Striatal Effective Connectivity to Predict Treatment Response in Cocaine Misuse

This project will use stochastic DCM, which is a recent DCM extension that takes into account
hidden fluctuations in neuronal and vascular responses, and thus is especially suited for
investigating effects of disease or drugs. In addition, this project will use nonlinear DCM,
a DCM extension that can measure gating effects by striatum on cortico-cortical pathways. The
overall aims of this project are: (1) To conduct functional magnetic resonance imaging-based
DCM studies of working memory and impulsivity in order to determine the effective
(directional) connectivity between PFC and striatum in treatment-seeking Cocaine Dependent
(CD) subjects compared to non-drug using controls. We hypothesize that DLPFC causally affects
ventral striatum in CDs, and that the strength of this connection is lower in CDs compared to
controls. (2) To determine whether the pretreatment gating effect by the dorsal striatum, as
a reflection of pretreatment hypodopaminergic state associated with chronic compulsive drug
use, predicts the treatment response to dopaminergic pharmacotherapy in CDs. We hypothesize
that lower pretreatment gating by the dorsal striatum on prefrontal-parietal effective
connectivity predicts greater 8-week improvement from treatment of CDs with DA enhancing
medications (combined with cognitive behavioral therapy [CBT]), but not from treatment with
placebo (combined with CBT).

Inclusion Criteria:

- Male and female subjects

- Age 18 to 50

- Meet current DSM-IV criteria for cocaine dependence who are seeking treatment.

Exclusion Criteria:

1. Current DSM-IV diagnosis of any psychoactive substance dependence other than cocaine,
marijuana, nicotine, or alcohol

2. Have a DSM-IV axis I psychiatric disorder or neurological disease or disorder
requiring ongoing treatment and/or making study participation unsafe

3. Significant current suicidal or homicidal ideation

4. Medical conditions contraindicating levodopa/carbidopa or pharmacotherapy (e.g.,
evidence of any movement disorder, clinically significant pulmonary disease,
cardiovascular disease, liver or kidney disease, seizure disorder)

5. Taking CNS active concomitant medications

6. Taking medications known to have significant drug interactions with the study
medication (e.g., CYP P-450-2D6 inhibitors, such as tamoxifen, iron salts, pyridoxine,
monoamine oxidase inhibitors, phenothiazines, selegiline, anesthetics)

7. Having conditions of probation or parole requiring reports of drug use to officers of
the court

8. Impending incarceration

9. Pregnant or breast feeding for female patients

10. Inability to read, write, or speak English

11. Having plans to leave the immediate geographical area within 3 months

12. Unwillingness or not competent to sign a written informed consent form

13. Individuals who have pacemakers, metal or electromechanical implants or metallic
foreign bodies

14. Patients who are known to be HIV positive will not be included due to possible CNS
effects of HIV.

15. Alcohol withdrawal symptoms or history of significant previous alcohol withdrawal
symptoms