A review of the kappa opioid receptor system in opioid use.

The kappa opioid receptor (KOR) system is implicated in dysphoria and as an "anti-reward system" during withdrawal from opioids. However, no clear consensus has been made in the field, as mixed findings have been reported regarding the relationship between the KOR system and opioid use. This review summarizes the studies to date on the KOR system and opioids. A systematic scoping review was reported following PRISMA guidelines and conducted based on the published protocol. Comprehensive searches of several databases were done in the following databases: MEDLINE, Embase, PsycINFO, Web of Science, Scopus, and Cochrane. We included preclinical and clinical studies that tested the administration of KOR agonists/antagonists or dynorphin and/or measured dynorphin levels or KOR expression during opioid intoxication or withdrawal from opioids. One hundred studies were included in the final analysis. Preclinical administration of KOR agonists decreased drug-seeking/taking behaviors and opioid withdrawal symptoms. KOR antagonists showed mixed findings, depending on the agent and/or type of withdrawal symptom. Administration of dynorphins attenuated opioid withdrawal symptoms both in preclinical and clinical studies. In the limited number of available studies, dynorphin levels were found to increase in cerebrospinal fluid (CSF) and peripheral blood lymphocytes (PBL) of opioid use disorder subjects (OUD). In animals, dynorphin levels and/or KOR expression showed mixed findings during opioid use. The KOR/dynorphin system appears to have a multifaceted and complex nature rather than simply functioning as an anti-reward system. Future research in well-controlled study settings is necessary to better understand the clinical role of the KOR system in opioid use.

Cocaine self-administration behavior is associated with subcortical and cortical morphometry measures in individuals with cocaine use disorder.

Background: Individual differences in gray-matter morphometry in the limbic system and frontal cortex have been linked to clinical features of cocaine use disorder (CUD). Self-administration paradigms can provide more direct measurements of the relationship between the regulation of cocaine use and gray-matter morphometry when compared to self-report assessments.Objectives: Our goal was to investigate associations with self-administration behavior in subcortical and cortical brain regions. We hypothesized the number of cocaine infusions self-administered would be correlated with gray-matter volumes (GMVs) in the striatum, amygdala, and hippocampus. Due to scarcity in human studies, we did not hypothesize subcortical directionality. In the frontal cortex, we hypothesized thickness would be negatively correlated with self-administered cocaine.Methods: We conducted an analysis of cocaine self-administration and structural MRI data from 33 (nFemales = 10) individuals with moderate-to-severe CUD. Self-administration lasted 60-minutes and cocaine (8, 16, or 32 mg/70 kg) was delivered on an FR1 schedule (5-minute lockout). Subcortical and cortical regression analyses were performed that included combined bilateral regions and age, experimental variables and use history as confounders.Results: Self-administered cocaine infusions were positively associated with caudal GMV (b = 0.18, p = 0.030) and negatively with putamenal GMV (b = -0.10, p = 0.041). In the cortical model, infusions were positively associated with insular thickness (b = 0.39, p = 0.008) and women appeared to self-administer cocaine more frequently (b = 0.23, p = 0.019).Conclusions: Brain morphometry features in the striatum and insula may contribute to cocaine consumption in CUD. These differences in morphometry may reflect consequences of prolonged use, predisposed vulnerability, or other possibilities.Clinical Trial Numbers: NCT01978431; NCT03471182.

Youth fatal drug overdose and suicide: Trends in Connecticut, 2019-2021.

