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A substantial body of evidence implicates dysfunction in N-methyl-d-aspartate receptors (NMDARs) in the pathophysiology of schizophrenia. This article illustrates how NMDAR dysfunction may give rise to many of the neurobiological phenomena frequently associated with schizophrenia with a particular focus on how NMDAR dysfunction affects the thalamic reticular nucleus (nRT) and pedunculopontine tegmental nucleus (PPTg). Furthermore, this article presents a model for schizophrenia illustrating how dysfunction in the nRT may interrupt prefrontal regulation of midbrain dopaminergic neurons, and how dysfunction in the PPTg may drive increased, irregular burst firing., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The estrogen hypothesis for schizophrenia suggests neuroprotective effects of estrogen for the development of the disorder and for symptom severity, including auditory hallucinations. Furthermore, estrogen has shown enhancing effects on cognitive control, a function that is also implicated in auditory hallucinations. Whether estrogen affects the tendency to hallucinate in healthy participants, and the potential mediating role of cognitive control, has not yet been studied. Therefore, the current study aimed to test these relationships by using a white noise paradigm in combination with a N-back working memory task in which cognitive load could be manipulated. The paradigm used simulates a hallucinatory state by induction of negative emotions and drainage of cognitive resources. The simultaneous exposure to white noise elicit experiences of hearing voices (false alarms). In a between-subject design, forty-two participants were tested during the menstrual cycle in either the early follicular phase (low estradiol) or late follicular phase (high estradiol). A 2(Cycle Phase) x2(N-back task) ANOVA showed a main-effect of cycle phase on number of experienced hallucinations in the white noise task, with a significantly higher number of reported hallucinations in the early follicular phase. Furthermore, estradiol was found to predict number of hallucinations. No interaction effect of cycle phase and available cognitive resources was found. The results suggest an estradiol-related change in hallucination proneness across the menstrual cycle, but the idea that cognitive functioning mediates this relationship was not supported. Overall, the study supports protective effects of estradiol on hallucination proneness in line with the estrogen-hypothesis of schizophrenia, and that such effects are not specific to the disease., Competing Interests: Declaration of Competing Interest Authors have no conflict of interests to declare., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Hypotheses: Auditory verbal hallucinations (AVHs) is not only a common symptom in schizophrenia but also observed in individuals in the general population. Despite extensive research, AVHs are poorly understood, especially their underlying neuronal architecture. Neuroimaging methods have been used to identify brain areas and networks that are activated during hallucinations. A characteristic feature of AVHs is, however, that they fluctuate over time, with varying frequencies of starts and stops. An unanswered question is, therefore, what neuronal events co-occur with the initiation and inhibition of an AVH episode., Study Design: We investigated brain activation with fMRI in 66 individuals who experienced multiple AVH-episodes while in the scanner. We extracted time-series fMRI-data and monitored changes second-by-second from 10 s before to 15 s after participants indicated the start and stop of an episode, respectively, by pressing a hand-held response-button., Study Results: We found a region in the ventromedial prefrontal cortex (VMPFC) which showed a significant increase in activation initiated a few seconds before participants indicated the start of an episode, and a corresponding decrease in activation initiated a few seconds before the end of an episode., Conclusions: The consistent increase and decrease in activation in this area in advance of the consciously experienced presence or absence of the "voice" imply that this region may act as a switch in turning episodes on and off. The activation is unlikely to be confounded by motor responses. The findings could have clinical implications for brain stimulation treatments, like transcranial magnetic stimulation., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Background: It has been theorized that hallucinations, a common symptom of schizophrenia, are caused by failures in reality monitoring. The paracingulate sulcus (PCS) has been implicated as a brain structure supporting reality monitoring with the absence or shorter length of PCS associated with an occurrence of hallucinations in schizophrenia. The absence or shorter length of PCS has been associated with an occurrence of hallucinations. There are inconsistent findings in the literature regarding the role of the asymmetry of this structure for hallucinations. Here, we investigated the length of the PCS and cortical thickness of surrounding structures in patients with a lifetime history of auditory verbal hallucinations (AVH)., Design: Seventy-seven patients and twenty-eight healthy controls (HC) underwent an anatomical MRI scan. PCS length and cortical thickness were estimated using Mango brain visualization and FreeSurfer, respectively. Patients with AVH (n = 45) and patients without AVH were compared (n = 32) to the controls., Results: PCS length significantly differed between HC and patient groups (F(2,102) = 3.57, P = .032) in the left but not in the right sulcus. We found significantly longer PCS between HC and AVH group but no difference between patient groups. Similarly, we found significant thinning of cortical structures including structures surrounding anterior parts of PCS between HC and patients either in general or per group, but no significant differences were observed between patient groups., Conclusions: PCS length in the left hemisphere is shorter in schizophrenia patients with hallucinations as compared to HC subjects. The patient group without hallucinations was in between those 2 groups. Cortical thickness of neighboring areas of PCS is diminished in patient groups relative to the healthy comparison subjects. The role of lateralization and functional involvement of the PCS region in processes underlying hallucinations, such as reality monitoring, needs further clarification., (The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. 
