse. While drug cue-reactivity in limbic
      processing regions (including the medial prefrontal cortex (MPFC), insula, and striatum) may
      predict relapse, activity in executive control regions (including the dorsolateral PFC
      (DLPFC)) is associated with sustained abstinence . Specifically, individuals that remain
      abstinent for 3 or more months have higher PFC gray matter integrity and baseline functional
      activity in their PFC relative to active users or recently abstinent peers . Most of these
      studies however are cross-sectional and assess these brain regions in isolation rather than
      as integrated networks.

      Through interleaved transcranial magnetic stimulation (TMS) in the MRI environment, it is
      possible to differentially activate executive control and limbic circuitry by applying pulses
      of stimulation to the dorsolateral PFC (DLPFC) and MPFC respectively [31]. Extending decades
      of knowledge about the top-down influence of executive control circuitry on limbic circuitry,
      functional connectivity analysis revealed that TMS-induced DLPFC activity is negatively
      correlated with frontal and striatal elements of limbic circuit activity, including the
      medial and orbital PFC and the caudate. This 'negative' functional connectivity between the
      DLPFC and limbic regions however, was not present in a cohort of cocaine users with a history
      of relapse (see Significance). The overarching goal of this longitudinal imaging study is to
      use the novel probe to determine the relationship between executive and limbic circuit
      integrity as it relates to immediate and extended outcomes after an intensive outpatient
      treatment program. This will be achieved by assessing functional connectivity in
      treatment-seeking cocaine users and non-drug using controls at baseline (Aim1), and after a
      28-day cognitive-behavioral treatment program (users only)(Aim 2). The relationship between
      the integrity of these circuits and clinically meaningful outcome measures will be determines
      60 days and 90 days after baseline (Aim 3).

      Aim 1: Investigate baseline executive and limbic circuit connectivity in treatment-seeking
      users and controls. Hypothesis: Interleaved imaging will demonstrate that cocaine users
      (n=55) have significantly lower % signal change in the DLPFC than controls, lower positive
      connectivity between the DLPFC (low integrity of executive circuitry) and the dorsal
      striatum, and lower negative connectivity between the DLPFC and the MPFC (low executive
      influence on limbic circuitry), suggesting that the DLPFC does not effectively modulate
      limbic circuitry in cocaine users.

      Aim 2: Quantify changes in executive and limbic circuit connectivity that may occur following
      a 28-day cognitive-behavioral treatment program. Hypothesis: Cocaine users will have an
      elevation in the % signal change in the DLPFC (relative to Aim1), and the functional
      connectivity between the DLPFC and the limbic circuitry will increase (elevated influence of
      executive on limbic circuitry). Secondary hypothesis: This change in functional connectivity
      will be associated with a change in cognitive control on a battery of tests.

      Aim 3: Determine the extent to which functional connectivity at baseline (Aim 1) or after
      treatment (Aim 2) is related to clinically-relevant metrics of drug use, cognitive control,
      and sustained connectivity after treatment commencement. Hypothesis: Within the 55 cocaine
      users, individuals that have the highest DLPFC % signal change or the highest negative
      correlation coefficient between the DLPFC and MPFC (at baseline and immediately after
      treatment), will be the individuals with the lowest number of drug positive urines, and will
      be the most likely to remain in the sample after 60 and 90 days of abstinence.
    

Intervention name(s): magnetic resonance imaging
Intervention type(s): Diagnostic Test
Intervention description(s): Participants will receive a 60 minute magnetic resonance imaging assessment
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Individuals enrolled in an intensive outpatient rehabilitation program will be invited to
        enroll in this observational study.