Cerebral changes and cognitive dysfunctions in medication-free schizophrenia - an fMRI study

Proposing cognitive impairment in working memory (wm) functions as a cognitive core deficit in schizophrenia, 23 first episode, medication-free schizophrenic patients in a comparison of healthy adults have been investigated by fMRI. Additionally, the effects of different attentional demands in wm tasks were analysed. A wm paradigm was applied, in which stimuli were presented in a 2-back and a 0-back condition in a non-degraded and degraded version. As hypothesized in healthy controls increased activity during both 2-back tasks was found in the ventrolateral prefrontal cortex (VLPFC), dorsolateral prefrontal cortex (DLPFC), parietal regions, the thalamus and the cerebellum. Different activation patterns were found for the cingulate cortex in the 2-back degraded conditions. The comparison between healthy controls and schizophrenic patients revealed decreased activity in the right VLPFC in patients as well as increased activity in temporal regions. Furthermore patients' task performance quality was significantly lower for 2-back conditions. Schizophrenic patients use different cognitive strategies to solve working memory tasks, reflected in significantly altered cerebral activity. However, the different fMRI working memory correlates found in schizophrenic patients seem to be insufficient in terms of overall task performance.     

The effect of working memory performance on functional MRI in schizophrenia

INTRODUCTION: Studies of prefrontal cortical (PFC) function in schizophrenia have been inconsistent, with studies showing both increased and decreased PFC activation compared to healthy controls. Discrepant findings may be due to task performance effects or demographic differences between samples. We report functional magnetic resonance imaging (fMRI) data comparing subjects with schizophrenia and healthy controls performing a 2-back working memory (WM) task, addressing the effects of task performance. METHODS: Twenty-two controls and 14 patients with DSM-IV schizophrenia, scanned on a Siemens 1.5 T scanner, performed a visual letter 2-back task and control task (CPT-X) during fMRI. Data were analyzed using Statistical Parametric Mapping (SPM)-99. RESULTS: After statistical adjustment for performance differences, persons with schizophrenia showed significantly greater activation than controls in the right medial frontal gyrus and left inferior parietal lobule/medial temporal gyrus region (BA 39/40), and a trend toward greater activation in the left ventrolateral PFC. This pattern was also observed in demographically matched subgroups of participants. CONCLUSIONS: Data are consistent with findings reported in recent studies showing increased PFC and parietal activation in schizophrenia when the effects of reduced WM task performance in patients with schizophrenia are addressed. Further studies are needed to clarify the pathophysiological basis of WM load sensitivity in schizophrenia and its relationship to genes.     

Blunted activation in right ventrolateral prefrontal cortex during motor response inhibition in schizophrenia

OBJECTIVES: Previous functional magnetic resonance imaging (fMRI) studies have reported abnormal brain activation in individuals with schizophrenia during performance of motor inhibition tasks. We aimed to clarify brain functional abnormalities related to motor response inhibition in schizophrenia by using event-related fMRI in combination with a Go-NoGo task designed to control for non-inhibitory cognitive processes involved in task performance. METHOD: We studied 21 schizophrenic patients and 21 healthy subjects, group-matched for age, sex, and performance accuracy on a Go-NoGo task during event-related fMRI. The task was designed so that Go and NoGo events were equally probable. Between-group activation differences were assessed using ANCOVAs with response time and IQ as covariates of non-interest. RESULTS: Compared to healthy subjects, schizophrenic patients exhibited a significant decrease in activation during motor response inhibition in the right ventrolateral prefrontal cortex (VLPFC) only. There were no areas of increased brain activation in patients compared to healthy subjects. CONCLUSIONS: Schizophrenic patients demonstrate a blunted activation in the right VLPFC, a region known to play a critical role in motor response inhibition. Further research should ascertain the contribution of the VLPFC dysfunction to the impulsive behavior observed in schizophrenia.     