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Although alterations of the default mode network (DMN) in schizophrenia (SZ) have been largely investigated, less research has been carried out on DMN alterations in different sub-phenotypes of this disorder. The aim of this pilot study was to compare DMN features among SZ patients with and without auditory verbal hallucinations (AVH). Three groups of 17 participants each were considered: patients with hallucinations (AVH-SZ), patients without hallucinations (nAVH-SZ) and age-matched healthy controls (HC). The DMN spatial pattern was similar between the nAVH-SZ and HC, but the comparison between these two groups and the AVH-SZ group revealed alterations in the left Angular Gyrus (lAG) node of the DMN. Using a novel approach based on normalized fractional Amplitude of Low-Frequency Fluctuations (fALFF), the AVH-SZ subgroup showed altered spectral activity in the DMN compared with the other two groups, especially in the lower-frequency bands (0.017-0.04 Hz). Significant positive correlations were found for both SZ groups collapsed, and for the nAVH-SZ group alone between delusional scores (PANSS-P1) and slow fALFF bands of the DMN. Narrowing the analysis to the ROI centered on the lAG, significant correlations were found in the AVH-SZ group for hallucination scores (PANSS-P3) and Slow-5 and Slow-4 (both positive), and Slow-3 (negative) fALFF bands. Our results reveal the central role of the lAG in relation to hallucinations, an important cortical area connecting auditory cortex with several hubs (including frontal linguistic centers) and involved in auditory process monitoring., Competing Interests: Declaration of competing interest The co-authors KH, ARC and LE own shares in the company NordicNeuroLab, Inc., https://www.nordicneurolab.com/, which produced add-on equipment for the fMRI acquisitions. The co-authors declare no conflicts of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Functional connectome alterations, including modular network organization, have been related to the experience of hallucinations. It remains to be determined whether individuals with hallucinations across the psychosis continuum exhibit similar alterations in modular brain network organization. This study assessed functional connectivity matrices of 465 individuals with and without hallucinations, including patients with schizophrenia and bipolar disorder, nonclinical individuals with hallucinations, and healthy controls. Modular brain network organization was examined at different scales of network resolution, including (1) global modularity measured as Qmax and Normalised Mutual Information (NMI) scores, and (2) within- and between-module connectivity. Global modular organization was not significantly altered across groups. However, alterations in within- and between-module connectivity were observed for higher-order cognitive (e.g., central-executive salience, memory, default mode), and sensory modules in patients with schizophrenia and nonclinical individuals with hallucinations relative to controls. Dissimilar patterns of altered within- and between-module connectivity were found bipolar disorder patients with hallucinations relative to controls, including the visual, default mode, and memory network, while connectivity patterns between visual, salience, and cognitive control modules were unaltered. Bipolar disorder patients without hallucinations did not show significant alterations relative to controls. This study provides evidence for alterations in the modular organization of the functional connectome in individuals prone to hallucinations, with schizophrenia patients and nonclinical individuals showing similar alterations in sensory and higher-order cognitive modules. Other higher-order cognitive modules were found to relate to hallucinations in bipolar disorder patients, suggesting differential neural mechanisms may underlie hallucinations across the psychosis continuum., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Objectives: Negative emotional valence of auditory verbal hallucinations (AVHs) in schizophrenia can be a source of distress and is considered a strong predictor of illness severity. Previous studies have found glutamate to mediate AVH severity in frontal and temporal brain regions, however, they do not specifically address emotional valence of AVH. The role of glutamate for the experience of negative- versus positive emotional valence of AVH is therefore unknown and was investigated in the current study., Methods: Using magnetic resonance spectroscopy (MRS), 37 schizophrenia patients had Glx (glutamate+glutamine) measured in the left superior temporal gyrus (STG), and additionally in the anterior cingulate cortex (ACC) and the right STG, or in the left inferior frontal gyrus (IFG). Self-reported emotional valence in AVH was measured with the Beliefs About Voices Questionnaire (BAVQ-R)., Results: Results from linear mixed models showed that negative emotional valence was associated with reduced Glx levels across all four measured brain regions in the frontal and temporal lobe. More specifically, voices that were experienced to be omnipotent (p = 0.04) and that the patients attempted to resist (p = 0.04) were related to lower Glx levels. Follow-up analysis of the latter showed that voices that evoked emotional resistance (i.e., fear, sadness, anger), rather than behavioral resistance, was a significant predictor of reduced glutamate (p = 0.02)., Conclusion: The findings could indicate aberrant glutamatergic signaling, or increased NMDA-receptor hypoactivity in patients who experience their voices to be more emotionally negative. Overall, the study provides support for the glutamate hypothesis of schizophrenia., (© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Background: Most studies investigating antipsychotic effectiveness report either total psychopathology or symptom cluster findings. Studies focusing on a separate symptom, such as hallucinations, a hallmark symptom in schizophrenia, are scarce.Therefore, the current study aims to compare the antihallucinatory effectiveness of 3 pharmacologically different antipsychotics: olanzapine, amisulpride, and aripiprazole., Methods: The present study is part of the Bergen-Stavanger-Innsbruck-Trondheim study, a 12-month prospective, randomized, pragmatic antipsychotic drug trial in active-phase schizophrenia spectrum disorders. The