1. Functional neurocircuits and neuroimaging biomarkers of tobacco use disorder. Drug abuse and addiction remain major public health issues, exemplified by the opioid epidemic currently devastating the United States. Treatment outcomes across substance use disorders remain unacceptably poor, wherein drug discovery/development for this multifaceted neuropsychiatric disorder focuses on single molecular-level targets. Rather, our opinion is that a systems-level neuroimaging perspective is crucial for identifying novel therapeutic targets, biomarkers to stratify patients, and individualized treatment strategies. Focusing on tobacco use disorder, we advocate a brain systems-level perspective linking two abuse-related facets (i.e., state-like withdrawal and trait-like addiction severity) with specific neurocircuitry (insula- and striatum-centered networks). To the extent that precise neurocircuits mediate distinct facets of abuse, treatment development must adopt not only a systems-level perspective, but also multi-intervention rather than mono-intervention practices. 2. Nicotine abstinence influences the calculation of salience in discrete insula circuits. Insular subdivisions show distinct patterns of resting-state functional connectivity (rsFC) with specific brain regions, each with different functional significance. Seeds in these subdivisions are employed to characterize the effects of acute nicotine abstinence on rsFC between insula subdivisions and brain networks implicated in addiction and attentional control. In a within-subjects design, resting-state blood oxygen level-dependent data were collected from treatment-seeking smokers (N= 20) following smoking satiety and again following 48 hours of nicotine abstinence. Three right hemisphere insular regions of interest (dorsal, ventral, and posterior) served as seeds for analyses. Indices of both static and dynamic rsFC were obtained and correlated with indices of subjective withdrawal and behavioral performance. Abstinence-induced physiological, subjective, and cognitive differences were observed. Overall dynamic rsFC was reduced during abstinence, and circuits containing each insular seed showed changes in rsFC as a function of nicotine abstinence. Specifically, dorsal and posterior insular connections to the default mode and salience networks were enhanced, while a previously undescribed ventral insular connection to the executive control network was reduced. Further, static rsFC was significantly correlated with subjective ratings of aversive affect and withdrawal in the modified ventral and posterior insular-seeded circuits. As predicted, divergent connections between insula subdivisions and anticorrelated resting brain networks were observed during abstinence. These changes reflect an attentional bias toward aversive affective processing and not directly away from exogenous cognitive processing, suggesting a coordinated modulation of circuits associated with interoceptive and affective processing that instantiates an aversive state during nicotine abstinence. 3. Evidence of subgroups in smokers as revealed in clinical measures and evaluated by neuroimaging data: A preliminary study. To date, fractionation of the nicotine addiction phenotype has been limited to that based primarily on characteristics of cigarette use, although it is widely appreciated that a variety of individual factors are associated with tobacco use disorder. Identifying subtypes of tobacco use disorder based on such factors may lead to better understanding of potential treatment targets, individualize treatments and improve outcomes. In this preliminary study, to identify potential subgroups, we applied hierarchical clustering to a broad range of assessments measuring personality, IQ and psychiatric symptoms, as well as various environmental and experiential characteristics from 102 otherwise healthy cigarette smokers. The identified subgroups were further compared on various resting-state fMRI measures from a subset (N = 65) of individuals who also underwent resting-state fMRI scanning. The clustering dendrogram indicated that smokers can be divided into three subgroups. Each subgroup had unique clinical assessment characteristics. The division yielded imaging differences between subgroups in the supplementary motor area/middle cingulate cortex and the cuneus. Regression analyses showed that amplitude of low frequency fluctuations in the supplementary motor area/middle cingulate cortex differed between groups and were negatively correlated with the Toronto Alexithymia Scale subscale Difficulty Describing Feelings. 4. Mapping cortical brain asymmetry in 17,141 healthy individuals worldwide: Findings from the ENIGMA Lateralization Working Group. Hemispheric asymmetry is a cardinal feature of human brain organization. Altered brain asymmetry has also been linked to some cognitive and neuropsychiatric disorders. Here, the ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) Consortium presents the largest-ever analysis of cerebral cortical asymmetry and its variability across individuals. Cortical thickness and surface area were assessed in MRI scans of 17,141 healthy individuals from 99 datasets worldwide. Results revealed widespread asymmetries at both hemispheric and regional levels, with a generally thicker cortex but smaller surface area in the left hemisphere relative to the right. Regionally, asymmetries of cortical thickness and/or surface area were found in the inferior frontal gyrus, transverse temporal gyrus, parahippocampal gyrus, and entorhinal cortex. These regions are involved in lateralized functions, including language and visuospatial processing. In addition to population-level asymmetries, variability in brain asymmetry was related to sex, age, and intracranial volume. Interestingly, we didnt find significant associations between asymmetries and handedness. Finally, with two independent pedigree datasets (n = 1,443 and 1,113, respectively), we found several asymmetries showing significant, replicable heritability. The structural asymmetries identified and their variabilities and heritability provide a reference resource for future studies on the genetic basis of brain asymmetry and altered laterality in cognitive, neurological, and psychiatric disorders.
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