Altered intrinsic connectivity distribution in internet gaming disorder and its associations with psychotherapy treatment outcomes.

Alterations in brain connectivity have been implicated in internet gaming disorder (IGD). However, little is known about alterations in whole-brain connectivity and their associations with long-term treatment outcomes. Here, we used a relatively new analytic approach, intrinsic connectivity distribution (ICD) analysis, to examine brain connectivity in 74 IGD participants and 41 matched healthy controls (HCs) and conducted post hoc seed-based resting-state functional connectivity (rsFC) analyses based on the ICD findings. We also examined how these findings related to outcomes involving a craving behavioral intervention (CBI) for IGD. IGD participants showed less whole-brain connectivity in the left angular gyrus and ventromedial prefrontal cortex (vmPFC) compared with HC participants. Seed-based rsFC analyses revealed that the left angular gyrus in the IGD group showed less connectivity with areas involved in the default-mode network and greater connectivity with areas in the salience and executive control networks. CBI was associated with improved connectivity within regions in the default-mode network and regions across the default-mode and salience networks. ICD-identified connectivity differences in the left angular gyrus and vmPFC were related to changes in craving and severity of addiction 6 months after the intervention. The findings suggest that IGD is associated with alterations in brain connectivity that may be sensitive to interventions. Thus, the findings have implications for understanding mechanisms underlying CBI effects and for further treatment development.

Neural Correlates of Personalized Spiritual Experiences.

Across cultures and throughout history, human beings have reported a variety of spiritual experiences and the concomitant perceived sense of union that transcends one's ordinary sense of self. Nevertheless, little is known about the underlying neural mechanisms of spiritual experiences, particularly when examined across different traditions and practices. By adapting an individualized guided-imagery task, we investigated neural correlates of personally meaningful spiritual experiences as compared with stressful and neutral-relaxing experiences. We observed in the spiritual condition, as compared with the neutral-relaxing condition, reduced activity in the left inferior parietal lobule (IPL), a result that suggests the IPL may contribute importantly to perceptual processing and self-other representations during spiritual experiences. Compared with stress cues, responses to spiritual cues showed reduced activity in the medial thalamus and caudate, regions associated with sensory and emotional processing. Overall, the study introduces a novel method for investigating brain correlates of personally meaningful spiritual experiences and suggests neural mechanisms associated with broadly defined and personally experienced spirituality.

Childhood trauma moderates inhibitory control and anterior cingulate cortex activation during stress.

OBJECTIVE: The anterior cingulate cortex (ACC) is critical for both stress and inhibitory control processes and has been implicated in childhood trauma. This prospective study tested the hypothesis that early trauma moderates the association between inhibitory control during late childhood and ACC stress reactivity during adolescence. METHOD: Sixty-four adolescents were stratified into higher- or lower-childhood-trauma groups. Inhibitory control was indicated by fewer errors on a Stroop Color-Word task. Personalized stress cues during functional magnetic resonance imaging assessed neural correlates of stress in adolescents. RESULTS: Using a priori-defined anterior (rCZa) and posterior rostral cingulate zones of the ACC, associated with Stroop Color-Word task performance in prior meta-analyses, Stroop errors correlated inversely with activation in the rCZa during stress-cue exposure (r = -.23, p = .04). Childhood trauma moderated the association between Stroop errors and rCZa stress reactivity (interaction = -1.26, p = .02, 95%CI = -2.33,-0.20), where Stroop errors were inversely associated with brain activation among those with higher childhood trauma (simple slopes = -.83, p = .007, 95%CI = -1.40,-0.25). Low stress-related rCZa activation inversely (R2 = 0.19, b = -0.43, p = .001, 95%CI = -4.11,-1.06) and Stroop errors directly (R2 = 0.09, b = 0.27, p = .048, 95%CI = 0.02, 5.8) associated with baseline subjective anxiety while controlling for childhood trauma. CONCLUSIONS: This is the first study to demonstrate a moderating role of childhood trauma on the relationship between inhibitory control and stress-related ACC activation. Childhood trauma may portend neurodevelopmental changes that impede recruitment of control-associated ACC-functioning during distress, which may relate to dysregulation of stress-induced affective responses. Further work is needed to elucidate relationships between childhood trauma and addictive behaviors precipitated by stress.

Dynamic neural activity during stress signals resilient coping.

