Sex-Dependent Differences in the Neural Correlates of Cocaine and Emotional Cue-Reactivity in Regular Cocaine Users and Non-Drug-Using Controls: Understanding the Role of Duration and Severity of Use.

INTRODUCTION: The development of cocaine use disorder in females is suggested to be more strongly related to neural mechanisms underlying stress-reactivity, whereas in males it is suggested to be more strongly related to neural mechanisms underlying drug cue-reactivity. Existing evidence, however, is based on neuroimaging studies that either lack a control group and/or have very small sample sizes that do not allow to investigate sex differences. METHODS: The main objective of the current study was to investigate sex differences in the neural correlates of cocaine and negative emotional cue-reactivity within high-risk intranasal cocaine users (CUs: 31 males and 26 females) and non-cocaine-using controls (non-CUs: 28 males and 26 females). A region of interest (ROI) analysis was applied to test for the main and interaction effects of group, sex, and stimulus type (cocaine cues vs. neutral cocaine cues and negative emotional cues vs. neutral emotional cues) on activity in the dorsal striatum, ventral striatum (VS), amygdala, and dorsal anterior cingulate cortex (dACC). RESULTS: There were no significant sex or group differences in cocaine cue-reactivity in any of the ROIs. Results did reveal significant emotional cue-reactivity in the amygdala and VS, but these effects were not moderated by group or sex. Exploratory analyses demonstrated that emotional cue-induced activation of the dACC and VS was negatively associated with years of regular cocaine use in female CUs, while this relationship was absent in male CUs. CONCLUSIONS: While speculative, the sex-specific associations between years of regular use and emotional cue-reactivity in the dACC and VS suggest that, with longer years of use, female CUs become less sensitive to aversive stimuli, including the negative consequences of cocaine use, which could account for the observed "telescoping effect" in female CUs.

The Moderating Role of Sex in the Relation between Cue-Induced Craving and Resting-State Functional Connectivity in the Salience Network of Non-Clinically Diagnosed Drinkers.

INTRODUCTION: Previous research indicates a relation between craving and increased connectivity in the resting-state salience network. However, the link between cue-induced craving and connectivity in the salience network remains unclear. Further investigation is needed to understand the effect of sex on the relationship between cue-induced craving and the salience network. We investigated the role of sex in the association between the resting-state functional connectivity (RSFC) salience network and subjective cue-induced craving. METHODS: Twenty-six males (mean age = 25.3) and 23 females (mean age = 26.0), with a score of 12 or higher on the alcohol use disorder identification test, were included in the current study. No significant difference in age was observed between males and females. Participants underwent a resting-state MRI scan for 6 min. Following the MRI scan, participants completed an alcohol cue-exposure task for 5.5 min to assess cue-induced craving using the desire to drink alcohol questionnaire. We applied independent component analysis methods to determine functional connectivity within the salience network. Subsequently, we investigated how cue-induced craving is related to the salience network's RSFC and if this relationship is moderated by sex. RESULTS: The association between the salience network and cue-induced craving was not statistically significant nor did we find a moderating effect for sex. CONCLUSION: The null findings in the study may be explained by a lack of power. Alternatively, alcohol use sex disparities may be more prevalent in the recreational/impulsive stage, whereas participants in our study were in the later stage of addiction.

Smoking Cessation Among Gender Minority Populations, Cis-women, and Cis-men: Findings From the International Tobacco Control Netherlands Survey.

