Neoadjuvant Immunotherapy With Ipilimumab Plus Nivolumab in Mismatch Repair Deficient/Microsatellite Instability-High Colorectal Cancer: A Preliminary Report of Case Series.

BACKGROUND: Although ipilimumab plus nivolumab have significantly improved the survival of metastatic colorectal cancer (CRC) with mismatch repair deficient (dMMR) /microsatellite instability-high (MSI-H), the data on neoadjuvant setting is limited. PATIENTS AND METHODS: We enrolled 11 patients with advanced dMMR/MSI-H CRC. 10 patients were locally advanced and 1 was metastatic. Ten patients were treated with 1 dose of ipilimumab (1 mg/kg) and 2 doses of nivolumab (3 mg/kg), and 1 patient was treated with 1 dose of ipilimumab (1 mg/kg) and 2 doses of nivolumab (3 mg/kg) with 2 cycles. All the patients underwent surgery after immunotherapy. The aim of the study was to evaluate the safety and short-term efficacy of this strategy. RESULTS: Pathologic responses were observed in 11/11 (100%) dMMR/MSI-H tumors, with 9/11 (81.8%) achieving complete responses. Among these 9 cases with complete responses, 1 achieved a radiological noncomplete response after treatment with 1 dose of ipilimumab (1 mg/kg) and 2 doses of nivolumab (3 mg/kg), so another cycle of treatment with 1 dose of ipilimumab (1 mg/kg) and 2 doses of nivolumab (3 mg/kg) was administered, followed by surgery. The postoperative pathological evaluation was a complete response. Seven patients (63.6%) developed grade I/II adverse events. No patients developed grade III/IV adverse events or postoperative complications. CONCLUSION: Neoadjuvant immunotherapy with ipilimumab plus nivolumab induced tumor regression with a major clinical and pathological response in advanced dMMR/MSI-H CRC. Notably, patients do not achieve a complete response to neoadjuvant immunotherapy, additional neoadjuvant immunotherapy may offer benefits. Further research is needed to assess the long-term efficacy of this strategy.

Machine Learning of Functional Connectivity to Biotype Alcohol and Nicotine Use Disorders.

BACKGROUND: Magnetic resonance imaging provides noninvasive tools to investigate alcohol use disorder (AUD) and nicotine use disorder (NUD) and neural phenotypes for genetic studies. A data-driven transdiagnostic approach could provide a new perspective on the neurobiology of AUD and NUD. METHODS: Using samples of individuals with AUD (n = 140), individuals with NUD (n = 249), and healthy control participants (n = 461) from the UK Biobank, we integrated clinical, neuroimaging, and genetic markers to identify biotypes of AUD and NUD. We partitioned participants with AUD and NUD based on resting-state functional connectivity (FC) features associated with clinical metrics. A multitask artificial neural network was trained to evaluate the cluster-defined biotypes and jointly infer AUD and NUD diagnoses. RESULTS: Three biotypes-primary NUD, mixed NUD/AUD with depression and anxiety, and mixed AUD/NUD-were identified. Multitask classifiers incorporating biotype knowledge achieved higher area under the curve (AUD: 0.76, NUD: 0.74) than single-task classifiers without biotype differentiation (AUD: 0.61, NUD: 0.64). Cerebellar FC features were important in distinguishing the 3 biotypes. The biotype of mixed NUD/AUD with depression and anxiety demonstrated the largest number of FC features (n = 5), all related to the visual cortex, that significantly differed from healthy control participants and were validated in a replication sample (p < .05). A polymorphism in TNRC6A was associated with the mixed AUD/NUD biotype in both the discovery (p = 7.3 × 10-5) and replication (p = 4.2 × 10-2) sets. CONCLUSIONS: Biotyping and multitask learning using FC features can characterize the clinical and genetic profiles of AUD and NUD and help identify cerebellar and visual circuit markers to differentiate the AUD/NUD group from the healthy control group. These markers support a new growing body of literature.

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.

Performances and mechanisms of simultaneous removal of nitrate and phosphate by biofilter assembled with sponge iron/copper and corn cobs.

