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

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

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

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

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

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

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.

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

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

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.

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.

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.

The Neural Processes Interlinking Social Isolation, Social Support, and Problem Alcohol Use.

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.

Interdependent Neural Correlates of Reward and Punishment Sensitivity During Rewarded Action and Inhibition of Action.

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.

Problem drinking alters gray matter volume and food cue responses of the lateral orbitofrontal cortex.

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.

Resting state hypothalamic and dorsomedial prefrontal cortical connectivity of the periaqueductal gray in cocaine addiction.

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.

Posterior Cingulate Cortical Response to Active Avoidance Mediates the Relationship between Punishment Sensitivity and Problem Drinking.

Many people drink to alleviate negative affect, reflecting an avoidance strategy which can lead to alcohol misuse. Individuals with heightened sensitivity to punishment (SP) are especially susceptible to problem drinking via this maladaptive coping mechanism. As imaging studies have largely focused on sensation-seeking traits and approach behavior, the neural substrates underlying behavioral avoidance as well as their relationship with punishment sensitivity and alcohol use remain unclear. Here, we examined in humans the cerebral correlates of response inhibition to avoid a penalty in relation to both problem drinking and SP, as evaluated by the Alcohol Use Disorders Identification Test and the Sensitivity to Punishment and Sensitivity to Reward Questionnaire, respectively. Seventy nondependent female and male drinkers performed a reward go/no-go task with approximately two-thirds go and one-third no-go trials. Correct go and no-go responses were rewarded, and incorrect responses were punished. The results showed that SP and Alcohol Use Disorders Identification Test scores were both positively correlated with brain activations during response inhibition, and these activations overlapped in the posterior cingulate cortex (PCC). Thus, the PCC may represent a shared neural substrate for avoidance, punishment sensitivity, and problem drinking. Mediation analyses further suggested that PCC response to avoidance completely and bidirectionally mediated the relationship between SP and hazardous alcohol use. These findings substantiated the role of the PCC in behavioral avoidance and its link to problem drinking in punishment-sensitive nondependent drinkers.SIGNIFICANCE STATEMENT Many people drink to alleviate negative affect, reflecting an avoidance strategy that can lead to alcohol misuse. Individuals with heightened punishment sensitivity (SP) trait are particularly vulnerable to this maladaptive coping mechanism. The current study examined the neural substrates underlying behavioral avoidance and their relationship with SP and problem drinking. Using a reward go/no-go task, we showed both SP and drinking severity were positively correlated with the posterior cingulate cortex (PCC) activation during action inhibition. Thus, the PCC may represent a shared neural substrate for avoidance behavior, punishment sensitivity, and problem drinking. Further, PCC response to avoidance mediated the relationship between SP and alcohol use. These findings substantiated the neural processes linking avoidance tendency to alcohol misuse in punishment-sensitive drinkers.

The effects of age on reward magnitude processing in the monetary incentive delay task.

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.

Gray matter volumetric correlates of behavioral activation and inhibition system traits in children: An exploratory voxel-based morphometry study of the ABCD project data.

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.

The interrelationship of body mass index with gray matter volume and resting-state functional connectivity of the hypothalamus.

BACKGROUND: The hypothalamus plays an important role in regulating body weight through its interactions with multiple brain circuits involved in distinct aspects of feeding behavior. Yet, how hypothalamic gray matter volume (GMV) and connectivity may be related to individual differences in body weight remains unclear. We tested the hypothesis that the hypothalamus shows enhanced resting-state functional connectivity (rsFC) with regions of the reward, motivation, and motor circuits in positive correlation with body mass index (BMI) and the opposite with those associated with inhibitory control. We further examined the interdependent relationships between hypothalamic GMV, connectivity, and body weight. METHODS: Using seed-based rsFC and voxel-based morphometry analyses, we examined the relationship between the rsFC and GMV of the hypothalamus and BMI in 105 healthy humans. Additionally, we employed mediation analyses to characterize the inter-relationships between hypothalamic connectivity, GMV, and BMI. RESULTS: A whole-brain multiple regression showed that BMI was positively correlated with hypothalamic rsFC with the insula, thalamus, globus pallidus, and cerebellum, and negatively correlated with hypothalamic rsFC with the superior parietal lobule. Thus, higher BMI was associated with enhanced hypothalamic connectivity with regions involved in motivated feeding and reduced connectivity with those in support of cognitive control of food intake. A second whole-brain multiple regression revealed a positive correlation between hypothalamic GMV and the hypothalamus-posterior insula connectivity. Finally, the relationship between hypothalamic GMV and BMI was significantly and bidirectionally mediated by the hypothalamus-posterior insula connectivity. CONCLUSIONS: The current findings suggest that the hypothalamus differentially interacts with the motivation, motor, and control circuits to regulate BMI. We further found evidence for the interdependence of hypothalamic structure, function, and body weight, which provides potential insights into the brain mechanisms of obesity.

Hypothalamic response to cocaine cues and cocaine addiction severity.

