Decreased efficiency of task-positive and task-negative networks during working memory in schizophrenia.

Working memory (WM) is one of the most impaired cognitive processes in schizophrenia. Functional magnetic resonance imaging (fMRI) studies in this area have typically found a reduction in information processing efficiency but have focused on the dorsolateral prefrontal cortex. In the current study using the Sternberg Item Recognition Test, we consider networks of regions supporting WM and measure the activation of functionally connected neural networks over different WM load conditions. We used constrained principal component analysis with a finite impulse response basis set to compare the estimated hemodynamic response associated with different WM load condition for 15 healthy control subjects and 15 schizophrenia patients. Three components emerged, reflecting activated (task-positive) and deactivated (task-negative or default-mode) neural networks. Two of the components (with both task-positive and task-negative aspects) were load dependent, were involved in encoding and delay phases (one exclusively encoding and the other both encoding and delay), and both showed evidence for decreased efficiency in patients. The results suggest that WM capacity is reached sooner for schizophrenia patients as the overt levels of WM load increase, to the point that further increases in overt memory load do not increase fMRI activation, and lead to performance impairments. These results are consistent with an account holding that patients show reduced efficiency in task-positive and task-negative networks during WM and also partially support the shifted inverted-U-shaped curve theory of the relationship between WM load and fMRI activation in schizophrenia.

Constrained principal component analysis reveals functionally connected load-dependent networks involved in multiple stages of working memory.

Constrained principal component analysis (CPCA) with a finite impulse response (FIR) basis set was used to reveal functionally connected networks and their temporal progression over a multistage verbal working memory trial in which memory load was varied. Four components were extracted, and all showed statistically significant sensitivity to the memory load manipulation. Additionally, two of the four components sustained this peak activity, both for approximately 3 s (Components 1 and 4). The functional networks that showed sustained activity were characterized by increased activations in the dorsal anterior cingulate cortex, right dorsolateral prefrontal cortex, and left supramarginal gyrus, and decreased activations in the primary auditory cortex and "default network" regions. The functional networks that did not show sustained activity were instead dominated by increased activation in occipital cortex, dorsal anterior cingulate cortex, sensori-motor cortical regions, and superior parietal cortex. The response shapes suggest that although all four components appear to be invoked at encoding, the two sustained-peak components are likely to be additionally involved in the delay period. Our investigation provides a unique view of the contributions made by a network of brain regions over the course of a multiple-stage working memory trial.

Dual-stream modulation failure: a novel hypothesis for the formation and maintenance of delusions in schizophrenia.

Delusions, a cardinal feature of schizophrenia, are characterized by the development and preservation of false beliefs despite reason and evidence to the contrary. A number of cognitive models have made important contributions to our understanding of delusions, though it remains unclear which core cognitive processes are malfunctioning to enable individuals with delusions to form and maintain erroneous beliefs. We propose a modified dual-stream processing model that provides a viable and testable mechanism that can account for this debilitating symptom. Dual-stream models divide decision-making into two streams: a fast, intuitive and automatic form of processing (Stream 1); and a slower, conscious and deliberative process (Stream 2). Our novel model proposes two key influences on the way these streams interact in everyday decision-making: conflict and emotion. Conflict: in most decision-making scenarios one obvious answer presents itself and the two streams converge onto the same conclusion. However, in instances where there are competing alternative possibilities, an individual often experiences dissonance, or a sense of conflict. The detection of this conflict biases processing towards the more deliberative Stream 2. Emotion: highly emotional states can result in behavior that is reflexive and action-oriented. This may be due to the power of emotionally valenced stimuli to bias reasoning towards Stream 1. We propose that in schizophrenia, an abnormal response to these two influences results in a pathological schism between Stream 1 and Stream 2, enabling erroneous intuitive explanations to coexist with contrary logical explanations of the same event. Specifically, we suggest that delusions are the result of a failure to reconcile the two streams due to both a failure of conflict to bias decision-making towards Stream 2 and an accentuated emotional bias towards Stream 1.

