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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.

Background Negative emotions precipitate drug craving. Individuals vary in how they engage in negative emotions, as may be reflected in physiological arousal elicited by the emotions. It remains unclear whether physiological responses to negative emotions relate to cocaine craving and how regional brain activations support this relationship. Methods We examined brain activation and skin conductance responses (SCRs) among 40 cocaine-dependent (CD) subjects and 37 healthy control subjects during exposure to negative-emotional and neutral images. Imaging and SCR data were processed with published routines, and the results were evaluated at a corrected threshold. Results Relative to control subjects, CD subjects showed increased activation in the hippocampus, inferior parietal gyrus, and caudate in response to negative-emotional versus neutral images. CD subjects relative to control subjects showed diminished SCR to negative-emotional versus neutral images, and the difference (SCRNE-NU) was positively correlated with chronic craving, as evaluated by the Cocaine Craving Questionnaire, and craving rating (negative-emotional – neutral), in CD subjects. Activations of the midcingulate cortex (MCC) were positively correlated with both chronic cocaine craving and SCRNE-NU and completely mediated the correlation between chronic cocaine craving and SCRNE-NU. Further, path analyses suggested a directional influence of SCRNE-NU on craving rating (negative-emotional – neutral): chronic craving → MCC activation → SCRNE-NU → craving rating. Conclusions CD subjects demonstrate hypoactive SCRs to negative emotions. Less diminution of SCR is associated with higher cocaine craving and MCC response to negative emotions. A hub of the limbic motor circuit, the MCC may translate chronic cocaine craving into physiological responses that precipitate cocaine seeking.

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.

Background Subjective feeling of social isolation, as can be measured by perceived burdensomeness (PB), is a major risk factor for alcohol misuse. Heightened PB is associated with elevated stress response and diminished cognitive control, both of which contribute to problem drinking. Here, we sought to identify the neural substrates underlying the relationship between PB and alcohol misuse. Methods We employed resting-state functional magnetic resonance imaging data collected from 61 problem drinkers to characterize the functional connectivity of the hypothalamus and ventral striatum (VS) in relation to PB. We specifically examined whether the connectivities of the hypothalamus and VS were differentially influenced by PB to produce contrasting effects on alcohol use. Finally, we evaluated how individual differences in social support modulate the inter-relationships of social isolation, neural connectivity, and the severity of problem drinking. Results Whole-brain multiple regressions show a positive relationship between PB and hypothalamic connectivity with the hippocampus and an inverse pattern for VS connectivity with the middle frontal gyrus. Difference in strength between the 2 connectivities predicted the severity of problem drinking, suggesting an imbalance involving elevated hypothalamic and diminished prefrontal cortical modulation in socially isolated problem drinkers. A path analysis further revealed that the lack of social support was associated with a bias toward low prefrontal connectivity, which in turn increased PB and facilitated problem drinking. Conclusions Altered hypothalamus and VS connectivity may underlie problem drinking induced by social isolation. The current findings also highlight the important role of social support as a potential protective factor against alcohol misuse.

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.

Objective Studies have linked cocaine dependence to suicidality. According to the Interpersonal Theory of Suicide, suicidal behavior becomes likely with the simultaneous presence of perceived burdensomeness (PB), lack of (or thwarted) belongingness (TB), and acquired fearlessness about death (FAD). Here, we examined personality and other variables, including depression, self-esteem, childhood abuse, and substance use, as predictors of these risk factors in cocaine-dependent individuals (CDs). Methods Seventy CDs and 70 healthy controls (HCs) participated. We examined group differences in a group-by-sex analysis of variance and identified predictors of PB, TB, and FAD in stepwise regressions. Results CDs exhibited elevated PB and TB but not FAD, compared to HCs. CDs also exhibited elevated harm avoidance, novelty seeking, depression, and lower self-esteem and reward dependence. Females reported elevated sexual abuse, harm avoidance, reward dependence, depression, but lower FAD, relative to males, among CDs and HCs. Among CDs, PB was predicted by lower self-esteem and greater emotional abuse; TB was predicted by lower self-esteem and reward dependence, as well as greater emotional and sexual abuse; and FAD was predicted by lower harm avoidance and greater physical abuse. Conclusions Interventions targeting suicidality in cocaine dependence should take into consideration self-esteem, personality traits, and childhood abuse.