Active coping underlies a healthy stress response, but neural processes supporting such resilient coping are not well-known. Using a brief, sustained exposure paradigm contrasting highly stressful, threatening, and violent stimuli versus nonaversive neutral visual stimuli in a functional magnetic resonance imaging (fMRI) study, we show significant subjective, physiologic, and endocrine increases and temporally related dynamically distinct patterns of neural activation in brain circuits underlying the stress response. First, stress-specific sustained increases in the amygdala, striatum, hypothalamus, midbrain, right insula, and right dorsolateral prefrontal cortex (DLPFC) regions supported the stress processing and reactivity circuit. Second, dynamic neural activation during stress versus neutral runs, showing early increases followed by later reduced activation in the ventrolateral prefrontal cortex (VLPFC), dorsal anterior cingulate cortex (dACC), left DLPFC, hippocampus, and left insula, suggested a stress adaptation response network. Finally, dynamic stress-specific mobilization of the ventromedial prefrontal cortex (VmPFC), marked by initial hypoactivity followed by increased VmPFC activation, pointed to the VmPFC as a key locus of the emotional and behavioral control network. Consistent with this finding, greater neural flexibility signals in the VmPFC during stress correlated with active coping ratings whereas lower dynamic activity in the VmPFC also predicted a higher level of maladaptive coping behaviors in real life, including binge alcohol intake, emotional eating, and frequency of arguments and fights. These findings demonstrate acute functional neuroplasticity during stress, with distinct and separable brain networks that underlie critical components of the stress response, and a specific role for VmPFC neuroflexibility in stress-resilient coping.

Neural Correlates and Connectivity Underlying Stress-Related Impulse Control Difficulties in Alcoholism.

BACKGROUND: Stress triggers impulsive and addictive behaviors, and alcoholism has been frequently associated with increased stress sensitivity and impulse control problems. However, neural correlates underlying the link between alcoholism and impulsivity in the context of stress in patients with alcohol use disorders (AUD) have not been well studied. METHODS: This study investigated neural correlates and connectivity patterns associated with impulse control difficulties in abstinent AUD patients. Using functional magnetic resonance imaging, brain responses of 37 AUD inpatients, and 37 demographically matched healthy controls were examined during brief individualized imagery trials of stress, alcohol cue, and neutral-relaxing conditions. Stress-related impulsivity was measured using a subscale score of impulse control problems from Difficulties in Emotion Regulation Scale. RESULTS: Impulse control difficulties in AUD patients were significantly associated with hypo-active response to stress in the ventromedial prefrontal cortex (VmPFC), right caudate, and left lateral PFC (LPFC) compared to the neutral condition (p < 0.01, whole-brain corrected). These regions were used as seed regions to further examine the connectivity patterns with other brain regions. With the VmPFC seed, AUD patients showed reduced connectivity with the anterior cingulate cortex compared to controls, which are core regions of emotion regulation, suggesting AUD patients' decreased ability to modulate emotional response under distressed state. With the right caudate seed, patients showed increased connectivity with the right motor cortex, suggesting increased tendency toward habitually driven behaviors. With the left LPFC seed, decreased connectivity with the dorsomedial PFC (DmPFC), but increased connectivity with sensory and motor cortices were found in AUD patients compared to controls (p < 0.05, whole-brain corrected). Reduced connectivity between the left LPFC and DmPFC was further associated with increased stress-induced anxiety in AUD patients (p < 0.05, with adjusted Bonferroni correction). CONCLUSIONS: Hypo-active response to stress and altered connectivity in key emotion regulatory regions may account for greater stress-related impulse control problems in alcoholism.

Functional Connectivity During Exposure to Favorite-Food, Stress, and Neutral-Relaxing Imagery Differs Between Smokers and Nonsmokers.