primary outcome of the present study was change of hallucinations as measured by item P3 (hallucinatory behavior) from the Positive and Negative Syndrome Scale in the subgroup with hallucinations at baseline. Primary analyses were intention to treat., Results: A total of 144 participants were included in the study, where 105 (72%) had a score of 3 or more on the Positive and Negative Syndrome Scale P3 item at baseline, indicating the presence of hallucinations (HALL subgroup).In the HALL subgroup, a significantly less reduction of hallucinations was revealed for participants using olanzapine in weeks 12, 26, 39, and 52 when compared with amisulpride and in weeks 26 and 52 when compared with aripiprazole. In subanalyses for participants never exposed to antipsychotic drugs (antipsychotic-naive) and those who had used antipsychotics before entering the study, antihallucinatory differences were revealed only in the latter group., Conclusions: A differential antihallucinatory effect of the 3 study drugs was present. The inferior effect of olanzapine seems to be driven by the subgroup of participants exposed to antipsychotic treatment before entering the study., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Hallucinations may arise from an imbalance between sensory and higher cognitive brain regions, reflected by alterations in functional connectivity. It is unknown whether hallucinations across the psychosis continuum exhibit similar alterations in functional connectivity, suggesting a common neural mechanism, or whether different mechanisms link to hallucinations across phenotypes. We acquired resting-state functional MRI scans of 483 participants, including 40 non-clinical individuals with hallucinations, 99 schizophrenia patients with hallucinations, 74 bipolar-I disorder patients with hallucinations, 42 bipolar-I disorder patients without hallucinations, and 228 healthy controls. The weighted connectivity matrices were compared using network-based statistics. Non-clinical individuals with hallucinations and schizophrenia patients with hallucinations exhibited increased connectivity, mainly among fronto-temporal and fronto-insula/cingulate areas compared to controls (P < 0.001 adjusted). Differential effects were observed for bipolar-I disorder patients with hallucinations versus controls, mainly characterized by decreased connectivity between fronto-temporal and fronto-striatal areas (P = 0.012 adjusted). No connectivity alterations were found between bipolar-I disorder patients without hallucinations and controls. Our results support the notion that hallucinations in non-clinical individuals and schizophrenia patients are related to altered interactions between sensory and higher-order cognitive brain regions. However, a different dysconnectivity pattern was observed for bipolar-I disorder patients with hallucinations, which implies a different neural mechanism across the psychosis continuum.

Background: Schizophrenia (SZ) and bipolar disorder (BD) share substantial neurodevelopmental components affecting brain maturation and architecture. This necessitates a dynamic lifespan perspective in which brain aberrations are inferred from deviations from expected lifespan trajectories. We applied machine learning to diffusion tensor imaging (DTI) indices of white matter structure and organization to estimate and compare brain age between patients with SZ, patients with BD, and healthy control (HC) subjects across 10 cohorts., Methods: We trained 6 cross-validated models using different combinations of DTI data from 927 HC subjects (18-94 years of age) and applied the models to the test sets including 648 patients with SZ (18-66 years of age), 185 patients with BD (18-64 years of age), and 990 HC subjects (17-68 years of age), estimating the brain age for each participant. Group differences were assessed using linear models, accounting for age, sex, and scanner. A meta-analytic framework was applied to assess the heterogeneity and generalizability of the results., Results: Tenfold cross-validation revealed high accuracy for all models. Compared with HC subjects, the model including all feature sets significantly overestimated the age of patients with SZ (Cohen's d = -0.29) and patients with BD (Cohen's d = 0.18), with similar effects for the other models. The meta-analysis converged on the same findings. Fractional anisotropy-based models showed larger group differences than the models based on other DTI-derived metrics., Conclusions: Brain age prediction based on DTI provides informative and robust proxies for brain white matter integrity. Our results further suggest that white matter aberrations in SZ and BD primarily consist of anatomically distributed deviations from expected lifespan trajectories that generalize across cohorts and scanners., (Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Amisulpride, aripiprazole, and olanzapine are first-line atypical antipsychotics that have not previously been compared head-to-head in a pragmatic trial. We aimed to compare the efficacy and safety of these agents in a controlled trial., Methods: This pragmatic, rater-blind, randomised controlled trial was done in three academic centres of psychiatry in Norway, and one in Austria. Eligible patients were aged 18 years or older, met ICD-10 criteria for schizophrenia-spectrum disorders (F20-29), and had symptoms of active psychosis. Eligible patients were randomly assigned to receive oral amisulpride, aripiprazole, or olanzapine. Treatment allocation was open to patients and staff, and starting dose, treatment changes, and adjustments were left to the discretion of the treating physician. Computer-generated randomisation lists for each study centre were prepared by independent statisticians. Patients were followed up for 52 weeks after random assignment, during which assessments were done 8 times by researchers masked to treatment. The primary outcome was reduction of the Positive And Negative Syndrome Scale (PANSS) total score at 52 weeks, and primary analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01446328., Findings: Between Oct 20, 2011, and Dec 30, 2016, we assessed 359 patients for eligibility. 215 patients were excluded (107 did not meet inclusion criteria, 82 declined to participate, 26 other reasons). 