Effects of treatment with the atypical neuroleptic quetiapine on working memory function: a functional MRI follow-up investigation

Background Working memory as a part of higher-order executive functions is defined by the parallel storage and processing of information. Recent functional fMRI studies have revealed a functional, interregional disintegration of a neuronal network connecting cortical, subcortical and cerebellar regions in schizophrenic patients (SZ). Cognitive impairment in working memory is a core psychopathological correlate of schizophrenic symptoms. Atypical neuroleptics such as quetiapine have shown good efficacy in treating positive and negative symptoms. The presented study evaluated the impact of a neuroleptic steady state treatment with quetiapine on the altered working memory activation patterns in schizophrenia. Methods Patients were examined by fMRI at baseline and after 12 weeks of steady state treatment with quetiapine. Matched healthy controls (HC) underwent baseline examination. In the scanner, stimuli were presented in a 2-back and 0-back condition of a working memory (wm) paradigm, whereby a degraded and a non-degraded version were used each time. Additionally, behavioural responses (reaction time to target stimuli and error ratio) were measured. Results At baseline, healthy controls revealed increased activity in the frontal lobe, especially in regions of the prefrontal cortex. Compared to HC, SZ showed hypoactivation in the right dorsolateral prefrontal cortex (DLPFC) and the ventrolateral prefrontal cortex (VLPFC) bilaterally for the 2-back condition. In the 2-back degraded condition there was a hypoactivation in both, the right DLPFC and the VLPFC. Additionally, patients showed bilaterally decreased activation in the basalganglia in the 2-back and in the right caudatus in the 2-back degraded condition compared to healthy controls. After treatment with quetiapine, patients activations patterns were increased. The pre–post comparison of the 2-back condition revealed a significant increase of activation in the left VLPFC at a significance level of 0.001 (uncorrected). The 2-back degraded condition led to a significant activation pattern in the lingual gyrus and the right precuneus. In both wm conditions, at baseline there were no differences in reaction time but only a worse performance in SZ. After treatment, behavioural measurement of responses, including reaction time and performance, showed slight improvements in SZ, although these did not reach statistical significance. Conclusions The neuronal networks underlying working memory are clearly altered in schizophrenia. After 12 weeks of treatment with quetiapine monotherapy, patients showed significant clinical improvement and revealed increased BOLD activity in the VLPFC during a working memory task, although there was no improvement of cognitive performance.     

Impaired temporoparietal deactivation with working memory load in antipsychotic-naïve patients with first-episode schizophrenia

Abstract

Objectives. Neuroimaging studies have shown abnormal task-related deactivations during working memory (WM) in schizophrenia patients with recent emphasis on brain regions within the default mode network. Using fMRI, we tested whether antipsychotic-naïve schizophrenia patients were impaired at deactivating brain regions that do not subserve WM. Methods. Twenty-three antipsychotic-naïve patients with first-episode schizophrenia and 35 healthy individuals underwent whole-brain 3T fMRI scans while performing a verbal N-back task including 0-back (no WM load), 1-back (low WM load), and 2-back (high WM load) conditions. Results. Contrasting the 2-back and 0-back conditions revealed that patients deactivated default mode network regions to a similar degree as controls. However, patients were impaired in deactivating large bilateral clusters centred on the superior temporal gyrus with increasing WM load. These regions activated with the no WM load condition (0-back) in both groups. Conclusions. Because 0-back activation reflects verbal attention processes, patients’ persistent activation in the 1-back and 2-back conditions may reflect an inability to shift cognitive strategy with onset of WM demands. Since patients were antipsychotic-naïve and task performance was equal to controls, we infer that this impaired temporoparietal deactivation may represent a primary dysfunction in schizophrenia.     