Human and non-human primate studies have examined neural responses to action and inhibition of action. However, it remains unclear whether the cerebral processes supporting these two distinct responses are differentially modulated by reward. In a sample of 35 healthy human adults, we examined brain activations to action and inhibition of action in a reward go/no-go task, with approximately ⅔ go and ⅓ no-go trials. Correct go and no-go trials were rewarded with $1 or ¢5 in reward sessions. Behaviorally, reward facilitated go and impeded no-go. A conjunction analysis showed shared activation to rewarded go and no-go responses in the rostral anterior cingulate cortex (rACC) and inferior parietal cortex. A whole-brain two-way ANOVA of response (go vs no-go) and reward (dollar vs nickel) revealed a significant main effect of response, with greater activity for no-go vs go success in the middle frontal cortex and the reversed pattern in the dorsal ACC, insula, thalamus, and caudate. The thalamus and caudate also responded preferentially to dollar relative to nickel reward during go trials. The main effect of reward (dollar > nickel) involved not only regions associated with reward valuation (e.g., medial orbitofrontal cortex – mOFC) but also those implicated in motor control, saliency, and visual attention including the rACC, ventral striatum, insula, and occipital cortex. Finally, the mOFC distinguished go and no-go responses in the dollar but not nickel trials, suggesting a functional bias toward response execution that leads to larger rewards. Together, these findings identified both shared and non-overlapping neural processes underlying goal-directed action and inhibition of action as well as delineated the effects of reward magnitude on such processes.

Changes in physiological arousal frequently accompany cognitive and affective challenges. Many studies employed cue exposure paradigms to investigate the neural processes underlying cue-elicited drug and alcohol craving. However, whether cue-elicited craving relates to changes in physiological arousal and the neural bases underlying the potential relationship remain unclear. Here we examined cerebral cue-related activations in relation to differences in skin conductance responses (SCR) recorded during alcohol vs. neutral cue blocks in 61 non-dependent alcohol drinkers (30 men). Imaging and skin conductance data were collected and processed with published routines. Mediation analyses were conducted to examine the inter-relationship between regional activities, cue-elicited craving, and SCR. The results showed higher SCR during alcohol than during neutral cue exposure. Despite no differences in drinking characteristics, men as compared to women demonstrated higher craving rating, and men but not women demonstrated a positive correlation between alcohol (vs. neutral) cue-evoked craving and SCR. Further, across subjects, thalamic cue activity was positively correlated with differences in SCR between alcohol and neutral cue blocks in men but not in women. Mediation analyses suggested that thalamic activity mediated the correlation between craving and SCR across men and women, and in men but not women alone. These findings substantiate physiological and neural correlates of alcohol cue response and suggest important sex differences in the physiological and neural processes of cue evoked craving. Centered on the intralaminar and mediodorsal subregions, the thalamic correlate may represent a neural target for behavioral or pharmacological therapy to decrease cue-elicited arousal and craving.

Background Positive alcohol expectancy (AE) contributes to excessive drinking. Many imaging studies have examined cerebral responses to alcohol cues and how these regional processes related to problem drinking. However, it remains unclear how AE relates to cue response and whether AE mediates the relationship between cue response and problem drinking. Methods A total of 61 nondependent drinkers were assessed with the Alcohol Expectancy Questionnaire and Alcohol Use Disorder Identification Test and underwent functional magnetic resonance imaging while exposed to alcohol and neutral cues. Imaging data were processed and analyzed with published routines, and mediation analyses were conducted to examine the interrelationships among global positive score of the Alcohol Expectancy Questionnaire, Alcohol Use Disorder Identification Test score, and regional responses to alcohol versus neutral cues. Results Alcohol as compared with neutral cues engaged the occipital, retrosplenial, and medial orbitofrontal cortex as well as the left caudate head and red nucleus. The bilateral thalamus showed a significant correlation in cue response and in left superior frontal cortical connectivity with global positive score in a linear regression. Mediation analyses showed that global positive score completely mediated the relationship between thalamic cue activity as well as superior frontal cortical connectivity and Alcohol Use Disorder Identification Test score. The alternative models that AE contributed to problem drinking and, in turn, thalamic cue activity and connectivity were not supported. Conclusions The findings suggest an important role of the thalamic responses to alcohol cues in contributing to AE and at-risk drinking in nondependent drinkers. AEs may reflect a top-down modulation of the thalamic processing of alcohol cues, influencing the pattern of alcohol use.