144 patients (mean baseline PANSS total estimated score 78·4 [SD 1·4]) were randomly assigned 1:1:1 to receive amisulpride (44 patients), aripiprazole (48 patients) or olanzapine (52 patients). After 52 weeks, the patients allocated to amisulpride had a PANSS total score reduction of 32·7 points (SD 3·1) compared with 21·9 points reduction with aripiprazole (SD 3·9, p=0·027) and 23·3 points with olanzapine (2·9, p=0·025). We observed weight gain and increases of serum lipids and prolactin in all groups. 26 serious adverse events (SAEs) among 20 patients were registered (four [9%] of 44 patients allocated to amisulpride, ten [21%] of 48 patients allocated to aripiprazole, and six [12%] of 52 patients allocated to olanzapine), with no statistically significant differences between the study drugs. 17 (65%) of the 26 SAEs occurred during the use of the study drug, with readmission or protracted hospital admission accounting for 13 SAEs. One death by suicide, one unspecified death, and one life-threatening accident occurred during follow-up, after cessation of treatment., Interpretation: Amisulpride was more efficacious than aripiprazole or olanzapine for reducing the PANSS total scores in adults with schizophrenia-spectrum disorders. Side-effect differences among the groups were generally small. This study supports the notion that clinically relevant efficacy differences exist between antipsychotic drugs. Future research should aim to compare first-line antipsychotics directly in pragmatic clinical trials that reflect everyday clinical practice., Funding: The Research Council of Norway, the Western Norway Regional Health Trust, and participating hospitals and universities., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The arcuate fasciculus (AF) has been implicated in the pathology behind schizophrenia and auditory verbal hallucinations (AVHs). White matter tracts forming the arcuate fasciculus can be quantified and visualized using diffusion tensor imaging (DTI) tractography. Although there have been a number of studies on this topic, the results have been conflicting. Studying the underlying white matter structure of the AF could shed light on the constrains for interaction between temporal and frontal language areas in AVHs. The participants were 66 patients with a schizophrenia diagnosis, where AVHs were defined from the Positive and Negative Syndrome Scale (PANSS), and compared with a healthy control group. DTI was performed on a 3T MR scanner, and tensor estimation was done using deterministic streamline tractography. Statistical analysis of the data showed significantly longer reconstructed tracks along the AF in patients with severe and frequent AVHs, as well as an overall significant asymmetry with longer tracks in the left compared to the right side. In addition, there were significant positive correlations between PANSS scores and track length, track volume, and number of track streamlines for the posterior AF segment on the left side. It is concluded that the present DTI results may have implications for interpretations of functional imaging results., Competing Interests: Declaration of Competing Interests Co-authors Kenneth Hugdahl and Lars Ersland owns shares in the company NordicNeurolab Inc. (https://nordicneurolab.com/) that produced add-on equipment for the acquisition of the MR data. Kenneth Hugdahl and Lars Ersland declare no conflict of interest, as do all other co-authors., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Glutamate (Glu), gamma amino-butyric acid (GABA), and excitatory/inhibitory (E/I) imbalance have inconsistently been implicated in the etiology of schizophrenia. Elevated Glu levels in language regions have been suggested to mediate auditory verbal hallucinations (AVH), the same regions previously associated with neuronal hyperactivity during AVHs. It is, however, not known whether alterations in Glu levels are accompanied by corresponding GABA alterations, nor is it known if Glu levels are affected in brain regions with known neuronal hypo-activity. Using magnetic resonance spectroscopy (MRS), we measured Glx (Glu+glutamine) and GABA+ levels in the anterior cingulate cortex (ACC), left and right superior temporal gyrus (STG), and left inferior frontal gyrus (IFG), in a sample of 77 schizophrenia patients and 77 healthy controls. Two MRS-protocols were used. Results showed a marginally significant positive correlation in the left STG between Glx and AVHs, whereas a significant negative correlation was found in the ACC. In addition, high-hallucinating patients as a group showed decreased ACC and increased left STG Glx levels compared to low-hallucinating patients, with the healthy controls in between the 2 hallucinating groups. No significant differences were found for GABA+ levels. It is discussed that reduced ACC Glx levels reflect an inability of AVH patients to cognitively inhibit their "voices" through neuronal hypo-activity, which in turn originates from increased left STG Glu levels and neuronal hyperactivity. A revised E/I-imbalance model is proposed where Glu-Glu imbalance between brain regions is emphasized rather than Glu-GABA imbalance within regions, for the understanding of the underlying neurochemistry of AVHs., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

In the present article, we present a "Levels of Explanation" (LoE) approach to auditory verbal hallucinations (AVHs) in schizophrenia. Mental phenomena can be understood at different levels of explanation, including cultural, clinical, cognitive, brain imaging, cellular, and molecular levels. Current research on AVHs is characterized by accumulation of data at all levels, but with little or no interaction of findings between levels. A second advantage with a Levels of Explanation approach is that it fosters interdisciplinarity and collaboration across traditional borders, facilitating a real breakthrough in future research. We exemplify a Levels of Explanation approach with data from 3 levels where findings at 1 level provide predictions for another level. More specifically, we show how functional neuroimaging data at the brain level correspond with behavioral data at the cognitive level, and how data at these 2 levels correspond with recent findings of changes in neurotransmitter function at the cellular level. We further discuss implications for new therapeutic interventions, and the article is ended by suggestion how future research could incorporate genetic influences on AVHs at the molecular level of explanation by providing examples for animal work.