Working memory capacity in schizophrenia: a parametric fMRI study

Impaired working memory (WM) function in schizophrenia has been associated with abnormal activation of the dorsolateral prefrontal cortex (DLPFC). It is, however, not clear whether abnormal activation is a sign of DLPFC pathology, or a correlate of poor performance. We address this question by examining activity in the WM brain system at different levels of task difficulty. A parametric fMRI paradigm is used to examine how the WM system responds to increasing load. A parametric fMRI design with four levels of a spatial N-back task was used to examine the relationships between working memory load, functional output (performance) and brain activity in 10 schizophrenic patients on atypical antipsychotic medication and to compare these to 10 healthy controls. In spite of increasingly poor performance in schizophrenic patients, activity increased normally in DLPFC and inferior parietal cortex bilaterally and in anterior cingulate, with increasing load. At 3-back, activity dropped in DLPFC in comparison with controls, but not in the other regions. The results indicate that peak activation of the WM-system is reached at a lower processing load in schizophrenic patients than in healthy controls. As a decline of DLPFC activity at high processing loads in itself is not abnormal, WM dysfunction in schizophrenia appears to be the result of an impaired functional output of the whole WM system, causing elevation of the effective burden imposed by WM tasks.     

Altered brain activation in dorsolateral prefrontal cortex in adolescents and young adults at genetic risk for schizophrenia: an fMRI study of working memory

OBJECTIVE: Adult first-degree relatives of persons with schizophrenia carry elevated genetic risk for the illness, demonstrate working memory (WM) impairments, and manifest alterations in dorsolateral prefrontal cortical (DLPFC) function during WM. Because substantially less is known about these phenotypes in adolescent subjects we sought to demonstrate that young relatives of persons with schizophrenia manifest impaired WM and altered prefrontal activation. METHODS: Participants were 21 non-psychotic, unmedicated first-degree relatives of persons with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder, depressed type and 24 unmedicated controls, recruited from the community and hospitals in metropolitan Boston (ages 13-28). We compared groups on an auditory WM task with interference prior to scanning and used functional magnetic resonance imaging (fMRI) to compare groups while performing visual 2-back WM and control vigilance tasks. Blood oxygen level dependent signal change was measured using two whole-brain gradient echo EPI pulse acquisitions (21 contiguous, 5mm axial slices), acquired on a Siemens 1.5T MR scanner. Data were analyzed using Statistical Parametric Mapping-99. RESULTS: The high risk subjects were significantly impaired on the auditory WM task, had significantly greater Phobic Anxiety, and marginally greater Psychoticism than controls on the Symptom Checklist-90-Revised, and showed significantly greater task-elicited activation in the right DLPFC (BA 46). Psychopathology, IQ, and in-scanner WM performance did not account for group differences in brain activation. CONCLUSIONS: Data support a physiological difference (an exaggerated fMRI response) in DLPFC in adolescents at genetic risk for schizophrenia, independent of psychosis. Future work can study the relationship of these measures to possible onset of schizophrenia.     

Neural correlates of working memory dysfunction in first-episode schizophrenia patients: an fMRI multi-center study

Working memory dysfunction is a prominent impairment in patients with schizophrenia. Our aim was to determine cerebral dysfunctions by means of functional magnetic resonance imaging (fMRI) in a large sample of first-episode schizophrenia patients during a working memory task. 75 first-episode schizophrenia patients and 81 control subjects, recruited within a multi-center study, performed 2- and 0-back tasks while brain activation was measured with fMRI. In order to guarantee comparability between data quality from different scanners, we developed and adopted a standardized, fully automated quality assurance of scanner hard- and software as well as a measure for in vivo data quality. After these quality-control measures had been implemented, 48 patients and 57 controls were included in the final analysis. During attention-related processes, even when the performance between patients and controls was comparable, there was a recognizable emergence of cerebral dysfunctions with hypoactivations in the ventrolateral prefrontal cortex (VLPFC), in the superior temporal cortex and in the thalamus. During working memory performance, parietal hypoactivations, especially in the precuneus, were prominent and were accompanied by poorer performance in patients. A hyperfrontality emerged in the ventrolateral prefrontal cortex. Hence, results point to a dysfunctional ventrolateral prefrontal-parietal network during working memory in patients, suggesting impairments in basic functions such as retrieval, storage and maintenance. The brain activation pattern of this large and significant sample of first-episode schizophrenia patients indicates an imbalanced system failing to adjust the amount of brain activity required in the cerebral network involved in attention and working memory.     