Background Men and women show differences in sensitivity to reward and punishment, which may impact behavior in health and disease. However, the neural bases of these sex differences remain under-investigated. Here, by combining functional magnetic resonance imaging (fMRI) and a variant of the Monetary Incentive Delay Task (MIDT), we examined sex differences in the neural responses to wins and losses and how individual reward and punishment sensitivity modulates these regional activities. Methods Thirty-sex men and 27 women participated in the fMRI study. We assessed sensitivity to punishment (SP) and sensitivity to reward (SR) with the Sensitivity to Punishment and Sensitivity to Reward Questionnaire (SPSRQ). In the MIDT, participants pressed a button to collect reward ($1, 1¢, or nil), with the reaction time window titrated across trials so participants achieved a success rate of approximately 67%. We processed the Imaging data with published routines and evaluated the results with a corrected threshold. Results Women showed higher SP score than men and men showed higher SR score than women. Men relative to women showed higher response to the receipt of dollar or cent reward in bilateral orbitofrontal and visual cortex. Men as compared to women also showed higher response to dollar loss in bilateral orbitofrontal cortex. Further, in whole-brain regressions, women relative to men demonstrated more significant modulation by SP in the neural responses to wins and larger wins, and the sex differences were confirmed by slope tests. Conclusions Together, men showed higher SR and neural sensitivity to both wins, large or small, and losses than women. Individual differences in SP were associated with diminished neural responses to wins and larger wins in women only. These findings highlight how men and women may differ in reward-related brain activations in the MIDT and add to the imaging literature of sex differences in cognitive and affective functions.

Cocaine-dependent (CD) individuals demonstrate significant anxiety and dysphoria during withdrawal, a negative emotional state that may perpetuate drug seeking and consumption. An extensive body of work has focused on characterizing reward circuit dysfunction, but relatively little is known about the pain circuit during cocaine withdrawal. In an earlier study, we highlighted how cue-elicited functional connectivity between the periaqueductal gray (PAG), a subcortical hub of the pain circuit, and ventromedial prefrontal cortex supports tonic craving in recently abstinent CD. The functional organization of the brain can be characterized by intrinsic connectivities, and it is highly likely that the resting state functional connectivity (rsFC) of the PAG may also be altered in association with cocaine use variables. Here, we examined this issue in 52 CD and 52 healthy control (HC) participants. Imaging data were processed with published routines, and the findings were evaluated with a corrected threshold. In a covariance analysis, CD as compared with HC showed higher PAG rsFC with the hypothalamus, dorsomedial prefrontal, and inferior parietal cortices. Further, these connectivities were correlated negatively with tonic cocaine craving and recent cocaine use, respectively. Higher hypothalamic and frontoparietal rsFC with the PAG may reflect a compensatory process to regulate craving and compulsive drug use. The findings provide additional evidence in humans implicating the PAG circuit and may help research of the role of negative reinforcement in sustaining habitual drug use in cocaine addiction.

Working memory has been examined extensively using the N-back task. However, less is known about the neural bases underlying individual variation in the accuracy rate (AR) and reaction time (RT) as metrics of N-back performance. Whereas AR indexes the overall performance, RT may more specifically reflect the efficiency in updating target identify. Further, studies have associated fluid intelligence (Gf) with working memory, but the cerebral correlates shared between Gf and N-back performance remain unclear. We addressed these issues using the Human Connectome Project dataset. We quantified the differences in AR (critical success index or CSI) and RT between 2- and 0-backs (CSI2–0 and RT2–0) and identified the neural correlates of individual variation in CSI2–0, RT2–0, and Gf, as indexed by the number of correct items scored in the Raven’s Standard Progressive Matrices (RSPM) test. The results showed that CSI2–0 and RT2–0 were negatively correlated, suggesting that a prolonged response time did not facilitate accuracy. At voxel p 2–0 and positive correlation with RT2–0. In contrast, a cluster in the dorsal anterior cingulate cortex (dACC) bordering the SMA showed activities in positive correlation with CSI2–0 and negative correlation with RT2–0. Further, path analyses showed a significant fit of the model dACC → RT2–0 → CSI2–0, suggesting a critical role of target switching in determining performance accuracy. Individual variations in RT2–0 and Gf were positively correlated, although the effect size was small (f2 = 0.0246). RT2–0 and Gf shared activities both in positive correlation with the preSMA, biFPC, rAI, and dorsal precuneus. These results together suggest inter-related neural substrates of individual variation in N-back performance and highlight a complex relationship in the neural processes supporting 2-back and RSPM performance.