INTRODUCTION: Tobacco-use disorder is a complex condition involving multiple brain networks and presenting with multiple behavioral correlates including changes in diet and stress. In a previous functional magnetic resonance imaging (fMRI) study of neural responses to favorite-food, stress, and neutral-relaxing imagery, smokers versus nonsmokers demonstrated blunted corticostriatal-limbic responses to favorite-food cues. Based on other recent reports of alterations in functional brain networks in smokers, the current study examined functional connectivity during exposure to favorite-food, stress, and neutral-relaxing imagery in smokers and nonsmokers, using the same dataset. METHODS: The intrinsic connectivity distribution was measured to identify brain regions that differed in degree of functional connectivity between groups during each imagery condition. Resulting clusters were evaluated for seed-to-voxel connectivity to identify the specific connections that differed between groups during each imagery condition. RESULTS: During exposure to favorite-food imagery, smokers versus nonsmokers showed lower connectivity in the supramarginal gyrus, and differences in connectivity between the supramarginal gyrus and the corticostriatal-limbic system. During exposure to neutral-relaxing imagery, smokers versus nonsmokers showed greater connectivity in the precuneus, and greater connectivity between the precuneus and the posterior insula and rolandic operculum. During exposure to stress imagery, smokers versus nonsmokers showed lower connectivity in the cerebellum. CONCLUSIONS: These findings provide data-driven insights into smoking-related alterations in brain functional connectivity patterns related to appetitive, relaxing, and stressful states. IMPLICATIONS: This study uses a data-driven approach to demonstrate that smokers and nonsmokers show differential patterns of functional connectivity during guided imagery related to personalized favorite-food, stress, and neutral-relaxing cues, in brain regions implicated in attention, reward-related, emotional, and motivational processes. For smokers, these differences in connectivity may impact appetite, stress, and relaxation, and may interfere with smoking cessation.

Intrinsic connectivity demonstrates a shared role of the posterior cingulate for cue reactivity in both gambling and cocaine use disorders.

Cue reactivity is relevant across addictive disorders as a process relevant to maintenance, relapse, and craving. Understanding the neurobiological foundations of cue reactivity across substance and behavioral addictions has important implications for intervention development. The present study used intrinsic connectivity distribution methods to examine functional connectivity during a cue-exposure fMRI task involving gambling, cocaine and sad videos in 22 subjects with gambling disorder, 24 with cocaine use disorder, and 40 healthy comparison subjects. Intrinsic connectivity distribution implicated the posterior cingulate cortex (PCC) at a stringent whole-brain threshold. Post-hoc analyses investigating the nature of the findings indicated that individuals with gambling disorder and cocaine use disorder exhibited decreased connectivity in the posterior cingulate during gambling and cocaine cues, respectively, as compared to other cues and compared to other groups. Brain-related cue reactivity in substance and behavioral addictions involve PCC connectivity in a content-to-disorder specific fashion. The findings suggesting that PCC-related circuitry underlies cue reactivity across substance and behavioral addictions suggests a potential biomarker for targeting in intervention development.

Neural correlates of stress and favorite-food cue exposure in adolescents: a functional magnetic resonance imaging study.

Adolescence is a critical period of neurodevelopment for stress and appetitive processing, as well as a time of increased vulnerability to stress and engagement in risky behaviors. This study was conducted to examine brain activation patterns during stress and favorite-food-cue experiences relative to a neutral-relaxing condition in adolescents. Functional magnetic resonance imaging was employed using individualized script-driven guided imagery to compare brain responses with such experiences in 43 adolescents. Main effects of condition and gender were found, without a significant gender-by-condition interaction. Stress imagery, relative to neutral, was associated with activation in the caudate, thalamus, left hippocampus/parahippocampal gyrus, midbrain, left superior/middle temporal gyrus, and right posterior cerebellum. Appetitive imagery of favorite food was associated with caudate, thalamus, and midbrain activation compared with the neutral-relaxing condition. To understand neural correlates of anxiety and craving, subjective (self-reported) measures of stress-induced anxiety and favorite-food-cue-induced craving were correlated with brain activity during stress and appetitive food-cue conditions, respectively. High self-reported stress-induced anxiety was associated with hypoactivity in the striatum, thalamus, hippocampus, and midbrain. Self-reported favorite-food-cue-induced craving was associated with blunted activity in cortical-striatal regions, including the right dorsal and ventral striatum, medial prefrontal cortex, motor cortex, and left anterior cingulate cortex. These findings in adolescents indicate the activation of predominantly subcortical-striatal regions in the processing of stressful and appetitive experiences and link hypoactive striatal circuits to self-reported stress-induced anxiety and cue-induced favorite-food craving.

A preliminary investigation of Stroop-related intrinsic connectivity in cocaine dependence: associations with treatment outcomes.