Brain activation mediates the association between structural abnormality and symptom severity in schizophrenia.

Thought disorder is a symptom of schizophrenia expressed as disorganized or incoherent speech. Severity of thought disorder correlates with decreased left superior temporal gyrus grey matter volume and cortical activation in posterior temporal regions during the performance of language tasks. The goal of this study was to determine whether language-related activation mediates the association between thought disorder and left superior temporal lobe grey matter volume. 12 patients with schizophrenia were assessed for thought disorder. FMRI images were acquired for each subject while they listened to English speech, along with a high resolution structural image. Thought disorder was used as a covariate in the functional analysis to identify brain regions within which activation correlated with symptom severity. Voxel based morphometry was used to calculate grey matter volume of the planum temporale. A mediation model waste-tested using a four-step multiple regression approach incorporating cortical volume, functional activation and symptom severity. Thought disorder correlated with activation in a single cluster within the left posterior middle temporal gyrus during listening to speech. Grey matter volume within the planum temporale correlated significantly with severity of thought disorder and activation within the functional cluster. Regressing thought disorder on grey matter volume and BOLD response simultaneously led to a significant reduction in the correlation between grey matter volume and thought disorder. These results support the hypothesis that the association between decreased grey matter volume in the left planum temporale and severity of thought disorder is mediated by activation in the posterior temporal lobe during language processing.

Temporo-prefrontal coordination increases when semantic associations are strongly encoded.

Relational association of disparate semantic concepts can strengthen encoding of episodes. Previous research has shown that the left medial temporal lobe (MTL) and the left prefrontal cortex (PFC) are the primary brain regions activated during both verbal encoding and the association of disparate semantic concepts. In the current functional magnetic resonance imaging (fMRI) study, our goal was to compare the coordinated response of the left MTL and left PFC when disparate semantic associations are strongly encoded compared to when they are weakly encoded. To achieve this goal, subjects were scanned while creating sentences based on a presented pair of words, and were asked to free-recall these sentences at a later time. Half the word pairs were semantically unrelated, and half were semantically related. Analysis of relatedness activations (unrelated-related contrast) suggested that the PFC was active whether or not the items were free-recalled, and increased activation of the MTL was required to promote encoding. Analyses of coordination of relatedness activations comparing free-recalled items to not free-recalled items showed an increase in left MTL-left PFC coordination for relatedness activations on free-recalled items. These results suggest that formation of relational semantic associations that lead to strongly encoded episodes requires increased coordination of the left MTL-left PFC neural pathway.

Do you hear what I hear? Neural correlates of thought disorder during listening to speech in schizophrenia.

Thought disorder is a fundamental symptom of schizophrenia, observable as irregularities in speech. It has been associated with functional and structural abnormalities in brain regions involved in language processing, including left temporal regions, during language production tasks. We were interested in the neural correlates of thought disorder during receptive language processing, as this function is relatively preserved despite relying on the same brain regions as expressive language. Twelve patients with schizophrenia and 11 controls listened to 30-s speech samples while undergoing fMRI scanning. Thought disorder and global symptom ratings were obtained for each patient. Thought disorder but not global symptomatology correlated positively with the BOLD response in the left posterior superior temporal lobe while listening to comprehensible speech (cluster-level corrected p=.023). The pattern of brain activity associated with thought disorder during listening to comprehensible speech differs from that seen during language generation tasks, where a reduction of the leftward laterality of language has often been observed. As receptive language is spared in thought disorder, we propose that the increase in activation reflects compensatory processing allowing for normal performance.

Abnormal function of the brain system supporting motivated attention in medicated patients with schizophrenia: an fMRI study.

