Mahesh Menon

Auditory Hallucinations in Schizophrenia and Nonschizophrenia Populations: A Review and Integrated Model of Cognitive Mechanisms

While the majority of cognitive studies on auditory hallucinations (AHs) have been conducted in schizophrenia (SZ), an increasing number of researchers are turning their attention to different clinical and nonclinical populations, often using SZ findings as a model for research. Recent advances derived from SZ studies can therefore be utilized to make substantial progress on AH research in other groups. The objectives of this article were to (1) present an up-to-date review regarding the cognitive mechanisms of AHs in SZ, (2) review findings from cognitive research conducted in other clinical and nonclinical groups, and (3) integrate these recent findings into a cohesive framework. First, SZ studies show that the cognitive underpinnings of AHs include self-source-monitoring deficits and executive and inhibitory control dysfunctions as well as distortions in top-down mechanisms, perceptual and linguistic processes, and emotional factors. Second, consistent with SZ studies, findings in other population groups point to the role of top-down processing, abnormalities in executive inhibition, and negative emotions. Finally, we put forward an integrated model of AHs that incorporates the above findings. We suggest that AHs arise from an interaction between abnormal neural activation patterns that produce salient auditory signals and top-down mechanisms that include signal detection errors, executive and inhibition deficits, a tapestry of expectations and memories, and state characteristics that influence how these experiences are interpreted. Emotional factors play a particular prominent role at all levels of this hierarchy. Our model is distinctively powerful in explaining a range of phenomenological characteristics of AH across a spectrum of disorders.

The Formation of Abnormal Associations in Schizophrenia: Neural and Behavioral Evidence

It is hypothesized that due to an abnormal functioning of the reward system patients with schizophrenia form context-inappropriate associations. It has been shown that the dopamine target regions, especially the ventral striatum, are critical in the formation of reward associations. We wanted to examine how the ventral striatum responds as patients learn reward-related associations and how this neural response is linked to objective and subjective behavioral measures. Functional magnetic resonance imaging (fMRI) Blood oxygen level dependent (BOLD) responses were examined using aversive Pavlovian learning in 13 medicated patients with schizophrenia and 13 matched healthy controls. Colored circles served as conditioned stimulus (CS+) while a loud, individually adjusted, noise served as the unconditioned stimulus. Circles of another color served as neutral comparators (CS−). Subjective indices were assessed by a post-scan self-report, and galvanic skin responses (GSR) were used as objective measures of associative learning. fMRI data were analyzed using a random effects model in SPM2. Patients showed inappropriately strong activations in the ventral striatum in response to the neutral stimulus (CS−) as compared to the healthy controls. Consistent with this neural evidence of aberrant learning, patients also showed evidence of abnormal learning by self-report and as indexed by GSR. The main finding here is that patients with schizophrenia, when exposed to neutral stimuli in a threatening situation, show an abnormal pattern of learning. The aberrant activations and response are consistent with the idea that patients aberrantly assign motivational salience to neutral stimuli, and this process may be one of the aberrations that predisposes them to psychosis.

Temporal Difference Modeling of the Blood-Oxygen Level Dependent Response During Aversive Conditioning in Humans: Effects of Dopaminergic Modulation

BACKGROUND The prediction error (PE) hypothesized by the temporal difference model has been shown to correlate with the phasic activity of dopamine neurons during reward learning and the blood-oxygen level dependent (BOLD) response during reward and aversive conditioning tasks. We hypothesized that dopamine would modulate the PE related signal in aversive conditioning and that haloperidol would reduce PE related activity, while an acute dose of amphetamine would increase PE related activity in the ventral striatum. METHODS Healthy participants took an acute dose of amphetamine, haloperidol, or placebo. We used functional magnetic resonance imaging (fMRI) to measure the BOLD signal while they carried out an aversive conditioning task, using cutaneous electrical stimulation as the unconditioned stimulus (US) and yellow and blue circles as conditioned stimulus (CS+ and CS-, respectively). RESULTS Prediction error related BOLD activity was seen only in the ventral striatum in the placebo subjects. The subjects given amphetamine showed a wider network of PE related BOLD activity, including the ventral striatum, globus pallidus, putamen, insula, anterior cingulate, and substantia nigra/ventral tegmental area. Haloperidol subjects did not show PE related activity in any of these regions. CONCLUSIONS Our results provide the first demonstration that the modulation of dopamine transmission affects both the physiological correlates and PE related BOLD activity during aversive learning.

Belief inflexibility in schizophrenia.

