1. Default Network Dysfunction Underlying Visuospatial Attention Deficits in Schizophrenia. The default network of resting brain functions (DN) is thought to subserve stimulus-independent thought processes such as mind-wandering and deactivates during external processing tasks. This down-regulation is generally advantageous for task performance. Studies reported reduced task-induced DN deactivation in people with schizophrenia (PSZ), interpreted as a primary inability to suppress task-independent thought processes. However, reduced DN deactivation may be secondary to reduced task engagement due to a primary difficulty to recruit the processes and networks necessary to perform the cognitive tasks. In this study, PSZ and matched healthy control subjects (HCS) performed a visuospatial attention paradigm and a change detection peradigm while undergoing functional MRI. Subjects performed full-length versions of the tasks on a separate day preceding the scan, to ensure familiarity with the required operations. PSZ recruited frontoparietal attentional control regions in response to task demands to a lesser degree than HCS. Regions of the DN, functionally defined as task-negative regions, displayed a uniform pattern of effects: Relative to HCS, PSZ substantially hyperdeactivated the DN in response to attention task trials eliciting spatial shifts of attention and in response to the most challenging change detection condition. DN hyperdeactivation in PSZ was correlated with the reduced recruitment of top-down attentional control regions. We suggest DN hyperdeactivation to be a compensatory mechanism in PSZ for a failure to engage brain systems mediating the specific cognitive functions required by current task demands, perhaps reflecting non-specific effort. This can be observed under conditions allowing PSZ to engage in task performance to a similar degree as HCS. 2. Dopamine Function and Reward Processing in Schizophrenia. In the past year, we completed and analyzed data from an experiment on the rapid updating of value representations, in patients with schizophrenia (SZ) and healthy volunteers (HV). Based on our prior findings, we hypothesized that SZ patients would show a reduced ability to rapidly modulate the values assigned to food stimuli, within a session. We tested this hypothesis using a sensory-specific satiety (SSS) paradigm, in which participants were fed small amounts of two liquid foods (chocolate hazelnut drink and V8) before and after a session in which participants were asked to consume one or the other food to the point of being """"""""full, but not uncomfortable"""""""". We found that, while HV devalued the food stimulus fed to satiety to a greater degree than the food stimulus not fed to satiety, SZ patients tended to devalue the two foods equally, after consuming only one to satiety. This results suggests that, even if SZ patients appear to show normal hedonic experience, if probed in a cross-sectional way, they may still have an impairment in the rapid updating the value of stimuli, based on changing internal state. 3. Prenatal Drug Exposure (PDE): We examined the consequences of exposure to drugs in utero on prospective memory, the ability to complete an intended action at a specified future point in time (remembering to remember) in a cohort of adolescents exposed to drugs (primarily cocaine) in utero. 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. 4. Gender Differences in fMRI Social Stress Task: We modified the Trier Social Stress Test (TSST) for use in the MR environment. Participants were videotaped performing the TSST and viewed their own performance and that of a same sex other while being scanned. We hypothesized that the task would activate regions associated with emotional regulation and that males and females would have different patterns of activation. Robust activation in anterior cingulate, bilateral insula and other regions was seen. Males reported modest stress initially which quickly dissipated. Females reported modest stress that increased during the task. This behavioral result was coupled with increased activation in males in numerous regions including inferior frontal gyrus, a region known for its role in inhibition, and numerous other frontal, insular, cingulate and cerebellar regions. Females did not exhibit any regions with activity greater than males. The result illustrates gender differences in response to social stress that underlie the rapid suppression of social stress in males compared to females. 5. Nicotinic Modulation of the Default Network of Resting Brain Function. Many disorders where attentional problems are a hallmark display abnormal regulation of the default network of resting brain function that maintains internally directed thought when the mind is free to wander. There is indication that nicotine improves attention by aiding task-induced deactivation of the default network, and this mechanism may be of therapeutic benefit. We tested the effects of nicotine and the nicotinic antagonist mecamylamine on default network functioning during a visuospatial attention task and a letter N-back task in a population of never-smokers. In the attention task, nicotine reduced reaction time (RT) and omission errors across task conditions. The effects of mecamylamine were restricted to a long task block challenging sustained attention processes and consisted of RT slowing. Potentiation of cue-induced default network deactivation by nicotine emerged in several central regions of the default network in task blocks with a faster event rate. In blocks with a slower event rate and more time off task, cue-induced deactivation was more pronounced, and nicotine tended to reduce this deactivation. The effects of mecamylamine were not significant. In the N-back task, nicotine enhanced target detection across conditions, while mecamylamine slowed RT, particularly in the 2-back condition. Deactivation of the default network was more pronounced in the 2-back than 0-back condition. Mecamylamine reduced this deactivation in the medial prefrontal cortex and angular gyrus/precuneus, particularly in the 2-back condition in which it caused the largest performance impairment. No BOLD effects of nicotine were observed in this task. Thus, nicotinic receptor tone does impact default network functioning in non-smokers, but the effects appear to heavily depend on the specific task conditions and the basal level of task-induced deactivation of these regions.
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