Brain Oscillatory Correlates of Altered Executive Functioning in Positive and Negative Symptomatic Schizophrenia Patients and Healthy Controls.

Working Memory and executive functioning deficits are core characteristics of patients suffering from schizophrenia. Electrophysiological research indicates that altered patterns of neural oscillatory mechanisms underpinning executive functioning are associated with the psychiatric disorder. Such brain oscillatory changes have been found in local amplitude differences at gamma and theta frequencies in task-specific cortical areas. Moreover, interregional interactions are also disrupted as signified by decreased phase coherence of fronto-posterior theta activity in schizophrenia patients. However, schizophrenia is not a one-dimensional psychiatric disorder but has various forms and expressions. A common distinction is between positive and negative symptomatology but most patients have both negative and positive symptoms to some extent. Here, we examined three groups-healthy controls, predominantly negative, and predominantly positive symptomatic schizophrenia patients-when performing a working memory task with increasing cognitive demand and increasing need for executive control. We analyzed brain oscillatory activity in the three groups separately and investigated how predominant symptomatology might explain differences in brain oscillatory patterns. Our results indicate that differences in task specific fronto-posterior network activity (i.e., executive control network) expressed by interregional phase synchronization are able to account for working memory dysfunctions between groups. Local changes in the theta and gamma frequency range also show differences between patients and healthy controls, and more importantly, between the two patient groups. We conclude that differences in oscillatory brain activation patterns related to executive processing can be an indicator for positive and negative symptomatology in schizophrenia. Furthermore, changes in cognitive and especially executive functioning in patients are expressed by alterations in a task-specific fronto-posterior connectivity even in the absence of behavioral impairment.

EEG theta phase coupling during executive control of visual working memory investigated in individuals with schizophrenia and in healthy controls.

In healthy humans, it has been shown that executive functions are associated with increased frontal-midline EEG theta activity and theta phase coupling between frontal and posterior brain regions. In individuals with schizophrenia, central executive functions are supposed to be heavily impaired. Given that theta phase coupling is causally involved in central executive functions, one would expect that patients with an executive function deficit should display abnormal EEG theta synchronization. We therefore investigated executive functioning in 21 healthy controls and 21 individuals with schizophrenia while they performed a visuospatial delayed match to sample task. The task required either high executive demands (manipulation of content in working memory [WM]) or low executive demands (retention of WM content). In addition, WM load (one vs. three items) was varied. Results indicated higher frontal theta activity for manipulation processes than for retention processes in patients with schizophrenia, as compared with healthy controls, independently of WM load. Furthermore, individuals with schizophrenia revealed a reduction in theta phase coupling during early stages of the delay period for retention, as well as for manipulation processes at high-WM loads. Deviations in theta phase coupling in individuals with schizophrenia were mainly characterized by aberrant fronto-posterior connections, but also by attenuated posterior connections during manipulation of high-WM load. To conclude, fronto-parietal theta coupling seems to be substantially involved in executive control, whereas frontal theta activity seems to reflect general task demands, such as deployment of attentional resources during WM.

Influence of age and gender on risperidone plasma concentrations.

There is limited information on gender- and age-specific effects on plasma concentrations of risperidone and its active metabolite, 9-hydroxyrisperidone. The present study investigated dose- and weight-adjusted plasma concentrations of risperidone and its metabolite in three age groups (45 years, 45-60 years, over 60 years). Gender-specific differences were examined in the whole sample and for the premenopausal subgroup. One hundred and twenty-nine patients (18-93 years) were included in the study, 52 (40%) male and 77 (60%) female. Concentrations of risperidone and 9-hydroxyrisperidone were measured at steady-state by high-performance liquid chromatography with electrochemical detection (HPLC-ED). When total plasma concentrations (risperidone plus 9-hydroxyrisperidone) were adjusted for daily maintenance dose (ng/mL/mg C/D ratio), significant differences between all age groups were found. We found a mean increase of the C/D ratio by 34.8% per decade in patients older than 42 years. No significant sex-related differences in the average plasma concentrations were observed for the whole sample and for the premenopausal subgroup. This study shows clear evidence of higher risperidone total plasma concentrations for patients over 40 years of age. This linear increase (over 30% per decade) may then lead to an increased incidence of adverse effects in elderly patients.