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Abstract Physical pain and negative emotions represent two distinct drinking motives that contribute to harmful alcohol use. Proactive avoidance, in contrast, can reduce consumption in response to these motives but appears to be impaired in those with problem drinking. Despite such evidence, proactive avoidance and its underlying neural deficits have not been assessed experimentally. How these deficits inter-relate with drinking motives to influence alcohol use also remains unclear. The current study leveraged neuroimaging data in forty-one problem and forty-one social drinkers who performed a probabilistic learning go/nogo task featuring proactive avoidance of painful outcomes. We identified the brain responses to proactive avoidance and contrasted the neural correlates of drinking to avoid negative emotions vs. physical pain. Behavioral results confirmed proactive avoidance deficits in problem drinking individuals’ learning rate and performance accuracy, both which were associated with greater alcohol use. Imaging findings in the problem drinking group showed that negative emotions as a drinking motive predicted attenuated right anterior insula activation during proactive avoidance. In contrast, physical pain motive predicted reduced right putamen response. These regions’ activations as well as functional connectivity with the somatomotor cortex also demonstrated a negative relationship with drinking severity and positive relationship with proactive avoidance performance. Path modeling further delineated the pathways through which physical pain and negative emotions influenced the neural and behavioral measures of proactive avoidance. Taken together, the current findings provide experimental evidence for proactive avoidance deficits in alcohol misuse and establish the link between their neural underpinnings and drinking behavior.

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.

Abstract 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

Abstract 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.

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.

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 (β’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.

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.

Late childhood and early adolescence is characterized by substantial brain maturation which contributes to both adult-like and age-dependent resting-state network connectivity patterns. However, it remains unclear whether these functional network characteristics in children are subject to differential modulation by distinct cognitive demands as previously found in adults. We conducted network analyses on fMRI data from 60 children (aged 9–12) during resting and during three distinct tasks involving decision making, visual perception, and spatial working memory. Graph measures of network architecture, functional integration, and flexibility were calculated for each of the four states. During resting state, the children’s network architecture was similar to that in young adults (N = 60, aged 20–23) but the degree of similarity was age- and network-dependent. During the task states, the children's whole-brain network exhibited enhanced integration in response to increased cognitive demand. Additionally, the frontoparietal network showed flexibility in connectivity patterns across states while networks implicated in motor and visual processing remained relatively stable. Exploratory analyses suggest different relationships between behavioral performance and connectivity profiles for the working memory and perceptual tasks. Together, our findings demonstrate state- and age-dependent features in functional network connectivity during late childhood, potentially providing markers for brain and cognitive development.

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 (5491 girls, age 9–10 years) with 648 and 2697 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 (h2) 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.

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.

ObjectivesMany 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.MethodsMagnetic 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.ResultsCompared to HCs, PADs showed significant decreases 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.ConclusionsThe current results suggest the thickness of bilateral parietal and occipital temporal cortices as neural markers of apathy in PADs. These findings add to the literature by identifying the neural bases of a critical clinical feature of individuals with alcoholism.

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 (22–74 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.

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.

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.