Functional neuroanatomy of visuo-spatial working memory in Turner syndrome

Turner syndrome (TS), a genetic disorder characterized by the absence of an X chromosome in females, has been associated with cognitive and visuo-spatial processing impairments. We utilized functional MRI (fMRI) to investigate the neural substrates that underlie observed deficits in executive functioning and visuo-spatial processing. Eleven females with TS and 14 typically developing females (ages 7-20) underwent fMRI scanning while performing 1-back and 2-back versions of a standard visuo-spatial working memory (WM) task. On both tasks, TS subjects performed worse than control subjects. Compared with controls, TS subjects showed increased activation in the left and right supramarginal gyrus (SMG) during the 1-back task and decreased activation in these regions during the 2-back task. In addition, decreased activation in the left and right dorsolateral prefrontal cortex (DLPFC) and caudate nucleus was observed during the 2-back task in TS subjects. Activation differences localized to the SMG, in the inferior parietal lobe, may reflect deficits in visuo-spatial encoding and WM storage mechanisms in TS. In addition, deficits in the DLPFC and caudate may be related to deficits in executive function during WM performance. Together these findings point to deficits in frontal-striatal and frontal-parietal circuits subserving multiple WM functions in TS.     

Regional brain activation changes and abnormal functional connectivity of the ventrolateral prefrontal cortex during working memory processing in adults with attention‐deficit/hyperactivity disorder

Previous studies on working memory (WM) function in adults with attention‐deficit/hyperactivity disorder (ADHD) suggested aberrant activation of the prefrontal cortex and the cerebellum. Although it has been hypothesized that activation differences in these regions most likely reflect aberrant frontocerebellar circuits, the functional coupling of these brain networks during cognitive performance has not been investigated so far. In this study, functional magnetic resonance imaging (fMRI) and both univariate and multivariate analytic techniques were used to investigate regional activation changes and functional connectivity differences during cognitive processing in healthy controls (n = 12) and ADHD adults (n = 12). Behavioral performance during a parametric verbal WM paradigm did not significantly differ between adults with ADHD and healthy controls. During the delay period of the activation task, however, ADHD patients showed significantly less activation in the left ventrolateral prefrontal cortex (VLPFC), as well as in cerebellar and occipital regions compared with healthy control subjects. In both groups, independent component analyses revealed a functional network comprising bilateral lateral prefrontal, striatal, and cingulate regions. ADHD adults had significantly lower connectivity in the bilateral VLPFC, the anterior cingulate cortex, the superior parietal lobule, and the cerebellum compared with healthy controls. Increased connectivity in ADHD adults was found in right prefrontal regions, the left dorsal cingulate cortex and the left cuneus. These findings suggest both regional brain activation deficits and functional connectivity changes of the VLPFC and the cerebellum as well as functional connectivity abnormalities of the anterior cingulate and the parietal cortex in ADHD adults during WM processing. Hum Brain Mapp, 2009. © 2008 Wiley‐Liss, Inc.     

No hypofrontality,but absence of prefrontal lateralization comparing verbal and spatial working memory in schizophrenia

Hypofrontality and decreased lateralization have been two major, albeit controversial, results from functional neuroimaging studies of schizophrenia. We used fMRI to study cortical activation during a verbal and spatial working memory (WM) task (2-back) in 15 inpatients acutely ill with schizophrenia and 15 matched control subjects. We hypothesized (i) hypofrontality in patients in both tasks and (ii) decreased lateralization of prefrontal activation in patients under the assumption that, in controls, left prefrontal cortex (PFC) is engaged preferentially in the verbal task (verbal domain dominance) and the right prefrontal cortex is engaged preferentially in the spatial task (spatial domain dominance). Our results showed no significant differences in frontal activation between controls and patients, i.e. no hypofrontality in patients, even at a very liberal threshold (p<0.01). This may be explained by the fact that nearly all patients studied received atypical neuroleptics. Nonetheless, we found evidence for more subtle, domain-related prefrontal dysfunction. Whereas controls showed verbal WM domain dominance in left inferior frontal cortex and spatial WM domain dominance in right prefrontal cortex, these domain dominance effects were absent in the patient group, i.e. there were no lateralization effects. Finally, only patients showed an inverse correlation between performance and right prefrontal activation in verbal WM. We conclude that the finding of hypofrontality may depend on the medication of the patients and that there is prefrontal dysfunction even in the absence of hypofrontality.     