Expectancy of physical and social pleasure (PSP) promotes excessive drinking despite the potential aversive effects of misuse, suggesting an imbalance in the response to reward and pain in alcohol seeking. Here, we investigated the competing roles of the reward and pain circuits in PSP expectancy and problem drinking in humans. Using fMRI data during resting (n = 180) and during alcohol cue exposure (n = 71), we examined the antagonistic effects of the reward-related medial orbitofrontal cortex (mOFC) and pain-related periaqueductal gray (PAG) connectivities on PSP expectancy and drinking severity. The two regions’ connectivity maps and strengths were characterized to assess their shared substrates and net relationship with PSP expectancy. We evaluated mediation and path models to further delineate how mOFC and PAG connectivities interacted through the shared substrates to differentially impact expectancy and alcohol use. During resting, whole-brain regressions showed mOFC connectivity in positive and PAG connectivity in negative association with PSP scores, with convergence in the precentral gyrus (PrCG). Notably, greater PAG-PrCG relative to mOFC-PrCG connectivity strength predicted lower PSP expectancy. During the alcohol cue exposure task, the net strength of the PAG vs. mOFC cue-elicited connectivity with the occipital cortex again negatively predicted PSP expectancy. Finally, mediation and path models revealed that the PAG and mOFC connectivities indirectly and antagonistically modulated problem drinking via their opposing influences on expectancy and craving. Thus, the pain and reward circuits exhibit functional antagonism such that the mOFC connectivity increases expectancy of drinking pleasure whereas the PAG serves to counter that effect.

Aging is associated with structural and functional brain changes which may impact the regulation of motivated behaviors, including both action and inhibition of action. As behavioral regulation is often exercised in response to reward, it remains unclear how aging may influence reward-directed action and inhibition of action differently. Here we addressed this issue with the functional magnetic resonance imaging data of 72 participants (aged 21–74) performing a reward go/no-go (GNG) task with approximately 2/3 go and 1/3 no-go trials. The go and no-go success trials were rewarded with a dollar or a nickel, and the incorrect responses were penalized. An additional block of the GNG task without reward/punishment served as the control to account for age-related slowing in processing speed. The results showed a prolonged response time (RT) in rewarded (vs. control) go trials with increasing age. Whole-brain multiple regressions of rewarded (vs. control) go trials against age and RT both revealed an age-related reduced activity of the anterior insula, middle frontal gyrus, and rostral anterior cingulate cortex. Furthermore, activity from these regions mediated the relationship between age and go performance. During rewarded (vs. control) no-go trials, age was associated with increased accuracy rate but decreased activation in the medial superior frontal and postcentral gyri. As these regions also exhibited age-related activity reduction during rewarded go, the finding suggests aging effects on common brain substrates that regulate both action and action inhibition. Taken together, age shows a broad negative modulation on neural activations but differential effects on performance during rewarded action and inhibition of action.

Previous work suggests sex differences in reward sensitivity. However, it remains unclear how men and women differ in the neural processes of reward-driven impulsivity. With a data set of 968 subjects (502 women) curated from the Human Connectome Project, we investigated sex differences in regional activations to reward and to punishment in a gambling task. Individual variations in reward-driven impulsivity were quantified by the difference in reaction time between reward and punishment blocks in the gambling task, as well as by a behavioral measure of delay discounting. At a corrected threshold, men and women exhibited significant differences in regional activations to reward and to punishment. Longer reaction times during reward versus punishment blocks, indicative of more cautious responding, were associated with left-hemispheric lateral prefrontal cortical activation to reward in men but not women. Steeper discounting was associated with higher activation to reward in the right-hemispheric dorsal anterior cingulate cortex and angular gyrus in women but not men. These sex differences were confirmed in slope tests. Together, the results highlight the sex-specific neural processes of reward-driven impulsivity with left-hemispheric prefrontal cortex supporting impulse control in men and right-hemispheric saliency circuit playing a more important role in diminished impulse control in women.

Objectives: Many studies reported structural brain changes in patients with alcohol dependence (PADs). However, no studies identified structural correlates of apathy that might aggravate alcohol misuse. Here, we explored regional differences in cortical thickness in PADs relative to healthy controls (HCs), and examined the potential correlation of regional thickness with the severity of apathy. Methods: Magnetic resonance imaging data were collected from 33 male PADs and 35 male age- and education-matched HCs. We used the FreeSurfer software to investigate group differences in cortical thickness across 148 regions. Apathy was evaluated using the Lille Apathy Rating Scale-Informant (LARS-I). Regression analyses examined the relationship between cortical thickness of regions of interest and apathy score in PADs. Results: Compared to HCs, PADs significantly decreased in the cortical thickness of occipito-temporal cortex (OTC), including the left middle occipital gyrus and occipital pole, right superior occipital gyri, and bilateral lingual gyrus; bilateral superior parietal cortex (SPC), including the right intraparietal sulcus; and bilateral inferior parietal cortex (IPC). Furthermore, the cortical thickness of all of the three regions was negatively correlated with the apathy total scores. The cortical thickness of the IPC was also negatively correlated with the action initiation subscore of the LARS-I. Conclusions: The current results indicated that the thickness of bilateral parietal and occipital temporal cortices should be neural markers of apathy in PADs, which added to the literature by identifying the neural bases of a critical clinical feature of individuals with alcoholism.