BACKGROUND AND OBJECTIVES: Increasing rates of fatal drug overdose (FDO) among youth since 2016 have been driven by fentanyl and polysubstance use. Suicide by youth also increased steadily since 2007. The manner of FDO may be accidental (i.e., unintentional) or suicidal (i.e., intentional). This report examines the rate of youth intentional and unintentional FDO as well as specific drug toxicology in Connecticut, between the years 2019 and 2021, compared to a 2016-2018 report. METHODS: We reviewed N = 286 consecutive FDO files of youth, <26 years of age dated for 2019-2021 from the Connecticut Medical Examiner's office. RESULTS: FDO attributed to fentanyl increased significantly from 2016 to 2018 to 2019 to 2021. Xylazine FDO emerged in 2019 and reached 16% in 2021. Intentional FDO rates doubled between these periods from 3.8% to 7.7%. Most FDOs involved individuals aged 20-25 years, whereas 10% were among those aged 15-19. For the first time since 2018, FDO among 10-14 years old was detected. Analysis of gender found no differences. Within each gender, however, FDO attributed to fentanyl increased significantly between these periods. The FDO rate for Hispanics increased significantly, while the rate for Whites decreased significantly. DISCUSSION AND CONCLUSIONS: The availability of high lethality potential drugs leading to youth FDO including an increasing rate of intentional FDO, is a public health concern. It is prudent to identify modifiable acute high-risk circumstances for intentional FDO and prevention-intervention evidence-based approach to reduce FDO. SCIENTIFIC SIGNIFICANCE: This is the first study of FDO among youth examining the manner of death by suicide.

Resting-State Functional Connectivity of the Dorsal and Ventral Striatum, Impulsivity, and Severity of Use in Recently Abstinent Cocaine-Dependent Individuals.

BACKGROUND: Previous studies have focused on both ventral striatum (VS) and dorsal striatum (DS) in characterizing dopaminergic deficits in addiction. Animal studies suggest VS and DS dysfunction each in association with impulsive and compulsive cocaine use during early and later stages of addiction. However, few human studies have aimed to distinguish the roles of VS and DS dysfunction in cocaine misuse. METHODS: We examined VS and DS resting-state functional connectivity (rsFC) of 122 recently abstinent cocaine-dependent individuals (CDs) and 122 healthy controls (HCs) in 2 separate cohorts. We followed published routines in imaging data analyses and evaluated the results at a corrected threshold with age, sex, years of drinking, and smoking accounted for. RESULTS: CDs relative to HCs showed higher VS rsFC with the left inferior frontal cortex (IFC), lower VS rsFC with the hippocampus, and higher DS rsFC with the left orbitofrontal cortex. Region-of-interest analyses confirmed the findings in the 2 cohorts examined separately. In CDs, VS-left IFC and VS-hippocampus connectivity was positively and negatively correlated with average monthly cocaine use in the prior year, respectively. In the second cohort where participants were assessed with the Barratt Impulsivity Scale (BIS-11), VS-left IFC and VS-hippocampus connectivity was also positively and negatively correlated with BIS-11 scores in CDs. In contrast, DS-orbitofrontal cortex connectivity did not relate significantly to cocaine use metrics or BIS-11 scores. CONCLUSION: These findings associate VS rsFC with impulsivity and the severity of recent cocaine use. How DS connectivity partakes in cocaine misuse remains to be investigated.

Changes in synaptic markers after administration of ketamine or psychedelics: a systematic scoping review.