INTRODUCTION: Little is known about smoking cessation among gender minority populations compared to cisgender individuals (whose gender matches their sex assigned at birth). We examined differences between smokers from gender minority populations, cis-women, and cis-men in the heaviness of smoking, quit intentions, use of cessation assistance, quit attempts (ever tried and number), and triggers for thinking about quitting. AIMS AND METHODS: We used cross-sectional data from the 2020 International Tobacco Control Netherlands Survey. Among smoking respondents, we distinguished (1) cis-women (female sex, identified as women, and having feminine gender roles; n = 670), (2) cis-men (male sex, identified as men, and having masculine gender roles; n = 897), and (3) gender minorities (individuals who were intersex, who identified as nonbinary, genderqueer, had a sex/gender identity not listed, whose gender roles were not feminine or masculine, or whose gender identity and/or roles were not congruent with sex assigned at birth; n = 220). RESULTS: Although gender minorities did not differ from cis-women and cis-men in the heaviness of smoking, plans to quit smoking, and quit attempts, they were significantly more likely to use cessation assistance (20% in the past 6 months) than cis-women (12%) and cis-men (9%). Gender minorities were also significantly more likely to report several triggers for thinking about quitting smoking, for example, quit advice from a doctor, an anti-smoking message/campaign, and the availability of a telephone helpline. CONCLUSION: Despite equal levels of quit attempts and heaviness of smoking, gender minority smokers make more use of smoking assistance, and respond stronger to triggers for thinking about quitting smoking. IMPLICATIONS: Smoking cessation counselors should be sensitive to the stressors that individuals from any minority population face, such as stigmatization, discrimination, and loneliness, and should educate their smoking clients on effective coping mechanisms to prevent relapse into smoking after they experience these stressors. Developing tailored smoking cessation programs or campaigns specifically for gender minority populations can also be useful. Based on the results of our subgroup analyses, programs or campaigns for younger gender minority smokers could focus on the availability of telephone helplines and on how friends and family think about their smoking behavior.

The relationship between craving and insular morphometry in regular cocaine users: Does sex matter?

While it has been suggested that cocaine use and relapse in women is more strongly related to stress-relief craving, whereas cocaine use in men is more strongly related to reward craving, the neural mechanisms that underlie these differences are poorly understood. The aim of this study was to investigate sex-dependent differences in insular morphometry and associations with craving, in a sample of regular cocaine users (CUs) and non-drug using controls (non-CUs). It was hypothesized that insular volume, thickness and surface area would be lower in CU women, compared with CU men and non-CUs. It was furthermore hypothesized that insular morphometry, particularly insular thickness, would be negatively associated to reward craving in CU men, while being negatively associated with stress-relief craving in CU women. In contrast to the hypothesis, we did not find evidence of sex-specific differences in insular morphometry in CUs. However, sex-specific association between stress-relief craving and insular morphometry were found: Right insular volume was negatively associated with stress-relief craving in CU women, whereas this association was positive in CU men. Additionally, right insular surface area was negatively associated with stress-relief craving in cocaine-using men, whereas this association was positive in cocaine-using women. In conclusion, the current study provides first evidence of sex-specific differences in the association between craving and insular morphometry in a sample of regular cocaine users. Although speculative, these sex-specific alterations in insular morphometry may underlie higher stress-induced craving and relapse in CU women compared with CU men.

The role of sex in the association between cannabis use and working memory-related brain activity.

Although cannabis use patterns differ between men and women, studies on sex differences on the effects of cannabis on the brain and cognitive control are largely lacking. Working memory (WM) is a component of cognitive control believed to be involved in the development and maintenance of addiction. In this study, we evaluated the association between cannabis use and WM (load) related brain activity in a large sample, enabling us to assess sex effects in this association. The brain activity of 104 frequent cannabis users (63% men) and 85 controls (53% men) was recorded during an N-back WM task. Behavioral results showed a significant interaction between WM load and group for both accuracy and reaction time, with cannabis users showing a relatively larger decrease in performance with increasing WM load. Cannabis users compared to controls showed a relatively smaller reduction in WM (load) related activity in the precuneus and posterior cingulate cortex at higher WM load. This WM (load) related activity was not associated with performance nor cannabis use and related problems. An exploratory analysis showed higher WM-related activity in the superior frontal gyrus in men compared to women. While cannabis users showed higher WM (load) related activity in central nodes of the default mode network, this was not directly attributable to group specific worsening of performance under higher cognitive load. Further research is necessary to assess whether observed group differences increase with higher cognitive load, how group differences relate to measures of cannabis use, and how sex affects these group differences.

The relation between cannabis use, dependence severity and white matter microstructure: A diffusion tensor imaging study.