Individuals engage in alcohol consumption to seek reward and/or alleviate negative emotions. The neural processes subserving reward response and negative emotion thus likely play important roles in motivating alcohol use. Cognitive control, in contrast, is thought to regulate these motivational processes to keep drinking in check. As such, the balance between motivational and control processes may determine drinking behavior. Importantly, this balance is likely dictated by individual differences in drinking motives, including positive alcohol expectancy and perceived social isolation. Here, we characterized how the relative strength of the reward, negative emotion, and control circuit activities during alcohol cue exposure predicted alcohol use severity in 71 adult drinkers. Path models were employed to delineate the relationships between the neural, psychological, and drinking measures. We found that positive alcohol expectancy was associated heightened craving and greater activity of the reward relative to cognitive control circuit during cue exposure. The higher this circuit activity difference, the more severe subjects’ drinking. A similar relationship was found for social isolation, craving, activity difference of negative emotion vs. cognitive control circuits, and alcohol use severity. Thus, distinct neural pathways motivate alcohol use through reward seeking and negative emotion. By characterizing the neural circuits underlying cognitive control and motivational processes, the current study sheds light on how positive and negative reinforcement perpetuates problem drinking.

BACKGROUND: Many studies have investigated how cognitive control may be compromised in cocaine addiction. Here, we extend this literature by employing spatial Independent Component Analysis (ICA) to describe circuit dysfunction in relation to impairment in response inhibition in cocaine addiction. METHODS: Fifty-five cocaine-dependent (CD) and 55 age- and sex-matched non-drug-using healthy control individuals (HC) participated in the study. Task-relatedness of 40 independent components (ICs) was assessed using multiple regression analyses of component time courses with the modeled time courses of hemodynamic activity convolved with go success (GS), stop success (SS) and stop error (S ). This procedure produced beta-weights that represented the degree to which each IC was temporally associated with, or ‘engaged’, by each task event. RESULTS: Behaviorally, CD participants showed prolonged stop signal reaction times (SSRTs) as compared to HC participants (p

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.

Background Many studies employed cue exposure paradigms to investigate the neural processes underlying cue-elicited alcohol craving. Cue exposure elicits robust autonomic reactivity. However, whether or how cue-elicited autonomic response relates to the severity of alcohol misuse and the neural bases underlying the potential relationship remain unclear. Methods We examined cue-related brain activations in association with heart rate variability, as indexed by the root mean square of the successive differences (RMSSD), during alcohol versus neutral cue blocks in 50 adult alcohol drinkers (24 men). Imaging and heart rate variability data were collected and processed with published routines. Mediation analyses were conducted to examine the interrelationship between regional activities, cue-elicited changes in RMSSD, and the severity of problem alcohol use, as assessed with the Alcohol Use Disorders Identification Test (AUDIT). Results The results showed higher RMSSD during alcohol than during neutral cue exposures, with alcohol (vs. neutral) cue-evoked RMSSD positively correlated with AUDIT score. Further, alcohol (vs. neutral) cue-elicited activity in the ventromedial prefrontal cortex was negatively correlated both with increases in RMSSD and with the AUDIT score. Mediation analyses suggested that the RMSSD mediated the relationship between ventromedial prefrontal cortex cue activity and the AUDIT score. Conclusions These findings substantiate the neural correlates of the presumably parasympathetic response during alcohol cue exposure and the interrelationship among ventromedial prefrontal cortex activity, autonomic response, and problem alcohol use.

Alcohol misuse is associated with significant energy deficits. As feeding involves multiple sensory, cognitive, and affective processes, low food intake in problem drinkers likely reflects alterations in both regional and inter-regional responses. To investigate the effects of problem drinking on feeding-related neural activities and connectivities, we examined functional magnetic resonance imaging (fMRI) data in 82 drinkers who viewed palatable food and nonfood images in alternating blocks. Drinking severity was assessed with the Alcohol Use Disorders Identification Test (AUDIT). A whole-brain multiple regression with AUDIT scores as the predictor showed a negative correlation between drinking severity and activation to food vs nonfood cues in the lateral orbitofrontal cortex (lOFC). AUDIT scores were also negatively correlated with the gray matter volume (GMV) of the lOFC and regions that responded preferentially to food stimuli, including the left middle frontal gyrus, bilateral middle insula, and occipital cortices. Connectivity strength between the lOFC and these regions was negatively modulated by drinking severity. In contrast, there was no relationship between AUDIT scores and lOFC connectivity with regions that did not show either selectivity to food images or GMV loss. A mediation analysis further suggested that alcohol misuse may have compromised lOFC's structural integrity, which in turn disrupted lOFC interactions with regions that support the processing of visual food cues. Overall, the findings provide evidence for the effects of problem drinking on the brain substrates of feeding, potentially shedding light on the neural mechanisms underlying energy deficits in at-risk drinkers.