BACKGROUND: Patients with schizophrenia have an impaired ability to generate activity that is appropriate to current circumstances and goals. METHOD: We report a study using functional magnetic resonance imaging (fMRI) to examine cerebral activity during a three-tone auditory oddball target detection task in a sample of 28 patients with schizophrenia and 28 healthy controls. RESULTS: The patients exhibited significantly less activation in response to target stimuli relative to baseline in an extensive set of sites in association neocortex, paralimbic cortex, limbic structures and subcortical nuclei, yet demonstrated a normal level of activation in the sensorimotor cortex. Comparison of activity elicited by rare target stimuli with that elicited by equally rare novel stimuli makes it possible to distinguish cerebral activity associated with attention to behaviourally salient stimuli from activity associated with attending to other attention-capturing stimuli. This comparison revealed that the patients with schizophrenia also exhibited a deficit in activation of basal forebrain areas that mediate motivation during the processing of behaviourally salient stimuli, including the amygdala, ventral striatum, orbital frontal cortex and rostral anterior cingulate cortex. CONCLUSION: Patients with schizophrenia have a deficit in function of the brain system concerned with mediating motivation, in addition to a more general deficit in the cerebral response to attention-captivating stimuli.

Decreased encoding efficiency in schizophrenia.

BACKGROUND: Working memory deficits are a cardinal feature of schizophrenia that contribute to social and occupational dysfunction. METHODS: We used functional magnetic resonance imaging to compare the response to varying task demands during the performance of an item recognition task. Study design and analysis procedures were optimized for the detection of load dependent activity during the encoding phase of working memory. RESULTS: At the lowest load conditions the schizophrenia group performed as well as controls, however to achieve this equivalent performance the schizophrenia group had a significantly higher magnitude of activation compared to the controls. At the higher load conditions, the magnitude of activation between groups became more similar and we began to see performance deficits in the schizophrenic group. CONCLUSIONS: These results suggest that patients with schizophrenia have decreased efficiency in the cognitive processes that underlie the early encoding phase of this task. For lower demand tasks, patients with schizophrenia can compensate for decreased efficiency by working harder to achieve equivalent performance. Encoding utilizes attentional and perceptual cognitive operations that are likely common to many other cognitive tasks; therefore, inefficiency may underlie the deficits observed in a wide range of cognitive tasks in schizophrenia compared to healthy controls.

Short- and long-term changes in anterior cingulate activation during resolution of task-set competition.

Alternating between task sets involves detection that the current task set is unfavorable, initiation of a change in set, and application of the new task set while fine-tuning to optimally adjust to the demands of the environment. Functional magnetic resonance imaging (fMRI) studies of cognitive flexibility consistently report activation of the anterior cingulate cortex and/or adjacent pre-supplementary motor regions (ACC/pre-SMA, medial Brodmann's areas 24/32/6), suggesting that these cortical regions are involved in switching task set. In the current study, our objective was to probe whether ACC/pre-SMA activation would decrease for a number of trials following a switch in task set, implying longer-term involvement in fine-tuning adjustments. By measuring activation when switching between word reading and color naming in response to Stroop stimuli, ACC/pre-SMA activation was observed when actively countering the influence of the irrelevant task set, and this activation decreased as a function of the number of trials since a task switch. Basal ganglia and thalamic regions also displayed a decreased response over successive trials after task switches. These findings suggest that the ACC/pre-SMA are not only involved in generating a new course of action, but are also involved (along with subcortical regions) in fine-tuning operations that resolve competition between task sets over subsequent repetitions of the same task.

Processing efficiency of a verbal working memory system is modulated by amphetamine: an fMRI investigation.

