Jesse J. Suh

Prelude to passion: limbic activation by "unseen" drug and sexual cues.

Background The human brain responds to recognizable signals for sex and for rewarding drugs of abuse by activation of limbic reward circuitry. Does the brain respond in similar way to such reward signals even when they are “unseen”, i.e., presented in a way that prevents their conscious recognition? Can the brain response to “unseen” reward cues predict the future affective response to recognizable versions of such cues, revealing a link between affective/motivational processes inside and outside awareness? Methodology/Principal Findings We exploited the fast temporal resolution of event-related functional magnetic resonance imaging (fMRI) to test the brain response to “unseen” (backward-masked) cocaine, sexual, aversive and neutral cues of 33 milliseconds duration in male cocaine patients (n = 22). Two days after scanning, the affective valence for visible versions of each cue type was determined using an affective bias (priming) task. We demonstrate, for the first time, limbic brain activation by “unseen” drug and sexual cues of only 33 msec duration. Importantly, increased activity in an large interconnected ventral pallidum/amygdala cluster to the “unseen” cocaine cues strongly predicted future positive affect to visible versions of the same cues in subsequent off-magnet testing, pointing both to the functional significance of the rapid brain response, and to shared brain substrates for appetitive motivation within and outside awareness. Conclusions/Significance These findings represent the first evidence that brain reward circuitry responds to drug and sexual cues presented outside awareness. The results underscore the sensitivity of the brain to “unseen” reward signals and may represent the brains primordial signature for desire. The limbic brain response to reward cues outside awareness may represent a potential vulnerability in disorders (e.g., the addictions) for whom poorly-controlled appetitive motivation is a central feature.

Dopamine transporter genotype modulation of neural responses to smoking cues: confirmation in a new cohort

Previously we demonstrated profound effects of dopamine transporter (DAT) SLC6A3 genotype on limbic responses to smoking cues (SCs). Probands carrying at least one copy of the 9‐repeat allele (9‐repeat carriers) had greater neural responses to SCs in the anatomically interconnected rostral ventral striatum/medial orbitofrontal cortex (VS/mOFC), compared with homozygotes for the 10‐repeat allele (10/10‐repeats). To test the reliability of the initial findings, we examined perfusion functional magnetic resonance images acquired during SC exposure in a new cohort of smokers (N = 26) who were genotyped for the SLC6A3 polymorphism. In smokers overall, activity was enhanced in the VS/mOFC (t = 3.77). Contrasts between allelic groups revealed that 9‐repeat carriers had a greater response to SCs in the VS (t = 3.12) and mOFC (t = 3.19). In separate groups, 9‐repeat carriers showed increased activity in the VS (t = 5.47) and mOFC (T = 4.96), while no increases were observed in 10‐repeats. Subjective reports of craving correlated with increased activity in reward‐related structures including the extended amygdala, insula and post‐central gyrus, and decreased activity in the dorsolateral prefrontal cortex, and were DAT‐genotype dependent (r = 0.63–0.96). In secondary analyses, we found that The Fagerström Test for Nicotine Dependence scores correlated with enhanced SC‐induced perfusion in 10/10‐repeats in the insula, mOFC, medial temporal and superior frontal gyri (r = 0.50–0.82), while correlations were absent in 9‐repeat carriers. Despite heterogeneity introduced by a host of factors, including variance in other genes involved in smoking behavior, we confirm that DAT genotype predicts the direction and location of neural responses to SCs.