BACKGROUND: Cocaine-dependent individuals demonstrate neural and behavioral differences compared to healthy comparison subjects when performing the Stroop color-word interference test. Stroop measures also relate to treatment outcome for cocaine dependence. Intrinsic connectivity analyses assess the extent to which task-related regional brain activations are related to each other in the absence of defining a priori regions of interest. OBJECTIVE: This study examined 1) the extent to which cocaine-dependent and non-addicted individuals differed on measures of intrinsic connectivity during fMRI Stroop performance; and 2) the relationships between fMRI Stroop intrinsic connectivity and treatment outcome in cocaine dependence. METHODS: Sixteen treatment-seeking cocaine-dependent patients and matched non-addicted comparison subjects completed an fMRI Stroop task. Between-group differences in intrinsic connectivity were assessed and related to self-reported and urine-toxicology-based cocaine-abstinence measures. RESULTS: Cocaine-dependent patients vs. comparison subjects showed less intrinsic connectivity in cortical and subcortical regions. When adjusting for individual degree of intrinsic connectivity, cocaine-dependent vs. comparison subjects showed relatively greater intrinsic connectivity in the ventral striatum, putamen, inferior frontal gyrus, anterior insula, thalamus and substantia nigra. Non-mean-adjusted intrinsic-connectivity measures in the midbrain, thalamus, ventral striatum, substantia nigra, insula and hippocampus negatively correlated with measures of cocaine abstinence. CONCLUSION: The diminished intrinsic connectivity in cocaine-dependent vs. comparison subjects suggests poorer communication across brain regions during cognitive-control processes. In mean-adjusted analyses, the cocaine-dependent group displayed relatively greater Stroop-related connectivity in regions implicated in motivational processes in addictions. The relationships between treatment outcomes and connectivity in the midbrain and basal ganglia suggest that connectivity represents a potential treatment target.

Sex differences in neural responses to stress and drug cues predicts future drug use in individuals with substance use disorder.

BACKGROUND: Substance use disorders (SUDs) are chronically recurring illnesses, where stress and drug cues significantly increase drug craving and risk of drug use recurrence. This study examined sex differences in functional magnetic resonance imaging (fMRI) brain responses to stress and drug cue exposure and assessed their prospective association with future drug use post-treatment. METHODS: Inpatient, treatment engaged men (N = 46) and women (N = 26) with SUDs, including alcohol, cocaine and/or cannabis use disorders, participated in an fMRI scan that assessed subjective (anxiety, drug craving), heart rate and neural responses to brief individualized script-driven imagery of stress, drug, and neutral-relaxing trials. Prospective follow-up interviews post-treatment assessed future drug use recurrence over 90 days. RESULTS: During fMRI, stress and drug versus neutral cue exposure led to increased anxiety, heart rate and craving responses (p's < 0.004) in both men and women, but greater drug cue-induced anxiety (p < .017) and higher drug use days during follow-up (p < .006) in women relative to men. In whole brain analyses of stress and drug cues (p < .05 FWE corrected), and in whole brain correlation (p < .05, FWE corrected) with drug use days, significant sex differences revealed drug cue-related striatal hyperactivation (caudate, putamen) in men, but drug cue-related cortico-limbic (insula and dorsolateral prefrontal cortex) hypoactivation and stress-related hypoactivation in the ventromedial prefrontal cortex (VmPFC) in women; and these were significantly associated with higher future drug use days. CONCLUSIONS: Findings indicate sex-specific pathophysiology of SUD recurrence and support the need for differential treatment development for men and women with SUD to improve drug use outcomes.

Diagnostic group differences and exploratory sex differences in intrinsic connectivity during fMRI Stroop in individuals with and without cocaine use disorder.

