1. Dissociable effects of cocaine-dependence on reward processes: the role of acute cocaine and craving. Cocaine Dependents (CD) and healthy controls (HC) had 2 MRI scans while doing a monetary incentive delay task. Scans were identical across subjects/groups, except that CD received IV cocaine (30mg/70kg) before one session and saline in another. Drug condition (cocaine vs saline) and group (HC vs CD+cocaine or CD+saline) didnt influence valence-related activity. However, compared with HC, magnitude-related activity for gains was reduced in CD in the left cingulate gyrus post-cocaine and in the left putamen in the abstinence/saline condition. In contrast, magnitude-dependent activity for losses increased in CD vs HC in the right inferior parietal lobe post-cocaine and in the left superior frontal gyrus post-saline. Across outcomes (ie, successful and unsuccessful) activity in the right habenula decreased in CD in the abstinence/saline condition vs acute cocaine and HC. Cocaine-dependent variability in outcome- and loss-magnitude activity correlated negatively with ratings of cocaine craving and positively with how high subjects felt during scans. This suggests dissociable effects of acute cocaine on non-drug reward processes, with cocaine consumption partially ameliorating dependence-related insensitivity to reinforcing outcomes, 'liking,' but no discernible effect on dependence-related alterations in incentive salience, 'wanting'. The relationship of drug-related affective sequelae to non-drug reward processing suggests that CD experience a general alteration of reward function and may be motivated to continue using cocaine for reasons beyond desired drug-related effects. This may have implications for individual differences in treatment efficacy for approaches that rely on reinforcement strategies like contingency management and for long-term success of treatment. 2. Posterior hippocampal (pHp) regional cerebral blood flow (rCBF) predicts cocaine relapse: A replication study. The pHp plays a major role in processing and storage of drug-related cues and is linked to striatal-limbic brain circuits involved with craving and drug salience. We recently reported that increased basal rCBF in a pHp loci, as measured by pseudo-continuous arterial spin labeling MRI, predicted days to cocaine relapse following residential treatment. Here, we explored whether rCBF in this same pHp region would successfully predict 30-day point prevalence abstinence 60days after residential treatment in an independent group of previously studied participants with cocaine dependence (CD). rCBF was assessed with single photon emission computerized tomography during a saline infusion in 21 CD and 22 healthy controls. pHp rCBF was significantly higher in those endorsing substance use (n=10) relative to both abstinent (n=11) (p<0.001) and control (p<0.05) participants. There were no significant differences in measured demographic or clinical variables between actively using and non-using participants. This replicative finding suggests that heightened pHp activation is a significant predictor of substance use in CD individuals, possibly reflecting a neural susceptibility to continued drug cues. 3. Distress tolerance (DT) among substance users associated with connectivity between the prefrontal regions during a DT task. DT, defined as the ability to persist in goal directed behavior while experiencing affective distress, is implicated in the development and maintenance of substance use disorders. While theory and evidence indicate that cortico-limbic neural dysfunction may account for deficits in goal directed behavior while experiencing distress, the neurobiological mechanisms of DT are unknown. We modified a DT task for use in functional MRI, the Paced Auditory Serial Addition Task (PASAT-M) and examined the neural correlates and functional connectivity (fc) of DT among substance users (n=21; cocaine and nicotine users) and healthy controls (n=25). In response to distress during the task, we found greater activation in a priori cortico-limbic network ROIs, namely the right insula, anterior cingulate cortex (ACC), bilateral medial frontal gyrus (MFG), right inferior frontal gyrus (IFG) and right ventromedial prefrontal cortex (vmPFC) significantly predicted higher DT among substance users, but not in controls. Also, greater task-specific fc during distress between the right MFG and bilateral vmPFC/sgACC was associated with higher DT among substance users, but not controls. The observed positive relationship between DT and neural activation in cortico-limbic structures, as well as fc between the rMFG and vmPFC/sgACC, is in line with theory and research suggesting the importance of these structures for persisting in goal directed behavior while experiencing affective distress. 4. Report of transient events in a cocaine-dependent volunteer who received intermittent theta-burst stimulation (iTBS). The protocol was 100% of resting motor threshold (RMT) to deliver 600 biphasic pulses over 190s targeting left dorsal-lateral prefrontal cortex (l-dlPFC) 3x/day for 10d with at least 60 min between iTBS sessions. After session 2 om day 9, a 33yo female with no history of head injury or seizures noticed spontaneous right-hand supination/pronation at the wrist at about 12Hz, lasting about 3min then one twitch every 3-5sec, then resolved within 1h. Her iTBS was 20trains of increasing intensity (23- 43% MSO) with 15trains at her RMT. Urine tox and breathalyzer were negative; last alcohol and caffeine use was 11 and 15 days prior, respectively, and she slept 8hrs the night prior. MRI indicated mild cerebellar atrophy greater than expected for age possibly from chronic alcohol use. It was classified as a transient neurological event of uncertain etiology, possibly consistent with a focal seizure. She also had an episode of psychosis 13 days after event 1, with intermittent itchiness 1wk prior to reporting the psychosis, including feeling bugs crawling under her skin, sporadic stabbing pains all over her body, and believing hair was growing out of her eyes, mouth, and fingertips. Psychiatrist identified bilateral symmetric hyporeflexia, which the participant said had been present since childhood. Oral Olanzapine (10mg) was given in the ED and psychosis cleared within 4h. Symptoms didnt recur over the next 3wks of follow-up. 5. Graph theory reveals amygdala modules consistent with its anatomical subdivisions. Similarities on the cellular and neurochemical composition of the amygdaloid subnuclei suggests their clustering into subunits that exhibit unique functional organization. The topological principle of community structure has been used to identify functional subnetworks in neuroimaging data that reflect brain effective organization. We used modularity to examine the organization of the amygdala using resting state functional magnetic resonance imaging (rsfMRI) data to determine whether such topological organization would reliably reflect the known neurobiology of individual amygdaloid nuclei, allowing for human imaging studies to accurately reflect the underlying neurobiology. Modularity analysis identified amygdaloid elements consistent with the main anatomical subdivisions of the amygdala that embody distinct functional and structural properties. Also, functional connectivity pathways of these subunits and their correlation with task-induced amygdala activation revealed distinct functional profiles consistent with the neurobiology of the amygdala nuclei. These modularity findings corroborate the structure-function relationship between amygdala anatomical substructures, supporting the use of network analysis techniques to generate biologically meaningful partitions of brain structures.
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