Magnetic Resonance Spectroscopy (MRS) has become a valuable tool for investigating the biochemical bases of both normal processes in the healthy brain and elucidating the pathophysiology of neuropsychiatric disorders. As a rapidly advancing field, new developments in pulse sequence design have seen new possibilities arise in terms of what can be done with in vivo spectroscopy. While the applications of MRS are numerous, this review has been confined to the use of single voxel spectroscopy in the assessment of five key metabolites and their roles in schizophrenia: N-acetylaspartate (NAA), glutamate (Glu) and glutamine (Gln), γ-aminobutyric acid (GABA) and glutathione (GSH). This article will briefly cover the roles they play in schizophrenia, review current methods being used in their assessment and highlight new approaches that may potentially overcome some of the limitations current methods pose., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

In this invited review article, I present a translational perspective and overview of our research on auditory hallucinations in schizophrenia at the University of Bergen, Norway, with a focus on the neuronal mechanisms underlying the phenomenology of experiencing "hearing voices". An auditory verbal hallucination (i.e. hearing a voice) is defined as a sensory experience in the absence of a corresponding external sensory source that could explain the phenomenological experience. I suggest a general frame or scheme for the study of auditory verbal hallucinations, called Levels of Explanation. Using a Levels of Explanation approach, mental phenomena can be described and explained at different levels (cultural, clinical, cognitive, brain-imaging, cellular and molecular). Another way of saying this is that, to advance knowledge in a research field, it is not only necessary to replicate findings, but also to show how evidence obtained with one method, and at one level of explanation, converges with evidence obtained with another method at another level. To achieve breakthroughs in our understanding of auditory verbal hallucinations, we have to advance vertically through the various levels, rather than the more common approach of staying at our favourite level and advancing horizontally (e.g., more advanced techniques and data acquisition analyses). The horizontal expansion will, however, not advance a deeper understanding of how an auditory verbal hallucination spontaneously starts and stops. Finally, I present data from the clinical, cognitive, brain-imaging, and cellular levels, where data from one level validate and support data at another level, called converging of evidence. Using a translational approach, the current status of auditory verbal hallucinations is that they implicate speech perception areas in the left temporal lobe, impairing perception of and attention to external sounds. Preliminary results also show that amygdala is implicated in the emotional «colouring» of the voices and that excitatory neurotransmitters might be involved. What we do not know is why hallucinatory episodes occur spontaneously, why they fluctuate over time, and what makes them spontaneously stop. Moreover, is voice hearing a category or dimension in its own right, independent of diagnosis, and why is the auditory modality predominantly implicated in psychotic disorders, while the visual modality dominates in, for example, neurological diseases?

There is evidence for genetic overlap between cognitive abilities and schizophrenia (SCZ), and genome-wide association studies (GWAS) demonstrate that both SCZ and general cognitive abilities have a strong polygenic component with many single-nucleotide polymorphisms (SNPs) each with a small effect. Here we investigated the shared genetic architecture between SCZ and educational attainment, which is regarded as a "proxy phenotype" for cognitive abilities, but may also reflect other traits. We applied a conditional false discovery rate (condFDR) method to GWAS of SCZ (n = 82 315), college completion ("College," n = 95 427), and years of education ("EduYears," n = 101 069). Variants associated with College or EduYears showed enrichment of association with SCZ, demonstrating polygenic overlap. This was confirmed by an increased replication rate in SCZ. By applying a condFDR threshold <0.01, we identified 18 genomic loci associated with SCZ after conditioning on College and 15 loci associated with SCZ after conditioning on EduYears. Ten of these loci overlapped. Using conjunctional FDR, we identified 10 loci shared between SCZ and College, and 29 loci shared between SCZ and EduYears. The majority of these loci had effects in opposite directions. Our results provide evidence for polygenic overlap between SCZ and educational attainment, and identify novel pleiotropic loci. Other studies have reported genetic overlap between SCZ and cognition, or SCZ and educational attainment, with negative correlation. Importantly, our methods enable identification of bi-directional effects, which highlight the complex relationship between SCZ and educational attainment, and support polygenic mechanisms underlying both cognitive dysfunction and creativity in SCZ., (© The Author 2016. