Intrinsic Frontolimbic Connectivity and Mood Symptoms in Young Adult Cannabis Users.

Objective: The endocannbinoid system and cannabis exposure has been implicated in emotional processing. The current study examined whether regular cannabis users demonstrated abnormal intrinsic (a.k.a. resting state) frontolimbic connectivity compared to non-users. A secondary aim examined the relationship between cannabis group connectivity differences and self-reported mood and affect symptoms. Method: Participants included 79 cannabis-using and 80 non-using control emerging adults (ages of 18-30), balanced for gender, reading ability, and age. Standard multiple regressions were used to predict if cannabis group status was associated with frontolimbic connectivity after controlling for site, past month alcohol and nicotine use, and days of abstinence from cannabis. Results: After controlling for research site, past month alcohol and nicotine use, and days of abstinence from cannabis, cannabis users demonstrated significantly greater connectivity between left rACC and the following: right rACC (p = 0.001; corrected p = 0.05; f 2 = 0.55), left amygdala (p = 0.03; corrected p = 0.47; f 2 = 0.17), and left insula (p = 0.03; corrected p = 0.47; f 2 = 0.16). Among cannabis users, greater bilateral rACC connectivity was significantly associated with greater subthreshold depressive symptoms (p = 0.02). Conclusions: Cannabis using young adults demonstrated greater connectivity within frontolimbic regions compared to controls. In cannabis users, greater bilateral rACC intrinsic connectivity was associated with greater levels of subthreshold depression symptoms. Current findings suggest that regular cannabis use during adolescence is associated with abnormal frontolimbic connectivity, especially in cognitive control and emotion regulation regions

Resting-state abnormalities in heroin-dependent individuals

Drug addiction is a major health problem worldwide. Recent neuroimaging studies have shed light into the underlying mechanisms of drug addiction as well as its consequences to the human brain. The most vulnerable, to heroin addiction, brain regions have been reported to be specific prefrontal, parietal, occipital, and temporal regions, as well as, some subcortical regions. The brain regions involved are usually linked with reward, motivation/drive, memory/learning, inhibition as well as emotional control and seem to form circuits that interact with each other. So, along with neuroimaging studies, recent advances in resting-state dynamics might allow further assessments upon the multilayer complexity of addiction. In the current manuscript, we comprehensively review and discuss existing resting-state neuroimaging findings classified into three overlapping and interconnected groups: functional connectivity alterations, structural deficits and abnormal topological properties. Moreover, behavioral traits of heroin-addicted individuals as well as the limitations of the currently available studies are also reviewed. Finally, in need of a contemporary therapy a multimodal therapeutic approach is suggested using classical treatment practices along with current neurotechonologies, such as neurofeedback and goal-oriented video-games

Neurobiological Impact of HIV Infection and Chronic Cannabis Use

Neuroimaging research has identified brain alterations linked with the human immunodeficiency virus (HIV) that contribute to cognitive declines characterizing the disease. Given cannabis’s (CB’s) anti-inflammatory properties, use prevalence among people living with HIV (PLWH), and impact on neurocognition, my dissertation utilizes a between-groups study design to interrogate separate and interactive effects of HIV and CB on fMRI measures of brain activity. We investigate (1) task-based brain activity at the regional-level, (2) insular resting-state functional connectivity (rsFC) at the circuit-level, and (3) large-scale brain network interactions at the systems-level. Participants (N=114) were stratified into four groups (HIV+/CB+; HIV+/CB-; HIV-/CB+; HIV-/CB-) and underwent fMRI scanning while completing an Error Awareness Task (EAT) and while at rest. Participants also completed a battery of instruments including subjective reports of cognitive failures, and objective measures of cognition and medication management abilities. Blood samples quantified disease severity (viral load) and inflammation (tumor necrosis factor alpha [TNF-α]). Regarding task-based brain activity, PLWH displayed a lack of error-related deactivation in two default mode network (DMN) regions (posterior cingulate cortex [PCC], medial prefrontal cortex [mPFC]). Across all participants, reduced error-related PCC deactivation correlated with reduced medication management abilities and mediated the effect of HIV on such abilities. Regarding insular circuitry, we observed interactive HIVxCB effects on rsFC between two anterior insula (aI) subregions and sensorimotor cortices such that, CB use normalized altered rsFC that was observed among non-using PLWH and correlated with decreased somatic complaints and increased inflammation. Finally, regarding large-scale network interactions, PLWH displayed increased salience network (SN)-DMN rsFC that was associated with diminished error-awareness. These results demonstrate that insufficient error-related DMN suppression and heightened SN-DMN rsFC are linked with HIV and have consequences for error-processing and medication management. Additionally, these outcomes suggest a potential normalizing effect of CB on altered insula-sensorimotor neurocircuitries among PLWH and begin to elucidate inflammatory mechanisms through which CB use may impact brain function in the context of HIV