The dopaminergic motive system is compromised in cocaine addiction. Abundant research has examined the roles of the dopaminergic midbrain and ventral striatum (VS) in cue-induced craving and habitual drug consumption. Interconnected with the dopaminergic circuits, the hypothalamus is widely implicated in motivated behavior, including food and drug seeking. However, very few studies have investigated how the hypothalamus responds to drug cues and whether hypothalamic responses are related to clinical features such as craving and addiction severity. Here, in 23 cocaine-dependent individuals (CD) exposed to cocaine vs neutral cues during functional magnetic resonance imaging (fMRI), we examined regional responses using established routines. At a corrected threshold, CD demonstrated increased activation to cocaine vs neutral cues in bilateral visual cortex, inferior parietal and middle frontal gyri, and the hypothalamus. The extent of hypothalamus but not other regional response was correlated with craving and cocaine addiction severity, each as assessed by the Cocaine Craving Questionnaire (CCQ) and Cocaine Selective Severity Assessment (CSSA). In contrast, subjective "acute" craving as elicited by cocaine cues during fMRI involved deactivation of bilateral orbitofrontal cortex (OFC) and angular gyri (AG), and the OFC and AG responses were not related to CCQ or CSSA score. These findings distinguished tonic craving as a critical factor in capturing cocaine addiction severity and substantiated a role of the hypothalamus in motivational dysfunction in cocaine addiction.

Cerebral responses to self-initiated action during social interactions.

Social interaction involves self-initiated actions that engage subjective awareness of one's own volition. Individuals with social communication needs or social anxiety find it particularly difficult to initiate social interactions. However, extant studies have not specifically addressed how perceived exclusion may influence self-initiated actions during social interaction. As a first step to address this question, we scanned 24 healthy adults participating in a Cyberball game with two fictive players. By contrasting events of observing, receiving, and initiating ball toss during a scenario of fair game (FG) and of exclusion (EX), we examined the neural correlates of self-initiated action during social interactions. Behaviorally, participants were faster in catching but slower in tossing the ball in EX compared with FG, suggesting a burden during self-initiated actions during social exclusion. Tossing versus receiving (or observing) engaged higher activity during EX than FG in the precuneus and angular gyrus, regions that have been widely implicated in theory of mind processing and social emotions. Across subjects these cortical activities correlated positively with the difference between EX and FG in the percentage of trials where participants tossed the ball back to the same player (r = 0.69, p < 0.001). Together, the results suggested that, in healthy adults, social exclusion encumbered and engaged higher posterior cortical activations during self-initiated actions. The findings may facilitate future research of neural markers of social behavioral disorders.

Hypothalamic Responses to Cocaine and Food Cues in Individuals with Cocaine Dependence.

BACKGROUND: Individuals with cocaine addiction are characterized by under-responsiveness to natural reinforcers. As part of the dopaminergic pathways, the hypothalamus supports motivated behaviors. Rodent studies suggested inter-related roles of the hypothalamus in regulating drug and food intake. However, few studies have investigated hypothalamic responses to drugs and food or related cues in humans. METHODS: We examined regional responses in 20 cocaine-dependent and 24 healthy control participants exposed to cocaine/food (cocaine dependent) and food (healthy control) vs neutral cues during functional magnetic resonance imaging. We examined the relationship between imaging findings and clinical variables and performed mediation analyses to examine the inter-relationships between cue-related activations, tonic cocaine craving, and recent cocaine use. RESULTS: At a corrected threshold, cocaine-dependent participants demonstrated higher activation to cocaine than to food cues in the hypothalamus, inferior parietal cortex, and visual cortex. Cocaine-dependent participants as compared with healthy control participants also demonstrated higher hypothalamic activation to food cues. Further, the extent of these cue-induced hypothalamic activations was correlated with tonic craving, as assessed by the Cocaine Craving Questionnaire, and days of cocaine use in the prior month. In mediation analyses, hypothalamic activation to cocaine and food cues both completely mediated the relationship between the Cocaine Craving Questionnaire score and days of cocaine use in the past month. CONCLUSIONS: The results were consistent with the proposition that the mechanisms of feeding and drug addiction are inter-linked in the hypothalamus and altered in cocaine addiction. The findings provide new evidence in support of hypothalamic dysfunction in cocaine addiction.

Prolactin in combination with interferon-ß reduces disease severity in an animal model of multiple sclerosis.

Previous work has demonstrated that the hormone prolactin promotes oligodendrocyte precursor proliferation and remyelination following lysolecithin-induced demyelination of the mouse spinal cord. Prolactin, however, can elicit pro-inflammatory responses, and its use in the prototypical demyelinating and inflammatory condition, multiple sclerosis (MS), should thus be approached cautiously. Here, we sought to determine whether recombinant prolactin could alter the course of experimental autoimmune encephalomyelitis (EAE), an inflammatory animal model of MS. Consistent with previous literature, we found that prolactin activated leukocytes in vitro. Daily treatment with prolactin from around the time of onset of clinical signs, for 9 (days 9 to 17) or 25 (days 9 to 33) days did not increase clinical or histological signs of EAE over that of vehicle-treated mice. Instead, the combination of prolactin and a suboptimal dose of recombinant murine interferon-ß resulted in (days 9 to 17 group) or trended towards (days 9 to 33 group), a greater amelioration of clinical signs of EAE, compared to either treatment alone or to vehicle controls. Histological analyses corroborated the clinical EAE data. These results suggest that prolactin may be beneficial when administered in combination with interferon-ß in MS.