Brain activation patterns during a selective attention test-a functional MRI study in healthy volunteers and patients with schizophrenia

Functional magnetic resonance imaging was used to compare cortical activation patterns in healthy volunteers with those in patients with schizophrenia during a modified verbal Stroop task. Healthy subjects (n=13) and patients with schizophrenia (n=13) on stable antipsychotic treatment, matched on demographic variables, were included. Patients were preselected on the basis of good performance on a selective attention test. Patients with schizophrenia showed a significantly increased pattern of activation in the left and right inferior frontal cortex and the anterior cingulate cortex. A significant negative correlation between activation of the left prefrontal cortex and accuracy in the modified Stroop test was observed for healthy controls but not schizophrenia patients. Although both groups recruited the prefrontal cortex during the modified Stroop task, for the schizophrenia patients this activation was bilateral, whereas for the controls this activation was primarily in the left hemisphere, suggesting that patients with schizophrenia recruited more prefrontal regions to perform the task with the same accuracy as healthy controls. Our findings of increased activity across multiple areas of the brain, including dorsolateral frontal cortex and anterior cingulate, in patients with schizophrenia who perform relatively well on a task of selective attention give further evidence that task performance may be a confounding factor in the interpretation of neuroimaging results.     

Theory of mind and schizophrenia: a positron emission tomography study of medication-free patients

BACKGROUND: "Theory of mind" (TOM) refers to the ability to attribute mental states (ie, beliefs and goals) to one's self and others and to recognize that behaviors are guided by these mental states. This capacity, critical for social competence, is impaired in schizophrenia. We undertook a study of TOM in a group of patients with schizophrenia and healthy controls. METHOD: We used positron emission tomography to identify the neural circuits recruited during a verbal task that required participants to attribute mental states to a character in a story of their creation. The comparison task consisted of reading aloud a neutral story, controlling for the speech component of the task. RESULTS: Patients and controls generated the same percentage of TOM utterances. However, the two groups had markedly different patterns of brain activation. Compared with controls, patients had a lower blood flow in multiple regions in the left hemisphere including the frontal and visual association cortices, posterior hippocampus, and insula. The flow was also lower in contralateral areas in the lateral cerebellum and vermis, thalamus, and posterior insula. On the other hand, the flow was higher in the patients predominantly in the right hemisphere, including multiple frontal and parietal regions, insula, visual association cortex, and pulvinar. DISCUSSION: The areas of lower flow are consistent with previous studies indicating impairment in recruiting cortical-cerebellar circuitry in schizophrenia. The areas of higher flow may reflect a need to draw on the right hemisphere to compensate for deficits in left hemisphere networks that include frontal cortex, anterior cingulate, cerebellum, and thalamus.     

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.     

Hyperintentionality during automatic perception of naturalistic cooperative behavior in patients with schizophrenia

Social cognition and the corresponding functionality of involved brain networks are essential for effortless social interaction. Patients with schizophrenia exhibit impaired social functioning. In this study, we focused on the neural networks involved in the automatic perception of cooperative behavior and their alterations in schizophrenia.

We performed a functional magnetic resonance imaging study of 19 schizophrenia patients and 19 healthy matched controls. Participants watched a set of short videos with two actors manipulating objects, either with (C+) or without cooperation (C–). Additionally, we assessed delusional symptoms in patients using the Scales for the Assessment of Positive Symptoms and psychosis proneness in healthy controls using the brief schizotypal personality questionnaire.

The observed group-by-condition interaction revealed a contrasting activation pattern for patients versus healthy controls in the medial and lateral prefrontal cortex, the middle cingulate cortex, and the left angular gyrus. Furthermore, increased activation of the middle prefrontal areas, left angular gyrus, and the posterior sulcus temporalis superior in response to the noncooperative condition (C–) was positively correlated with delusional symptoms in patients.

Our findings suggest an overactivated “theory of mind” network in patients for the processing of noncooperative behavior. Thus, “overmentalizing” might be based on delusions and altered processing of cooperative behavior in patients with schizophrenia.     

