Cannabis Dependence is Associated with Reduced Hippocampal Subregion Volumes Independently of Sex: Findings from an ENIGMA Addiction Working Group Multi-Country Study.

Background: Males and females who consume cannabis can experience different mental health and cognitive problems. Neuroscientific theories of addiction postulate that dependence is underscored by neuroadaptations, but do not account for the contribution of distinct sexes. Further, there is little evidence for sex differences in the neurobiology of cannabis dependence as most neuroimaging studies have been conducted in largely male samples in which cannabis dependence, as opposed to use, is often not ascertained. Methods: We examined subregional hippocampus and amygdala volumetry in a sample of 206 people recruited from the ENIGMA Addiction Working Group. They included 59 people with cannabis dependence (17 females), 49 cannabis users without cannabis dependence (20 females), and 98 controls (33 females). Results: We found no group-by-sex effect on subregional volumetry. The left hippocampal cornu ammonis subfield 1 (CA1) volumes were lower in dependent cannabis users compared with non-dependent cannabis users (p<0.001, d=0.32) and with controls (p=0.022, d=0.18). Further, the left cornu ammonis subfield 3 (CA3) and left dentate gyrus volumes were lower in dependent versus non-dependent cannabis users but not versus controls (p=0.002, d=0.37, and p=0.002, d=0.31, respectively). All models controlled for age, intelligence quotient (IQ), alcohol and tobacco use, and intracranial volume. Amygdala volumetry was not affected by group or group-by-sex, but was smaller in females than males. Conclusions: Our findings suggest that the relationship between cannabis dependence and subregional volumetry was not moderated by sex. Specifically, dependent (rather than non-dependent) cannabis use may be associated with alterations in selected hippocampus subfields high in cannabinoid type 1 (CB1) receptors and implicated in addictive behavior. As these data are cross-sectional, it is plausible that differences predate cannabis dependence onset and contribute to the initiation of cannabis dependence. Longitudinal neuroimaging work is required to examine the time-course of the onset of subregional hippocampal alterations in cannabis dependence, and their progression as cannabis dependence exacerbates or recovers over time.

Measuring white matter microstructure in 1,457 cannabis users and 1,441 controls: A systematic review of diffusion-weighted MRI studies.

Introduction: Cannabis is the most widely used regulated substance by youth and adults. Cannabis use has been associated with psychosocial problems, which have been partly ascribed to neurobiological changes. Emerging evidence to date from diffusion-MRI studies shows that cannabis users compared to controls show poorer integrity of white matter fibre tracts, which structurally connect distinct brain regions to facilitate neural communication. However, the most recent evidence from diffusion-MRI studies thus far has yet to be integrated. Therefore, it is unclear if white matter differences in cannabis users are evident consistently in selected locations, in specific diffusion-MRI metrics, and whether these differences in metrics are associated with cannabis exposure levels. Methods: We systematically reviewed the results from diffusion-MRI imaging studies that compared white matter differences between cannabis users and controls. We also examined the associations between cannabis exposure and other behavioral variables due to changes in white matter. Our review was pre-registered in PROSPERO (ID: 258250; https://www.crd.york.ac.uk/prospero/). Results: We identified 30 diffusion-MRI studies including 1,457 cannabis users and 1,441 controls aged 16-to-45 years. All but 6 studies reported group differences in white matter integrity. The most consistent differences between cannabis users and controls were lower fractional anisotropy within the arcuate/superior longitudinal fasciculus (7 studies), and lower fractional anisotropy of the corpus callosum (6 studies) as well as higher mean diffusivity and trace (4 studies). Differences in fractional anisotropy were associated with cannabis use onset (4 studies), especially in the corpus callosum (3 studies). Discussion: The mechanisms underscoring white matter differences are unclear, and they may include effects of cannabis use onset during youth, neurotoxic effects or neuro adaptations from regular exposure to tetrahydrocannabinol (THC), which exerts its effects by binding to brain receptors, or a neurobiological vulnerability predating the onset of cannabis use. Future multimodal neuroimaging studies, including recently developed advanced diffusion-MRI metrics, can be used to track cannabis users over time and to define with precision when and which region of the brain the white matter changes commence in youth cannabis users, and whether cessation of use recovers white matter differences. Systematic review registration: www.crd.york.ac.uk/prospero/, identifier: 258250.

Do mindfulness-based interventions change brain function in people with substance dependence? A systematic review of the fMRI evidence.