Background: Ketamine and psychedelics have abuse liability. They can also induce "transformative experiences" where individuals experience enhanced states of awareness. This enhanced awareness can lead to changes in preexisting behavioral patterns which could be beneficial in the treatment of substance use disorders (SUDs). Preclinical and clinical studies suggest that ketamine and psychedelics may alter markers associated with synaptic density, and that these changes may underlie effects such as sensitization, conditioned place preference, drug self-administration, and verbal memory performance. In this scoping review, we examined studies that measured synaptic markers in animals and humans after exposure to ketamine and/or psychedelics. Methods: A systematic search was conducted following PRISMA guidelines, through PubMed, EBSCO, Scopus, and Web of Science, based on a published protocol (Open Science Framework, DOI: 10.17605/OSF.IO/43FQ9). Both in vivo and in vitro studies were included. Studies on the following synaptic markers were included: dendritic structural changes, PSD-95, synapsin-1, synaptophysin-1, synaptotagmin-1, and SV2A. Results: Eighty-four studies were included in the final analyses. Seventy-one studies examined synaptic markers following ketamine treatment, nine examined psychedelics, and four examined both. Psychedelics included psilocybin/psilocin, lysergic acid diethylamide, N,N-dimethyltryptamine, 2,5-dimethoxy-4-iodoamphetamine, and ibogaine/noribogaine. Mixed findings regarding synaptic changes in the hippocampus and prefrontal cortex (PFC) have been reported when ketamine was administered in a single dose under basal conditions. Similar mixed findings were seen under basal conditions in studies that used repeated administration of ketamine. However, studies that examined animals during stressful conditions found that a single dose of ketamine counteracted stress-related reductions in synaptic markers in the hippocampus and PFC. Repeated administration of ketamine also counteracted stress effects in the hippocampus. Psychedelics generally increased synaptic markers, but results were more consistently positive for certain agents. Conclusion: Ketamine and psychedelics can increase synaptic markers under certain conditions. Heterogeneous findings may relate to methodological differences, agents administered (or different formulations of the same agent), sex, and type of markers. Future studies could address seemingly mixed results by using meta-analytical approaches or study designs that more fully consider individual differences.

Age-related reduction in trait anxiety: Behavioral and neural evidence of automaticity in negative facial emotion processing.

Trait anxiety diminishes with age, which may result from age-related decline in registering salient emotional stimuli and/or enhancement in emotion regulation. We tested the hypotheses in 88 adults 21 to 85 years of age and studied with fMRI of the Hariri task. Age-related decline in stimulus registration would manifest in delayed reaction time (RT) and diminished saliency circuit activity in response to emotional vs. neutral stimuli. Enhanced control of negative emotions would manifest in diminished limbic/emotional circuit and higher prefrontal cortical (PFC) responses to negative emotion. The results showed that anxiety was negatively correlated with age. Age was associated with faster RT and diminished activation of the medial PFC, in the area of the dorsal and rostral anterior cingulate cortex (dACC/rACC) - a hub of the saliency circuit - during matching of negative but not positive vs. neutral emotional faces. A slope test confirmed the differences in the regressions. Further, age was not associated with activation of the PFC in whole-brain regression or in region-of-interest analysis of the dorsolateral PFC, an area identified from meta-analyses of the emotion regulation literature. Together, the findings fail to support either hypothesis; rather, the findings suggest age-related automaticity in processing negative emotions as a potential mechanism of diminished anxiety. Automaticity results in faster RT and diminished anterior cingulate activity in response to negative but not positive emotional stimuli. In support, analyses of psychophysiological interaction demonstrated higher dACC/rACC connectivity with the default mode network, which has been implicated in automaticity in information processing. As age increased, individuals demonstrated faster RT with higher connectivity during matching of negative vs. neutral images. Automaticity in negative emotion processing needs to be investigated as a mechanism of age-related reduction in anxiety.

The effects of age on the severity of problem drinking: Mediating effects of positive alcohol expectancy and neural correlates.

Aging is associated with reduction in the severity of alcohol misuse. However, the psychological and neural mechanisms underlying the age-related changes remain unclear. Here, we tested the hypothesis that age-related diminution of positive alcohol expectancy (AE) mediated the effects of age on problem drinking and investigated the neural correlates of the mediating effects. Ninety-six drinkers 21-85 years of age, including social drinkers and those with mild/moderate alcohol use disorder (AUD), were assessed for global positive (GP) AE and problem drinking, each with the Alcohol Expectancy Questionnaire and Alcohol Use Disorders Identification Test (AUDIT), and with brain imaging during alcohol cue exposure. We processed imaging data with published routines; identified the correlates shared between whole-brain regression against age, GP and AUDIT scores; and performed mediation and path analyses to explore the interrelationships between the clinical and neural variables. The results showed that age was negatively correlated with both GP and AUDIT scores, with GP score completely mediating the correlation between age and AUDIT score. Lower age and higher GP correlated with shared cue responses in bilateral parahippocampal gyrus and left middle occipital cortex (PHG/OC). Further, higher GP and AUDIT scores were associated with shared cue responses in bilateral rostral anterior cingulate cortex and caudate head (ACC/caudate). Path analyses demonstrated models with significant statistical fit and PHG/OC and ACC/caudate each interrelating age to GP and GP to AUDIT scores. These findings confirmed change in positive AE as a psychological mechanism mitigating alcohol misuse as individuals age and highlighted the neural processes of cue-reactivity interrelating age and alcohol use severity.

