1. Prenatal Drug Exposure (PDE): PDE adolescents showed a trend toward a reduced ability to remember items previously paired with an emotionally charged or neutral picture. Compared to controls, they also had an enhanced amygdala response to affectively charged pictures while amygdala activation disrupted subsequent retrieval of paired objects rather than enhancing it. PDE adolescents did not differ from unexposed adolescents in prospective memory. Prospective memory in all adolescents was related to cortical thickness in frontal and parietal regions as well as volume of putamen and hippocampus. PDE adolescents were also found to have reduced volume in several frontal regions after controlling for total cortical gray matter volume, age, gender, and tobacco and cigarette exposure in utero. In general, regional volumes were inversely related to various measures of behavioral problems. 2. Dopamine Function and Reward Processing in Schizophrenia (SZ): We examined brain activity related to reinforcement processing, reinforcement-driven learning, and decision making in SZ and their possible relationship to clinical symptoms. fMRI data analyses from a Sensory-specific Satiety paradigm, indicate that when fed to satiety on a specific food (smooth, sweet drink, or grainy, savory drink) SZ show devaluation of food stimuli that is more generalized and less sensory-specific than healthy controls. Analysis is ongoing. 3. Gene x environment effects on the risk for addiction: People with certain genes are more vulnerable to positive and negative environmental influences than others. Previous studies suggest that those who carry these genes and have experienced negative environmental factors will be at higher risk for psychological disorders such as depression and ADHD. Due to the high rate of comorbidity between these disorders and addiction, we hypothesized that there is a GxE effect on addiction such that individuals who carry certain susceptibility genes and have faced negative environmental influences will be at higher risk for smoking and addiction. Also, that this interaction will be mediated by factors such as impulsivity, harm avoidance, or novelty seeking. The 5 genes of interest were DRD2, DRD4, MAOA, 5HTTLPR, and HTR2A. Individuals were dichotomized by whether or not they carried 3 or more of these genes. We measured adversity through the Childhood Trauma Questionnaire and the Barratt Impulsivity Scale (BIS) and Temperament and Character Inventory to analyze differences between groups. We found a GxE effect on addiction as well as on motor impulsivity and reward dependence (RD) and a significant interaction of BIS and RD on smoking status. We also used rs-fMRI to study differences in functional connectivity between groups and found a main effect of gene on a dorsal striatum to right basolateral amygdala pathway. 4. Acute nicotine administration effects on fractional anisotropy (FA) of cerebral white matter and associated attention performance: Nicotinic acetylcholine receptors are present in the cerebral white matter (WM). We hypothesized that WM response to nicotine can be detected by diffusion tensor imaging (DTI);and that such responses may be associated with nicotine-led cognitive enhancement in sustained attention using a randomized, nicotine-placebo patch, crossover, double-blind clinical trial in two non-overlapping cohorts of smokers. WM integrity was measured by FA values for the whole brain and 9 preselected WM tracts using tract-based-spatial-statistics. Nicotine significantly enhanced FA values for the genu of corpus callosum compared with placebo in smokers with low recent smoking exposure. This finding was replicated in the second cohort, with values explained 22% of variance in performance of a sustained attention task during the nicotine session, but only in SZ patients. Acute pharmacological influence of nicotine patch on WM integrity appeared present, but was dependent on nicotine intake from recent smoking. Change in the WM integrity in the genu of corpus callosum was associated with a significant proportion of variability of nicotine-led changes in sustained attention/WM of the smokers. 5. Insula's functional connectivity with ventromedial prefrontal cortex mediates the impact of trait alexithymia on state tobacco craving. Alexithymia is a personality trait characterized by difficulty identifying and describing subjective emotional experiences. Decreased aptitude in the perception, evaluation, and communication of affectively laden mental states is associated with reduced emotion regulation, more severe drug craving in addicts, and structural/functional alterations in insula and anterior cingulate cortex (ACC). The insula and ACC represent sites of convergence between the putative neural substrates of alexithymia and those perpetuating smoking. Higher alexithymia in smokers predicted reduced rsFC strength between the right anterior insula (aI) and ventromedial prefrontal cortex (vmPFC) and more severe tobacco craving during nicotine withdrawal. The aI-vmPFC circuit fully mediated this alexithymia-craving relation. That is, elevated alexithymia predicted decreased aI-vmPFC rsFC and, in turn, decreased aI-vmPFC rsFC predicted increased craving during withdrawal. A moderated mediation analysis indicated that effect was not observed following drug administration, suggesting that a weakened right aI-vmPFC functional circuit confers increased liability for tobacco craving during abstinence. 6. Disruption of anterior insula modulation of large-scale brain networks in schizophrenia (SZ). Systems level modeling of fMRI data has demonstrated dysfunction of several large-scale brain networks in SZ, which could be due to diffuse pathology across multiple networks or, alternatively, dysfunction at converging control(s) common to these networks. We tested the hypothesis that right anterior insula modulation of central executive and default mode networks is disrupted in SZ and associated with cognitive deficits. We found compelling, corroborative evidence of disruption of right anterior insula modulation of central executive and default mode networks in patients with SZ. The strength of right anterior insula modulation of these networks predicted cognitive performance. 7. Reward, default, and executive control networks in set-shifting impairments in SZ. PRL deficits may be largely due to processes downstream from feedback processing, involving both the activation of executive control task regions and deactivation of default mode network (DMN) components. SZ patients and 21 controls were presented with eight pairs of fractal stimuli, for 50 trials each. For each pair, subjects learned to choose the more frequently-rewarded (better) stimulus. Each time a criterion was reached, the better stimulus became the worse one, and the worse became the better. SZ patients showed comparable deactivation of VS in response to negative feedback, but reduced deactivation of DMN components including mPFC. The magnitudes of patients'punishment-evoked deactivations in VS and ventromedial PFC correlated significantly with clinical ratings for avolition/anhedonia, suggesting that SZ is associated with a reduced ability to deactivate components of default mode networks, following the presentation of informative feedback and that motivational deficits in SZ relate closely to feedback-evoked activity in reward circuit components. These results also confirm a role for ventrolateral and dorsomedial PFC in the execution of response-set shifts.
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