Nipping Cue Reactivity in the Bud: Baclofen Prevents Limbic Activation Elicited by Subliminal Drug Cues

Relapse is a widely recognized and difficult to treat feature of the addictions. Substantial evidence implicates cue-triggered activation of the mesolimbic dopamine system as an important contributing factor. Even drug cues presented outside of conscious awareness (i.e., subliminally) produce robust activation within this circuitry, indicating the sensitivity and vulnerability of the brain to potentially problematic reward signals. Because pharmacological agents that prevent these early cue-induced responses could play an important role in relapse prevention, we examined whether baclofen—a GABAB receptor agonist that reduces mesolimbic dopamine release and conditioned drug responses in laboratory animals—could inhibit mesolimbic activation elicited by subliminal cocaine cues in cocaine-dependent individuals. Twenty cocaine-dependent participants were randomized to receive baclofen (60 mg/d; 20 mg t.i.d.) or placebo. Event-related BOLD fMRI and a backward-masking paradigm were used to examine the effects of baclofen on subliminal cocaine (vs neutral) cues. Sexual and aversive cues were included to examine specificity. We observed that baclofen-treated participants displayed significantly less activation in response to subliminal cocaine (vs neutral) cues, but not sexual or aversive (vs neutral) cues, than placebo-treated participants in a large interconnected bilateral cluster spanning the ventral striatum, ventral pallidum, amygdala, midbrain, and orbitofrontal cortex (voxel threshold p < 0.005; cluster corrected at p < 0.05). These results suggest that baclofen may inhibit the earliest type of drug cue-induced motivational processing—that which occurs outside of awareness—before it evolves into a less manageable state.

Reward-related Brain Response and Craving Correlates of Marijuana Cue Exposure: A Preliminary Study in Treatment-Seeking Marijuana-Dependent Subjects

Objective: Determining the brain substrates underlying the motivation to abuse addictive drugs is critical for understanding and treating addictive disorders. Laboratory neuroimaging studies have demonstrated differential activation of limbic and motivational circuitry (eg, amygdala, hippocampus, ventral striatum, insula, and orbitofrontal cortex) triggered by cocaine, heroin, nicotine, and alcohol cues. The literature on neural responses to marijuana cues is sparse. Thus, the goals of this study were to characterize the brains response to marijuana cues, a major motivator underlying drug use and relapse, and determine whether these responses are linked to self-reported craving in a clinically relevant population of treatment-seeking marijuana-dependent subjects. Methods: Marijuana craving was assessed in 12 marijuana-dependent subjects using the Marijuana Craving Questionnaire–Short Form. Subsequently, blood oxygen level dependent functional magnetic resonance imaging data were acquired during exposure to alternating 20-second blocks of marijuana-related versus matched nondrug visual cues. Results: Brain activation during marijuana cue exposure was significantly greater in the bilateral amygdala and the hippocampus. Significant positive correlations between craving scores and brain activation were found in the ventral striatum and the medial and lateral orbitofrontal cortex (P < 0.0001). Conclusions: This study presents direct evidence for a link between reward-relevant brain responses to marijuana cues and craving and extends the current literature on marijuana cue reactivity. Furthermore, the correlative relationship between craving and brain activity in reward-related regions was observed in a clinically relevant sample (treatment-seeking marijuana-dependent subjects). Results are consistent with prior findings in cocaine, heroin, nicotine, and alcohol cue studies, indicating that the brain substrates of cue-triggered drug motivation are shared across abused substances.

Neural responses to subliminally presented cannabis and other emotionally evocative cues in cannabis-dependent individuals

