Kanchana Jagannathan

The Effects of Chronic Cigarette Smoking on Gray Matter Volume: Influence of Sex

Cigarette smoke contains nicotine and toxic chemicals and may cause significant neurochemical and anatomical brain changes. Voxel-based morphometry studies have examined the effects of smoking on the brain by comparing gray matter volume (GMV) in nicotine dependent individuals (NDs) to nonsmoking individuals with inconsistent results. Although sex differences in neural and behavioral features of nicotine dependence are reported, sex differences in regional GMV remain unknown. The current study examined sex differences in GMV in a large sample of 80 NDs (41 males) and 80 healthy controls (41 males) using voxel-based morphometry. Within NDs, we explored whether GMV was correlated with measures of cigarette use and nicotine dependence. High-resolution T1 structural scans were obtained from all participants. Segmentation and registration were performed in SPM8 using the optimized DARTEL approach. Covariates included age and an estimate of total global GMV. Differences were considered significant at p≤0.001, with a whole brain FWE-corrected cluster probability of p<0.025. Among NDs compared to Controls less GMV was observed in the thalamus and bilateral cerebellum and greater GMV was observed in the bilateral putamen and right parahippocampus. Lower thalamic GMV was observed in both female and male NDs compared to Controls. Female NDs also had lower GMV in the left cerebellum and in the ventral medial and orbitofrontal cortices with no areas of greater GMV. Male NDs had lower GMV in bilateral cerebellum and greater GMV in bilateral parahippocampus and left putamen. Within male NDs, GMV in the left putamen was correlated with number of pack years. This study, conducted in a large cohort, contributes to our knowledge of brain morphology in nicotine addiction and provides additional evidence of sex-specific effects on GMV in NDs. Identifying brain vulnerabilities with respect to sex provides a methodological framework for personalized therapies to improve relapse rates for both sexes.

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.

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.

Sex differences in resting state neural networks of nicotine-dependent cigarette smokers

Although several sex differences in nicotine dependence have been identified, the neural mechanisms underlying these sex differences are not clear. The present study examines sex differences in resting-state brain activity using an arterial spin labeling (ASL) perfusion imaging technique. Fifty-one (31 males) sated nicotine-dependent cigarette smokers underwent perfusion functional magnetic resonance imaging during the resting state. Using functionally defined hippocampus/amygdala (HIP/AMY) seed regions, we observed sex differences in correlation strength between the HIP/AMY and the bilateral anterior insula, rostral anterior cingulate cortex, and inferior parietal lobule with females showing stronger functional coupling than males. This pattern of synchronous variations in dynamic cerebral blood flow is consistent with recent models of nicotine dependence, and as such, our findings provide a novel perspective on the neural mechanisms that may contribute to sex differences in nicotine dependence.

Neural correlates of attentional bias for smoking cues: modulation by variance in the dopamine transporter gene.

Cigarette‐dependent smokers automatically and involuntarily orient attention toward smoking cues (SCs). This attentional bias is clinically significant, as it may contribute to relapse. Thus, identifying neural and genetic correlates of attentional bias is critical for improving interventions. Our previous studies show that the dopamine transporter (DAT) SLC6A3 genotype exerts profound effects on limbic responses to SCs. One potential mechanism underlying these effects is greater attentional bias for SCs. Here, we explored associations between attentional bias for SCs and neural responses to SCs among ‘sated’ smokers genotyped for the SLC6A3 polymorphism. Pseudo‐continuous arterial spin‐labeled perfusion functional magnetic resonance imaging images were acquired during SC exposure in 35 smokers genotyped for the SLC6A3 variable number of tandem repeats polymorphism (n = 16, 9‐repeats; n = 19, 10/10‐repeats). Participants completed a visual dot‐probe attentional bias task, which contained pictures of smoking and non‐smoking pictures, to examine whether genetic variation in DAT influences attentional bias and to investigate relationships between attentional bias and neural responses to SCs. Although attentional bias to smoking pictures was not significantly different between 9‐repeats and 10/10‐repeats, 9‐repeats showed a positive correlation between attentional bias and increased SC‐induced brain activity in the amygdala, whereas 10/10‐repeats showed an inverse correlation in the medial orbitofrontal cortex (mOFC). In group comparisons, 9‐repeats exhibited positive correlations between attentional bias and SCs in the mOFC and amygdala, relative to 10/10‐repeats. Findings suggest that genetic variation in the DAT gene influences brain responses associated with attentional bias; thus, providing additional support for a SC‐vulnerable endophenotype.

Influence of Menstrual Cycle Phase on Neural and Craving Responses to Appetitive Smoking Cues in Naturally Cycling Females

INTRODUCTION Functional magnetic resonance imaging (fMRI) has been used extensively in an attempt to understand brain vulnerabilities that mediate maladaptive responses to drug cues. Using perfusion fMRI, we have consistently shown reward-related activation (medial orbitofrontal cortex/ventral striatum) to smoking cues (SCs). Because preclinical and clinical studies generally show that progesterone may reduce reward and craving, we hypothesized that females in the follicular phase of the cycle (FPs; when progesterone levels are low) would have greater reward-related neural responses to SCs compared with females in the luteal phase (LPs). METHODS Sated cigarette-dependent premenopausal naturally cycling females underwent pseudo-continuous arterial spin-labeled perfusion fMRI during exposure to 10-min audio visual clips of appetitive SCs and non-SCs. Brain responses to SCs relative to non-SCs were examined among females grouped according to menstrual cycle (MC) phase at the time of scanning (22 FPs, 15 LPs). Craving scores were acquired pre- and post-SC exposure. RESULTS FPs showed increased neural responses to SCs compared with non-SCs in the medial orbitofrontal cortex (p ≤ .05 corrected), whereas LPs did not. FPs reported SC-elicited craving (p ≤ .005), whereas LPs did not. Within FPs, SC-induced craving correlated with increased neural responses in the anterior insula (r = 0.73, p < .0001). CONCLUSIONS FPs may be more vulnerable to relapse during appetitive SC exposure than LPs. Because the influence of MC phase on drug cue neural activity has not been examined, these results contribute to our knowledge of the neurobiological underpinnings of responses to drug cues, and they highlight the importance of monitoring menstrual cycle phase in all areas of addiction research.