Previous studies have suggested age-related differences in reward-directed behavior and cerebral processes in support of the age effects. However, it remains unclear how age may influence the processing of reward magnitude. Here, with 54 volunteers (22 to 74 years of age) participating in the Monetary Incentive Delay Task (MIDT) with explicit cues ($1, ¢1, or nil) and timed response to win, we characterized brain activations during anticipation and feedback and the effects of age on these regional activations. Behaviorally, age was associated with less reaction time (RT) difference between dollar and cent trials, as a result of slower response to the dollar trials; i.e., age was positively correlated with RT dollar – RT cent, with RT nil as a covariate. Both age and the RT difference ($1 - ¢1) were correlated with diminished activation of the right caudate head, right anterior insula, supplementary motor area (SMA)/pre-SMA, visual cortex, parahippocampal gyrus, right superior/middle frontal gyri, and left primary motor cortex during anticipation of $1 vs. ¢1 reward. Further, these regional activities mediated the age effects on RT differences. In responses to outcomes, age was associated with decreases in regional activations to dollar vs. cent loss but only because of higher age-related responses to cent losses. Together, these findings suggest age-related differences in sensitivity to the magnitude of reward. With lower cerebral responses during anticipation to win large rewards and higher responses to outcomes of small loss, aging incurs a constricted sensitivity to the magnitude of reward.

Background An earlier study characterized the neural correlates of self-initiated actions in a Cyberball game in healthy individuals. It remains unclear how social anxiety may influence these neural processes. Methods We examined regional activations to self-initiated actions in 25 adults with low and 25 with high social anxiety (LA and HA, respectively). Skin conductance was recorded concurrently with fMRI. We followed published routines in the analyses of imaging and skin conductance data. Results We hypothesized that HA as compared to LA individuals would demonstrate increased cortical limbic activations during self-initiated actions (tossing or T > receiving or R trials, to control for motor activities) in social exclusion (EX) vs. fair game (FG) scenario. At a corrected threshold, HA as compared with LA group showed increases in bilateral posterior insula activation during T vs. R trials in EX as compared to FG. Further, HA as compared to LA showed higher skin conductance response to tossing trials during EX as compared to FG. Limitations With a limited sample size, we did not examine potential sex effects. Further, we cannot rule out the effects of depression on the findings. Conclusions Together, the results suggest that individuals with more severe social anxiety engaged the somatosensory insula to a greater extent and exhibited higher physiological arousal when initiating ball toss during social exclusion in the Cyberball game. Posterior insula response to self-initiated action may represent a biomarker of social anxiety. It remains to be investigated whether interventions to decrease physiological arousal may alleviate social anxiety.

Background Peer influences figure prominently in young adult binge drinking. Women have trended to show a level of alcohol use on par with men during the last decades. It would be of interest to investigate the neural processes of social cognition that may underlie binge drinking and the potential sex differences. Methods Here, we examined the data of the Human Connectome Project where we identified a total of 175 binge drinkers (125 men) and 285 non-binge drinkers (97 men) performing a social cognition task during brain imaging. We analyzed the imaging data with published routines and evaluated the results at a corrected threshold. Results Both male and female binge relative to non-binge drinkers showed higher perceived friendship. Binge relative to non-binge drinkers demonstrated diminished activations in the anterior medial orbitofrontal cortex (amOFC) during perception of social vs. random interaction, with a more prominent effect size in women. Further, whole-brain regression identified activity of the right posterior insula (rPI) in negative correlation with perceived friendship score in non-binge drinking women. Post-hoc analyses showed significant correlation of rPI activity with perceived friendship, amOFC activity, and a summary measure of alcohol use severity identified by principal component analysis, across all subjects. Mediation and path analysis demonstrated a significant model: amOFC activity → rPI activity → perceived friendship → severity of alcohol use. Conclusions These findings support peer influences on binge drinking and suggest neural correlates that may relate altered social cognitive processing to alcohol misuse in young adults.

Highlights • Self-efficacy is negatively correlated with perceived stress in young adult drinkers. • Binge vs. non-binge drinking men show diminished PCC thickness and dmPFC GMV. • The metrics are positively/negatively each correlated with self-efficacy/stress. • Path analyses show daily drinks → neural metrics → low self-efficacy → high stress., 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 → lower PCC thickness and dmPFC GMV → lower self-efficacy → 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.