Despite the significant societal and personal burden of cannabis use, the impact of long-term use and Cannabis Use Disorder (CUD) on white matter microstructure is still unclear. Previous studies show inconsistent findings, in part due to heterogeneity in methodology, variable severity of cannabis use, and potential confounding effects of other mental health issues and substance use. The goal of this diffusion tensor imaging (DTI) study was to compare whole-brain white matter microstructure between 39 near daily cannabis users and 28 controls closely matched on age, sex, alcohol use, cigarette use and mental health. Within the group of cannabis users, associations between white matter microstructure and recent cannabis use, dependence severity, and age of onset and duration of weekly use were investigated. White matter microstructure did not differ between cannabis users and controls and did not covary with recent cannabis use, dependence severity, or duration of use. Earlier onset of weekly cannabis use was related to lower fractional anisotropy (FA) in various sections of the right inferior longitudinal fasciculus and uncinate fasciculus. These findings suggest that long-term near-daily cannabis use does not necessarily affect white matter microstructure, but vulnerability may be higher during adolescence. These findings underscore the importance of sample composition and warrant further studies that investigate the moderating role of age of onset in the impact of cannabis on the brain.

Targeting working memory to modify emotional reactivity in adult attention deficit hyperactivity disorder: a functional magnetic resonance imaging study.

Understanding the neural mechanisms of emotional reactivity in Attention-Deficit/Hyperactivity Disorder (ADHD) may help develop more effective treatments that target emotion dysregulation. In adult ADHD, emotion regulation problems cover a range of dimensions, including emotional reactivity (ER). One important process that could underlie an impaired ER in ADHD might be impaired working memory (WM) processing. We recently demonstrated that taxing WM prior to the exposure of emotionally salient stimuli reduced physiological and subjective reactivity to such cues in heavy drinkers, suggesting lasting effects of WM activation on ER. Here, we investigated neural mechanisms that could underlie the interaction between WM and ER in adult ADHD participants. We included 30 male ADHD participants and 30 matched controls. Participants performed a novel functional magnetic resonance imaging paradigm in which active WM-blocks were alternated with passive blocks of negative and neutral images. We demonstrated group-independent significant main effects of negative emotional images on amygdala activation, and WM-load on paracingulate gyrus and dorsolateral prefrontal cortex activation. Contrary to earlier reports in adolescent ADHD, no impairments were found in neural correlates of WM or ER. Moreover, taxing WM did not alter the neural correlates of ER in either ADHD or control participants. While we did find effects on the amygdala, paCG, and dlPFC activation, we did not find interactions between WM and ER, possibly due to the relatively unimpaired ADHD population and a well-matched control group. Whether targeting WM might be effective in participants with ADHD with severe ER impairments remains to be investigated.

Sex-dependent prefrontal cortex activation in regular cocaine users: A working memory functional magnetic resonance imaging study.

Although two thirds of patients with a cocaine use disorder (CUD) are female, little is known about sex differences in the (neuro)pathology of CUD. The aim of this explorative study was to investigate sex-dependent differences in prefrontal cortex (PFC) functioning during a working memory (WM) functional magnetic resonance imaging (fMRI) task in regular cocaine users (CUs), as PFC deficits are implicated in the shift from recreational cocaine use to CUD. Neural activation was measured using fMRI during a standard WM task (n-back task) in 27 male and 28 female CUs and in 26 male and 28 female non-cocaine users (non-CUs). Although there were no main or interaction effects of sex and group on n-back task performance, WM-related (2-back > 0-back) PFC functioning was significantly moderated by sex and group: female compared with male CUs displayed higher WM-related activation of the middle frontal gyrus (MFG), whereas female compared with male non-CUs displayed lower WM-related MFG activation. Additionally, WM-related activation of the inferior frontal gyrus, insula, and putamen was negatively associated with cocaine use severity in female but not male CUs. These data support the hypothesis of sex-dependent PFC differences in CUs and speculatively suggest that PFC deficits may be more strongly implicated in the development, continuation, and possibly treatment of CUD in females. Most importantly, the current data stress the importance of studying both males and females in psychiatry research as not doing so could greatly bias our knowledge of CUD and other psychiatric disorders.

