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.

Alcohol Expectancy and Cerebral Responses to Cue-Elicited Craving in Adult Nondependent Drinkers.

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

Problem Drinking, Alcohol Expectancy, and Thalamic Resting-State Functional Connectivity in Nondependent Adult Drinkers.

Alcohol misuse is associated with thalamic dysfunction. The thalamus comprises subnuclei that relay and integrate information between cortical and subcortical structures. However, it is unclear how the subnuclei contribute to thalamic dysfunctions in problem drinking. We investigated resting-state functional connectivity (rsFC) of thalamic subregions in 107 nondependent drinkers (57 women), using masks delineated by white matter tractography. Thalamus was parceled into motor, somatosensory, visual, premotor, frontal association, parietal association, and temporal association subregions. Whole-brain linear regression, each against Alcohol Use Disorders Identification Test (AUDIT) and positive alcohol expectancy (AE) score with age as a covariate, was performed for each seed, for men and women combined, and separately. Overall, problem drinking was associated with increased thalamic connectivities, whereas AE was associated with a mixed pattern of increased and decreased connectivities. Motor, premotor, somatosensory, and frontal association thalamic connectivity with bilateral caudate head was positively correlated with AUDIT score in men and women combined. Connectivity of the right caudate head with frontal association and premotor thalamus was also positively correlated with AE score in men and women combined. In contrast, motor and premotor thalamic connectivity with a number of cortical and subcortical structures showed sex differences in the correlation each with AUDIT and AE score. In mediation analyses, AE score completely mediated the correlation between thalamic caudate connectivity and AUDIT score, whereas the model where AE contributed to problem drinking and, in turn, altered thalamic caudate connectivity was not supported. To conclude, thalamic subregional rsFCs showed both shared and distinct changes and sex differences in association with problem drinking and AE. Increased thalamic caudate connectivity may contribute to problem drinking via enhanced AE. The findings suggest the importance of examining thalamic subdivisions and sex in investigating the functional roles of thalamus in problem drinking.

A cerebellar thalamic cortical circuit for error-related cognitive control.

Error detection and behavioral adjustment are core components of cognitive control. Numerous studies have focused on the anterior cingulate cortex (ACC) as a critical locus of this executive function. Our previous work showed greater activation in the dorsal ACC and subcortical structures during error detection, and activation in the ventrolateral prefrontal cortex (VLPFC) during post-error slowing (PES) in a stop signal task (SST). However, the extent of error-related cortical or subcortical activation across subjects was not correlated with VLPFC activity during PES. So then, what causes VLPFC activation during PES? To address this question, we employed Granger causality mapping (GCM) and identified regions that Granger caused VLPFC activation in 54 adults performing the SST during fMRI. These brain regions, including the supplementary motor area (SMA), cerebellum, a pontine region, and medial thalamus, represent potential targets responding to errors in a way that could influence VLPFC activation. In confirmation of this hypothesis, the error-related activity of these regions correlated with VLPFC activation during PES, with the cerebellum showing the strongest association. The finding that cerebellar activation Granger causes prefrontal activity during behavioral adjustment supports a cerebellar function in cognitive control. Furthermore, multivariate GCA described the "flow of information" across these brain regions. Through connectivity with the thalamus and SMA, the cerebellum mediates error and post-error processing in accord with known anatomical projections. Taken together, these new findings highlight the role of the cerebello-thalamo-cortical pathway in an executive function that has heretofore largely been ascribed to the anterior cingulate-prefrontal cortical circuit.

Increased error-related thalamic activity during early compared to late cocaine abstinence.

Altered cognitive control is implicated in the shaping of cocaine dependence. One of the key component processes of cognitive control is error monitoring. Our previous imaging work highlighted greater activity in distinct cortical and subcortical regions including the dorsal anterior cingulate cortex (dACC), thalamus and insula when participants committed an error during the stop signal task (Li et al., 2008b). Importantly, dACC, thalamic and insular activity has been associated with drug craving. One hypothesis is that the intense interoceptive activity during craving prevents these cerebral structures from adequately registering error and/or monitoring performance. Alternatively, the dACC, thalamus and insula show abnormally heightened responses to performance errors, suggesting that excessive responses to salient stimuli such as drug cues could precipitate craving. The two hypotheses would each predict decreased and increased activity during stop error (SE) as compared to stop success (SS) trials in the SST. Here we showed that cocaine dependent patients (PCD) experienced greater subjective feeling of loss of control and cocaine craving during early (average of day 6) compared to late (average of day 18) abstinence. Furthermore, compared to PCD during late abstinence, PCD scanned during early abstinence showed increased thalamic as well as insular but not dACC responses to errors (SE>SS). These findings support the hypothesis that heightened thalamic reactivity to salient stimuli co-occur with cocaine craving and loss of self control.