Faculty Bibliography

RATIONALE:The indirect dopamine agonist methylphenidate remediates cognitive deficits in psychopathology, but the individual characteristics that determine its effects on the brain are not known. OBJECTIVES:We aimed to determine whether targeted dopaminergically modulated traits and individual differences could predict neural response to methylphenidate across multiple functional magnetic resonance imaging (fMRI) procedures. METHODS:We combined neural measures from three separate procedures (two inhibitory control tasks differing in their degree of emotional salience and resting-state functional connectivity) during methylphenidate (20 mg oral, versus randomized and counterbalanced placebo) and correlated these aggregated responses with cocaine use disorder diagnosis (22 cocaine abusers, 21 controls), symptoms of attention deficit hyperactivity disorder, and working memory capacity. RESULTS:Cocaine abusers, relative to controls, had a lower response in the dorsolateral prefrontal cortex to methylphenidate across all three procedures, driven by responses to the two inhibitory control tasks; reduced methylphenidate fMRI response in this region further correlated with more frequent cocaine use. CONCLUSIONS:Cocaine abuse (and its frequency), associated with lower tonic dopamine levels, correlated with a reduction in activation to methylphenidate (versus placebo). These initial results provide feasibility to the idea that multimodal fMRI tasks can be meaningfully aggregated, and that these aggregated procedures show a common disruption in addiction in a highly anticipated region relevant to cognitive control. Results also suggest that drug use frequency may represent an important modulatory variable in interpreting the efficacy of pharmacologically enhanced cognitive interventions in addiction.

Background: Impulsivity is a core feature of substance use disorders. Temporal discounting (TD) paradigms provide a modelbased approach to studying the dynamics of impulsive decisionmaking as drug-addicted individuals undergo treatment. Here we examine (1) how TD changes as opioid use disorder (OUD) subjects stabilize on maintenance therapy; and (2) how TD is predicted by (or is predictive of) relevant clinical outcomes. Methods: 30 individuals initiating treatment for OUD and 29 matched community controls (CC) were assessed weekly (up to 15 weeks) on a TD task. Drug use was monitored by urine toxicology and chart review. We analyzed the data with a hyperbolic discounting model and derived subject-specific parameters forTD rate, and the non-parametric proportion of immediate choices. Results: OUD subjects showed higher TD rates than CC (Means: 0.039 versus 0.139 respectively, p = 0.005). Although this measure had high test-retest reliability, OUD subjects exhibited more variability across the repeated measures. Subjects in the initial phase of treatment showed a progressive decrease of TD (p = 0.007). Recent heroin use predicted subjects' level of impulsivity: positive use in the previous week correlated with a significantly higher proportion of immediate choices (p = 0.02). We did not And a predictive effect of TD on heroin use the following week. Conclusions: These results suggest that TD greatly fluctuates in treatment-seeking heroin users, in contrast to its stability in CC. TD is both sensitive to the initial phase of treatment for OUD and to recent heroin use, but not predictive of future use in this population

There is some evidence that cocaine addiction manifests as more severe in women than men. Here, we examined whether these sex-specific differences in the clinical setting parallel differential neurobehavioral sensitivity to rewards in the laboratory setting. Twenty-eight (14 females/14 males) cocaine-dependent and 25 (11 females/14 males) healthy individuals completed a monetary reward task during fMRI. Results showed that the effects of cocaine dependence and sex overlapped in regions traditionally considered part of the mesocorticolimbic brain circuits including the hippocampus and posterior cingulate cortex (PCC), as well as those outside of this circuit (e.g., the middle temporal gyrus). The nature of this 'overlap' was such that both illness and female sex were associated with lower activations in these regions in response to money. Diagnosis-by-sex interactions instead emerged in the frontal cortex, such that cocaine-dependent females exhibited lower precentral gyrus and greater inferior frontal gyrus (IFG) activations relative to cocaine-dependent males and healthy females. Within these regions modulated both by diagnosis and sex, lower activation in the hippocampus and PCC, and higher IFG activations, correlated with increased subjective craving during the task. Results suggest sex-specific differences in addiction extend to monetary rewards and may contribute to core symptoms linked to relapse.

