Longitudinal Assessment of Functional Connectivity in Treatment Engaged Cocaine Users

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