Win and Loss Responses in the Monetary Incentive Delay Task Mediate the Link between Depression and Problem Drinking.

Depression and alcohol misuse, frequently comorbid, are associated with altered reward processing. However, no study has examined whether and how the neural markers of reward processing are shared between depression and alcohol misuse. We studied 43 otherwise-healthy drinking adults in a monetary incentive delay task (MIDT) during fMRI. All participants were evaluated with the Alcohol Use Disorders Identification Test (AUDIT) and Beck's Depression Inventory (BDI-II) to assess the severity of drinking and depression. We performed whole brain regressions against each AUDIT and BDI-II score to investigate the neural correlates and evaluated the findings at a corrected threshold. We performed mediation analyses to examine the inter-relationships between win/loss responses, alcohol misuse, and depression. AUDIT and BDI-II scores were positively correlated across subjects. Alcohol misuse and depression shared win-related activations in frontoparietal regions and parahippocampal gyri (PHG), and right superior temporal gyri (STG), as well as loss-related activations in the right PHG and STG, and midline cerebellum. These regional activities (ß's) completely mediated the correlations between BDI-II and AUDIT scores. The findings suggest shared neural correlates interlinking depression and problem drinking both during win and loss processing and provide evidence for co-morbid etiological processes of depressive and alcohol use disorders.

Hypothalamic Functional Connectivity and Apathy in People with Alzheimer's Disease and Cognitively Normal Healthy Controls.

BACKGROUND: Earlier studies have described the neural markers of apathy in Alzheimer's disease (AD) and mild cognitive impairment (MCI), but few focused on the motivation circuits. Here, we targeted hypothalamus, a hub of the motivation circuit. OBJECTIVE: To examine hypothalamic resting state functional connectivity (rsFC) in relation to apathy. METHODS: We performed whole-brain regression of hypothalamic rsFC against Apathy Evaluation Scale (AES) total score and behavioral, cognitive, and emotional subscores in 29 patients with AD/MCI and 28 healthy controls (HC), controlling for age, sex, education, cognitive status, and depression. We evaluated the results at a corrected threshold and employed path analyses to assess possible interaction between hypothalamic rsFCs, apathy and depression/memory. Finally, we re-examined the findings in a subsample of amyloid-ß-verified AD. RESULTS: AES total score correlated negatively with hypothalamic precuneus (PCu)/posterior cingulate cortex (PCC) and positively with left middle temporal gyrus (MTG) and supramarginal gyrus rsFCs. Behavioral subscore correlated negatively with hypothalamic PCu/PCC and positively with middle frontal gyrus rsFC. Cognitive subscore correlated positively with hypothalamic MTG rsFC. Emotional subscore correlated negatively with hypothalamic calcarine cortex rsFC. In path analyses, hypothalamic-PCu/PCC rsFC negatively modulated apathy and, in turn, depression. The model where hypothalamic MTG rsFC and memory independently modulated apathy also showed a good fit. The findings of diminished hypothalamic-PCu/PCC rsFC in relation to apathy and, in turn, depression were confirmed in amyloid-verified AD. CONCLUSION: The findings together support a role of altered hypothalamic connectivity in relation to apathy and depression, and modulation of apathy by memory dysfunction.

Hypothalamic connectivities predict individual differences in ADT-elicited changes in working memory and quality of life in prostate cancer patients.