Family History of Alcohol Abuse Associated with Higher Impulsivity in Patients with Alcohol Use Disorder: A Multisite Study.

BACKGROUND: Alcohol use disorder (AUD) is to a high degree heritable, and in clinical practice it is common to assert presence of alcohol abuse family history (FH) in treatment-seeking AUD patients. Patients with AUD also exhibit cognitive deficits, including elevated impulsivity and impairments in executive functions (EF), but less is known regarding the relation between FH and these cognitive domains. The aim of the current study was to investigate if alcohol abuse FH in AUD patients is associated with a specific cognitive profile. METHODS: Patients with AUD (n = 197) from Sweden (n = 106) and Belgium (n = 91) were recruited. Self-rated impulsivity was assessed by the Barratt Impulsiveness Scale (BIS). EF assessed were response inhibition (stop signal task), attention (rapid visual processing task), and working memory (digit span). A series of linear regression models were run to explore the effect of FH on cognitive outcomes. RESULTS: A FH of alcohol abuse was associated with elevated score in self-rated impulsivity assessed by the BIS, with the greatest effect on the subscale of nonplanning. There was no statistically significant association between FH and any of the other neuropsychological task outcomes. CONCLUSION: Presence of alcohol abuse FH within AUD patients could be a marker of higher impulsivity, which may have clinical implications regarding diagnostic evaluation and treatment.

The effect of N-acetylcysteine and working memory training on neural mechanisms of working memory and cue reactivity in regular cocaine users.

The current study investigated the combined effects of N-acetylcysteine and working memory (WM) training on behavioral and neural mechanisms of cue reactivity and WM in cocaine users in a randomized, double-blind design. Twenty-four of 38 cocaine-using men completed a 25-day treatment with either 2400 mg/day NAC or placebo. Both groups performed WM-training. During pre- and post-test lab-visits, neural mechanisms of cue reactivity and WM, and cue-induced craving and WM performance were assessed. Additionally, exploratory whole brain analyses were performed. Overall, the hypotheses were not confirmed, possibly due to small sample size, low WM-training adherence and/or ongoing substance use.

Appetitive to aversive counter-conditioning as intervention to reduce reinstatement of reward-seeking behavior: the role of the serotonin transporter.

Counter-conditioning can be a valid strategy to reduce reinstatement of reward-seeking behavior. However, this has not been tested in laboratory animals with extended cocaine-taking backgrounds nor is it well understood, which individual differences may contribute to its effects. Here, we set out to investigate the influence of serotonin transporter (5-HTT) genotype on the effectiveness of counter-conditioning after extended access to cocaine self-administration. To this end, 5-HTT+/+ and 5-HTT-/- rats underwent a touch screen-based approach to test if reward-induced reinstatement of responding to a previously counter-conditioned cue is reduced, compared with a non-counter-conditioned cue, in a within-subject manner. We observed an overall extinction deficit of cocaine-seeking behavior in 5-HTT-/- rats and a resistance to punishment during the counter-conditioning session. Furthermore, we observed a significant decrease in reinstatement to cocaine and sucrose associated cues after counter-conditioning but only in 5-HTT+/+ rats. In short, we conclude that the paradigm we used was able to produce effects of counter-conditioning of sucrose seeking behavior in line with what is described in literature, and we demonstrate that it can be effective even after long-term exposure to cocaine, in a genotype-dependent manner.

Striatal alcohol cue-reactivity is stronger in male than female problem drinkers.