Compensatory activations in patients with multiple sclerosis during preserved performance on the auditory N-back task

Recent fMRI studies have suggested that multiple sclerosis (MS) patients show adaptive cortical changes (i.e., compensatory mechanisms) during motor and cognitive tasks to limit the clinical impact of tissue injury. In this study, we investigated the activation pattern during the auditory n-back working memory (WM) paradigm in a group of 17 MS patients and 10 healthy controls with preserved performance in WM tasks. Compared with healthy controls, MS patients showed significantly greater bilateral activation in prefrontal cortex (BA 44), and the insula. These findings were similar to those obtained in previous studies showing that compensatory mechanisms during WM tasks in MS may be based on the use of prefrontal areas adjacent to those involved in the task.     

An fMRI study of reduced left prefrontal activation in schizophrenia during normal inhibitory function

Functional magnetic resonance imaging (fMRI) was used to investigate the hypothesis that schizophrenia is associated with a dysfunction of prefrontal brain regions during motor response inhibition. Generic brain activation of six male medicated patients with schizophrenia was compared to that of seven healthy comparison subjects matched for sex, age, and education level while performing 'stop' and 'go-no-go' tasks. No group differences were observed in task performance. Patients, however, showed reduced BOLD signal response in left anterior cingulate during both inhibition tasks and reduced left rostral dorsolateral prefrontal and increased thalamus and putamen BOLD signal response during stop task performance. Despite good task performance, patients with schizophrenia thus showed abnormal neural network patterns of reduced left prefrontal activation and increased subcortical activation when challenged with motor response inhibition.     

Alterations in functional activation in euthymic bipolar disorder and schizophrenia during a working memory task

Dysfunctions in prefrontal cortical networks are thought to underlie working memory (WM) impairments consistently observed in both subjects with bipolar disorder and schizophrenia. It remains unclear, however, whether patterns of WM‐related hemodynamic responses are similar in bipolar and schizophrenia subjects compared to controls. We used fMRI to investigate differences in blood oxygen level dependent activation during a WM task in 21 patients with euthymic bipolar I, 20 patients with schizophrenia, and 38 healthy controls. Subjects were presented with four stimuli (abstract designs) followed by a fifth stimulus and required to recall whether the last stimulus was among the four presented previously. Task‐related brain activity was compared within and across groups. All groups activated prefrontal cortex (PFC), primary and supplementary motor cortex, and visual cortex during the WM task. There were no significant differences in PFC activation between controls and euthymic bipolar subjects, but controls exhibited significantly increased activation (cluster‐corrected P < 0.05) compared to patients with schizophrenia in prefrontal regions including dorsolateral prefrontal cortex (DLPFC). Although the bipolar group exhibited intermediate percent signal change in a functionally defined DLPFC region of interest with respect to the schizophrenia and control groups, effects remained significant only between patients with schizophrenia and controls. Schizophrenia and bipolar disorder may share some behavioral, diagnostic, and genetic features. Differences in the patterns of WM‐related brain activity across groups, however, suggest some diagnostic specificity. Both patient groups showed some regional task‐related hypoactivation compared to controls across the brain. Within DLPFC specifically, patients with schizophrenia exhibited more severe WM‐related dysfunction than bipolar subjects. Hum Brain Mapp, 2009. © 2009 Wiley‐Liss, Inc.     