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Neuroimaging studies have demonstrated associations between smaller auditory cortex volume and auditory hallucinations (AH) in schizophrenia. Reduced cortical volume can result from a reduction of either cortical thickness or cortical surface area, which may reflect different neuropathology. We investigate for the first time how thickness and surface area of the auditory cortex relate to AH in a large sample of schizophrenia spectrum patients., Methods: Schizophrenia spectrum (n = 194) patients underwent magnetic resonance imaging. Mean cortical thickness and surface area in auditory cortex regions (Heschl's gyrus [HG], planum temporale [PT], and superior temporal gyrus [STG]) were compared between patients with (AH+, n = 145) and without (AH-, n = 49) a lifetime history of AH and 279 healthy controls., Results: AH+ patients showed significantly thinner cortex in the left HG compared to AH- patients (d = 0.43, P = .0096). There were no significant differences between AH+ and AH- patients in cortical thickness in the PT or STG, or in auditory cortex surface area in any of the regions investigated. Group differences in cortical thickness in the left HG was not affected by duration of illness or current antipsychotic medication., Conclusions: AH in schizophrenia patients were related to thinner cortex, but not smaller surface area of the left HG, a region which includes the primary auditory cortex. The results support that structural abnormalities of the auditory cortex underlie AH in schizophrenia., (© The Author 2016. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Most people are right-handed and show left-hemispheric language lateralization, but a minority exhibits left-handedness and right-hemispheric language lateralization. This atypical laterality pattern is observed significantly more often in schizophrenia patients than in the general population, which led several authors to conclude that there is a genetic link between laterality and schizophrenia. It has even been suggested that a failure in the lateralization process, orchestrated by genes, could be the primary cause of schizophrenia. However, the molecular genetic evidence for a link between laterality and schizophrenia is weak. Recent genetic evidence indicates that schizophrenia is not a single disorder but a group of heritable disorders caused by different genotypic networks leading to distinct clinical symptoms. To uncover the link between schizophrenia and laterality we therefore suggest a paradigm shift where genetics are not mapped on schizophrenia as a whole but on discrete schizophrenia symptoms. In addition, we provide a critical evaluation of current theories on the genetic link between schizophrenia and brain asymmetry., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Schizophrenia (SZ) is characterized by cognitive dysfunction and disorganized thought, in addition to hallucinations and delusions, and is regarded a disorder of brain connectivity. Recent efforts have been made to characterize the underlying brain network organization and interactions. However, to which degree connectivity alterations in SZ vary across different levels of cognitive effort is unknown. Utilizing independent component analysis (ICA) and methods for delineating functional connectivity measures from functional magnetic resonance imaging (fMRI) data, we investigated the effects of cognitive effort, SZ and their interactions on between-network functional connectivity during 2 levels of cognitive load in a large and well-characterized sample of SZ patients (n = 99) and healthy individuals (n = 143). Cognitive load influenced a majority of the functional connections, including but not limited to fronto-parietal and default-mode networks, reflecting both decreases and increases in between-network synchronization. Reduced connectivity in SZ was identified in 2 large-scale functional connections across load conditions, with a particular involvement of an insular network. The results document an important role of interactions between insular, default-mode, and visual networks in SZ pathophysiology. The interplay between brain networks was robustly modulated by cognitive effort, but the reduced functional connectivity in SZ, primarily related to an insular network, was independent of cognitive load, indicating a relatively general brain network-level dysfunction., (© The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Schizophrenia (SZ) is a psychotic disorder with significant cognitive dysfunction. Abnormal brain activation during cognitive processing has been reported, both in task-positive and task-negative networks. Further, structural cortical and subcortical brain abnormalities have been documented, but little is known about how task-related brain activation is associated with brain anatomy in SZ compared to healthy controls (HC). Utilizing linked independent component analysis (LICA), a data-driven multimodal analysis approach, we investigated structure-function associations in a large sample of SZ (n = 96) and HC (n = 142). We tested for associations between task-positive (fronto-parietal) and task-negative (default-mode) brain networks derived from fMRI activation during an n-back working memory task, and brain structural measures of surface area, cortical thickness, and gray matter volume, and to what extent these associations differed in SZ compared to HC. A significant association (p < .05, corrected for multiple comparisons) was found between a component reflecting the task-positive fronto-parietal network and another component reflecting cortical thickness in fronto-temporal brain regions in SZ, indicating increased activation with increased thickness. Other structure-function associations across, between and within groups were generally moderate and significant at a nominal p-level only, with more numerous and stronger associations in SZ compared to HC. These results indicate a complex pattern of moderate associations between brain activation during cognitive processing and brain morphometry, and extend previous findings of fronto-temporal brain abnormalities in SZ by suggesting a coupling between cortical thickness of these brain regions and working memory-related brain activation.

