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.

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.

Inclusion Criteria:

• Currently enrolled in an intensive outpatient treatment program for cocaine dependence

Exclusion Criteria:

• metal in the body below the neck
• history of traumatic brain injury

Individuals enrolled in an intensive outpatient rehabilitation program will be invited to enroll in this observational study.

Deidentified data will be shared on the NIH neuroimaging biorepository at the conclusion of data analysis

These data will be shared within 6 months of the final enrollment and data analysis.

Access is open to the public