Impaired working-memory after cerebellar infarcts paralleled by changes in BOLD signal of a cortico-cerebellar circuit

A considerable body of evidence supports the notion that cerebellar lesions lead to neuropsychological deficits, including impairments in working-memory, executive tasks and verbal fluency. Studies employing functional magnetic resonance imaging (fMRI) and anatomical tracing in primates provide evidence for a cortico-cerebellar circuitry as the functional substrate of working-memory. The present fMRI study explores the activation pattern during an n-back working-memory task in patients with an isolated cerebellar infarct. To determine each patient's cognitive impairment, neuropsychological tests of working-memory and attention were carried out. We conducted fMRI in nine patients and nine healthy age-matched controls while they performed a 2-back task in a blocked-design. In both groups we found bilateral activations in a widespread cortico-cerebellar network, consisting of the ventrolateral prefrontal cortex (BA 44, 45), dorsolateral prefrontal cortex (BA 9, 46), parietal cortex (BA 7, 40), pre-supplementary motor area (BA 6) anterior cingulate (BA 32). Relative to healthy controls, patients with isolated cerebellar infarcts demonstrated significantly more pronounced BOLD-activations in the precuneus and the angular gyrus during the 2-back task. The significant increase in activation in the posterior parietal areas of the cerebellar patients could be attributed to a compensatory recruitment to maintain task performance. We conclude that cerebellar lesions affect remote cortical regions that are part of a putative cortico-cerebellar network.     

Evaluation of a novel event-related parametric fMRI paradigm investigating prefrontal function

While prefrontal pathology is considered to be a core feature in schizophrenia, evidence from functional magnetic resonance imaging (fMRI) studies using cognitive activation tasks is less reliable in terms of demonstrating 'functional hypofrontality'. Here we present a new event-related fMRI paradigm specifically developed to assess the gradual recruitment of brain areas during verbal working memory (WM) by taking into account theoretical and pragmatic limitations of activation tools used in clinical cognitive neuroscience. We studied 15 healthy subjects during the performance of a WM task that required the manipulation of verbal information. We observed a robust recruitment of frontoparietal areas with increasing load. Comparing the two highest loads, we found further bilateral striatal activation. A median split into good and poor performers revealed significant positive correlations of prefrontal activation in the group of good performers and correlations with striato-thalamic activation in the poor-performance group, thus emphasizing a crucial role of subcortical structures for performance in highly demanding WM tasks. Because it induces a robust bilateral frontoparietal activation pattern along with performance-related effects of cerebral activation, we consider this paradigm to be suitable to test prefrontal function in schizophrenic patients during the manipulation of items held in WM.     

Schizophrenic subjects activate dorsolateral prefrontal cortex during a working memory task, as measured by fMRI.

BACKGROUND: Neuroimaging studies of schizophrenic subjects performing working memory (WM) tasks have demonstrated a relative hypoactivity of prefrontal cortex compared with normal subjects. METHODS: Using functional magnetic resonance imaging (fMRI), we compared dorsolateral prefrontal cortex (DLPFC) activation in 12 schizophrenic and 10 normal subjects during rewarded performance of a WM task. Subjects performed a modified version of the Sternberg Item Recognition Paradigm (SIRP), a continuous performance, choice reaction time (RT) task that requires WM. We compared a high WM load condition with a nonWM choice RT condition and with a low WM load condition. RESULTS: Schizophrenic subjects performed the tasks better than chance but worse than normal subjects. They showed greater activation than normal subjects in the left DLPFC but did not differ in the right DLPFC or in the control region. In the schizophrenic group, left DLPFC activation was inversely correlated with task performance, as measured by errors. CONCLUSIONS: These findings contrast with previous studies that demonstrated task-related hypofrontality in schizophrenia. Task parameters that may contribute to this difference are discussed. We hypothesize that the performance and activation differences we observed are also manifestations of prefrontal dysfunction in schizophrenia. They reflect inefficient functioning of the neural circuitry involved in WM.     