Studies have examined sex differences in emotion processing in health and illness. However, it remains unclear how these neural processes may relate to individual differences in affective traits. We addressed this issue with a dataset of 970 subjects (508 women) curated from the Human Connectome Project. Participants were assessed with the NIH Toolbox Emotion Measures and fMRI while identifying negative facial emotion and neutral shape targets in alternating blocks. Imaging data were analyzed with published routines and the results were reported at a corrected threshold. Men scored similarly in Anger- but lower in Fear-Affect, as compared to women. Men as compared with women engaged the occipital-temporal visual cortex, retrosplenial cortex (RSC), and both anterior and posterior cingulate cortex to a greater extent during face versus shape identification. Women relative to men engaged higher activation of bilateral middle frontal cortex. In regional brain responses to face versus shape identification, men relative to women showed more significant modulations by both Anger- and Fear- Affect traits. The left RSC and right RSC/precuneus each demonstrated activities during face vs. shape identification in negative correlation with Anger- and Fear- Affect scores in men only. Anger affect was positively correlated with prolonged RT in identifying face vs. shape target in men but not women. In contrast, women relative to men showed higher Fear-Affect score and higher activation in the right middle frontal cortex, which was more strongly correlated with prolonged RT during face vs. shape identification. Together, men and women with higher Fear-Affect demonstrated lower accuracy in identifying negative facial emotion versus neutral shape target, a relationship mediated by activity of the RSC. These findings add to the literature of sex and trait individual differences in emotion processing and may help research of sex-shared and sex-specific behavioral and neural markers of emotional disorders.

BACKGROUND: Withdrawal from chronic cocaine use leads to anxiety and dysphoria that may perpetuate habitual drug use. The pain circuit is widely implicated in the processing and manifestations of negative emotions. Numerous studies have focused on characterizing reward circuit dysfunction but relatively little is known about the pain circuit response during cocaine withdrawal. METHODS: Here we examined the activity and connectivity of the periaqueductal gray (PAG), which is an important brain region in the pain circuit, during cocaine cue exposure in 52 recently abstinent cocaine dependent participants (CD, 42 men). Imaging data are processed with published routines, and the results were evaluated at a corrected threshold. RESULTS: CD showed higher activation of the PAG and connectivity of the PAG with the ventromedial prefrontal cortex (vmPFC) during cocaine as compared to neutral cue exposure. PAG-vmPFC connectivity was positively and negatively correlated with tonic cocaine craving, as assessed by the Cocaine Craving Questionnaire, in male and female CD, respectively, and the sex difference was confirmed by a slope test. Granger causality analyses showed that the PAG Granger caused vmPFC time series in men and the reverse was true in women, substantiating sex differences in the directional interactions of the PAG and vmPFC. CONCLUSION: The findings provide the first evidence in humans implicating the PAG circuit in cocaine withdrawal and cocaine craving and advance our understanding of the role of the pain circuit and negative reinforcement in sustaining habitual drug use in cocaine addiction.

Approach and avoidance represent two fundamental behavioral traits that develop early in life. Previous studies have examined the neural correlates of approach and avoidance traits in adults and adolescents. Here, using the data set of the Adolescent Brain Cognition Development project, we investigated the structural cerebral bases of behavioral activation system (BAS) and behavioral inhibition system (BIS) in children. We employed voxel-based morphometry to examine how gray matter volumes (GMV) related specifically to BAS and BIS traits in 11,542 children (5,491 girls, age 9 to 10 years) with 648 and 2,697 identified as monozygotic twins (MZ) and dizygotic twins/siblings (DZ), respectively. After accounting for the BIS score, higher BAS scores (residuals) were positively correlated with the GMV of the ventral striatum (VS), and the correlation was stronger in MZ than in DZ and unrelated children, with a heritability (h(2)) of 0.8463. Higher BAS scores were negatively correlated with the GMV of bilateral visual, lateral orbitofrontal, temporal, and inferior frontal cortex, as well as the precuneus. Higher BIS (after accounting for BAS) scores were negatively correlated with the GMVs of the ventral caudate and bilateral putamen/pallidum, hypothalamus, and right anterior insula, and the correlation was stronger in MZ than in DZ and unrelated children, with a heritability of 0.8848. A cluster in the VS showed positive and negative correlation with the BAS and BIS scores, respectively. These findings suggest shared and distinct cerebral volumetric bases of the BAS and BIS traits in children. Whereas both traits have a strong genetic basis, the BAS relative to BIS appears to be more amenable to environmental influences. These findings add to the literature of developmental neuroscience and may help identify genetic risk factors of externalizing and internalizing psychopathology.

