An fMRI study of visual attention and sensorimotor function before and after antipsychotic treatment in first-episode schizophrenia.

While much is known about receptor affinity profiles of antipsychotic medications, less is known about their impact on functional brain systems in patients with schizophrenia. We conducted functional magnetic resonance imaging (fMRI) studies with first-episode schizophrenia patients as they made saccades to unpredictable visual targets before and after 4-6 weeks of antipsychotic treatment. Matched healthy individuals were scanned at similar time intervals. Pretreatment, patients had less activation in frontal and parietal eye fields and cerebellum. After treatment these disturbances were not present, suggesting improved function in attentional and sensorimotor systems. Other pretreatment abnormalities were noted in sensory and ventromedial prefrontal cortex, but after treatment these abnormalities were absent or less prominent, in line with improved function in attentional systems. In addition, although not abnormal at baseline, there was reduced activity after treatment in dorsal prefrontal cortex, dorsal striatum, and dorsomedial thalamus, suggesting a potential adverse effect of treatment on frontostriatal systems, perhaps related to dopamine blockade in the caudate. These findings provide evidence for a complex impact of antipsychotic medication on functional brain systems in schizophrenia and illustrate the potential of neuroimaging biomarkers for both adverse and beneficial drug effects on functional brain systems.

What aspects of emotional functioning are impaired in schizophrenia?

Disturbances in emotional functioning are a major cause of persistent functional disability in schizophrenia. However, it is not clear what specific aspects of emotional functioning are impaired. Some studies have indicated diminished experience of positive affect in individuals with schizophrenia, while others have not. The current study assessed emotional responses by 34 individuals with schizophrenia and 35 demographically matched healthy participants to 131 images sampling a wide range of emotional arousal and valence levels. Ratings of affective response elicited by individual images were highly correlated across the groups (r's>.90), indicating similar emotional experiences at the moment of stimulus exposure. However, the data did not indicate strong relationships between ratings of the emotional impact of the images and most measures of day-to-day emotional processing. These results demonstrate that individuals with schizophrenia report "normal" emotional responses to emotional stimuli, and thus suggests that deficits in emotional functioning associated with the disorder are likely to occur further downstream, and involve the effective integration of emotion and cognition for adaptive functioning in areas such as goal-setting, motivation, and memory.

Oculomotor and neuropsychological effects of antipsychotic treatment for schizophrenia.

Cognitive enhancement has become an important target for drug therapies in schizophrenia. Treatment development in this area requires assessment approaches that are sensitive to procognitive effects of antipsychotic and adjunctive treatments. Ideally, new treatments will have translational characteristics for parallel human and animal research. Previous studies of antipsychotic effects on cognition have relied primarily on paper-and-pencil neuropsychological testing. No study has directly compared neurophysiological biomarkers and neuropsychological testing as strategies for assessing cognitive effects of antipsychotic treatment early in the course of schizophrenia. Antipsychotic-naive patients with schizophrenia were tested before treatment with risperidone and again 6 weeks later. Matched healthy participants were tested over a similar time period. Test-retest reliability, effect sizes of within-subject change, and multivariate/univariate analysis of variance were used to compare 3 neurophysiological tests (visually guided saccade, memory-guided saccade, and antisaccade) with neuropsychological tests covering 4 cognitive domains (executive function, attention, memory, and manual motor function). While both measurement approaches showed robust neurocognitive impairments in patients prior to risperidone treatment, oculomotor biomarkers were more sensitive to treatment-related effects on neurocognitive function than traditional neuropsychological measures. Further, unlike the pattern of modest generalized cognitive improvement suggested by neuropsychological measures, the oculomotor findings revealed a mixed pattern of beneficial and adverse treatment-related effects. These findings warrant further investigation regarding the utility of neurophysiological biomarkers for assessing cognitive outcomes of antipsychotic treatment in clinical trials and in early-phase drug development.

Antipsychotic drugs exacerbate impairment on a working memory task in first-episode schizophrenia.

BACKGROUND: This study sought to replicate previous findings of worsened performance on a translational spatial working memory task among antipsychotic-naïve first-episode schizophrenia patients after antipsychotic treatment and to extend these findings by examining whether changes in the allocation of covert attention contribute to this effect. METHODS: Fourteen antipsychotic-naïve schizophrenia patients performed an oculomotor delayed response task before and 6 weeks after antipsychotic treatment (risperidone n = 11; olanzapine n = 3). Fifteen matched healthy individuals were studied in parallel. RESULTS: Patients' pretreatment deficit in accurately remembering spatial locations was exacerbated by antipsychotic treatment, consistent with previous findings; however, this occurred only when covert attention was directed away from remembered locations during delay periods. CONCLUSIONS: Disruption in the allocation of covert attention might contribute to patients' decline in spatial working memory after antipsychotic treatment. Alterations in prefrontal dopaminergic systems or reduced thalamocortical drive might account for this apparent adverse cognitive effect of antipsychotic treatment.

Failure of positive but not negative emotional valence to enhance memory in schizophrenia.

Abnormalities in the integration of emotion and cognition have long been considered hallmark characteristics of schizophrenia. Study authors used a well-established emotional memory model from the neuroscience literature to assess the facilitative impact of emotional valence of information on long-term memory consolidation in schizophrenia. Participants with schizophrenia (n=33) indicated somewhat higher levels of emotional intensity in response to emotional images than did healthy (n=28) participants. However, when recognition memory was tested 24 hr later, schizophrenia participants did not show enhancement of memory for positive images as was found in healthy participants. Their memory enhancement for negative images did not differ from that of healthy participants. Correlations between self-reported physical and social anhedonia were significantly inversely correlated with intensity ratings of positive stimuli during the encoding phase for healthy participants but were negligible for schizophrenia participants. These results suggest a failure to adequately integrate positive emotional experience in memory consolidation processes in schizophrenia participants, despite appropriate initial response to positive stimuli, which may contribute to symptoms such as anhedonia by reducing the long-term impact of positive experiences in motivating hedonic behavior in day-to-day life.

Reduced attentional engagement contributes to deficits in prefrontal inhibitory control in schizophrenia.

BACKGROUND: Problems with the voluntary control of behavior, such as those leading to increased antisaccade errors, are accepted as evidence of prefrontal dysfunction in schizophrenia. We previously reported that speeded prosaccade responses, i.e., shorter response latencies for automatic shifts of attention to visual targets, were associated with higher antisaccade error rates in schizophrenia. This suggests that dysregulation of automatic attentional processes may contribute to disturbances in prefrontally mediated control of voluntary behavior. METHODS: Twenty-four antipsychotic-naïve schizophrenia patients and 30 healthy individuals completed three tasks: a no-gap prosaccade task in which subjects shifted gaze toward a peripheral target that appeared coincident with the disappearance of a central fixation target and separate prosaccade and antisaccade tasks in which a temporal gap or overlap of the central target offset and peripheral target onset occurred. Sixteen patients were retested after 6 weeks of antipsychotic treatment. RESULTS: Patients' prosaccade latencies in the no-gap task were speeded compared with healthy individuals. While patients were not atypical in the degree to which response latencies were speeded or slowed by the gap and overlap manipulations, those patients with diminished attentional engagement on the prosaccade task (i.e., reduced overlap effect) had significantly elevated antisaccade error rates. This effect persisted in patients evaluated after antipsychotic treatment. CONCLUSIONS: This study provides evidence that a reduced ability to engage attention may render patients more distracted by sensory inputs, thereby further compromising impaired executive control during antisaccade tasks. Thus, alterations in attentional and executive control functions can synergistically disrupt voluntary behavioral responses in schizophrenia.