Background. Previous studies using delusion-neutral material have demonstrated that patients with schizophrenia, particularly those with delusions, display a bias against disconfirmatory evidence (BADE). In the current study we investigated the moderating impact of belief strength on this effect. Methods. Thirty-three schizophrenia patients, 18 patients with obsessive compulsive disorder, and 25 healthy control participants, were consecutively presented with delusion-neutral statements that provided increasingly detailed information about a scenario. They were asked to re-rate the plausibility of four descriptions of the scenario. The correct (“true”) interpretation appeared poor on the first statement and then increasingly gained plausibility, whereas “lure” interpretations appeared plausible initially to varying degrees, but became implausible once all information was presented. Results. Schizophrenia patients displayed a BADE for strong beliefs, in that they were biased against revising their ratings of lure items in light of new disconfirming evidence compared to the mixed control group. However, like controls, patients with schizophrenia were willing to revise weak beliefs. Conclusion. This confirms that schizophrenia patients are generally impaired in their ability to integrate disconfirmatory evidence, even for material that does not touch on delusional themes. This response pattern was more pronounced for strong beliefs, and this may contribute to the fixation of false ideas (i.e., delusions).

Probabilistic reasoning in schizophrenia: A comparison of the performance of deluded and nondeluded schizophrenic patients and exploration of possible cognitive underpinnings

Introduction. A number of studies have suggested that deluded patients show a “jumping to conclusions” reasoning style on probabilistic reasoning tasks. In order to systematically explore the cognitive underpinnings of this task, we compared deluded and nondeluded patients on a number of experimental manipulations to investigate the role of memory and task pragmatics on performance. This research was collected as part of the first authors doctoral dissertation. A portion of these data were presented at the Schizophrenia Congress, March 2003, Colorado Springs, USA. The first author was supported by studentships from the Overseas Research Scholarship Scheme and the Cambridge Commonwealth Trust. No conflicts of interest exist that could affect the collection or interpretation of these data. The authors would like to thank Dr Mike Aitken for his input on statistical analysis, and Dr Todd Woodward and Dr Steffen Moritz for useful comments on earlier drafts of this paper. Methods. In Study 1, the performance of deluded and nondeluded schizophrenia patient groups was compared to nonpsychiatric controls on a battery of probabilistic reasoning tests. In Study 2, two variants of the standard “beads in jars” task were compared in order to explore the possible role of working memory load on task performance. Results. In Study 1, there were no significant differences between any of the groups on any of the probabilistic reasoning tasks. In Study 2, we found a significant difference between the two schizophrenic groups and the controls, but no difference in performance between deluded and nondeluded patient groups. The deluded group responded fastest in the memory intensive condition. Conclusions. Deluded and nondeluded schizophrenic patients perform similarly on probabilistic reasoning tasks and only show the “jumping to conclusions” response pattern under some conditions but not under others. Memory demands may influence the appearance of this pattern of responding in schizophrenia.

Correspondences between theory of mind, jumping to conclusions, neuropsychological measures and the symptoms of schizophrenia

Tasks measuring reasoning biases and social cognition were originally applied to the study of schizophrenia in order to shed light on the cognitive underpinnings of positive symptoms. However, the empirical evidence for overlap between these tasks, and their association with positive symptoms, remains preliminary. In the current study we explore these associations using multivariate methodology, with primary interest in two commonly studied paradigms: jumping to conclusions (JTC) and theory of mind (ToM). We also included measures of memory, executive function and fluency performance, in order to relate the cognitive constructs to more traditional neuropsychological constructs. Forty-six schizophrenia inpatients were administered JTC, ToM, verbal fluency, executive functioning, and verbal memory tasks. A principal component analysis resulted in three components interpreted as Memory, Elaboration and Flexibility. ToM loaded with verbal fluency on the Elaboration component, whereas JTC loaded with executive functioning on the Flexibility component. The negative susbscale of the Positive and Negative Syndrome Scale (PANSS) correlated with the Elaboration component, but no other component-subscale correlations reached significance. Implications of these results are that impairments in elaboration may underlie the commonly observed correlation between ToM and negative symptoms, but argue against a common neurocognitive system for JTC, ToM and positive symptoms.

Cognitive performance of individuals with schizophrenia across seven decades: a study using the MATRICS consensus cognitive battery.

OBJECTIVES The objectives of this study were to determine the effect of aging, schizophrenia, and their interaction on cognitive function. DESIGN Cross-sectional controlled study. SETTING Community living. PARTICIPANTS A total of 235 subjects with schizophrenia age 19-79 and 333 comparison subjects age 20-81. MEASUREMENTS The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB). RESULTS Older age was associated with poorer performance on 9 of 10 MCCB tests in both subjects with schizophrenia and comparison subjects. Subjects with schizophrenia were impaired relative to comparison subjects on each of the 10 tests. However, there was no interaction between aging and schizophrenia on any test. Essentially the same results were observed when analyzing performance on the seven MCCB cognitive domains and MCCB global composite score. CONCLUSIONS Consistent with other reports, schizophrenia appears to be a disorder marked by generalized cognitive dysfunction. However, the rate of cognitive decline appears to be similar to that observed in healthy comparison subjects. They do not experience acceleration in cognitive aging, which supports the hypothesis that schizophrenia is a syndrome of premature aging. Longitudinal studies including very old patients are needed to confirm and extend these findings.