Sponge iron (SI) is a potential material for removing nitrate and phosphate from water. We decorated the SI with copper (Cu) to enhance its removal performance. To gain insight into the nitrate and phosphate removal utilizing SI/Cu and microbial coupling systems, three biofilters filled with corn cob (CC), corn cob + sponge iron (CS) and corn cob + sponge iron/copper (CSCu) were constructed. The results showed that the effluent NO3--N and PO43--P concentrations of CSCu remained consistently below 1 and 0.1 mg/L. The introduction of SI/Cu led to the enrichment of the Dechloromonas genus, making it the dominant microbial group, occupying 42.65% of the effective sequences. Modification of SI with Cu increased nitrogen cycle-related functional genes abundance in CSCu, with a 634% increase in nirS compared to CS. These findings proved that SI/Cu was a promising material, providing an approach to concomitantly removing nitrate and phosphate.

Cognitive Challenges Are Better in Distinguishing Binge From Nonbinge Drinkers: An Exploratory Deep-Learning Study of fMRI Data of Multiple Behavioral Tasks and Resting State.

BACKGROUND: Studies have identified imaging markers of binge drinking. Functional connectivity during both task challenges and resting state was shown to distinguish binge and nonbinge drinkers. However, no studies have compared the efficacy of task and resting data in the classification. HYPOTHESIS: Task outperforms resting-state functional magnetic resonance imaging (fMRI) data in the differentiation of binge and nonbinge drinkers. We tested the hypothesis via multiple deep learning algorithms. STUDY TYPE: Cross-sectional; retrospective. POPULATION: A total of 149 binge (107 men) and 151 demographically matched, nonbinge (92 men) drinkers curated from the Human Connectome Project, with 80% randomly selected for model development and 20% for validation/test. FIELD STRENGTH/SEQUENCE: A 3 T; fMRI with a blood oxygen level-dependent (BOLD) gradient-echo echo-planar sequence. ASSESSMENT: FMRI data of resting state and seven behavioral tasks were acquired. Graph convolutional network (GCN), long short-term memory, convolutional, and recurrent neural network models were built to distinguish bingers and nonbingers using connectivity matrices of 8, 116, and 268 regions of interest (ROI). Nodal metrics including betweenness centrality, degree centrality, clustering coefficient, efficiency, local efficiency, and shortest path length were calculated from the GCN model. STATISTICAL TESTS: Model performance was quantified by the area under the curve (AUC) in receiver operating characteristic analysis. A P value < 0.05 was considered statistically significant. RESULTS: Task outperformed resting data in classification by approximately 8% by AUC in the test set. Across models and ROI sets, the gambling, motor, language and working memory tasks, each with AUC of 0.614, 0.612, 0.605, and 0.603, performed better than resting data (AUC = 0.548). Models with 116 ROIs (AUC = 0.602) consistently outperformed those with 8 ROIs (AUC = 0.569). Task data performed best with GCN (AUC = 0.619). Nodal metrics of left supplementary motor area and right cuneus showed significant group main effect across tasks. CONCLUSION: Neural responses to cognitive challenges relative to resting state better characterize binge drinking. The performance of different network models may depend on behavioral tasks and the number of ROIs. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.

Sensitivity, specificity, and tolerability of the BACTrack Skyn compared to other alcohol monitoring approaches among young adults in a field-based setting.

BACKGROUND: There is a need for novel alcohol biosensors that are accurate, able to detect alcohol concentration close in time to consumption, and feasible and acceptable for many clinical and research applications. We evaluated the field accuracy and tolerability of novel (BACTrack Skyn) and established (Alcohol Monitoring Systems SCRAM CAM) alcohol biosensors. METHODS: The sensor and diary data were collected in a larger study of a biofeedback intervention and compared observationally in the present sub-study. Participants (high-risk drinkers, 40% female; median age 21) wore both Skyn and SCRAM CAM sensors for 1-6 days and were instructed to drink as usual. Data from the first cohort of participants (N = 27; 101 person-days) were used to find threshold values of transdermal alcohol that classified each day as meeting or not meeting defined levels of drinking (heavy, above-moderate, any). These values were used to develop scoring metrics that were subsequently tested using the second cohort (N = 20; 57 person-days). Data from both biosensors were compared to mobile diary self-report to evaluate sensitivity and specificity in relation to a priori standards established in the literature. RESULTS: Skyn classification rules for Cohort #1 within 3 months of device shipment showed excellent sensitivity for heavy drinking (94%) and exceeded expectations for above-moderate and any drinking (78% and 69%, respectively), while specificity met expectations (91%). However, classification worsened when Cohort #1 devices ≥3 months from shipment were tested (area under curve for receiver operator characteristic 0.87 vs. 0.79) and the derived classification threshold when applied to Cohort #2 was inadequately specific (70%). Skyn tolerability metrics were excellent and exceeded the SCRAM CAM (p ≤ 0.001). CONCLUSIONS: Skyn tolerability was favorable and accuracy rules were internally derivable but did not yield useful scoring metrics going forward across device lots and months of usage.