Investigating resting-state functional connectivity differences in cannabis use disorder and exploring their mitigation through brief mindfulness-based intervention

Cannabis Use Disorder (CUD) affects 22 million people globally and can lead to adverse psychosocial outcomes, including failed attempts to cut down/quit despite the experience of mental health and cognitive problems. Such problems have been (partly) ascribed to neurobiological alterations within pathways of the addiction neurocircuitry and high in cannabinoid receptors type 1 (CB1R), to which delta-9-tetrahydrocannabinol binds to exert its psychoactive effects. Emerging functional neuroimaging (fMRI) evidence show that cannabis users vs controls showed altered brain function while resting (i.e., without performing cognitively demanding tasks), measured via resting-state functional connectivity (rsFC); the evidence has not been synthesised systematically. Study 1 is a PROSPERO pre-registered systematic literature review of 21 studies examining rsFC differences between 737 cannabis users and 659 controls, and their associations with metrics of cannabis exposure and related problems. Cannabis users vs controls showed altered rsFC in fronto-frontal, frontostriatal, and fronto-temporal region pairings, and selected brain pathways correlated with cannabis exposure metrics. Methodological limitations precluded a detailed understanding of the nature of rsFC alterations. For example, it was unclear if rsFC changes were driven by dependent use/CUD, because no study had measured if cannabis users endorsed a CUD using current diagnostic tools (i.e., DSM-5). Furthermore, if rsFC alterations are specific to cannabis use was unclear due to inconsistent accounting for key demographics and substance use/mental health confounders entrenched with cannabis use known to affect brain function. Finally, the behavioural significance of rsFC alterations remained unclear, as it has seldom been examined in relation to cannabis exposure and related problems. Study 2 aimed to address the limitations of the literature, via examining 107 people aged 18-56 years (35 female) via fMRI scanning, socio-demographic, substance use, mental health, and cognitive testing. The primary aim was to compare rsFC between 65 individuals with a moderate-to-severe CUD who had tried to cut down or quit, and 42 controls, controlling for age, sex, alcohol and nicotine exposure, and depression symptom scores. Regions implicated in addiction neurocircuitry, dense in CB1R, and implicated in cognitive processes altered in cannabis users were selected as regions-of-interest (ROIs). Associations between CUD group rsFC changes and metrics of cannabis exposure and related problems were explored. People with a CUD vs controls showed greater rsFC between the following region pairings: nucleus accumbens (NAc)-frontal; pallidum-occipital/occipito-parietal, in correlation with CUD severity and cannabis use days/month; and putamen-occipito-parietal, in correlation with an earlier age of cannabis use onset; and lower hippocampus-occipital rsFC. Thus far, it is unclear if altered rsFC in CUD can be mitigated using psychological interventions. Study 3 examined if altered rsFC shown in the CUD group in Study 2 (n=56, aged 18-51 years), could be mitigated using one of the following ~2-week interventions: a mindfulness-based intervention (MBI, n=19), active placebo (relaxation; n=18), and passive placebo (daily monitoring; n=19). It used a double-blind, pseudo-randomised design based on age and sex. The primary aim was to examine intervention-group-by-time effects on rsFC in a priori ROIs with altered rsFC identified in Study 2 (i.e., NAc, putamen, pallidum, hippocampus), and how changes in rsFC correlated with those in cannabis exposure and related variables. Pre-to-post MBI, putamen-superior frontal gyrus (SFG)/frontal pole rsFC decreased; and hippocampus-anterior cingulate rsFC increased (correlated with more cannabis use days). Pre-to-post active placebo, putamen-frontal pole rsFC increased, correlated with decreased cannabis grams; putamen-SFG/cerebellum/brainstem rsFC increased; and pallidum-anterior superior temporal gyrus (aSTG) rsFC decreased. Pre-to-post passive placebo, putamen-frontal pole rsFC increased, correlated with less cannabis use days; pallidum-aSTG rsFC increased; and hippocampus-anterior cingulate and putamen-SFG/cerebellum/brainstem rsFC decreased. Findings from the thesis demonstrated rsFC alterations in cannabis users and confirmed existence of such alterations in CUD, and that alterations can be mitigated with a brief MBI, as well as relaxation and daily monitoring. rsFC alterations may reflect cannabis exposure or related problem (or both), or a neurobiological vulnerability predating the onset of cannabis use/CUD. Future fMRI studies with larger samples are required to confirm findings and to track over time if continuation of MBI, active and passive placebo interventions consolidate the effects reported herein. The results from this thesis expand upon neuroscientific theories of addiction validated in substances other than cannabis, by confirming partially overlapping alterations in CUD, and by showing that brief psychological interventions can target brain dysfunction in CUD