RATIONALE: Working memory performance may be improved or decreased by amphetamine, depending on baseline working memory capacity and amphetamine dosage. This variable effect suggests an optimal range of monaminergic activity for working memory, either below or above which it is compromised. We directly tested this possibility with human participants by varying amphetamine dosage and measuring the efficiency of cortical processing in brain regions associated with working memory. OBJECTIVES: The modulation of cortical processing in a verbal working memory network by dextroamphetamine (D-amph) was examined using BOLD functional magnetic resonance imaging (fMRI) with healthy participants. The goal of the study was to test the hypothesis of an inverted U-shaped relationship between D-amph dose and processing efficiency of a verbal working memory system. METHODS: D-amph dosage was increased cumulatively every 2 h across four scanning sessions collected in a single day. The primary measure used for analyses in this study was the extent of activation in brain regions empirically defined as a working memory network. RESULTS: An inverted U-shaped relationship was observed between the amount of D-amph administered and working memory processing efficiency. This relationship was specific to brain areas functionally defined as working memory regions and to the encoding/maintenance phase (as opposed to the response phase) of the task. CONCLUSION: The results are consistent with the hypothesis that the neurochemical effects of amphetamine modulate the efficiency of a verbal working memory system. The effect of amphetamine on working memory in healthy individuals may provide insight regarding the working memory deficits seen in schizophrenia, given the overlap between neurochemical systems affected by amphetamine, and those disordered in schizophrenia.

Attention orienting dysfunction during salient novel stimulus processing in schizophrenia.

Schizophrenia is characterised by marked disturbances of attention and information processing. Patients experience difficulty focusing on relevant cues and avoiding distraction by irrelevant stimuli. Event-related potential recordings indicate an amplitude reduction in the P3a component elicited by involuntary orienting to task-irrelevant, infrequent novel stimuli presented during auditory oddball detection in patients with schizophrenia. The goal of the present study was to elucidate the functional abnormality underlying the disturbed orienting to novel stimuli in schizophrenia. Twenty-eight stable, partially remitted, medicated patients with schizophrenia and 28 healthy control participants completed a novelty oddball variant during event-related fMRI. Relative to healthy participants, patients with schizophrenia were characterised by underactivity during novel stimulus processing in the right amygdala-hippocampus, within paralimbic cortex in the rostral anterior cingulate and posterior cingulate cortices and the right frontal operculum, and in association cortex at the right temporo-parietal-occipital junction, bilateral intraparietal sulcus, and bilateral dorsal frontal cortex. Subcortically, relative hypoactivation during novelty processing was apparent in the cerebellum, thalamus, and basal ganglia. These results suggest that patients less efficiently reorient processing resources away from the ongoing task of detecting and responding to the task-relevant target stimuli. In addition, trend results suggest that patients experienced increased distraction by novel stimuli.

The influence of working memory load on phase specific patterns of cortical activity.

This study investigated patterns of cortical activity associated with the temporally separated encoding, maintenance and retrieval phases of a working memory (WM) task. Eighteen healthy subjects completed a variable load version of the Sternberg Item Recognition Task. Brain regions showing activity on average across load were determined for each task phase. In addition, brain regions showing activity that increased linearly with load were determined for encoding and retrieval. Although previous fMRI studies have used event-related designs to isolate phase specific activity, this study differed in that design and analysis methods were optimized to ensure low multicollinearity between the conditions of interest: the duration of the intermediate phase (maintenance) was varied and load was selectively modeled for the encoding and retrieval phases. The brain areas showing activity on average across load for each phase combine to encompass regions identified in previous studies that have not attempted to separate phase specific activity. Encoding is associated with extensive load dependent activity, with the most robust activity in bilateral occipital and posterior parietal regions. Retrieval is associated with more selective load dependent activity, primarily in the anterior supplementary motor region and the right posterior cerebellum. The analysis strategies employed in this study could be used to further delineate the phases of WM that are most severely compromised in clinical populations with WM disturbances.

State dependent changes in error monitoring in schizophrenia.