BACKGROUND: Sex-/gender-related differences in cognitive control and how they relate to addictions may inform novel treatment options. Cognitive control, including Stroop performance, has been linked to addictions and treatment outcomes. The extent to which women and men with cocaine use disorder (CUD) show brain and behavioral differences relating to Stroop performance has not been previously studied. We examined sex-related differences in Stroop-related brain connectivity in female and male CUD and healthy-comparison (HC) subjects. METHODS: 40 individuals with CUD (20 female) and 40 HC (20 female) subjects matched on age, race, and ethnicity completed an fMRI Stroop task. Intrinsic connectivity distribution (ICD) and mean-adjusted ICD analyses were conducted to identify differences related to sex and diagnostic group. Stroop task performance was also considered. RESULTS: Behavioral results confirmed a Stroop effect. A main effect of diagnostic group indicated that the CUD versus HC group showed lower connectivity in the prefrontal cortex, frontal gyrus, cingulate gyrus, precuneus, cerebellum, and somatosensory, visual, and auditory areas. An exploratory main effect of sex suggested that males may show relatively lower connectivity than females in the cerebellum and brainstem, although connectivity was largely similar across sexes. CONCLUSIONS: Intrinsic connectivity during cognitive control varied by diagnostic group and possibly by sex. The findings suggest that interventions targeting cognitive control in CUD should consider sex.

Connectome-based prediction of craving in gambling disorder and cocaine use disorder.

INTRODUCTION: Craving, involving intense and urgent desires to engage in specific behaviours, is a feature of addictions. Multiple studies implicate regions of salience/limbic networks and basal ganglia, fronto-parietal, medial frontal regions in craving in addictions. However, prior studies have not identified common neural networks that reliably predict craving across substance and behavioural addictions. METHODS: Functional magnetic resonance imaging during an audiovisual cue-reactivity task and connectome-based predictive modelling (CPM), a data-driven method for generating brain-behavioural models, were used to study individuals with cocaine-use disorder and gambling disorder. Functions of nodes and networks relevant to craving were identified and interpreted based on meta-analytic data. RESULTS: Craving was predicted by neural connectivity across disorders. The highest degree nodes were mostly located in the prefrontal cortex. Overall, the prediction model included complex networks including motor/sensory, fronto-parietal, and default-mode networks. The decoding revealed high functional associations with components of memory, valence ratings, physiological responses, and finger movement/motor imagery. CONCLUSIONS: Craving could be predicted across substance and behavioural addictions. The model may reflect general neural mechanisms of craving despite specificities of individual disorders. Prefrontal regions associated with working memory and autobiographical memory seem important in predicting craving. For further validation, the model should be tested in diverse samples and contexts.

Brain Registration and Evaluation for Zebrafish (BREEZE)-mapping: A pipeline for whole-brain structural and activity analyses.

Here, we present Brain Registration and Evaluation for Zebrafish (BREEZE)-mapping, a user-friendly pipeline for the registration and analysis of whole-brain images in larval zebrafish. We describe steps for pre-processing, registration, quantification, and visualization of whole-brain phenotypes in zebrafish mutants of genes associated with neurodevelopmental and neuropsychiatric disorders. By utilizing BioImage Suite Web, an open-source software package originally developed for processing human brain imaging data, we provide a highly accessible whole-brain mapping protocol developed for users with general computational proficiency. For complete details on the use and execution of this protocol, please refer to Weinschutz Mendes et al. (2023).1.

High-throughput functional analysis of autism genes in zebrafish identifies convergence in dopaminergic and neuroimmune pathways.

Advancing from gene discovery in autism spectrum disorders (ASDs) to the identification of biologically relevant mechanisms remains a central challenge. Here, we perform parallel in vivo functional analysis of 10 ASD genes at the behavioral, structural, and circuit levels in zebrafish mutants, revealing both unique and overlapping effects of gene loss of function. Whole-brain mapping identifies the forebrain and cerebellum as the most significant contributors to brain size differences, while regions involved in sensory-motor control, particularly dopaminergic regions, are associated with altered baseline brain activity. Finally, we show a global increase in microglia resulting from ASD gene loss of function in select mutants, implicating neuroimmune dysfunction as a key pathway relevant to ASD biology.

A preliminary study of the neural correlates of the intensities of self-reported gambling urges and emotions in men with pathological gambling.