Long noncoding RNA LINC01606 protects colon cancer cells from ferroptotic cell death and promotes stemness by SCD1-Wnt/ß-catenin-TFE3 feedback loop signalling.

BACKGROUND: Ferroptosis is principally caused by iron catalytic activity and intracellular lipid peroxidation. Long noncoding RNAs (lncRNAs) play crucial roles in tumorigenesis. However, the potential interplay between lncRNA LINC01606 and ferroptosis in colon cancer remains elusive. METHODS: The expression level of LNC01606 in colon cancer tissue was detected by quantitative real-time polymerase chain reaction. The functional role of LNC01606 was investigated by gain- and loss-of-function assays both in vitro and in vivo. The LINC01606-SCD1-Wnt/ß-catenin-TFE3 axis were screened and validated by DNA/RNA pull down, gas chromatography-mass spectrometry, RNA immunoprecipitation and dual-luciferase reporter. RESULTS: The expression of lncRNA LINC01606 was frequently upregulated in human colon cancer and strongly associated with a poor prognosis. LINC01606 functioned as an oncogene and promotes colon cancer cell growth, invasion and stemness both in vitro and in vivo. Moreover, LINC01606 protected colon cancer cells from ferroptosis by decreasing the concentration of iron, lipid reactive oxygen species, mitochondrial superoxide and increasing mitochondrial membrane potential. Mechanistically, LINC01606 enhanced the expression of stearoyl-CoA desaturase 1 (SCD1), serving as a competing endogenous RNA to modulate miR-423-5p expression, subsequently activating the canonical Wnt/ß-catenin signaling, and transcription factor binding to IGHM enhancer 3 (TFE3) increased LINC01606 transcription after recruitment to the promoter regions of LINC01606. Furthermore, we confirmed that upregulated LINC01606 and Wnt/ß-catenin formed a positive feedback regulatory loop, further inhibiting ferroptosis and enhancing stemness. CONCLUSIONS: LINC01606 functions as an oncogene to facilitate tumor cell stemness, proliferation and inhibit ferroptosis and is a promising therapeutic target for colon cancer.

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.

Gray matter volumes of the insula and anterior cingulate cortex and their dysfunctional roles in cigarette smoking.

The salience network, including the insula and anterior cingulate cortex (ACC), has been implicated in nicotine addiction. Structural imaging studies have reported diminished insula and ACC gray matter volumes (GMVs) in smokers as compared to nonsmokers. However, it remains unclear how insula and ACC GMVs may relate to years of smoking, addiction severity, or behavioral traits known to dispose individuals to smoking. Here, with a dataset curated from the Human Connectome Project and voxel-based morphometry, we replicated the findings of smaller GMVs of the insula and medial prefrontal cortex, including the dorsal ACC and supplementary motor area (dACC/SMA), in (70 heavy < 209 light < 209 never) smokers matched in age, sex, and average daily num ber of drinks. The GMVs of the insula or dACC/SMA were not significantly correlated with years of smoking or Fagerstrom Test for Nicotine Dependence (FTND) scores. Heavy relative to never smokers demonstrated higher externalizing and internalizing scores, as evaluated by the NIH Emotion. In heavy smokers, the dACC/SMA but not insula GMV was positively correlated with both externalizing and internalizing scores. The findings together confirm volumetric changes in the salience network in heavy smokers and suggest potentially distinct dysfunctional roles of the insula and dACC/SMA in chronic smoking.

Magnetic Microdimer as Mobile Meter for Measuring Plasma Glucose and Lipids.

With the development of designed materials and structures, a wide array of micro/nanomachines with versatile functionalities are employed for specific sensing applications. Here, we demonstrated a magnetic propelled microdimer-based point-of-care testing system, which can be used to provide the real-time data of plasma glucose and lipids relying on the motion feedback of mechanical properties. On-demand and programmable speed and direction of the microdimers can be achieved with the judicious adjustment of the external magnetic field, while their velocity and instantaneous postures provide estimation of glucose, cholesterol, and triglycerides concentrations with high temporal accuracy. Numerical simulations reveal the relationship between motility performance and surrounding liquid properties. Such technology presents a point-of-care testing (POCT) approach to adapt to biofluid measurement, which advances the development of microrobotic system in biomedical fields.

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.

PRDX2 promotes the proliferation of colorectal cancer cells by increasing the ubiquitinated degradation of p53.