Androgen deprivation therapy (ADT) has been associated with adverse effects on cognition. However, we currently lack understanding of the neurobiology and prognostic markers of these effects. Given that ADT acts via the hypothalamus-pituitary-gonadal axis, we assessed whether baseline hypothalamic resting state functional connectivity (rsFC) could predict changes in working memory and quality of life in prostate cancer patients following androgen deprivation. In a prospective observational study, 28 men with non-metastatic prostate cancer receiving ADT and 38 patients not receiving ADT (controls), matched in age, years of education and Montreal Cognitive Assessment score, participated in brain imaging at baseline, and N-back task and quality-of-life (QoL) assessments at baseline and at 6 months follow-up. Imaging data were processed with published routines and evaluated at a corrected threshold. ADT and control groups did not differ in N-back performance or QoL across time points. In ADT, the changes in 0-back correct response rate (follow-up-baseline) were correlated with baseline hypothalamus-precentral gyrus rsFC; the changes in 1-back correct response rate and reaction time were each correlated with hypothalamus-middle frontal gyrus and superior parietal lobule rsFC. The changes in physical well-being subscore of QoL were correlated with baseline hypothalamus-anterior cingulate and cuneus rsFC. The hypothalamus rsFCs predicted N-back and QoL change with an area under the receiver operating characteristic curve of 0.93 and 0.73, respectively. Baseline hypothalamus-frontoparietal and salience network rsFC's predict inter-subject variations in the changes in working-memory and QoL following 6 months of ADT. Whether and how hypothalamic rsFCs may predict the cognitive and QoL effects with longer-term ADT remain to be investigated.

Acute effects of ketamine and esketamine on cognition in healthy subjects: A meta-analysis.

BACKGROUND: Impairment in cognition is frequently associated with acute ketamine administration. However, some questions remain unanswered as to which deficits are most prominent and what variables modulate these effects. METHODS: A literature search yielded 56 experimental studies of acute ketamine administration that assessed cognition in 1041 healthy volunteers. A multivariate meta-analysis was performed, and effect sizes were estimated for eleven cognitive domains: attention, executive function, response inhibition, social cognition, speed of processing, verbal / language, verbal learning, verbal memory, visual learning & memory, visuospatial abilities, and working memory. RESULTS: There were small-to-moderate impairments across all cognitive domains. Deficits in verbal learning / memory were most prominent, whereas response inhibition was the least affected. Meta-regression analysis revealed that the negative effects of ketamine on cognition are dependent on infusion dose and plasma level, but unaffected by enantiomer type, route of administration, sex or age. A publication bias was observed. DISCUSSION: Acute ketamine broadly impairs cognition across all domains among healthy individuals. Verbal learning and memory figures most prominently in cognitive impairment elicited by acute ketamine administration.

The effects of androgen deprivation on working memory and quality of life in prostate cancer patients: The roles of hypothalamic connectivity.

BACKGROUND: Androgen deprivation therapy (ADT) has been associated with adverse effects on the brain. ADT alters testosterone levels via its action on the hypothalamus-pituitary-gonadal axis and may influence hypothalamic functions. Given the wide regional connectivity of the hypothalamus and its role in regulating cognition and behavior, we assessed the effects of ADT on hypothalamic resting state functional connectivity (rsFC) and their cognitive and clinical correlates. METHODS: In a prospective observational study, 22 men with nonmetastatic prostate cancer receiving ADT and 28 patients not receiving ADT (controls), matched in age, years of education, and Montreal Cognitive Assessment score, participated in N-back task and quality of life (QoL) assessments and brain imaging at baseline and at 6 months. Imaging data were processed with published routines and the results of a group by time flexible factorial analysis were evaluated at a corrected threshold. RESULTS: ADT and control groups did not differ in N-back performance or QoL across time points. Relative to controls, patients receiving ADT showed significantly higher hypothalamus-right mid-cingulate cortex (MCC) and precentral gyrus (PCG) rsFC during follow-up versus baseline. Further, the changes in MCC and PCG rsFC were correlated positively with the change in QoL score and 0-back correct response rate, respectively, in patients with undergoing ADT. CONCLUSION: Six-month ADT affects hypothalamic functional connectivity with brain regions critical to cognitive motor and affective functions. Elevated hypothalamic MCC and PCG connectivity likely serve to functionally compensate for the effects of ADT and sustain attention and overall QoL. The longer-term effects of ADT remain to be investigated.

