1. Probing the Dynamic Updating of Value in Schizophrenia Using a Sensory-Specific Satiety Paradigm. Positive and negative symptoms in schizophrenia (SZ) may derive, at least in part, from a disrupted ability to accurately and flexibly represent the value of stimuli and actions. To assess relationships between dimensions of psychopathology in SZ, and the tendency to devalue food stimuli, we administered a sensory-specific satiety (SSS) paradigm to SZ patients and controls. Within-group tests revealed that, while controls showed an effect of satiety that was sensory specific, patients showed an effect of satiety that was not, devaluing the sated and unsated foods similarly. In SZ patients, we observed correlations between the magnitude of SSS effects and measures of both positive and negative symptoms. We argue that the ability to flexibly and rapidly update representations of the value of stimuli and actions figures critically in the ability of patients with psychotic illness to process salient events and adaptively engage in goal-directed behavior. 2. Do schizophrenia patients show aberrant salience signaling in observational environments? The aberrant signaling of salience has been proposed as a mechanism of delusion formation in schizophrenia (SZ), and a growing body of evidence has emerged in support of this hypothesis. Salience, however, can take many forms in task environments, and may refer to outcomes that are unexpected, called reward prediction errors (RPEs), and also cues associated with uncertain outcomes. Furthermore, salient stimuli may have incentive value, or not. Our goal was to test if patients showed intact signaling of RPEs and other forms of salience in the context of a passive RPE-signaling task. Whole-brain analyses revealed main effects of unexpected reward omission in VS and DS, bilaterally, ventromedial PFC, VLPFC, R IPL, and R PHG. Regions showing a main effect of unexpected reward delivery included dorsolateral PFC, bilaterally, R precentral gyrus, and R IPL. Regions-of-interest analyses revealed main effects of unsigned RPE magnitude in bilateral AI, bilateral IPL, and DMPFC in the entire sample, with unexpected rewards and unexpected reward omissions evoking the greatest BOLD-signal activations. These same regions also showed main effects of outcome uncertainty, with cues associated with the more uncertain outcomes evoking the greater activations than cues associated with the more certain outcomes. Importantly, no group differences were observed in any of the ROIs associated with RPE-signaling (VS or DS), or any of the ROIs activated by salient cues or outcomes (AI, IPL, or DMPFC). Group differences were, however, observed in anterior medial PFC, a hypothesized default mode network (DMN) node deactivated by salient events, with SZs showing reduced deactivation of this area. Results suggest that, in an observational environment, patients with SZ may show an intact ability to activate striatal and cortical regions involved in the signaling of rewarding and non-rewarding salient events. By contrast, numerous findings of aberrant salience signaling in SZ patients, in the context of operant tasks, suggest that VS and AI responses to salient events in SZ patients may be particularly disrupted when events have motivational salience - implications for behavioral modification. Finally, our observation of reduced deactivation of a hypothesized DMN node in SZs suggests that abnormalities in schizophrenia may particularly affect interactions of the SN with other brain networks, such as the DMN. 3. Default Network Hyperdeactivation in Schizophrenia. When studying selective attention in people with schizophrenia (PSZ), a counterintuitive but replicated finding has been that PSZ display larger performance benefits by a spatial cue that predicts the location of an upcoming target stimulus relative to a non-predictive cue. Possible explanations are that PSZ hyperfocus attention in response to predictive cues, or that an inability to maintain a broad attentional window impairs performance when the cue does not predict the target location. Over-recruitment in response to predictive cues of regions typically involved in top-down focusing of spatial attention would support the former possibility, and an inappropriate recruitment of these regions in response to non-predictive cues the latter. We probed regions of the attentional orienting network while PSZ and matched control subjects performed a visuospatial attention task. As predicted, PSZ displayed a larger RT difference between predictive and non-predictive cue trials than HCS. Activity in frontoparietal and occipital regions was greater for predictive than for non-predictive cues. This effect was remarkably similar for PSZ and HCS. There was no sign that these regions were over-recruited when the cue was predictive, or that they were inappropriately recruited when the cue was non-predictive. However, PSZ differed from HCS in their cue-dependent deactivation of the default mode network (DMN). Unexpectedly, PSZ displayed significantly greater DMN deactivation than HCS in predictive cue trials, which may reflect a tendency to expend more processing resources when focusing attention in space. 4. Nicotinic Modulation of the Default Network of Resting Brain Function in Non-Smokers. In this study, we tested whether effects would generalize to non-smokers and how these effects would compare to the nicotinic antagonist mecamylamine (MEC). In the VAP, nicotine reduced reaction time (RT), omission errors, and the trial-by-trial variability of RT across task conditions. The effects of MEC were restricted to a task block that was twice as long as other blocks, presumably challenging sustained attention processes. In the N-back task, nicotine enhanced target detection across conditions, while MEC slowed RT, particularly in the 2-back condition. In the attention paradigm, the previously reported potentiation of cue-induced DMN deactivation by nicotine was not apparent overall. However, this effect did emerge in mPFC, PCC, and superior frontal cortex, central regions of the DMN, in task blocks with a faster event rate. In blocks with a slower event rate and more time off task, in which DMN regions were overall more active, cue-induced deactivation was more pronounced, and nicotine tended to reduce rather than enhance this deactivation. Within the regions modulated by nicotine, the effects of MEC trended into the same direction as those of nicotine. In the N-back task, deactivation of the DMN was more pronounced in the 2-back condition. MEC reduced this deactivation in the mPFC. Despite robust effects of nicotine on N-back task performance, no BOLD effects of nicotine were observed in this task. The potentiating effects of nicotine on task-induced DMN deactivation previously described appear to generalize to non-smokers, but they heavily depend on the specific task conditions and the basal level of task-induced deactivation of these regions. The pattern of activity with MEC suggests that, at least in part, these effects may be mediated by nicotinic receptor desensitization.
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