Despite apparent sex differences in the development and treatment of alcohol use disorder, relatively little is known about the underlying neural mechanisms. In this study, we therefore investigated neural cue-reactivity in a sample of male (n = 28) and female (n = 27) problem drinkers (matched on age and alcohol use severity) with an average alcohol use disorder identification test score of 12 which is indicative of a likely alcohol use disorder. Neural cue-reactivity data were extracted from four regions of interest: the ventral and dorsal striatum and the ventral and dorsal anterior cingulate cortex, with a significance level set at p < 0.05. While the cue-reactivity paradigm induced similar levels of self-reported craving in men and women, visual alcohol cues induced significantly stronger striatal activation in men compared to drinkers. While sex differences in ventral striatal cue-reactivity were partly explained by sex differences in alcohol intake, cannabis use, negative affect and anxiety, this was not the case for sex differences in dorsal striatal cue-reactivity. These results suggest that alcohol cues are differentially processed by men and women and that the neurobiological mechanisms behind cue-reactivity differ between the sexes. Consequently, paradigms using alcohol-related pictures may not be optimal to induce cue-reactivity in female drinkers and may not be optimal to measure neurobiological markers of alcohol use severity and relapse. Future alcohol cue-reactivity studies should, in addition to including both men and women, include different types of cues (e.g., stressors and imagery in addition to pictures) to assess sex differences in alcohol cue-reactivity.

Enhanced Amygdala-Striatal Functional Connectivity during the Processing of Cocaine Cues in Male Cocaine Users with a History of Childhood Trauma.

BACKGROUND AND AIMS: Childhood trauma is associated with increased levels of anxiety later in life, an increased risk for the development of substance use disorders, and neurodevelopmental abnormalities in the amygdala and frontostriatal circuitry. The aim of this study was to investigate the (neurobiological) link among childhood trauma, state anxiety, and amygdala-frontostriatal activity in response to cocaine cues in regular cocaine users. METHODS: In this study, we included 59 non-treatment seeking regular cocaine users and 58 non-drug using controls. Blood oxygenation level-dependent responses were measured using functional magnetic resonance imaging while subjects performed a cue reactivity paradigm with cocaine and neutral cues. Psychophysiological interaction analyses were applied to assess functional connectivity between the amygdala and other regions in the brain. Self-report questionnaires were used to measure childhood trauma, state anxiety, drug use, drug use severity, and craving. RESULTS: Neural activation was increased during the presentation of cocaine cues, in a widespread network including the frontostriatal circuit and amygdala in cocaine users but not in controls. Functional coupling between the amygdala and medial prefrontal cortex was reduced in response to cocaine cues, in both cocaine users and controls, which was further diminished with increasing state anxiety. Importantly, amygdala-striatal connectivity was positively associated with childhood trauma in regular cocaine users, while there was a negative association in controls. At the behavioral level, state anxiety was positively associated with cocaine use severity and craving related to negative reinforcement. CONCLUSION: Childhood trauma is associated with enhanced amygdala-striatal connectivity during cocaine cue reactivity in regular cocaine users, which may contribute to increased habit behavior and poorer cognitive control. While we cannot draw conclusions on causality, this study provides novel information on how childhood trauma may contribute to the development and persistence of cocaine use disorder.

A high working memory load prior to memory retrieval reduces craving in non-treatment seeking problem drinkers.

BACKGROUND: Reconsolidation-based interventions have been suggested to be a promising treatment strategy for substance use disorders. In this study, we aimed to investigate the effectiveness of a working memory intervention to interfere with the reconsolidation of alcohol-related memories in a sample of non-treatment seeking heavy drinkers. METHODS: Participants were randomized to one of the two conditions that underwent a 3-day intervention: in the experimental condition, a 30-min working memory training was performed immediately after a 15-min memory retrieval session (i.e., within the memory reconsolidation time-window), whereas in the control condition, the working memory training was performed prior to a memory retrieval session. RESULTS: In contrast to our original hypothesis, a high working memory load after memory retrieval did not interfere with the reconsolidation of those memories while a high working memory load prior to memory retrieval (the original control condition) strongly reduced retrieval-induced craving and craving for alcohol at follow-up. CONCLUSION: Whereas the neurocognitive mechanism behind this effect needs to be further investigated, the current findings suggest that, if replicated, working memory training prior to addiction-related memory retrieval has the potential to become an effective (adjunctive) intervention in the treatment of substance use disorders.

Prefrontal Glx and GABA concentrations and impulsivity in cigarette smokers and smoking polysubstance users.