Although self-reported gambling urge intensities have clinical utility in the treatment of pathological gambling (PG), prior studies have not investigated their neural correlates. Functional magnetic resonance imaging (fMRI) was conducted while 10 men with PG and 11 control comparison (CON) men viewed videotaped scenarios of gambling, happy or sad content. Participants rated the intensity of their emotions and motivations and reported the qualities of their responses. Relative to the CON group, the PG group reported similar responses to sad and happy scenarios, but stronger emotional responses and gambling urges when viewing the gambling scenarios. Correlations between self-reported responses and brain activations were typically strongest during the period of reported onset of emotional/motivational response and more robust in PG than in CON subjects for all conditions. During this epoch, corresponding with conscious awareness of an emotional/motivational response, subjective ratings of gambling urges in the PG group were negatively correlated with medial prefrontal cortex activation and positively correlated with middle temporal gyrus and temporal pole activations. Sadness ratings in the PG group correlated positively with activation of the medial orbitofrontal cortex, middle temporal gyrus, and retrosplenial cortex, while self-reported happiness during the happy videos demonstrated largely inverse correlations with activations in the temporal poles. Brain areas identified in the PG subjects have been implicated in explicit, self-referential processing and episodic memory. The findings demonstrate different patterns of correlations between subjective measures of emotions and motivations in PG and CON subjects when viewing material of corresponding content, suggesting in PG alterations in the neural correlates underlying experiential aspects of affective processing.

Graph theory analysis of whole brain functional connectivity to assess disturbances associated with suicide attempts in bipolar disorder.

Brain targets to lower the high risk of suicide in Bipolar Disorder (BD) are needed. Neuroimaging studies employing analyses dependent on regional assumptions could miss hubs of dysfunction critical to the pathophysiology of suicide behaviors and their prevention. This study applied intrinsic connectivity distribution (ICD), a whole brain graph-theoretical approach, to identify hubs of functional connectivity (FC) disturbances associated with suicide attempts in BD. ICD, from functional magnetic resonance imaging data acquired while performing a task involving implicit emotion regulation processes important in BD and suicide behaviors, was compared across 40 adults with BD with prior suicide attempts (SAs), 49 with BD with no prior attempts (NSAs) and 51 healthy volunteers (HVs). Areas of significant group differences were used as seeds to identify regional FC differences and explore associations with suicide risk-related measures. ICD was significantly lower in SAs than in NSAs and HVs in bilateral ventromedial prefrontal cortex (vmPFC) and right anterior insula (RaIns). Seed connectivity revealed altered FC from vmPFC to bilateral anteromedial orbitofrontal cortex, left ventrolateral PFC (vlPFC) and cerebellum, and from RaIns to right vlPFC and temporopolar cortices. VmPFC and RaIns ICD were negatively associated with suicidal ideation severity, and vmPFC ICD with hopelessness and attempt lethality severity. The findings suggest that SAs with BD have vmPFC and RaIns hubs of dysfunction associated with altered FC to other ventral frontal, temporopolar and cerebellar cortices, and with suicidal ideation, hopelessness, and attempt lethality. These hubs may be targets for novel therapeutics to reduce suicide risk in BD.

Sex differences in neural responses to stress and alcohol context cues.

Stress and alcohol context cues are each associated with alcohol-related behaviors, yet neural responses underlying these processes remain unclear. This study investigated the neural correlates of stress and alcohol context cue experiences and examined sex differences in these responses. Using functional magnetic resonance imaging, brain responses were examined while 43 right-handed, socially drinking, healthy individuals (23 females) engaged in brief guided imagery of personalized stress, alcohol-cue, and neutral-relaxing scenarios. Stress and alcohol-cue exposure increased activity in the cortico-limbic-striatal circuit (P < 0.01, corrected), encompassing the medial prefrontal cortex (mPFC), orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), left anterior insula, striatum, and visuomotor regions (parietal and occipital lobe, and cerebellum). Activity in the left dorsal striatum increased during stress, while bilateral ventral striatum activity was evident during alcohol-cue exposure. Men displayed greater stress-related activations in the mPFC, rostral ACC, posterior insula, amygdala, and hippocampus than women, whereas women showed greater alcohol-cue-related activity in the superior and middle frontal gyrus (SFG/MFG) than men. Stress-induced anxiety was positively associated with activity in emotion-modulation regions, including the medial OFC, ventromedial PFC, left superior-mPFC, and rostral ACC in men, but in women with activation in the SFG/MFG, regions involved in cognitive processing. Alcohol craving was significantly associated with the striatum (encompassing dorsal, and ventral) in men, supporting its involvement in alcohol "urge" in healthy men. These results indicate sex differences in neural processing of stress and alcohol-cue experiences and have implications for sex-specific vulnerabilities to stress- and alcohol-related psychiatric disorders.

GABAergic polygenic risk for cocaine use disorder is negatively correlated with precuneus activity during cognitive control in African American individuals.