Colorectal cancer is the most common gastrointestinal cancer and causes severe damage to human health. PRDX2 is a member of the peroxiredoxin family reported to have a high level of expression in colorectal cancer. However, the mechanisms by which PRDX2 promotes the proliferation of colorectal cancer are still unclear. Here, the results indicated that PRDX2 expression was upregulated in colorectal cancer and closely correlated with poor prognosis. Functionally, PRDX2 promoted the proliferation of colorectal cancer cells. Mechanistically, PRDX2 could bind RPL4, reducing the interaction between RPL4 and MDM2. These findings demonstrate that the oncogenic property of PRDX2 may be attributed to its regulation of the RPL4-MDM2-p53 pathway, leading to p53 ubiquitinated degradation.

Neural correlates of individual variation in two-back working memory and the relationship with fluid intelligence.

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 < 0.05, FWE-corrected, the pre-supplementary motor area (preSMA), bilateral frontoparietal cortex (biFPC) and right anterior insula (rAI) showed activities in negative correlation with CSI2-0 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.

Heavy iron in large gem diamonds traces deep subduction of serpentinized ocean floor.

Subducting tectonic plates carry water and other surficial components into Earth's interior. Previous studies suggest that serpentinized peridotite is a key part of deep recycling, but this geochemical pathway has not been directly traced. Here, we report Fe-Ni-rich metallic inclusions in sublithospheric diamonds from a depth of 360 to 750 km with isotopically heavy iron (δ56Fe = 0.79 to 0.90‰) and unradiogenic osmium (187Os/188Os = 0.111). These iron values lie outside the range of known mantle compositions or expected reaction products at depth. This signature represents subducted iron from magnetite and/or Fe-Ni alloys precipitated during serpentinization of oceanic peridotite, a lithology known to carry unradiogenic osmium inherited from prior convection and melt depletion. These diamond-hosted inclusions trace serpentinite subduction into the mantle transition zone. We propose that iron-rich phases from serpentinite contribute a labile heavy iron component to the heterogeneous convecting mantle eventually sampled by oceanic basalts.

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.

Perceived friendship and binge drinking in young adults: A study of the Human Connectome Project data.

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.

Sex differences in neural responses to reward and the influences of individual reward and punishment sensitivity.

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.

Noradrenergic correlates of chronic cocaine craving: neuromelanin and functional brain imaging.

Preclinical studies have implicated noradrenergic (NA) dysfunction in cocaine addiction. In particular, the NA system plays a central role in motivated behavior and may partake in the regulation of craving and drug use. Yet, human studies of the NA system are scarce, likely hampered by the difficulty in precisely localizing the locus coeruleus (LC). Here, we used neuromelanin imaging to localize the LC and quantified LC neuromelanin signal (NMS) intensity in 44 current cocaine users (CU; 37 men) and 59 nondrug users (NU; 44 men). We also employed fMRI to investigate cue-induced regional responses and LC functional connectivities, as quantified by generalized psychophysiological interaction (gPPI), in CU. Imaging data were processed by published routines and the findings were evaluated with a corrected threshold. We examined how these neural measures were associated with chronic cocaine craving, as assessed by the Cocaine Craving Questionnaire (CCQ). Compared to NU, CU demonstrated higher LC NMS for all probabilistic thresholds defined of 50-90% of the peak. In contrast, NMS of the ventral tegmental area/substantia nigra (VTA/SN) did not show significant group differences. Drug as compared to neutral cues elicited higher activations of many cortical and subcortical regions, none of which were significantly correlated with CCQ score. Drug vs. neutral cues also elicited "deactivation" of bilateral parahippocampal gyri (PHG) and PHG gPPI with a wide array of cortical and subcortical regions, including the ventral striatum and, with small volume correction, the LC. Less deactivation of the PHG (r = 0.40, p = 0.008) and higher PHG-LC gPPI (r = 0.44, p = 0.003) were positively correlated with the CCQ score. In contrast, PHG-VTA/SN connectivity did not correlate with the CCQ score. Together, chronic cocaine exposure may induce higher NMS intensity, suggesting neurotoxic effects on the LC. The correlation of cue-elicited PHG LC connectivity with CCQ score suggests a noradrenergic correlate of chronic cocaine craving. Potentially compensating for memory functions as in neurodegenerative conditions, cue-elicited PHG LC circuit connectivity plays an ill-adaptive role in supporting cocaine craving.

Midcingulate Cortical Activations Interrelate Chronic Craving and Physiological Responses to Negative Emotions in Cocaine Addiction.

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.