BACKGROUND: Substance use disorders (SUDs) affect ~ 35 million people globally and are associated with strong cravings, stress, and brain alterations. Mindfulness-based interventions (MBIs) can mitigate the adverse psychosocial outcomes of SUDs, but the underlying neurobiology is unclear. Emerging findings were systematically synthesised from fMRI studies about MBI-associated changes in brain function in SUDs and their associations with mindfulness, drug quantity, and craving. METHODS: PsycINFO, Medline, CINAHL, PubMed, Scopus, and Web of Science were searched. Seven studies met inclusion criteria. RESULTS: Group by time effects indicated that MBIs in SUDs (6 tobacco and 1 opioid) were associated with changes in the function of brain pathways implicated in mindfulness and addiction (e.g., anterior cingulate cortex and striatum), which correlated with greater mindfulness, lower craving and drug quantity. CONCLUSIONS: The evidence for fMRI-related changes with MBI in SUD is currently limited. More fMRI studies are required to identify how MBIs mitigate and facilitate recovery from aberrant brain functioning in SUDs.

Effects of cannabinoids on resting state functional brain connectivity: A systematic review.

Cannabis products are widely used for medical and non-medical reasons worldwide and vary in content of cannabinoids such as delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Resting state functional connectivity offers a powerful tool to investigate the effects of cannabinoids on the human brain. We systematically reviewed functional neuroimaging evidence of connectivity during acute cannabinoid administration. A pre-registered (PROSPERO ID: CRD42020184264) systematic review of 13 studies comprising 318 participants (mean age of 25 years) was conducted and reported using the PRISMA checklist. During THC and THCv exposure vs placebo reduced connectivity with the NAcc was widely reported. Limited evidence shows that such effects are offset by co-administration of CBD. NAcc-frontal region connectivity was associated with intoxication levels. Cannabis intoxication vs placebo was associated with lower striatal-ACC connectivity. CBD and CBDv vs placebo were associated with both higher and lower connectivity between striatal-prefrontal/other regions. Overall, cannabis and cannabinoids change functional connectivity in the human brain during resting state as a function of the type of cannabinoid examined.

No influence of sex on the relationship between schizotypy factors and executive control across the schizophrenia spectrum.

Sex differences in symptoms and executive control across schizophrenia spectrum disorders (SSD) are consistently reported. Similarly, these findings of sex differences are also observed in schizotypy, that is, schizophrenia-like features occurring in healthy individuals in the absence of a clinical diagnosis. This study aimed to examine the relationships between performance on three major domains of executive control: performance monitoring, response inhibition, and cognitive set-shifting, and schizotypy factor scores in both SSD patients and healthy controls (HCs), and whether sex moderated any relationships observed. A total of 111 (67 males and 44 females) patients with SSD and 258 (129 males and 129 females) HCs were included in this study. Schizotypal personality traits (in both SSD and HC) was assessed using the Oxford-Liverpool Inventory of Feelings and Experiences (O-LIFE). Executive control performance was assessed using seven tasks. Stepwise linear regressions revealed that performance on cognitive set-shifting tasks was significantly associated with the introvertive anhedonia, cognitive disorganisation, and unusual experiences subscales of the O-LIFE. When sex was examined as a moderator, it was not a significant moderator of any of the relationships between cognitive set-shifting tasks and schizotypy factors. The results suggest that independent of sex, cognitive set-shifting ability is associated to an increased vulnerability to schizotypal personality traits, although performance monitoring and response inhibition did not.

Sex differences in executive control: A systematic review of functional neuroimaging studies.

The number of studies investigating sex differences in executive functions, particularly those using human functional neuroimaging techniques, has risen dramatically in the past decade. However, the influences of sex on executive function are still underexplored and poorly characterized. To address this, we conducted a systematic literature review of functional neuroimaging studies investigating sex differences in three prominent executive control domains of cognitive set-shifting, performance monitoring, and response inhibition. PubMed, Web of Science, and Scopus were systematically searched. Following the application of exclusion criteria, 21 studies were included, with a total of 677 females and 686 males. Ten of these studies were fMRI and PET, eight were EEG, and three were NIRS. At present, there is evidence for sex differences in the neural networks underlying all tasks of executive control included in this review suggesting males and females engage different strategies depending on task demands. There was one task exception, the 2-Back task, which showed no sex differences. Due to methodological variability and the involvement of multiple neural networks, a simple overarching statement with regard to gender differences during executive control cannot be provided. As such, we discuss limitations within the current literature and methodological considerations that should be employed in future research. Importantly, sex differences in neural mechanisms are present in the majority of tasks assessed, and thus should not be ignored in future research. PROSPERO registration information: CRD42019124772.

A systematic review and meta-analysis of behavioural sex differences in executive control.