Impaired cognitive control has been implicated in cocaine use disorder (CUD). GABAergic treatments have been proposed for CUD. Here we examined relationships between GABAergic genes and neural correlates of cognitive control in CUD. We analyzed two independent African American cohorts: one of >3000 genomewide-genotyped subjects with substance dependence and another of 40 CUD and 22 healthy control (HC) subjects who were exome-array genotyped and completed an fMRI Stroop task. We used five association thresholds to select variants of GABAergic genes in the reference cohort, yielding five polygenic risk scores (i.e., CUD-GABA-PRSs) for the fMRI cohort. At p < 0.005, the CUD-GABA-PRSs, which aggregated relative risks of CUD from 89 variants harboring in 16 genes, differed between CUD and HC individuals in the fMRI sample (p = 0.013). This CUD-GABA-PRS correlated inversely with Stroop-related activity in the left precuneus in CUD (r = -80.58, pFWE < 0.05) but not HC participants. Post-hoc seed-based connectivity analysis of the left precuneus identified reduced functional connectivity to the posterior cingulate cortex (PCC) in CUD compared to HC subjects (p = 0.0062) and the degree of connectivity correlated with CUD-GABA-PRSs in CUD individuals (r = 0.287, p = 0.036). Our findings suggest that the GABAergic genetic risk of CUD in African Americans relates to precuneus/PCC functional connectivity during cognitive control. Identification of these GABAergic processes may be relevant targets in CUD treatment. The novel identification of 16 GABAergic genes may be investigated further to inform treatment development efforts for this condition that currently has no medication with a formal indication for its treatment.

Ketamine Normalizes the Structural Alterations of Inferior Frontal Gyrus in Depression.

BACKGROUND: Ketamine is a novel fast-acting antidepressant. Acute ketamine treatment can reverse microstructure deficits and normalize functional alterations in the brain, but little is known about the impacts of ketamine on brain volumes in individuals with depression. METHODS: We used 3 T magnetic resonance imaging (MRI) and tensorbased morphological methods to investigate the regional volume differences for 29 healthy control (HC) subjects and 21 subjects with major depressive disorder (MDD), including 10 subjects with comorbid post-traumatic stress disorder (PTSD). All the subjects participated in MRI scanning before and 24 h post intravenous ketamine infusion. The effects of acute ketamine administration on HC, MDD, and MDD/PTSD groups were examined separately by whole-brain voxel-wise t-tests. RESULTS: Our data showed smaller volume of inferior frontal gyrus (IFG, opercular part) in MDD and MDD/PTSD subjects compared to HC, and a significant correlation between opercular IFG volume and depressive severity in MDD subjects only. Ketamine administration normalized the structural alterations of opercular IFG in both MDD and MDD/PTSD groups, and significantly improved depressive and PTSD symptoms. Twenty-four hours after a single ketamine infusion, there were two clusters of voxels with volume changes in MDD subjects, including significantly increased volumes of opercular IFG. No significant structural alterations were found in the MDD/PTSD or HC groups. CONCLUSION: These findings provide direct evidence that acute ketamine administration can normalize structural alterations associated with depression and highlight the importance of IFG in the guidance of future therapeutic targets.

Preliminary evidence for progressive prefrontal abnormalities in adolescents and young adults with bipolar disorder.

Previous cross-sectional study of ventral prefrontal cortex (VPFC) implicated progressive volume abnormalities during adolescence in bipolar disorder (BD). In the present study, a within-subject, longitudinal design was implemented to examine brain volume changes during adolescence/young adulthood. We hypothesized that VPFC volume decreases over time would be greater in adolescents/young adults with BD than in healthy comparison adolescents/young adults. Eighteen adolescents/young adults (10 with BD I and 8 healthy comparison participants) underwent two high-resolution magnetic resonance imaging scans over approximately 2 years. Regional volume changes over time were measured. Adolescents/young adults with BD displayed significantly greater volume loss over time, compared to healthy comparison participants, in a region encompassing VPFC and rostral PFC and extending to rostral anterior cingulate cortex (p < .05). Additional areas where volume change differed between groups were observed. While data should be interpreted cautiously due to modest sample size, this study provides preliminary evidence to support the presence of accelerated loss in VPFC and rostral PFC volume in adolescents/young adults with BD.