Emotion Processing Dysfunction in Alzheimer's Disease: An Overview of Behavioral Findings, Systems Neural Correlates, and Underlying Neural Biology.

We described behavioral studies to highlight emotional processing deficits in Alzheimer's disease (AD). The findings suggest prominent deficit in recognizing negative emotions, pronounced effect of positive emotion on enhancing memory, and a critical role of cognitive deficits in manifesting emotional processing dysfunction in AD. We reviewed imaging studies to highlight morphometric and functional markers of hippocampal circuit dysfunction in emotional processing deficits. Despite amygdala reactivity to emotional stimuli, hippocampal dysfunction conduces to deficits in emotional memory. Finally, the reviewed studies implicating major neurotransmitter systems in anxiety and depression in AD supported altered cholinergic and noradrenergic signaling in AD emotional disorders. Overall, the studies showed altered emotions early in the course of illness and suggest the need of multimodal imaging for further investigations. Particularly, longitudinal studies with multiple behavioral paradigms translatable between preclinical and clinical models would provide data to elucidate the time course and underlying neurobiology of emotion processing dysfunction in AD.

Gray matter volumetric correlates of dimensional impulsivity traits in children: Sex differences and heritability.

Previous research investigated the cerebral volumetric correlates of impulsivity largely in moderate-sized samples and few have examined the distinct correlates of dimensions of impulsivity, sex differences, or heritability of the correlates. Here, we performed voxel-based morphometry analysis of data (n = 11,474; 5,452 girls, 9-10 years) curated from the Adolescent Brain Cognition Development project. In a linear regression with all five UPPS-P subscores as regressors and age in months, total intracranial volume, study site, and scanner model as covariates, higher levels of lack of premeditation, and sensation seeking were correlated with larger cortical and subcortical gray matter volumes (GMVs). In contrast, higher positive urgency was correlated with smaller GMVs in many of the same regions. The dimensional impulsivity traits also involved distinct volumetric correlates, with, for instance, sensation seeking and positive urgency specifically implicating bilateral caudate head/mid-cingulate cortex and bilateral lateral orbitofrontal cortex/left precentral gyrus, respectively. Boys relative to girls scored higher in all impulsivity dimensions. Girls relative to boys showed significantly stronger positive and negative correlations between sensation seeking and insula, putamen, and inferior frontal gyrus (IFG) GMVs and between positive urgency and cingulate cortex, insula, and IFG GMVs, respectively. With a subsample of twins, the dimensional impulsivity traits were weakly to moderately heritable in both girls and boys, and the GMV correlates were highly heritable in girls and boys combined. These findings collectively suggest shared and nonshared as well as sex differences in the cerebral volumetric bases of dimensional impulsivity traits and may facilitate research of externalizing psychopathology in children.

Cerebral Volumetric Correlates of Apathy in Alzheimer's Disease and Cognitively Normal Older Adults: Meta-Analysis, Label-Based Review, and Study of an Independent Cohort.