The spatial distribution and strength of information processing 'hubs' are essential features of the brain׳s network topology, and may thus be particularly susceptible to neuropsychiatric disease. Despite growing evidence that drug addiction alters functioning and connectivity of discrete brain regions, little is known about whether chronic drug use is associated with abnormalities in this network-level organization, and if such abnormalities could be targeted for intervention. We used functional connectivity density (FCD) mapping to evaluate how chronic and acute stimulants affect brain hubs (i.e., regions with many short-range or long-range functional connections). Nineteen individuals with cocaine use disorders (CUD) and 15 healthy controls completed resting-state fMRI scans following a randomly assigned dose of methylphenidate (MPH; 20mg) or placebo. Short-range and long-range FCD maps were computed for each participant and medication condition. CUD participants had increased short-range and long-range FCD in the ventromedial prefrontal cortex, posterior cingulate/precuneus, and putamen/amygdala, which in areas of the default mode network correlated with years of use. Across participants, MPH decreased short-range FCD in the thalamus/putamen, and decreased long-range FCD in the supplementary motor area and postcentral gyrus. Increased density of short-range and long-range functional connections to default mode hubs in CUD suggests an overrepresentation of these resource-expensive hubs. While the effects of MPH on FCD were only partly overlapping with those of CUD, MPH-induced reduction in the density of short-range connections to the putamen/thalamus, a network of core relevance to habit formation and addiction, suggests that some FCD abnormalities could be targeted for intervention.

We explore various sparse regularization techniques for analyzing fMRI data, such as the â„“1 norm (often called LASSO in the context of a squared loss function), elastic net, and the recently introduced k-support norm. Employing sparsity regularization allows us to handle the curse of dimensionality, a problem commonly found in fMRI analysis. In this work we consider sparse regularization in both the regression and classification settings. We perform experiments on fMRI scans from cocaine-addicted as well as healthy control subjects. We show that in many cases, use of the k-support norm leads to better predictive performance, solution stability, and interpretability as compared to other standard approaches. We additionally analyze the advantages of using the absolute loss function versus the standard squared loss which leads to significantly better predictive performance for the regularization methods tested in almost all cases. Our results support the use of the k-support norm for fMRI analysis and on the clinical side, the generalizability of the I-RISA model of cocaine addiction.

Chronic exposure to drugs of abuse perturbs the endogenous opioid system, which plays a critical role in the development and maintenance of addictive disorders. Opioid genetics may therefore play an important modulatory role in the expression of substance use disorders, but these genes have not been extensively characterized, especially in humans. In the current imaging genetics study, we investigated a single nucleotide polymorphism (SNP) of the protein-coding proenkephalin gene (PENK: rs2609997, recently shown to be associated with cannabis dependence) in 55 individuals with cocaine use disorder and 37 healthy controls. Analyses tested for PENK associations with fMRI response to error (during a classical color-word Stroop task) and gray matter volume (voxel-based morphometry) as a function of Diagnosis (cocaine, control). Results revealed whole-brain Diagnosis×PENK interactions on the neural response to errors (fMRI error>correct contrast) in the right putamen, left rostral anterior cingulate cortex/medial orbitofrontal cortex, and right inferior frontal gyrus; there was also a significant Diagnosis×PENK interaction on right inferior frontal gyrus gray matter volume. These interactions were driven by differences between individuals with cocaine use disorders and controls that were accentuated in individuals carrying the higher-risk PENK C-allele. Taken together, the PENK polymorphism-and potentially opioid neurotransmission more generally-modulates functioning and structural integrity of brain regions previously implicated in error-related processing. PENK could potentially render a subgroup of individuals with cocaine use disorder (i.e., C-allele carriers) more sensitive to mistakes or other related challenges; in future studies, these results could contribute to the development of individualized genetics-informed treatments.