How cognitive performance‐induced stress can influence right VLPFC activation: An fMRI study in healthy subjects and in patients with social phobia

The neural bases of interactions between anxiety and cognitive control are not fully understood. We conducted an fMRI study in healthy participants and in patients with an anxiety disorder (social phobia) to determine the impact of stress on the brain network involved in cognitive control. Participants performed two working memory tasks that differed in their level of performance‐induced stress. In both groups, the cognitive tasks activated a frontoparietal network, involved in working memory tasks. A supplementary activation was observed in the right ventrolateral prefrontal cortex (VLPFC) in patients during the more stressful cognitive task. Region of interest analyses showed that activation in the right VLPFC decreased in the more stressful condition as compared to the less stressful one in healthy subjects and remain at a similar level in the two cognitive tasks in patients. This pattern was specific to the right when compared to the left VLPFC activation. Anxiety was positively correlated with right VLPFC activation across groups. Finally, left dorsolateral prefrontal cortex (DLPFC) activation was higher in healthy subjects than in patients in the more stressful task. These findings demonstrate that in healthy subjects, stress induces an increased activation in left DLPFC, a critical region for cognitive control, and a decreased activation in the right VLPFC, an area associated with anxiety. In patients, the differential modulation between these dorsal and ventral PFC regions disappears. This absence of modulation may limit anxious patients' ability to adapt to demanding cognitive control tasks. Hum Brain Mapp, 2012. © 2011 Wiley Periodicals, Inc     

Ventrolateral prefrontal cortex and the effects of task demand context on facial affect appraisal in schizophrenia

Schizophrenia patients display impaired performance and brain activity during facial affect recognition. These impairments may reflect stimulus-driven perceptual decrements and evaluative processing abnormalities. We differentiated these two processes by contrasting responses to identical stimuli presented under different contexts. Seventeen healthy controls and 16 schizophrenia patients performed an fMRI facial affect detection task. Subjects identified an affective target presented amongst foils of differing emotions. We hypothesized that targeting affiliative emotions (happiness, sadness) would create a task demand context distinct from that generated when targeting threat emotions (anger, fear). We compared affiliative foil stimuli within a congruent affiliative context with identical stimuli presented in an incongruent threat context. Threat foils were analysed in the same manner. Controls activated right orbitofrontal cortex (OFC)/ventrolateral prefrontal cortex (VLPFC) more to affiliative foils in threat contexts than to identical stimuli within affiliative contexts. Patients displayed reduced OFC/VLPFC activation to all foils, and no activation modulation by context. This lack of context modulation coincided with a 2-fold decrement in foil detection efficiency. Task demands produce contextual effects during facial affective processing in regions activated during affect evaluation. In schizophrenia, reduced modulation of OFC/VLPFC by context coupled with reduced behavioural efficiency suggests impaired ventral prefrontal control mechanisms that optimize affective appraisal.     

Reduced prefrontal-parietal effective connectivity and working memory deficits in schizophrenia

The neural mechanisms behind cognitive deficits in schizophrenia still remain unclear. Functional neuroimaging studies on working memory (WM) yielded inconsistent results, suggesting task performance as a moderating variable of prefrontal activation. Beyond regional specific activation, disordered integration of brain regions was supposed as a critical pathophysiological mechanism of cognitive deficits in schizophrenia. Here, we first hypothesized that prefrontal activation implicated in WM depends primarily on task performance and therefore stratified participants into performance subgroups. Second, in line with the dysconnectivity hypothesis, we asked whether connectivity in the prefrontal-parietal network underlying WM is altered in all patients. We used functional magnetic resonance imaging in human subjects (41 schizophrenia patients, 42 healthy controls) and dynamic causal modeling to examine effective connectivity during a WM task. In line with our first hypothesis, we found that prefrontal activation was differentially modulated by task performance: there was a significant task by group by performance interaction revealing an increase of activation with performance in patients and a decrease with performance in controls. Beyond that, we show for the first time that WM-dependent effective connectivity from prefrontal to parietal cortex is reduced in all schizophrenia patients. This finding was independent of performance. In conclusion, our results are in line with the highly influential hypothesis that the relationship between WM performance and prefrontal activation follows an inverted U-shaped function. Moreover, this study in a large sample of patients reveals a mechanism underlying prefrontal inefficiency and cognitive deficits in schizophrenia, thereby providing direct experimental evidence for the dysconnectivity hypothesis.