RationaleAddiction theories posit that drug-related cues maintain and contribute to drug use and relapse. Indeed, our recent study in cocaine-dependent patients demonstrated that subliminally presented cocaine-related stimuli activate reward neurocircuitry without being consciously perceived. Activation of reward neurocircuitry may provoke craving and perhaps prime an individual for subsequent drug-seeking behaviors.ObjectivesUsing an equivalent paradigm, we tested whether cannabis cues activate reward neurocircuitry in treatment-seeking, cannabis-dependent individuals and whether activation was associated with relevant behavioral anchors: baseline cannabis craving (drug-seeking behavior) and duration of use (degree of conditioning).MethodsTwenty treatment-seeking, cannabis-dependent individuals (12 males) underwent event-related blood oxygen level-dependent functional magnetic resonance imaging during exposure to 33-ms cannabis, sexual, and aversive cues presented in a backward-masking paradigm. Drug use history and cannabis craving were assessed prior to imaging.ResultsParticipants showed increased activity to backward-masked cannabis cues in regions supporting reward detection and interoception, including the left anterior insula, left ventral striatum/amygdala, and right ventral striatum. Cannabis cue-related activity in the bilateral insula and perigenual anterior cingulate cortex was positively associated with baseline cannabis craving, and cannabis cue-related activity in the medial orbitofrontal cortex was positively correlated with years of cannabis use. Neural responses to backward-masked sexual cues were similar to those observed during cannabis cue exposure, while activation to aversive cues was observed only in the left anterior insula and perigenual anterior cingulate cortex.ConclusionsThese data highlight the sensitivity of the brain to subliminal reward signals and support hypotheses promoting a common pathway of appetitive motivation.

Gender Differences in Predictors of Treatment Attrition with High Dose Naltrexone in Cocaine and Alcohol Dependence

Recently, we reported that naltrexone at 150 mg/day significantly decreased cocaine and alcohol use for men but not women with co-occurring cocaine and alcohol dependence. The present study is an exploratory investigation of predictors that explain the different gender responses to naltrexone, with a particular focus on differential predictors of treatment attrition. No significant predictors were associated with treatment discontinuation in men. Women, however, were more likely to discontinue treatment when reporting severe pre-treatment psychiatric problems or nausea while in treatment. Further research on the impact of pre-treatment and in-treatment gender differences with naltrexone is warranted.

Risperidone in cocaine-dependent patients with comorbid psychiatric disorders.

Background. A high percentage of individuals with cocaine dependence have a comorbid psychiatric illness, which complicates treatment of the substance abuse. This report will describe clinical experience using risperidone in cocaine-dependent patients with psychiatric disorders. Method. Sixteen male patients with cocaine dependence and comorbid psychiatric disorder (DSM-III-R) diagnoses, who were admitted to a voluntary, post-detoxification, intermediate-care inpatient substance abuse program, were started on risperidone (mean starting dose 2.3 mg/day) in an open-label, naturalistic trial. Patients were assessed weekly using the Clinical Global Impressions scale to assess overall functioning, a Likert scale for craving, the Abnormal Involuntary Movement Scale, interviews with substance abuse counselors and patients, and laboratory tests. All patients had at least one other substance use diagnosis besides cocaine dependence, and 13 patients were taking another psychiatric medication. Results. Of the 16 patients, 13 (81%) were rated improved or much improved on the CGI scale, and all patients reported mild or no craving at the last assessment (after a mean of 32.6 days of risperidone treatment). No patient developed extrapyramidal symptoms or hypomania. Compared to a 32% historical completion rate for patients receiving treatment as usual, fourteen (88%) of these patients completed the program, and 9 moved on to the next level of care. Conclusion. The results of this naturalistic trial suggest that risperidone is safe and well tolerated in patients with cocaine dependence and comorbid psychiatric illness. In the short term, risperidone may also be effective in reducing cocaine craving and use and may increase the likelihood of completing substance abuse treatment.

Emotional, physical and sexual abuse are associated with a heightened limbic response to cocaine cues