Learning can be guided by unexpected success or failure, signaled via dopaminergic positive reward prediction error (+RPE) and negative reward-prediction error (-RPE) signals, respectively. Despite conflicting empirical evidence, RPE signaling is thought to be impaired in drug addiction. To resolve this outstanding question, we studied as a measure of RPE the feedback negativity (FN) that is sensitive to both reward and the violation of expectation. We examined FN in 25 healthy controls; 25 individuals with cocaine-use disorder (CUD) who tested positive for cocaine on the study day (CUD+), indicating cocaine use within the past 72 h; and in 25 individuals with CUD who tested negative for cocaine (CUD-). EEG was acquired while the participants performed a gambling task predicting whether they would win or lose money on each trial given three known win probabilities (25, 50, or 75%). FN was scored for the period in each trial when the actual outcome (win or loss) was revealed. A significant interaction between prediction, outcome, and group revealed that controls showed increased FN to unpredicted compared with predicted wins (i.e., intact +RPE) and decreased FN to unpredicted compared with predicted losses (i.e., intact -RPE). However, neither CUD subgroup showed FN modulation to loss (i.e., impaired -RPE), and unlike CUD+ individuals, CUD- individuals also did not show FN modulation to win (i.e., impaired +RPE). Thus, using FN, the current study directly documents -RPE deficits in CUD individuals. The mechanisms underlying -RPE signaling impairments in addiction may contribute to the disadvantageous nature of excessive drug use, which can persist despite repeated unfavorable life experiences (e.g., frequent incarcerations).

Despite the high prevalence and consequences associated with externalizing psychopathologies, little is known about their underlying neurobiological mechanisms. Studying multiple externalizing disorders, each characterized by compromised inhibition, could reveal both common and distinct mechanisms of impairment. The present study therefore compared individuals with intermittent explosive disorder (IED) (N = 11), individuals with cocaine use disorder (CUD) (N = 21), and healthy controls (N = 17) on task performance and functional magnetic resonance imaging (fMRI) activity during an event-related color-word Stroop task; self-reported trait anger expression was also collected in all participants. Results revealed higher error-related activity in the two externalizing psychopathologies as compared with controls in two subregions of the dorsolateral prefrontal cortex (DLPFC) (a region known to be involved in exerting cognitive control during this task), suggesting a neural signature of inhibitory-related error processing common to these psychopathologies. Interestingly, in one DLPFC subregion, error-related activity was especially high in IED, possibly indicating a specific neural correlate of clinically high anger expression. Supporting this interpretation, error-related DLPFC activity in this same subregion positively correlated with trait anger expression across all participants. These collective results help to illuminate common and distinct neural signatures of impaired self-control, and could suggest novel therapeutic targets for increasing self-control in clinical aggression specifically and/or in various externalizing psychopathologies more generally.

BACKGROUND:Gene polymorphisms that affect serotonin signaling modulate reactivity to salient stimuli and risk for emotional disturbances. Here, we hypothesized that these serotonin genes, which have been primarily explored in depressive disorders, could also have important implications for drug addiction, with the potential to reveal important insights into drug symptomatology, severity, and/or possible sequelae such as dysphoria. METHODS:Using an imaging genetics approach, the current study tested in 62 cocaine abusers and 57 healthy controls the separate and combined effects of variations in the serotonin transporter (5-HTTLPR) and monoamine oxidase A (MAOA) genes on processing of aversive information. Reactivity to standardized unpleasant images was indexed by a psychophysiological marker of stimulus salience (i.e., the late positive potential (LPP) component of the event-related potential) during passive picture viewing. Depressive symptomatology was assessed with the Beck Depression Inventory (BDI). RESULTS:Results showed that, independent of diagnosis, the highest unpleasant LPPs emerged in individuals with MAOA-Low and at least one 'Short' allele of 5-HTTLPR. Uniquely in the cocaine participants with these two risk variants, higher unpleasant LPPs correlated with higher BDI scores. CONCLUSIONS:Taken together, these results suggest that a multilocus genetic composite of monoamine signaling relates to depression symptomatology through brain function associated with the experience of negative emotions. This research lays the groundwork for future studies that can investigate clinical outcomes and/or pharmacogenetic therapies in drug addiction and potentially other psychopathologies of emotion dysregulation.