Cigarette smoking is associated with amplified age-related volume loss in subcortical brain regions

BACKGROUND: Magnetic resonance imaging studies of cigarette smoking-related effects on human brain structure have primarily employed voxel-based morphometry, and the most consistently reported finding was smaller volumes or lower density in anterior frontal regions and the insula. Much less is known about the effects of smoking on subcortical regions. We compared smokers and non-smokers on regional subcortical volumes, and predicted that smokers demonstrate greater age-related volume loss across subcortical regions than non-smokers. METHODS: Non-smokers (n=43) and smokers (n=40), 22-70 years of age, completed a 4T MRI study. Bilateral total subcortical lobar white matter (WM) and subcortical nuclei volumes were quantitated via FreeSurfer. In smokers, associations between smoking severity measures and subcortical volumes were examined. RESULTS: Smokers demonstrated greater age-related volume loss than non-smokers in the bilateral subcortical lobar WM, thalamus, and cerebellar cortex, as well as in the corpus callosum and subdivisions. In smokers, higher pack-years were associated with smaller volumes of the bilateral amygdala, nucleus accumbens, total corpus callosum and subcortical WM. CONCLUSIONS: Results provide novel evidence that chronic smoking in adults is associated with accelerated age-related volume loss in subcortical WM and GM nuclei. Greater cigarette quantity/exposure was related to smaller volumes in regions that also showed greater age-related volume loss in smokers. Findings suggest smoking adversely affected the structural integrity of subcortical brain regions with increasing age and exposure. The greater age-related volume loss in smokers may have implications for cortical-subcortical structural and/or functional connectivity, and response to available smoking cessation interventions

Reduced executive and default network functional connectivity in cigarette smokers

Altered functional connectivity has been associated with acute and chronic nicotine use. Connectivity alterations, specifically in the right and left executive control networks (RECN/LECN) and the default mode network (DMN), may contribute to the addiction cycle. The objective of this study was to determine if executive control network (ECN) and DMN connectivity is different between non‐smokers and smokers and whether reductions in connectivity are related to chronic cigarette use. The RECN, LECN, and DMN were identified in resting state functional magnetic resonance imaging data in 650 subjects. Analyses tested for group differences in network connectivity strength, controlling for age and alcohol use. There was a significant group effect on LECN and DMN connectivity strength with smokers (n = 452) having lower network strengths than non‐smokers (n = 198). Smokers had lower connectivity than non‐smokers associated with key network hubs: the dorsolateral prefrontal cortex, and parietal nodes within ECNs. Further, ECN connectivity strength was negatively associated with pack years of cigarette use. Our data suggest that chronic nicotine use negatively impacts functional connectivity within control networks that may contribute to the difficulty smokers have in quitting. Hum Brain Mapp 36:872–882, 2015. © 2014 Wiley Periodicals, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/110754/1/hbm22672.pd

Associations of cannabis use disorder with cognition, brain structure, and brain function in African Americans