BACKGROUND: Affecting nearly half of the patients with Alzheimer's disease (AD), apathy is associated with higher morbidity and reduced quality of life. Basal ganglia and cortical atrophy have been implicated in apathy. However, the findings have varied across studies and left unclear whether subdomains of apathy may involve distinct neuroanatomical correlates. OBJECTIVE: To identify neuroanatomical correlates of AD-associated apathy. METHODS: We performed a meta-analysis and label-based review of the literature. Further, following published routines of voxel-based morphometry, we aimed to confirm the findings in an independent cohort of 19 patients with AD/mild cognitive impairment and 25 healthy controls assessed with the Apathy Evaluation Scale. RESULTS: Meta-analysis of 167 AD and 56 healthy controls showed convergence toward smaller basal ganglia gray matter volume (GMV) in apathy. Label-based review showed anterior cingulate, putamen, insula, inferior frontal gyrus (IFG) and middle temporal gyrus (MTG) atrophy in AD apathy. In the independent cohort, with small-volume-correction, right putamen and MTG showed GMVs in negative correlation with Apathy Evaluation Scale total, behavioral, and emotional scores, and right IFG with emotional score (p < 0.05 family-wise error (FWE)-corrected), controlling for age, education, intracranial volume, and depression. With the Mini-Mental State Examination scores included as an additional covariate, the correlation of right putamen GMV with behavioral and emotional score, right MTG GMV with total and emotional score, and right IFG GMV with emotional score were significant. CONCLUSION: The findings implicate putamen, MTG and IFG atrophy in AD associated apathy, potentially independent of cognitive impairment and depression, and suggest potentially distinct volumetric correlates of apathy.

Perceived stress, self-efficacy, and the cerebral morphometric markers in binge-drinking young adults.

Studies have identified cerebral morphometric markers of binge drinking and implicated cortical regions in support of self-efficacy and stress regulation. However, it remains unclear how cortical structures of self-control play a role in ameliorating stress and alcohol consumption or how chronic alcohol exposure alters self-control and leads to emotional distress. We examined the data of 180 binge (131 men) and 256 non-binge (83 men) drinkers from the Human Connectome Project. We obtained data on regional cortical thickness from the HCP and derived gray matter volumes (GMVs) with voxel-based morphometry. At a corrected threshold, binge relative to non-binge drinking men showed diminished posterior cingulate cortex (PCC) thickness and dorsomedial prefrontal cortex (dmPFC) GMV. PCC thickness and dmPFC GMVs were positively and negatively correlated with self-efficacy and perceived stress, respectively, as assessed with the NIH Emotion Toolbox. Mediation and path analyses to query the inter-relationships between the neural markers and clinical variables showed a best fit of the model with daily drinks â†’ lower PCC thickness and dmPFC GMV â†’ lower self-efficacy â†’ higher perceived stress in men. In contrast, binge and non-binge drinking women did not show significant differences in regional cortical thickness or GMVs. These findings suggest a pathway whereby chronic alcohol consumption alters cortical structures and self-efficacy mediates the effects of cortical structural deficits on perceived stress in men. The findings also suggest the need to investigate multimodal neural markers underlying the interplay between stress, self-control and alcohol use behavior in women.

Depression Mediates the Relationship between Childhood Trauma and Internet Addiction in Female but Not Male Chinese Adolescents and Young Adults.

Internet addiction is associated with a range of psychological risk factors such as childhood trauma and depression. Studies have also suggested sex differences in internet and other behavioral addictions. However, it remains unclear how childhood trauma, depression and internet addiction inter-relate differently between the sexes. A total of 1749 adolescents and young adults aged 12-27 participated in a survey of sociodemographic characteristics and standardized assessments to evaluate internet addiction (Internet Addiction Test), childhood trauma (Childhood Trauma Questionnaire) and depression (Beck Depression Inventory). Mediation and path analyses were used to examine the relationship between childhood trauma, depression and internet addiction. Internet-addicted females relative to males showed more severe depression but the control participants showed the opposite. Childhood trauma was associated with depression for both internet-addicted males and females; however, internet-addicted females but not males showed significant associations between depression and the severity of internet addiction as well as between childhood trauma and the severity of internet addiction. Further, in females, depression mediated the correlations between all types of childhood trauma and the severity of internet addiction. A path analysis suggested that sexual abuse and emotional neglect contributed most significantly to internet addiction when all types of childhood trauma were examined in one model. The findings suggest sex differences in the relationship between childhood trauma, depression and internet addiction. Childhood trauma contributes to internet addiction through depression only in females. The findings may guide future prevention and intervention strategies of internet addiction.