FMRI indices of auditory attention in schizophrenia

The present study sought to identify abnormalities in activation in several brain regions in response to an auditory attention task in patients with schizophrenia. Ten patients and twenty healthy control participants were examined using Functional Magnetic Resonance Imaging (FMRI) measures acquired during an auditory attention task. Region of interest analyses of activation of targeted regions implicated in attention included: anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC), hippocampus, parahippocampal gyrus (PHG), and superior temporal gyrus (STG). The results indicated over-activation in patients with schizophrenia. While the control group showed notable coherence in activation within and across hemispheres the schizophrenia group showed relatively less coherence overall that was only present in the right hemisphere. These findings suggest that patients with schizophrenia show both an over-engagement of brain regions during attention task as well as a lack of communication among neural regions involved.     

Brain activation patterns during a selective attention test--a functional MRI study in healthy volunteers and unmedicated patients during an acute episode of schizophrenia

In a previous functional magnetic resonance imaging (fMRI) study of high functioning outpatients with remitted schizophrenia, we found increased activity compared with healthy subjects across multiple areas of the brain, including the dorsolateral frontal cortex and the anterior cingulate, during a modified Stroop task. The same fMRI procedure was used in this subsequent study to investigate eight unmedicated patients during an acute episode of schizophrenia and eight healthy control subjects. Patients showed a reduced activation in dorsolateral prefrontal, anterior cingulate and parietal regions and a higher activation in temporal regions and posterior cingulate compared to healthy controls. Healthy controls showed a trend towards higher accuracy in the modified Stroop task compared to schizophrenia patients. Treatment with second generation antipsychotics may improve executive performance in patients with schizophrenia and facilitate a normalization of functional hypofrontality after symptomatic improvement.     

Brain activation patterns during a selective attention test — a functional MRI study in healthy volunteers and unmedicated patients during an acute episode of schizophrenia

In a previous functional magnetic resonance imaging (fMRI) study of high functioning outpatients with remitted schizophrenia, we found increased activity compared with healthy subjects across multiple areas of the brain, including the dorsolateral frontal cortex and the anterior cingulate, during a modified Stroop task. The same fMRI procedure was used in this subsequent study to investigate eight unmedicated patients during an acute episode of schizophrenia and eight healthy control subjects. Patients showed a reduced activation in dorsolateral prefrontal, anterior cingulate and parietal regions and a higher activation in temporal regions and posterior cingulate compared to healthy controls. Healthy controls showed a trend towards higher accuracy in the modified Stroop task compared to schizophrenia patients. Treatment with second generation antipsychotics may improve executive performance in patients with schizophrenia and facilitate a normalization of functional hypofrontality after symptomatic improvement.     

Working memory dysfunction in schizophrenia patients with obsessive-compulsive symptoms: An fMRI study

BackgroundA substantial proportion of schizophrenia patients also meets DSM-IV criteria for obsessive-compulsive disorder (OCD). Schizophrenia with OCD (“schizo-obsessive”) patients are characterized by distinct clinical characteristics, treatment response and prognosis. Whether schizo-obsessive patients exhibit a distinct pattern of brain activation is yet unknown. To address this question, the present functional magnetic resonance imaging (fMRI) study explicitly compared alterations in brain activation and functional connectivity (FC) underlying a working memory deficit in schizophrenia patients with and without OCD.MethodsfMRI was applied during the N-back working memory (WM) task in three groups: schizo-obsessive (n = 16), schizophrenia (n = 17) and matched healthy volunteers (n = 20). WM-related activation in the right dorsolateral prefrontal cortex (DLPFC) and the right caudate nucleus, brain areas relevant to schizophrenia and OCD, and FC analysis were used for the evaluation.ResultsThe two schizophrenia groups with and without OCD exhibited a similar reduction in activation in the right DLPFC and right caudate, as well as decreased FC compared to the healthy controls. Notably, reduced regional brain activation was not related to severity of schizophrenic or OCD symptoms.ConclusionsSchizo-obsessive patients do not differ from their non-OCD schizophrenia counterparts in brain activation patterns during the N-back WM task. Cognitive paradigms taping alternative neural networks (e.g., orbitofrontal cortex) particularly relevant to OCD, are warranted in the search for potential distinctive brain activation patterns of the schizo-obsessive subgroup.     