Schizophrenia has been recently increasingly linked with a number of structural brain morphological changes which can be associated with functional deficiencies. The aim of this study is to relate electrophysiological changes with structural changes of Heschl's gyrus (HG) volume in schizophrenia. Fifteen schizophrenia patients were compared with control group by magnetic resonance imaging (MRI) volumetry and auditory evoked potentials. A significantly lower bilateral HG volumes and a significantly lower global field power value of the N1P2 component were detected in the schizophrenia group. The auditory evoked potentials have been used as a functional correlate that displayed a significant amplitude reduction that matched the reduction in the HG volume with the chronicity of the disease. This trend may be utilized as a vehicle to assess follow-up of the disorder by means of MRI and electrophysiology., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

This is a (1)H MR spectroscopy (MRS) study of glutamate (Glu), measured as Glx, levels in temporal and frontal lobe regions in patients with schizophrenia compared with a healthy control group with the objective of revealing aspects of the underlying neurochemistry of auditory hallucinations. We further compared and correlated Glu(Glx) levels for the patients-only against frequency and severity of auditory hallucinations and the sum of Positive symptoms, and also for frequency and severity of emotional withdrawal, and sum of Negative symptoms. The sample included 23 patients with an ICD-10 and DSM-IV diagnosis of schizophrenia, and 26 healthy control subjects without any known psychiatric or neurological disorders. Symptom scores were obtained from the Positive and Negative Syndrome Scale (PANSS). (1)H MRS data were acquired on a 3T MR scanner from two temporal and two frontal voxels, using standard sequences and analysis parameters. The results showed that schizophrenia patients as a group had reduced Glu(Glx) levels in the voxels of interest compared to the healthy control subjects, while increased levels were found for patients with frequent and severe auditory hallucinations, relative to patients with less frequent and severe hallucination. We further found significant positive correlations between frequency and severity of auditory hallucinations, and for sum Positive symptoms, and Glu(Glx) levels in all regions, not seen when the analysis was done for negative symptoms. It is concluded that the results show for the first time that glutamate may be a mediating factor in auditory hallucinations in schizophrenia., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: The notion that schizophrenia is characterised by increased non-right-handedness is a cornerstone of the theory that schizophrenia arises from, and is genetically linked to, abnormal brain lateralisation. Reviews and meta-analyses have reported higher rates of non-right-handers in patients with schizophrenia. However, this was suggested to be the result of a gender artefact or a hidden bias in self-report handedness questionnaires., Aims: To investigate using a meta-analytical approach whether the excess of non-right-handedness is seen in both females and males, and also when handedness is assessed behaviourally., Method: Electronic databases were searched for studies that reported (a) the rate of female and male non-right-handers in schizophrenia compared with controls and (b) the rate of non-right-handers in schizophrenia (regardless of gender) based on behavioural handedness assessment., Results: The odds ratios (ORs) for females (OR = 1.63; based on 621 patients, 3747 controls) and males (OR = 1.50; based on 1213 patients, 3800 controls) differed significantly from 1.0, indicating both female and male patients were more often non-right-handed than controls. Moreover, there was an excess of non-right-handedness in patients with schizophrenia when handedness was assessed behaviourally: OR = 1.84 (1255 patients, 6260 controls). Even when both gender and behavioural handedness assessment were controlled for simultaneously, the excess of non-right-handedness persisted., Conclusions: The findings clearly demonstrate that the excess of non-right-handedness in schizophrenia does not result from a gender artefact or from biased handedness questionnaires. It is a true empirical effect and may indeed reflect a genetic link between schizophrenia and brain lateralisation., (Royal College of Psychiatrists.)

Schizophrenia is characterized by impaired cognitive functioning, and brain regions involved in cognitive control processes show marked glutamatergic abnormalities. However, it is presently unclear whether aberrant neuronal response is directly related to the observed deficits at the metabolite level in schizophrenia. Here, 17 medicated schizophrenia patients and 17 matched healthy participants underwent functional magnetic resonance imaging (fMRI) when performing an auditory cognitive control task, as well as proton magnetic resonance spectroscopy ((1)H-MRS) in order to assess resting-state glutamate in the anterior cingulate cortex. The combined fMRI-(1)H-MRS analysis revealed that glutamate differentially predicted cortical blood-oxygen level-dependent (BOLD) response in patients and controls. While we found a positive correlation between glutamate and BOLD response bilaterally in the inferior parietal lobes in the patients, the corresponding correlation was negative in the healthy control participants. Further, glutamate levels predicted task performance in patients, such that lower glutamate levels were related to impaired cognitive control functioning. This was not seen for the healthy controls. These findings suggest that schizophrenia patients have a glutamate-related dysregulation of the brain network supporting cognitive control functioning. This could be targeted in future research on glutamatergic treatment of cognitive symptoms in schizophrenia.