Literature investigating whether an individuals' sex affects their executive control abilities and performance on cognitive tasks in a normative population has been contradictory and inconclusive. Using meta-analytic procedures (abiding by PRISMA guidelines), this study attempts to identify the magnitude of behavioural sex differences in three prominent executive control domains of cognitive set-shifting, performance monitoring, and response inhibition. PubMed, Web of Science, and Scopus were systematically searched. Across 46 included studies, a total of 1988 females and 1884 males were included in the analysis. Overall, males and females did not differ on performance in any of the three domains of performance monitoring, response inhibition, or cognitive set-shifting. Task-specific sex differences were observed in the domains of performance monitoring, in the CANTAB Spatial Working Memory task-males scored statistically higher than females (Hedges' g = -0.60), and response inhibition, in the Delay Discounting task-females scored statistically higher than males (Hedges' g = 0.64). While the meta-analysis did not detect overall behavioural sex differences in executive control, significant heterogeneity and task-specific sex differences were found. To further understand sex differences within these specific tasks and domains, future research must better control for age and sex hormone levels.

Greater activation of the response inhibition network in females compared to males during stop signal task performance.

Previous neuroimaging studies have reported differences in regional brain activation between males and females during stop signal task performance, suggesting the presence of sex-linked differences in brain network organization of inhibitory ability. Despite a growing literature on sex differences during stop signal task performance, a consensus still has not been reached due to variations in task design and analysis methods. Due to these disparate findings we used up to date stop signal task methods to compare behavioral performance and associated brain activation between males and females using an event-related functional magnetic resonance imaging design. We observed that males were faster in inhibiting their responses, but females exhibited marked increased in stopping network activation, in addition to increased activation of the anterior insula and left amygdala. These findings suggest that males and females process stop signals differently.

Direct current stimulation of prefrontal cortex modulates error-induced behavioral adjustments.

Commission of errors and conflict between choices might induce behavioral modulations through adjustments in the executive control of behavior and altered patterns of these modulations are detected in neuropsychiatric disorders. We examined the effects of transcranial Direct Current Stimulation (tDCS) applied over the dorsolateral prefrontal cortex (DLPFC) on error- and conflict-induced behavioral modulations. Two separate cohorts of participants performed two clinically relevant tests of executive control, respectively. In the Wisconsin Card Sorting Test (WCST), the relevant rule for matching items frequently changed and therefore participants had to detect these unannounced changes by trial and error and alter their rule-based behavior. In the Stop task, participants had to rapidly respond to a directional go-signal but inhibit their responses when a stop signal appeared after the go-signal. Each participant received tDCS (sham, cathodal or anodal) in three separate sessions. Errors led to a slower response in the next trial (post-error slowing) in both tasks. The tDCS significantly modulated the post-error slowing in both tasks but did not affect the behavioral adjustments induced by the conflict. The modulation of post-error slowing by tDCS were polarity-dependent and also trial specific appearing immediately after errors. In the WCST and Stop task, the post-error slowing may reflect different processes involved in shifting the behavior-guiding rule and adjustments in inhibitory control of responses, respectively, and we found that the effective tDCS polarity differed between the two tasks. Here, we show that in two separate cognitive tasks direct current stimulation of DLPFC significantly modulated error-induced behavioral modulations.

Sex dependency of inhibitory control functions.

BACKGROUND: Inhibition of irrelevant responses is an important aspect of cognitive control of a goal-directed behavior. Females and males show different levels of susceptibility to neuropsychological disorders such as impulsive behavior and addiction, which might be related to differences in inhibitory brain functions. METHODS: We examined the effects of 'practice to inhibit', as a model of rehabilitation approach, and 'music', as a salient contextual factor in influencing cognition, on the ability of females and males to perform a stop-signal task that required inhibition of initiated or planned responses. In go trials, the participants had to rapidly respond to a directional go cue within a limited time window. In stop trials, which were presented less frequently, a stop signal appeared immediately after the go-direction cue and the participants had to stop their responses. RESULTS: We found a significant difference between females and males in benefiting from practice in the stop-signal task: the percentage of correct responses in the go trials increased, and the ability to inhibit responses significantly improved, after practice in females. While listening to music, females became faster but males became slower in responding to the go trials. Both females and males became slower in performing the go trials following an error in the stop trials; however, music significantly affected this post-error slowing depending on the sex. Listening to music decreased post-error slowing in females but had an opposite effect in males. CONCLUSIONC: Here, we show a significant difference in executive control functions and their modulation by contextual factors between females and males that might have implications for the differences in their propensity for particular neuropsychological disorders and related rehabilitation approaches.