The aim of this study was to determine if error negativity/error-related negativity (N(e)/ERN), error positivity (P(e)), correct response negativity (CRN) or correct response positivity (P(c)) amplitude are influenced by state changes in schizophrenia. Event-related potentials (ERPs) were recorded from nine schizophrenic patients while they performed a simple go/no-go task during the early stages of an acute episode and again following 6 weeks of treatment with antipsychotics. ERPs were also recorded from nine healthy participants while they performed the same task. Response-locked potentials were computed for errors of commission and for correct responses. Scores for reality distortion syndrome, psychomotor poverty syndrome and disorganization syndrome were determined for the schizophrenic participants before and after treatment using the Signs and Symptoms of Psychotic Illness (SSPI) Scale. N(e)/ERN amplitude was significantly reduced, compared with that in healthy participants, in the schizophrenic patients when acutely ill, and increased significantly following treatment. N(e)/ERN amplitude remained significantly larger in the healthy group than in the patients with schizophrenia after treatment. This study suggests that N(e)/ERN and CRN amplitude are modulated by clinical state in schizophrenia and provides further support to findings that decreased N(e)/ERN amplitude is a potentially useful trait marker for schizophrenia, while P(c) and P(e) amplitude are not abnormal.

Immediate effects of risperidone on cerebral activity in healthy subjects: a comparison with subjects with first-episode schizophrenia.

OBJECTIVE: To test the hypothesis that administration of risperidone to healthy subjects produces reductions in metabolism in the frontal cortex similar to those produced by administration of risperidone to patients experiencing a first episode of schizophrenia. METHODS: Positron emission tomography was used to measure the changes in regional metabolism produced by a single 2-mg dose of risperidone and by placebo, administered under randomized, double-blind conditions, in 9 healthy subjects. Conjunction analysis was used to identify those cerebral sites where changes in metabolism in the healthy subjects coincided with similar changes in metabolism observed in patients with schizophrenia. RESULTS: Compared with placebo, risperidone produced reductions in metabolism in the left lateral frontal cortex and right medial frontal cortex in healthy subjects. Conjunction analysis revealed that these changes occurred at locations similar to the loci of change produced by risperidone in patients with schizophrenia. CONCLUSION: Because the reduction in metabolism in the medial frontal cortex produced by risperidone is associated with alleviation of positive symptoms in patients with schizophrenia, the observation of a reduction in metabolism at a similar site in healthy subjects supports the hypothesis that the antipsychotic effect of risperidone arises, at least in part, from a physiologic effect that occurs in both patients with schizophrenia and healthy subjects.

Abnormal processing of speech during oddball target detection in schizophrenia.

Healthy subjects show increased activation in left temporal lobe regions in response to speech sounds compared to complex nonspeech sounds. Abnormal lateralization of speech-processing regions in the temporal lobes has been posited to be a cardinal feature of schizophrenia. Event-related fMRI was used to test the hypothesis that schizophrenic patients would show an abnormal pattern of hemispheric lateralization when detecting speech compared with complex nonspeech sounds in an auditory oddball target-detection task. We predicted that differential activation for speech in the vicinity of the superior temporal sulcus would be greater in schizophrenic patients than in healthy subjects in the right hemisphere, but less in patients than in healthy subjects in the left hemisphere. Fourteen patients with schizophrenia (selected from an outpatient population, 2 females, 12 males, mean age 35.1 years) and 29 healthy subjects (8 females, 21 males, mean age 29.3 years) were scanned while they performed an auditory oddball task in which the oddball stimuli were either speech sounds or complex nonspeech sounds. Compared to controls, individuals with schizophrenia showed greater differential activation between speech and nonspeech in right temporal cortex, left superior frontal cortex, and the left temporal-parietal junction. The magnitude of the difference in the left temporal parietal junction was significantly correlated with severity of disorganized thinking. This study supports the hypothesis that aberrant functional lateralization of speech processing is an underlying feature of schizophrenia and suggests the magnitude of the disturbance in speech-processing circuits may be associated with severity of disorganized thinking.

Rostral anterior cingulate cortex dysfunction during error processing in schizophrenia.