Glutamate and GABA play an important role in substance dependence. However, it remains unclear whether this holds true for different substance use disorders and how this is related to risk-related traits such as impulsivity. We, therefore, compared Glx (as a proxy measure for glutamate) and GABA concentrations in the dorsal anterior cingulate cortex (dACC) of 48 male cigarette smokers, 61 male smoking polysubstance users, and 90 male healthy controls, and investigated the relationship with self-reported impulsivity and substance use. Glx and GABA concentrations were measured using proton Magnetic Resonance Spectroscopy. Impulsivity, smoking, alcohol and cocaine use severity and cannabis use were measured using self-report instruments. Results indicate a trend towards group differences in Glx. Post-hoc analyses showed a difference between smokers and healthy controls (p=0.04) and a trend towards higher concentrations in smoking polysubstance users and healthy controls (p=0.09), but no differences between smokers and smoking polysubstance users. dACC GABA concentrations were not significantly different between groups. Smoking polysubstance users were more impulsive than smokers, and both groups were more impulsive than controls. No significant associations were observed between dACC neurotransmitter concentrations and impulsivity and level and severity of smoking, alcohol or cocaine use or the presence of cannabis use. The results indicate that differences in dACC Glx are unrelated to type and level of substance use. No final conclusion can be drawn on the lack of GABA differences due to assessment difficulties. The relationship between dACC neurotransmitter concentrations and cognitive impairments other than self-reported impulsivity should be further investigated.

White matter alterations in cocaine users are negatively related to the number of additionally (ab)used substances.

Diffusion tensor imaging studies have provided evidence for white matter (WM) alterations in cocaine users. While polysubstance use is a widespread phenomenon among cocaine users, its role in WM alterations in cocaine users is currently unknown. This study examined the relation between the number of substances that are used(cocaine, alcohol and marijuana) and WM alterations in 67 male non-drug users and 67 male regular cocaine users, who were classified into five groups based on the number of used substances. Diffusion-weighted images were acquired on a 3.0 T magnetic resonance imaging scanner. Using tract-based spatial statistics we demonstrated that there was a negative relation between the number of used substances and fractional anisotropy, a global measure of WM integrity. Also, we demonstrated a positive relation between the number of used substance and radial diffusivity within the prefrontal lobe, suggesting an increase in demyelination with the number of used substances. We did not find a dose-effect between the level of substance use and WM alterations. The results of the current study may reflect the presence of a pre-existing vulnerability to polysubstance use resulting from prefrontal WM abnormalities and related impaired cognitive control although WM alterations because of polysubstance use cannot be fully excluded. This study is an important first step in understanding the problems related to polysubstance use among cocaine users.

Aversive Counterconditioning Attenuates Reward Signaling in the Ventral Striatum.

Appetitive conditioning refers to the process of learning cue-reward associations and is mediated by the mesocorticolimbic system. Appetitive conditioned responses are difficult to extinguish, especially for highly salient reward such as food and drugs. We investigate whether aversive counterconditioning can alter reward reinstatement in the ventral striatum in healthy volunteers using functional magnetic resonance imaging (fMRI). In the initial conditioning phase, two different stimuli were reinforced with a monetary reward. In the subsequent counterconditioning phase, one of these stimuli was paired with an aversive shock to the wrist. In the following extinction phase, none of the stimuli were reinforced. In the final reinstatement phase, reward was reinstated by informing the participants that the monetary gain could be doubled. Our fMRI data revealed that reward signaling in the ventral striatum and ventral tegmental area following reinstatement was smaller for the stimulus that was counterconditioned with an electrical shock, compared to the non-counterconditioned stimulus. A functional connectivity analysis showed that aversive counterconditioning strengthened striatal connectivity with the hippocampus and insula. These results suggest that reward signaling in the ventral striatum can be attenuated through aversive counterconditioning, possibly by concurrent retrieval of the aversive association through enhanced connectivity with hippocampus and insula.

Hyperresponsiveness of the Neural Fear Network During Fear Conditioning and Extinction Learning in Male Cocaine Users.

