This study aims to characterize cognitive deficits in schizophrenia based on assumptions about the effects of low dopamine (DA) on prefrontal function. We sought to determine if a representative group of young chronic patients with schizophrenia (SCZ) would demonstrate selective impairments in set shifting processes of the CANTAB intra-dimensional/extra-dimensional (IDED) task. Based on the results of cortical hypodopaminergic states in non-human primates (for C_D) and effects of dorsolateral prefrontal (DLPFC) cortical lesions on set shifting and prior results in SCZ, we predicted that patients would have prominent difficulties with Compound Discrimination (where irrelevant stimuli is introduced into the task) and Extra-Dimensional Shifting (EDS) (where new stimulus dimension must be attended). We found evidence that patients were susceptible to introduction of unreinforced irrelevant stimuli at the C_D stage, such that the previously rewarded target stimuli no longer held hegemony as a representation. This type of processing failure may reflect difficulties in stabilizing a representation and is consistent with effects of prefrontal (PF) hypodopaminergia in primates. Secondarily, survivors of this stage experienced marked difficulties on ED-stage, suggestive of classic prefrontal failures.? ? Efforts to enhance prefrontal-related cognition, which have focused on catecholaminergic stimulant drugs, have been unsatisfactory. The demonstration that a functional polymorphism in the catechol-o-methyltransferase (COMT) gene impacts PF cognition raises the possibility of a novel pharmacological approach for the treatment of PF lobe executive dysfunction. We performed a randomized, double blind, placebo controlled, and crossover design of this drug in normal subjects stratified by COMT genotype. COMT enzyme activity was measured in peripheral blood. We found significant drug effects on measures of executive function and verbal episodic memory and a significant drug effect by genotype interaction, such that COMT Val/Val improved, whereas Met/Met worsened on Tolcapone. Functional magnetic resonance imaging (fMRI) revealed a significant tolcapone-induced improvement in the efficiency of information processing in prefrontal cortex (PFC) during a working memory (WM) test. This study demonstrates enhancement of PF cortical function in normal human subjects with a nonstimulant drug having COMT inhibitory activity. Our results are consistent with data from animal studies and from computational models of the effects of selective enhancement of DA signaling in the PFC. ? ? Incoherent discourse, with a disjointed flow of ideas, is a cardinal symptom in several psychiatric and neurological conditions. We sought to validate an objective, intrinsically reliable, computational approach to quantifying speech incoherence. Patients with SCZ and healthy controls were administered a variety of language tasks. The speech generated was transcribed and the coherence computed using Latent Sematic Analysis (LSA). The discourse was also analyzed with a standard clinical measure of thought disorder. In word association and generation tasks LSA derived coherence scores were sensitive to differences between SCZ and controls, and correlated with clinical measures of thought disorder. In speech samples LSA could be used to localize where in sentence production incoherence occurs, predict levels of incoherence as well as whether discourse belonged to a SCZ or control. In conclusion, LSA can be used to assay disordered language production so as to both complement human clinical ratings as well as experimentally parse this incoherence in a theory-driven manner. ? ? A wide-range of neuropsychological tests is typically necessary to identify cognitive deficits in SCZ and routinely measure multiple cognitive processes, with many tests leading to the problem of multiple comparisons. This study investigated the feasibility of using factor analysis to reduce the number of phenotypic variables and to better understand the underlying cognitive architecture in SCZ. Using factor analysis, we identified factor parameters for SCZ, their unaffected siblings, and control subjects, both separately and as a composite group. Our analysis yielded a 7-factor model that included verbal memory, working memory, visual memory, IQ/speed/fluency, executive function, attention and digit span. Because we were able to identify a factor structure representative of all the groups, reduced 9 neuropsychological tests with 24 total variables to 7 variables of interests. This reduced the complexity of large batteries of cognitive measures to more manageable numbers of phenotypic variables. Furthermore, these findings provide the first confirmation that cognitive structure is comparable in family members of SCZ patients, as well as in patients themselves and controls. The difference in cognition between affected individuals, their siblings and controls is mainly in the level of performance on neuropsychological tests, and not in the fundamental cognitive architecture underlying performance. In addition, this work serves as further proof of the concept that factor analysis can be useful in reducing the complexity of cognitive measures. Reducing variables will decrease redundant comparisons and increase replicability by reducing type 1 error due to multiple comparisons. This approach may lead to the development of improved pharmacological treatments, although more research is needed in order to understand whether specific cognitive domains are linked to separate abnormalities at the neurological level. ? ? Emotion plays a crucial role in regulating the interactions humans have with their social environment. The amygdala complex in the medial temporal cortex has been considered a central structure in the generation of both normal and pathological emotional behaviors, especially involving fear mechanisms. Several studies have consistently shown strong amygdala activity in positron emission tomography (PET) and fMRI in response to angry and fearful faces and in response to negative words. However, these methods are limited by the restricted temporal resolution inherent in these methods. Magnetoencephalography (MEG) provides an alternative method to combine the spatiotemporal characteristics ('where' and 'when') of information processing with superior temporal resolution. Synthetic aperture magnetometry (SAM) used in the analysis of MEG data identifies micro-oscillatory power changes (event-related synchronization (ERS) or event-related desynchronization (ERD) in specific frequency evoked by stimuli. We used MEG to examine amygdala activity during a linguistic affective priming task. In the analysis of MEG data, we identified a left amygdala power increase in the theta frequency range during priming involving negative words. This study provides evidence for theta power changes in the amygdala and demonstrates that the analysis of brain oscillations provides a powerful tool to explore mechanisms implicated in emotional processing. This is the first experiment using MEG to report an increase in left amygdala activation synchronizing in the theta frequency range during affective priming with negative word pairs. Moreover, we found that the amygdala displayed a time-dependent increase in responsiveness (between 150 and 400ms) after the target presentation. These results indicate that theta power changes in the amygdala are related to performance on an emotional priming paradigm. SAM analysis of MEG provides a powerful tool for examining the mechanisms involved in emotional processing. Further analysis using such time frequency methods promise to clarify further the dynamic interactions of the amygdala and the neocortex.
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