Cognitive dysfunction and cerebral volumetric deficits in individuals with Alzheimer's disease, alcohol use disorder, and dual diagnosis.

Epidemiological surveys suggest that excessive drinking is associated with higher risk of Alzheimer's disease (AD). The present study utilized data from the National Alzheimer's Coordinating Center to examine cognition as well as gray/white matter and ventricular volumes among participants with AD and alcohol use disorder (AD/AUD, n = 52), AD only (n = 701), AUD only (n = 67), and controls (n = 1283). AUD diagnosis was associated with higher Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) in AD than in non-AD. AD performed worse on semantic fluency and Trail Making Test A + B (TMT A + B) and showed smaller total GMV, WMV, and larger ventricular volume than non-AD. AD had smaller regional GMV in the inferior/superior parietal cortex, hippocampal formation, occipital cortex, inferior frontal gyrus, posterior cingulate cortex, and isthmus cingulate cortex than non-AD. AUD had significantly smaller somatomotor cortical GMV and showed a trend towards smaller volume in the hippocampal formation, relative to non-AUD participants. Misuse of alcohol has an additive effect on dementia severity among AD participants. Smaller hippocampal volume is a common feature of both AD and AUD. Although AD is associated with more volumetric deficits overall, AD and AUD are associated with atrophy in largely distinct brain regions.

Distinct patterns of prefrontal cortical disengagement during inhibitory control in addiction: A meta-analysis based on population characteristics.

Prefrontal cortical dysfunctions underlying inhibitory control deficits in addiction are complex and likely dependent on population characteristics. Here, we conducted a meta-analysis to examine alterations in brain activations during response inhibition in addicted individuals. We characterized imaging findings based on substance use status, diagnosis, substance classes, and task performance. Results revealed in those with active drug addiction hypoactivation of the left dorsal anterior cingulate cortex (dACC) and right middle frontal gyrus (MFG), compared with healthy controls. Weakening of the dACC and MFG activations was particularly pronounced in nicotine users, respectively. Impaired task performance was also associated with diminished MFG activation. In contrast, abstinent users did not exhibit any significant differences compared with healthy controls. Those with behavioral addictions were characterized by higher midcingulate cortical activation. Thus, the neural disengagement during response inhibition in active drug addiction was limited to a small number of prefrontal cortical regions and dependent on population characteristics. Finally, the evidence for potential normalization of hypofrontality following substance use cessation highlights the benefits of abstinence in restoring cerebral functions.

Reward-Related Responses and Tonic Craving in Cocaine Addiction: An Imaging Study of the Monetary Incentive Delay Task.

BACKGROUND: Cocaine addiction is associated with altered sensitivity to natural reinforcers and intense drug craving. However, previous findings on reward-related responses were mixed, and few studies have examined whether reward responses relate to tonic cocaine craving. METHODS: We combined functional magnetic resonance imaging and a monetary incentive delay task to investigate these issues. Imaging data were processed with published routines, and the results were evaluated with a corrected threshold. We compared reward responses of 50 cocaine-dependent individuals (CDs) and 45 healthy controls (HCs) for the ventral striatum (VS) and the whole brain. We also examined the regional responses in association with tonic cocaine craving, as assessed by the Cocaine Craving Questionnaire (CCQ) in CDs. We performed mediation analyses to evaluate the relationship between regional responses, CCQ score, and recent cocaine use. RESULTS: The VS showed higher activation to large as compared with small or no wins, but this reward-related activity did not differ between CDs and HCs. The precentral gyrus (PCG), anterior insula, and supplementary motor area showed higher activation during large vs no wins in positive correlation with the CCQ score in CDs. Mediation analyses suggested that days of cocaine use in the prior month contributed to higher CCQ scores and, in turn, PCG reward responses. CONCLUSIONS: The results highlight a unique relationship between reward responses of the primary motor cortex, tonic cocaine craving, and recent cocaine use. The motor cortex may partake in the cognitive motor processes critical to drug-seeking behavior in addicted individuals.