Alterations of theory of mind network activation in chronic cannabis users

Chronic cannabis use is associated with cognitive impairment and has been identified as a risk factor for schizophrenia. Patients with schizophrenia show profound deficits in social cognition such as the ability to attribute mental states to others, referred to as "theory of mind" (ToM). Aberrant activation of the ToM network has been demonstrated across different phases of schizophrenia, including at-risk stages. Accordingly, we aimed to investigate the ToM network in chronic cannabis users. Fifteen cannabis users received functional brain imaging during performance of a ToM cartoon story task. Findings were compared with 14 control subjects. Cannabis users showed less activation in the left parahippocampal gyrus, the right precuneus and cuneus, but greater activation in the left cuneus and the right anterior cingulate gyrus compared to healthy controls. These activation patterns resemble those found in at-risk populations, suggesting that cannabis use can affect the processing of social information similar to other risk factor constellations for psychosis.     

Changes over time in frontotemporal activation during a working memory task in patients with schizophrenia

Studies on working memory (WM) dysfunction in schizophrenia have reported several functionally aberrant brain areas including prefrontal and temporal cortex. Longitudinal studies have shown changes in prefrontal activation during treatment. We used event-related functional magnetic resonance imaging and a parametric verbal WM task to investigate cerebral function during WM performance in healthy subjects and medicated patients with schizophrenia with an acute symptom exacerbation. Patients were scanned twice: within the first week after admission to the hospital and after 7-8 weeks of a multimodal treatment including atypical antipsychotic agents. There were no differences in activation of lateral prefrontal regions in patients relative to healthy controls neither at baseline nor after 7-8 weeks. Controls showed relatively more activation in parietal, striatal and cerebellar regions. In patients with schizophrenia, frontotemporal function was bilaterally enhanced after 7-8 weeks. This activation change was associated with improved accuracy in a verbal WM task, improved verbal WM-span and symptom reduction as measured by the BPRS global score and the BPRS factor for thought disturbance. Although we could not replicate findings of functional hypofrontality in the patients with schizophrenia, frontotemporal activation changed with treatment and was associated with verbal WM performance and significant reduction of psychopathology.     

Exploring the social brain in schizophrenia: left prefrontal underactivation during mental state attribution

OBJECTIVE: Evidence suggests that patients with schizophrenia have a deficit in "theory of mind," i.e., interpretation of the mental state of others. The authors used functional magnetic resonance imaging (MRI) to investigate the hypothesis that patients with schizophrenia have a dysfunction in brain regions responsible for mental state attribution. METHOD: Mean brain activation in five male patients with schizophrenia was compared to that in seven comparison subjects during performance of a task involving attribution of mental state. RESULTS: During performance of the mental state attribution task, the patients made more errors and showed less blood-oxygen-level-dependent signal in the left inferior frontal gyrus. CONCLUSIONS: To the authors' knowledge, this is the first functional MRI study to show a deficit in the left prefrontal cortex in schizophrenia during a socioemotional task.     

Temporally anticorrelated brain networks during working memory performance reveal aberrant prefrontal and hippocampal connectivity in patients with schizophrenia

Functional neuroimaging studies on cognitive dysfunction in schizophrenia have suggested regional brain activation changes in the dorsolateral prefrontal cortex and the medial temporal lobe. However, less is known about the functional coupling of these areas during cognitive performance. In this study, we used functional magnetic resonance imaging, a verbal working memory (WM) task and multivariate statistical techniques to investigate the functional coupling of temporally anticorrelated neural networks during cognitive processing in patients with schizophrenia (n = 16) compared to healthy controls (n = 16). Independent component analysis identified 18 independent components (ICs) among which two ICs were selected for further analyses. These ICs included temporally anticorrelated networks which were most highly associated with the delay period of the task in both healthy controls and patients with schizophrenia. Functional network abnormalities in patients with schizophrenia were detected within a “task-positive” lateral frontoparietal network, where increased functional connectivity was found in bilateral dorsolateral prefrontal regions. In addition, aberrant functional coupling of the hippocampal cortex in patients with schizophrenia was detected within a “task-negative” medial frontotemporal network. In patients with schizophrenia, functional connectivity indices in the left dorsolateral prefrontal cortex and the right hippocampal cortex were positively correlated with accuracy during the WM task, while the connectivity strength in the right dorsolateral prefrontal cortex was negatively correlated with measures of symptom severity. These data suggest that within two temporally anticorrelated network states, patients with schizophrenia exhibit increased and persistent dorsolateral prefrontal and hippocampal connectivity during WM performance.     