Imaging studies have distinguished the brain correlates of approach and avoidance behaviors and suggested the influence of individual differences in trait sensitivity to reward (SR) and punishment (SP) on these neural processes. Theoretical work of reinforcement sensitivity postulates that SR and SP may interdependently regulate behavior. Here, we examined the distinct and interrelated neural substrates underlying rewarded action versus inhibition of action in relation to SR and SP as evaluated by the Sensitivity to Punishment and Sensitivity to Reward Questionnaire. Forty-nine healthy adults performed a reward go/no-go task with approximately 2/3 go and 1/3 no-go trials. Correct go and no-go responses were rewarded and incorrect responses were penalized. The results showed that SR and SP modulated rewarded go and no-go, respectively, both by recruiting the rostral anterior cingulate cortex and left middle frontal gyrus (rACC/left MFG). Importantly, SR and SP influenced these regional activations in opposite directions, thus exhibiting an antagonistic relationship as suggested by the reinforcement sensitivity theory. Furthermore, mediation analysis revealed that heightened SR contributed to higher rewarded go success rate via enhanced rACC/left MFG activity. The findings demonstrate interrelated neural correlates of SR and SP to support the diametric processes of behavioral approach and avoidance.

Skin conductance response (SCR) is used in psychophysiological research to measure the reactions of the autonomic nervous system to reward and punishment. While there is consistent evidence that SCR increases to both aversive and appetitive stimuli, it remains unclear whether SCR simply represents a general index of arousal to motivationally significant outcomes or may also differentiate action or inhibition of action that lead to such outcomes. Furthermore, individual differences in trait sensitivity to reward and punishment can influence physiological arousal during approach and avoidance behaviors. Yet, their inter-relationships have not been examined. To address these gaps, we employed a reward go/no-go task with ⅔ go and ⅓ no-go trials and an individually titrated go response window. Correct go and no-go responses were rewarded while incorrect responses were penalized. We examined whether SCR varied with outcome (win vs. loss), action (go vs. no-go), and individual differences in reward sensitivity (SR) and sex. The results showed greater SCRs to loss vs. win, to go vs. no-go success, and to go success in positive correlation with SR. Further, SCR mediated the relationship between SR and go success rate. In sex differences, men exhibited greater SCR which was more predictive of go success rate relative to women. In contrast, SCR was more predictive of no-go success rate in women. Thus, SCR varies according to behavioral contingency, outcome, sex, and reward sensitivity. These findings add to the literature by characterizing the individual and behavioral factors that may influence physiological arousal in response to salient events.

The present study examined the impacts of major depressive disorder (MDD) on visual and prefrontal cortical activity as well as their connectivity during visual working memory updating and related them to the core clinical features of the disorder. Impairment in working memory updating is typically associated with the retention of irrelevant negative information which can lead to persistent depressive mood and abnormal affect. However, performance deficits have been observed in MDD on tasks involving little or no demand on emotion processing, suggesting dysfunctions may also occur at the more basic level of information processing. Yet, it is unclear how various regions in the visual working memory circuit contribute to behavioral changes in MDD. We acquired functional magnetic resonance imaging data from 18 unmedicated participants with MDD and 21 age-matched healthy controls (CTL) while they performed a visual delayed recognition task with neutral faces and scenes as task stimuli. Selective working memory updating was manipulated by inserting a cue in the delay period to indicate which one or both of the two memorized stimuli (a face and a scene) would remain relevant for the recognition test. Our results revealed several key findings. Relative to the CTL group, the MDD group showed weaker postcue activations in visual association areas during selective maintenance of face and scene working memory. Across the MDD subjects, greater rumination and depressive symptoms were associated with more persistent activation and connectivity related to no-longer-relevant task information. Classification of postcue spatial activation patterns of the scene-related areas was also less consistent in the MDD subjects compared to the healthy controls. Such abnormalities appeared to result from a lack of updating effects in postcue functional connectivity between prefrontal and scene-related areas in the MDD group. In sum, disrupted working memory updating in MDD was revealed by alterations in activity patterns of the visual association areas, their connectivity with the prefrontal cortex, and their relationship with core clinical characteristics. These results highlight the role of information updating deficits in the cognitive control and symptomatology of depression., Highlights • Unmedicated individuals with major depressive disorder showed several forms of deficits during visual working memory updating. • Impaired visual working memory updating performance. • Diminished category-specific response patterns in visual association areas, particularly those involved in scene processing. • Loss of frontal functional connectivity with the scene-selective visual region during updating of scene information. • Rumination is associated with heightened activity and functional connectivity for obsolete information in working memory.