Drug‐reward cues trigger motivational circuitry, a response linked to drug‐seeking in animals and in humans. Adverse life events have been reported to increase sensitivity to drug rewards and to bolster drug reward signaling. Therefore, we hypothesized that cocaine‐dependent individuals with prior emotional, physical and sexual abuse might have a heightened mesolimbic brain response to cues for drug reward in a new brief‐cue probe. Cocaine‐dependent human individuals (N = 68) were stabilized in an inpatient setting and then completed an event‐related blood‐oxygen‐level dependent functional magnetic resonance imaging task featuring 500‐ms evocative (cocaine, sexual, aversive) and comparator (neutral) cues. Responses to three questions about emotional, physical and sexual abuse from the Addiction Severity Index were used to divide the patients into subgroups (history of Abuse [n = 40] versus No Abuse [n = 28]). When subjects were grouped by the historical presence or absence of emotional, physical or sexual abuse, the Abuse group showed a heightened midbrain, thalamic, caudate, and caudal orbitofrontal cortex response to cocaine cues; a similar result was found in other evocative cues, as well. These findings are the first reported for a 500‐ms cocaine‐cue probe, and they highlight the ability of very brief evocative cues to activate the brains motivational circuitry. Although all participants had severe cocaine use disorders, individuals reporting prior abuse had a heightened mesolimbic response to evocative cues. To our knowledge, this is the first study in humans linking a history of abuse to a brain vulnerability (heightened mesolimbic response to drug cues) previously shown to contribute to drug‐seeking.

A hypo-status in drug-dependent brain revealed by multi-modal MRI

Drug addiction is a chronic brain disorder with no proven effective cure. Assessing both structural and functional brain alterations by using multi‐modal, rather than purely unimodal imaging techniques, may provide a more comprehensive understanding of the brain mechanisms underlying addiction, which in turn may facilitate future treatment strategies. However, this type of research remains scarce in the literature. We acquired multi‐modal magnetic resonance imaging from 20 cocaine‐addicted individuals and 19 age‐matched controls. Compared with controls, cocaine addicts showed a multi‐modal hypo‐status with (1) decreased brain tissue volume in the medial and lateral orbitofrontal cortex (OFC); (2) hypo‐perfusion in the prefrontal cortex, anterior cingulate cortex, insula, right temporal cortex and dorsolateral prefrontal cortex and (3) reduced irregularity of resting state activity in the OFC and limbic areas, as well as the cingulate, visual and parietal cortices. In the cocaine‐addicted brain, larger tissue volume in the medial OFC, anterior cingulate cortex and ventral striatum and smaller insular tissue volume were associated with higher cocaine dependence levels. Decreased perfusion in the amygdala and insula was also correlated with higher cocaine dependence levels. Tissue volume, perfusion, and brain entropy in the insula and prefrontal cortex, all showed a trend of negative correlation with drug craving scores. The three modalities showed voxel‐wise correlation in various brain regions, and combining them improved patient versus control brain classification accuracy. These results, for the first time, demonstrate a comprehensive cocaine‐dependence and craving‐related hypo‐status regarding the tissue volume, perfusion and resting brain irregularity in the cocaine‐addicted brain.

Low prefrontal perfusion linked to depression symptoms in methadone-maintained opiate-dependent patients.

BACKGROUND Clinically depressed patients without substance use disorders, compared to controls, exhibit significantly lower resting regional cerebral blood flow (rCBF) in the prefrontal cortex (PFC). In this study, we examined the link between resting rCBF in the PFC and current depressive symptoms in methadone-maintained opiate-dependent (MM) patients with or without major depression. METHODS Arterial spin labeled perfusion fMRI at 3 Tesla was used to measure resting rCBF in 21 MM patients. Perfusion data were analyzed using SPM2. The relationship between Beck Depression Inventory (BDI) score and resting rCBF was examined in a single regression analysis. RESULTS The BDI scores ranged between 0 and 18 (m=7.0, S.D.=4.8), and 30% of the sample had mild to moderate depression symptoms according to BDI scores. A negative correlation was observed between BDI scores and relative rCBF in the bilateral ventrolateral prefrontal cortex, and middle frontal gyri. CONCLUSIONS The inverse relationship between prefrontal paralimbic rCBF and depression scores suggests a link between reduced fronto-limbic activity and depressive symptoms in MM patients. A significant subgroup of opiate-dependent patients has clinical or sub-clinical depression that is often undetected; our data identify brain substrates of depression symptoms that may also be a potential marker of relapse in this population. Treatment strategies targeting these brain regions may improve outcomes in depressed substance abusers.