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.     

Polygenic Risk for Schizophrenia Associated With Working Memory-related Prefrontal Brain Activation in Patients With Schizophrenia and Healthy Controls

Schizophrenia is a highly heritable and polygenic disease, and identified common genetic variants have shown weak individual effects. Many studies have reported altered working memory (WM)-related brain activation in schizophrenia, preferentially in the frontal lobe. Such differences in brain activations could reflect inherited alterations possibly involved in the disease etiology, or rather secondary disease-related mechanisms. The use of polygenic risk scores (PGRS) based on a large number of risk polymorphisms with small effects is a valuable approach to examine the effect of cumulative genetic risk on brain functioning. This study examined the impact of cumulative genetic risk for schizophrenia on WM-related brain activations, assessed with functional magnetic resonance imaging. For each participant (63 schizophrenia patients and 118 healthy controls), we calculated a PGRS for schizophrenia based on 18 862 single-nucleotide polymorphism in a large multicenter genome-wide association study including 9146 schizophrenia patients and 12 111 controls, performed by the Psychiatric Genomics Consortium. As expected, the PGRS was significantly higher in patients compared with healthy controls. Further, the PGRS was related to differences in frontal lobe brain activation between high and low WM demand. Specifically, even in absence of main effects of diagnosis, increased PGRS was associated with decreased activation difference in the right middle-superior prefrontal cortex (BA 10/11) and the right inferior frontal gyrus (BA 45). This effect was seen in both cases and controls, and was not influenced by sex, age, or task performance. The findings support the notion of dysregulation of frontal lobe functioning as an inherited vulnerability factor in schizophrenia.Key words: polygenic, schizophrenia, fMRI     

Altered Amygdala Connectivity Within the Social Brain in Schizophrenia

Background: Impairments in social cognition have been described in schizophrenia and relate to core symptoms of the disorder. Social cognition is subserved by a network of brain regions, many of which have been implicated in schizophrenia. We hypothesized that deficits in connectivity between components of this social brain network may underlie the social cognition impairments seen in the disorder. Methods: We investigated brain activation and connectivity in a group of individuals with schizophrenia making social judgments of approachability from faces (n = 20), compared with a group of matched healthy volunteers (n = 24), using functional magnetic resonance imaging. Effective connectivity from the amygdala was estimated using the psychophysiological interaction approach. Results: While making approachability judgments, healthy participants recruited a network of social brain regions including amygdala, fusiform gyrus, cerebellum, and inferior frontal gyrus bilaterally and left medial prefrontal cortex. During the approachability task, healthy participants showed increased connectivity from the amygdala to the fusiform gyri, cerebellum, and left superior frontal cortex. In comparison to controls, individuals with schizophrenia overactivated the right middle frontal gyrus, superior frontal gyrus, and precuneus and had reduced connectivity between the amygdala and the insula cortex. Discussion: We report increased activation of frontal and medial parietal regions during social judgment in patients with schizophrenia, accompanied by decreased connectivity between the amygdala and insula. We suggest that the increased activation of frontal control systems and association cortex may reflect a compensatory mechanism for impaired connectivity of the amygdala with other parts of the social brain networks in schizophrenia.Key words: fMRI, social cognition, approachability, psychosis, neural, psychophysiological interaction     

Dorsolateral prefrontal cortex activity during maintenance and manipulation of information in working memory in patients with schizophrenia