Although previous studies have highlighted associations of cannabis use with cognition and brain morphometry, critical questions remain with regard to the association between cannabis use and brain structural and functional connectivity. In a cross-sectional community sample of 205 African Americans (age 18–70) we tested for associations of cannabis use disorder (CUD, n = 57) with multi-domain cognitive measures and structural, diffusion, and resting state brain-imaging phenotypes. Post hoc model evidence was computed with Bayes factors (BF) and posterior probabilities of association (PPA) to account for multiple testing. General cognitive functioning, verbal intelligence, verbal memory, working memory, and motor speed were lower in the CUD group compared with nonusers (p \u3c .011; 1.9 \u3c BF \u3c 3,217). CUD was associated with altered functional connectivity in a network comprising the motor-hand region in the superior parietal gyri and the anterior insula (p \u3c .04). These differences were not explained by alcohol, other drug use, or education. No associations with CUD were observed in cortical thickness, cortical surface area, subcortical or cerebellar volumes (0.12 \u3c BF \u3c 1.5), or graph-theoretical metrics of resting state connectivity (PPA \u3c 0.01). In a large sample collected irrespective of cannabis used to minimize recruitment bias, we confirm the literature on poorer cognitive functioning in CUD, and an absence of volumetric brain differences between CUD and non-CUD. We did not find evidence for or against a disruption of structural connectivity, whereas we did find localized resting state functional dysconnectivity in CUD. There was sufficient proof, however, that organization of functional connectivity as determined via graph metrics does not differ between CUD and non-user group

Acute and chronic effects of betel quid chewing on brain functional connectivity

Background: The active alkaloid in Betel quid is arecoline. Consumption of betel quid is associated with both acute effects and longer-term addictive effects. Despite growing evidence that betel quid use is linked with altered brain function and connectivity, the neurobiology of this psychoactive substance in initial acute chewing, and long-term dependence, is not clear. Methods: In this observational study, functional magnetic resonance imaging in a resting-state was performed in 24 male betel quid-dependent chewers and 28 male controls prior to and promptly after betel quid chewing. Network-based statistics were employed to determine significant differences in functional connectivity between brain networks for both acute effects and in long-term betel users versus controls. A support vector machine was employed for pattern classification analysis. Results: Before chewing betel quid, higher functional connectivity in betel quid-dependent chewers than in controls was found between the temporal, parietal and frontal brain regions (right medial orbitofrontal cortex, right lateral orbital frontal cortex, right angular gyrus, bilateral inferior temporal gyrus, superior parietal gyrus, and right medial superior frontal gyrus). In controls, the effect of betel quid chewing was significantly increased functional connectivity between the subcortical regions (caudate, putamen, pallidum, and thalamus), and the visual cortex (superior occipital gyrus and right middle occipital gyrus). Conclusion: These findings show that individuals who chronically use betel quid have higher functional connectivity than controls of the orbitofrontal cortex, and inferior temporal and angular gyri. Acute effects of betel quid are to increase the functional connectivity of some visual cortical areas (which may relate to the acute symptoms) and the basal ganglia and thalamus

Childhood maltreatment and amygdala connectivity in methamphetamine dependence: a pilot study.

IntroductionChildhood maltreatment, a well-known risk factor for the development of substance abuse disorders, is associated with functional and structural abnormalities in the adult brain, particularly in the limbic system. However, almost no research has examined the relationship between childhood maltreatment and brain function in individuals with drug abuse disorders.MethodsWe conducted a pilot study of the relationship between childhood maltreatment (evaluated with the Childhood Trauma Questionnaire; Bernstein and Fink 1998) and resting-state functional connectivity of the amygdala (bilateral region of interest) with functional magnetic resonance imaging in 15 abstinent, methamphetamine-dependent research participants. Within regions that showed connectivity with the amygdala as a function of maltreatment, we also evaluated whether amygdala connectivity was associated positively with negative affect and negatively with healthy emotional processing.ResultsThe results indicated that childhood maltreatment was positively associated with resting-state connectivity between the amygdala and right hippocampus, right parahippocampal gyrus, right inferior temporal gyrus, right orbitofrontal cortex, cerebellum, and brainstem. Furthermore, connectivity between the amygdala and hippocampus was positively related to measures of depression, trait anxiety, and emotion dysregulation, and negatively related to self-compassion and dispositional mindfulness.ConclusionsThese findings suggest that childhood maltreatment may contribute to increased limbic connectivity and maladaptive emotional processing in methamphetamine-dependent adults, and that healthy emotion regulation strategies may serve as a therapeutic target to ameliorate the associated behavioral phenotype. Childhood maltreatment warrants further investigation as a potentially important etiological factor in the neurobiology and treatment of substance use disorders