Exploring the Neural Correlates of Delusions of Reference

BACKGROUND Referential delusions are the most common symptom of schizophrenia and offer an opportunity to examine the neural correlates of delusions because they occur in discrete episodes that can be studied in the scanner. The cortical midline structures (CMS) and subcortical regions, including the amygdala and striatum, are linked with self-reference in healthy adults. Less is known about the neural substrates of altered self-reference in schizophrenia. METHODS In this study, patients with schizophrenia experiencing prominent referential delusions (n = 18) and healthy control subjects (n = 17) were presented with ambiguous sentences while in the magnetic resonance imaging scanner and asked to rate whether they felt the sentences had been written specifically about them. The sentences were either generic (nonpersonalized) or individually tailored personalized sentences, designed to induce referential ideation. We hypothesized that both groups would show activity in the CMS, limbic, and striatal regions and that induced referential ideation would be associated with greater activity in striatal areas in patients with schizophrenia. RESULTS A robust main effect of endorsement (endorsed vs. nonendorsed) was observed in the CMS, as well as subcortical regions, including the nucleus accumbens/ventral striatum, amygdala, insula, and midbrain dopamine regions. A group-by-endorsement interaction was seen in the medial prefrontal cortex, insula and nucleus accumbens/ventral striatum. Activity in insula and ventral striatum also correlated with the strength of the delusions of reference. CONCLUSIONS Referential ideation in persons with delusions is associated with heightened CMS, limbic and striatal activity and reduced differentiation between self- and non-self-relevant information.

Aberrant Effective Connectivity in Schizophrenia Patients during Appetitive Conditioning

It has recently been suggested that schizophrenia involves dysfunction in brain connectivity at a neural level, and a dysfunction in reward processing at a behavioral level. The purpose of the present study was to link these two levels of analyses by examining effective connectivity patterns between brain regions mediating reward learning in patients with schizophrenia and healthy, age-matched controls. To this aim, we used functional magnetic resonance imaging and galvanic skin recordings (GSR) while patients and controls performed an appetitive conditioning experiment with visual cues as the conditioned (CS) stimuli, and monetary reward as the appetitive unconditioned stimulus (US). Based on explicit stimulus contingency ratings, conditioning occurred in both groups; however, based on implicit, physiological GSR measures, patients failed to show differences between CS+ and CS− conditions. Healthy controls exhibited increased blood-oxygen-level dependent (BOLD) activity across striatal, hippocampal, and prefrontal regions and increased effective connectivity from the ventral striatum to the orbitofrontal cortex (OFC BA 11) in the CS+ compared to the CS− condition. Compared to controls, patients showed increased BOLD activity across a similar network of brain regions, and increased effective connectivity from the striatum to hippocampus and prefrontal regions in the CS− compared to the CS+ condition. The findings of increased BOLD activity and effective connectivity in response to the CS− in patients with schizophrenia offer insight into the aberrant assignment of motivational salience to non-reinforced stimuli during conditioning that is thought to accompany schizophrenia.

Impaired insight into illness and cognitive insight in schizophrenia spectrum disorders: Resting state functional connectivity

BACKGROUND Impaired insight into illness (clinical insight) in schizophrenia has negative effects on treatment adherence and clinical outcomes. Schizophrenia is described as a disorder of disrupted brain connectivity. In line with this concept, resting state networks (RSNs) appear differentially affected in persons with schizophrenia. Therefore, impaired clinical, or the related construct of cognitive insight (which posits that impaired clinical insight is a function of metacognitive deficits), may reflect alterations in RSN functional connectivity (fc). Based on our previous research, which showed that impaired insight into illness was associated with increased left hemisphere volume relative to right, we hypothesized that impaired clinical insight would be associated with increased connectivity in the DMN with specific left hemisphere brain regions. METHODS Resting state MRI scans were acquired for participants with schizophrenia or schizoaffective disorder (n=20). Seed-to-voxel and ROI-to-ROI fc analyses were performed using the CONN-fMRI fc toolbox v13 for established RSNs. Clinical and cognitive insight were measured with the Schedule for the Assessment of Insight-Expanded Version and Beck Cognitive Insight Scale, respectively, and included as the regressors in fc analyses. RESULTS As hypothesized, impaired clinical insight was associated with increased connectivity in the default mode network (DMN) with the left angular gyrus, and also in the self-referential network (SRN) with the left insula. Cognitive insight was associated with increased connectivity in the dorsal attention network (DAN) with the right inferior frontal cortex (IFC) and left anterior cingulate cortex (ACC). CONCLUSION Increased connectivity in DMN and SRN with the left angular gyrus and insula, respectively, may represent neural correlates of impaired clinical insight in schizophrenia spectrum disorders, and is consistent with the literature attributing impaired insight to left hemisphere dominance. Increased connectivity in the DAN with the IFC and ACC in relation to cognitive insight may facilitate enhanced mental flexibility in this sample.