CONTEXT: It remains unclear whether altered regional brain physiological activity in patients with schizophrenia during working memory tasks relates to maintenance-related processes, manipulation-related (ie, executive) processes, or both. OBJECTIVE: To examine regional functional activations of the brain during maintenance- and manipulation-related working memory processing in patients with schizophrenia and in healthy comparison subjects. DESIGN: Functional images of the brain were acquired in 11 schizophrenic patients and 12 healthy control subjects (matched for age, sex, handedness, and parental education) during 2 spatial working memory paradigms, one contrasting maintenance-only processing with maintenance and manipulation processing and the other contrasting parametrically varying maintenance demands. RESULTS: Patients and controls showed activation of a large, spatially distributed network of cortical and subcortical regions during spatial working memory processing. When task demands required explicit manipulation of information held in memory, controls recruited right dorsolateral prefrontal cortex (Brodmann areas 45 and 46) to a significantly greater extent than patients. A similar effect was observed for the larger memory set sizes of the memory set size task. No other brain regions showed activation differences between groups for either task. These differences persisted when comparing activation maps for memory set sizes in which the 2 groups were equivalent in behavioral accuracy and when comparing subgroups of patients and controls matched for behavioral accuracy on either task. CONCLUSIONS: Physiological disturbances in the dorsolateral prefrontal cortex contribute differentially to patients' difficulties with maintaining spatial information across a brief delay, as well as with manipulating the maintained representation. These differences persisted when comparing conditions in which the 2 groups were equivalent in behavioral accuracy.     

Aberrant visual circuitry associated with normal spatial match-to-sample accuracy in schizophrenia

A goal of this study was to evaluate the function of the anterior cingulate cortex (ACC) and of the dorsolateral prefrontal cortex (DLPFC) in medicated patients with schizophrenia (SZ), a small group of first-degree relatives, and healthy controls using a visual delayed match-to-sample task in conjunction with functional magnetic resonance imaging (fMRI). To mitigate performance differences between SZ and healthy controls, we used a novel task that allows for individualized adjustment of task difficulty to match ability level. We also trained participants on the task prior to scanning. Using an event-related design, we modeled three components of the match-to-sample trial: visual encoding, delay, and discrimination. We did not find significant differences in ACC/medial frontal cortex activation between the groups. However, compared to healthy controls, SZ showed decreased activation in visual processing areas during the encoding and discrimination phases of the task and in the ventrolateral prefrontal cortex during the delay. These findings emphasize the tendency of schizophrenia subjects to solve perceptual memory problems by engaging diverse regions.     

Neurodegeneration in friedreich's ataxia is associated with a mixed activation pattern of the brain. A fMRI study

Friedreich's ataxia (FRDA) is associated with a distributed pattern of neurodegeneration in the spinal cord and the brain secondary to selective neuronal loss. We used functional MR Imaging (fMRI) to explore brain activation in FRDA patients during two motor-sensory tasks of different complexity, i.e. continuous hand tapping and writing of "8" figure, with the right dominant hand and without visual feedback. Seventeen FRDA patients and two groups of age-matched healthy controls were recruited. Task execution was monitored and recorded using MR-compatible devices. Hand tapping was correctly performed by 11 (65%) patients and writing of the "8" by 7 (41%) patients. After correction for behavioral variables, FRDA patients showed in both tasks areas of significantly lower activation in the left primary sensory-motor cortex and right cerebellum. Also left thalamus and right dorsolateral prefrontal cortex showed hypo-activation during hand tapping. During writing of the "8" task FRDA patients showed areas of higher activation in the right parietal and precentral cortex, globus pallidus, and putamen. Activation of right parietal cortex, anterior cingulum, globus pallidus, and putamen during writing of the "8" increased with severity of the neurological deficit. In conclusion fMRI demonstrates in FRDA a mixed pattern constituted by areas of decreased activation and areas of increased activation. The decreased activation in the primary motor cortex and cerebellum presumably reflects a regional neuronal damage, the decreased activation of the left thalamus and primary sensory cortex could be secondary to deafferentation phenomena, and the increased activation of right parietal cortex and striatum might have a possible compensatory significance.