OBJECTIVE: The authors investigated whether cocaine use disorder is associated with abnormalities in the neural underpinnings of aversive conditioning and extinction learning, as these processes may play an important role in the development and persistence of drug abuse. METHOD: Forty male regular cocaine users and 51 male control subjects underwent a fear conditioning and extinction protocol during functional MRI. Skin conductance response was measured throughout the experiment as an index of conditioned responses. RESULTS: Cocaine users showed hyperresponsiveness of the amygdala and insula during fear conditioning, as well as hyporesponsiveness of the dorsomedial prefrontal cortex during extinction learning. In cocaine users, but not in control subjects, skin conductance responses were positively correlated with responsiveness of the insula, amygdala, and dorsomedial prefrontal cortex during fear conditioning but negatively correlated with responsiveness of the ventromedial prefrontal cortex during extinction learning. CONCLUSIONS: Increased sensitivity to aversive conditioned cues in cocaine users might be a risk factor for stress-relief craving in cocaine use disorder. These results support the postulated role of altered aversive conditioning in cocaine use disorder and may be an important step in understanding the role of aversive learning in the pathology of cocaine use disorder.

Dysfunctional amygdala activation and connectivity with the prefrontal cortex in current cocaine users.

OBJECTIVES: Stimulant use is associated with increased anxiety and a single administration of dexamphetamine increases amygdala activation to biologically salient stimuli in healthy individuals. Here, we investigate how current cocaine use affects amygdala activity and amygdala connectivity with the prefrontal cortex in response to biologically salient stimuli in an emotional face matching task (EFMT). EXPERIMENTAL DESIGN: Amygdala activity and amygdala connectivity during the EFMT were assessed in 51 cocaine using males and 32 non-drug-using healthy males using functional magnetic resonance imaging (fMRI). Within the cocaine use group, we explored whether amygdala activation was associated with age of first use of cocaine and duration of cocaine use to distinguish between amygdala activation alterations as a cause or a consequence of cocaine use. PRINCIPAL OBSERVATIONS: We observed hyperactivity of the amygdala, thalamus, and hippocampus and reduced amygdala connectivity with the anterior cingulate gyrus in response to angry and fearful facial expressions in current cocaine users compared to controls. Increased amygdala activation was independently associated with earlier age of first cocaine use and with longer exposure to cocaine. CONCLUSIONS: Our findings suggest that amygdala hyperactivity to biologically salient stimuli may represent a risk factor for an early onset of cocaine use and that prolonged cocaine use may further sensitize amygdala activation. High amygdala activation to emotional face processing in current cocaine users may result from low prefrontal control of the amygdala response to such stimuli.

Relationship between trait impulsivity and cortical volume, thickness and surface area in male cocaine users and non-drug using controls.

BACKGROUND: Trait impulsivity is commonly associated with cocaine dependence. The few studies that have investigated the relation between trait impulsivity and cortical morphometry, have shown a distinct relation between impulsivity and cortical volume (CV) of temporal, frontal and insula cortex. As CV is the function of cortical surface area (SA) and cortical thickness (CT) impulsivity may be differently associated to SA than to CT. METHOD: Fifty-three cocaine users (CU) and thirty-five controls (HC) (males aged 18-55 years) completed the Barrat impulsiveness scale and a structural scan was made on a 3T MRI scanner. CV, SA and CT were measured using Freesurfer. Multivariate analysis was used to test for group differences and group by impulsivity interaction effects in CV, SA and ST across nine regions of interest in the temporal, frontal and insular cortices. Possible confounding effects of drug- and alcohol exposure were explored. RESULTS: Compared to HC, CU had a smaller SA of the superior temporal cortex but a larger SA of the insula. There were divergent relations between trait impulsivity and SA of the superior temporal cortex and insula (positive in HC, negative in CU) and CT of the anterior cingulate cortex (negative in HC, positive in CU). Within CU, there was a negative association between monthly cocaine use and CT of the insula and superior temporal cortex. DISCUSSION: The distinct relation between trait impulsivity and cortical morphometry in CU and HC might underlie inefficient control over behavior resulting in maladaptive impulsive behaviour such as cocaine abuse.