Previous research has demonstrated that patients with schizophrenia have an impaired ability to monitor erroneous responses to stimuli internally. Event-related potential (ERP) studies of error-eliciting tasks indicate that, in healthy adults, the commission of an erroneous response is associated with a fronto-centrally distributed negative voltage component termed the error negativity (Ne) or error-related negativity (ERN). In patients with schizophrenia, the Ne/ERN elicited by errors of commission (EoC) is reduced in amplitude compared with that elicited in healthy participants. Functional MRI (fMRI) studies and source localization analyses of ERP data in healthy participants suggest that EoC are associated with activity in the rostral anterior cingulate cortex (ACC). Using event-related fMRI, we examined the brain activity associated with EoC in a group of 10 patients with schizophrenia and 16 matched healthy participants. Patients were stable, partially remitted, medicated out-patients recruited from the community. Participants performed a Go/NoGo task variant that was shown previously to elicit a reduced Ne/ERN during EoC in patients with schizophrenia relative to healthy participants, as well as robust rostral ACC activation during EoC in healthy participants. Patients with schizophrenia were characterized by relative underactivity in the rostral ACC compared with healthy participants. There was also evidence for more widespread underactivity in the limbic system. In contrast to these regions of relative hypoactivity, patients with schizophrenia demonstrated hyperactivity relative to healthy participants in bilateral parietal cortex during both EoC and correctly rejected NoGo trials. Our results are consistent with previous ERP research demonstrating functional abnormalities during error processing in schizophrenia. In light of the role of the rostral ACC and other limbic structures in mediating affective and motivational behaviour, our results suggest there may be a disturbed affective or motivational response to the commission of errors in schizophrenia.

Thought and Language Index: an instrument for assessing thought and language in schizophrenia.

BACKGROUND: Subtle formal thought disorders are difficult to quantify. Their relationship to florid thought disorder is unknown. AIMS: To assess the interrater reliability, sensitivity and factor structure of a new assessment instrument, the Thought and Language Index (TLI), and to determine if minor aberrations detectable in the speech of healthy individuals are related to the more severe formal thought disorders characteristic of schizophrenia. METHOD: Interrater reliability was evaluated by determining the intraclass correlation for the ratings by five assessors. Factor analysis of the TLI scores of 87 patients was performed, and TLI scores in matched patients and controls were compared. RESULTS: The intraclass correlation was good for individual TLI items, and excellent for sub-scale scores. Factor analysis identified three groups of approximately orthogonal disorders. Mild speech aberrations were observed in healthy participants and in patients with schizophrenia. The prevalence of mild aberrations was correlated with the prevalence of definite formal thought disorders. CONCLUSIONS: The TLI is reliable and capable of detecting subtle disorders. Some mild aberrations occurring in the speech of healthy individuals appear to be attenuated forms of the florid disorders characteristic of schizophrenia.

Signs and Symptoms of Psychotic Illness (SSPI): a rating scale.

BACKGROUND: In the rating scales commonly used for assessing response to antipsychotic treatment, individual items embrace symptoms that apparently arise from distinguishable pathophysiological processes and might be expected to respond differently to treatment. AIMS: To test the reliability, sensitivity to change and factor structure of a new scale for the assessment of the Signs and Symptoms of Psychotic Illness (the SSPI). METHOD: Interrater reliability was evaluated by determining the intraclass correlation for the ratings of 63 patients. Sensitivity to change was assessed in a longitudinal study of 33 patients. Factor structure was determined from scores for 155 patients. RESULTS: The intraclass correlation was satisfactory for all individual items and excellent for the total score. Scores were sensitive to change. A change in Clinical Global Impression of one unit corresponded to an SSPI total score change of 31%. Factor analysis revealed five clusters of symptoms. CONCLUSIONS: The SSPI provides a sensitive and reliable measure of the five major clusters of symptoms that occur commonly in psychotic illness.