The impact of sex on brain responses to smoking cues: a perfusion fMRI study.

BackgroundAnecdotal and clinical theories purport that females are more responsive to smoking cues, yet few objective, neurophysiological examinations of these theories have been conducted. The current study examines the impact of sex on brain responses to smoking cues.MethodsFifty-one (31 males) cigarette-dependent sated smokers underwent pseudo- continuous arterial spin-labeled perfusion functional magnetic resonance imaging during exposure to visual smoking cues and non-smoking cues. Brain responses to smoking cues relative to non-smoking cues were examined within males and females separately and then compared between males and females. Cigarettes smoked per day was included in analyses as a covariate.ResultsBoth males and females showed increased responses to smoking cues compared to non-smoking cues with males exhibiting increased medial orbitofrontal cortex and ventral striatum/ventral pallidum responses, and females showing increased medial orbitofrontal cortex responses. Direct comparisons between male and female brain responses revealed that males showed greater bilateral hippocampal/amygdala activation to smoking cues relative to non-smoking cues.ConclusionsMales and females exhibit similar responses to smoking cues relative to non-smoking cues in a priori reward-related regions; however, direct comparisons between sexes indicate that smoking cues evoke greater bilateral hippocampal/amygdalar activation among males. Given the current literature on sex differences in smoking cue neural activity is sparse and incomplete, these results contribute to our knowledge of the neurobiological underpinnings of drug cue reactivity.

Cannabis, Cigarettes, and Their Co-Occurring Use: Disentangling Differences in Gray Matter Volume.

Background: Structural magnetic resonance imaging techniques are powerful tools for examining the effects of drug use on the brain. The nicotine and cannabis literature has demonstrated differences between nicotine cigarette smokers and cannabis users compared to controls in brain structure; however, less is known about the effects of co-occurring cannabis and tobacco use. Methods: We used voxel-based morphometry to examine gray matter volume differences between four groups: (1) cannabis-dependent individuals who do not smoke tobacco (Cs); (2) cannabis-dependent individuals who smoke tobacco (CTs); (3) cannabis-naïve, nicotine-dependent individuals who smoke tobacco (Ts); and (4) healthy controls (HCs). We also explored associations between gray matter volume and measures of cannabis and tobacco use. Results: A significant group effect was observed in the left putamen, thalamus, right precentral gyrus, and left cerebellum. Compared to HCs, the Cs, CTs, and Ts exhibited larger gray matter volumes in the left putamen. Cs also had larger gray matter volume than HCs in the right precentral gyrus. Cs and CTs exhibited smaller gray matter volume than HCs in the thalamus, and CTs and Ts had smaller left cerebellar gray matter volume than HCs. Conclusions: This study extends previous research that independently examined the effects of cannabis or tobacco use on brain structure by including an examination of co-occurring cannabis and tobacco use, and provides evidence that cannabis and tobacco exposure are associated with alterations in brain regions associated with addiction.

Differential reward response to palatable food cues in past and current dieters: a fMRI study.

Prior neuroimaging research has shown that restrained and unrestrained eaters demonstrate differential brain activation in response to food cues that parallels their food intake in lab studies. These findings were extended by comparing brain activation in response to food cues in normal weight nondieters, historical dieters, and current dieters under the conditions that mimicked past lab studies.

Cannabis, cigarettes, and their co-occurring use: Disentangling differences in default mode network functional connectivity.

BACKGROUND Resting-state functional connectivity is a noninvasive, neuroimaging method for assessing neural network function. Altered functional connectivity among regions of the default-mode network have been associated with both nicotine and cannabis use; however, less is known about co-occurring cannabis and tobacco use. METHODS We used posterior cingulate cortex (PCC) seed-based resting-state functional connectivity analyses to examine default mode network (DMN) connectivity strength differences between four groups: (1) individuals diagnosed with cannabis dependence who do not smoke tobacco (n=19; ages 20-50), (2) cannabis-dependent individuals who smoke tobacco (n=23, ages 21-52), (3) cannabis-naïve, nicotine-dependent individuals who smoke tobacco (n=24, ages 21-57), and (4) cannabis- and tobacco-naïve healthy controls (n=21, ages 21-50), controlling for age, sex, and alcohol use. We also explored associations between connectivity strength and measures of cannabis and tobacco use. RESULTS PCC seed-based analyses identified the core nodes of the DMN (i.e., PCC, medial prefrontal cortex, inferior parietal cortex, and temporal cortex). In general, the cannabis-dependent, nicotine-dependent, and co-occurring use groups showed lower DMN connectivity strengths than controls, with unique group differences in connectivity strength between the PCC and the cerebellum, medial prefrontal cortex, parahippocampus, and anterior insula. In cannabis-dependent individuals, PCC-right anterior insula connectivity strength correlated with duration of cannabis use. CONCLUSIONS This study extends previous research that independently examined the differences in resting-state functional connectivity among individuals who smoke cannabis and tobacco by including an examination of co-occurring cannabis and tobacco use and provides further evidence that cannabis and tobacco exposure is associated with alterations in DMN connectivity.