Background: Schizophrenia and bipolar disorder are severe mental disorders with overlapping genetic and clinical characteristics, including cognitive impairments. An important question is whether these disorders also have overlapping neuronal deficits., Aims: To determine whether large-scale brain networks associated with working memory, as measured with functional magnetic resonance imaging (fMRI), are the same in both schizophrenia and bipolar disorder, and how they differ from those in healthy individuals., Method: Patients with schizophrenia (n = 100) and bipolar disorder (n = 100) and a healthy control group (n = 100) performed a 2-back working memory task while fMRI data were acquired. The imaging data were analysed using independent component analysis to extract large-scale networks of task-related activations., Results: Similar working memory networks were activated in all groups. However, in three out of nine networks related to the experimental task there was a graded response difference in fMRI signal amplitudes, where patients with schizophrenia showed greater activation than those with bipolar disorder, who in turn showed more activation than healthy controls. Secondary analysis of the patient groups showed that these activation patterns were associated with history of psychosis and current elevated mood in bipolar disorder., Conclusions: The same brain networks were related to working memory in schizophrenia, bipolar disorder and controls. However, some key networks showed a graded hyperactivation in the two patient groups, in line with a continuum of neuronal abnormalities across psychotic disorders.

Schizophrenia is characterized by cognitive impairment, especially in relation to executive functions. Brain structural abnormalities are also often seen in schizophrenia although little is known of the relationship between cognitive impairment and structural brain changes. Our aim was therefore to investigate this relationship further using MRI and a dichotic listening (DL) task with simple speech sounds and with instructions to focus attention and report only from the left or right ear stimulus. When instructed to focus attention on the left ear syllable a cognitive conflict is induced requiring the allocation of executive resources to be resolved. Grey matter (GM) volume was measured with MRI from four volumes of interests (VOIs), left and right frontal and temporal cortex, respectively, and correlated with DL performance. The results showed significant differences between the groups in their ability to focus attention on and report the left ear stimulus, which was accompanied by reduced GM volume in the left frontal and right temporal lobe VOIs. There was also a significant positive correlation between left frontal GM volume and performance on the DL task, for the groups combined. The results did not support a conclusion that an impairment in cognitive function in schizophrenia was driven by an corresponding impairment in brain structure, since there were no significant correlations when the groups were analyzed separately. It is however concluded that patients with schizophrenia are impaired in executive functions and that they also show reduced GM volumes in left frontal and right temporal lobe areas, compared to healthy controls., (© 2013 The Scandinavian Psychological Associations.)

Background: Hallucinations are prevalent in schizophrenia and related psychotic disorders and may have severe consequences for the affected patients. Antipsychotic drug trials that specifically address the anti-hallucinatory effectiveness of the respective drugs in representative samples are rare. The aims of the present study were to investigate the rate and severity of hallucinations in acutely admitted psychotic patients at hospital admission and discharge or after 6 weeks at the latest, if not discharged earlier (discharge/6 weeks); and to compare the anti-hallucinatory effectiveness of risperidone, olanzapine, quetiapine, and ziprasidone with up to 2 years' follow-up., Methods: Adult patients acutely admitted to an emergency ward for psychosis were consecutively randomized to risperidone, olanzapine, quetiapine, or ziprasidone and followed for up to 2 years in a pragmatic design. Participants were assessed repeatedly using the hallucinatory behavior item of the Positive and Negative Syndrome Scale (PANSS)., Results: A total of 226 patients, 30.5% of those assessed for eligibility, were randomized and 68% were hallucinating at baseline. This proportion was reduced to 33% at discharge/6 weeks. In the primary analyses based on intention to treat groups of patients experiencing frequent hallucinations, the quetiapine and ziprasidone groups both had faster decreases of the mean hallucination scores than the risperidone group., Conclusions: Hallucinations are fairly responsive to antipsychotic drug treatment and differential anti-hallucinatory effectiveness may be found among existing antipsychotic drugs. If replicated, this could pave the way for a more targeted pharmacotherapy based on individual symptom profiles, rather than on the diagnostic category., Trial Registration: ClinicalTrials.gov ID; NCT00932529.

Auditory verbal hallucinations (AVHs) are speech perceptions that lack an external source, phenomenologically experienced as "hearing voices". A perceptual origin of an AVH experience in patients with schizophrenia can however not explain why the "voices" drain the attentional and cognitive capacity of the patients, making them unable to direct attention away from the "voices" and to cognitively suppress the experience. We recently reported how AVHs interfere with the perception of speech sounds, using a dichotic listening experimental paradigm. We now extend this finding by reporting on the interference caused by AVHs on attention and cognitive control, using a slight variation of the same dichotic listening paradigm. The patients (N=148) were instructed to pay attention to and report from either the right or left ear syllable of the dichotic pair. We then correlated their PANSS score for the hallucination item (P3) with the performance score on the dichotic listening task. The results showed that AVHs interfered with the ability to report the right ear syllable when instructed to pay attention to the right side, which is a marker of inability to attend to an external speech stimulus. When instructed to pay attention to the left side, AVHs interfered with the ability to report the left ear syllable, which is a marker of inability to use cognitive control to suppress attending to the "voices". The corresponding correlations for the emotional withdrawal (N2) negative symptom were all non-significant. The correlations were substantiated in an ANOVA with corresponding significant group differences between high versus low symptom score groups. The results thus extend our previous findings of a perceptual origination for AVHs by showing that AVHs interfere with the ability to attend to the outer world around the patient, and the ability to inhibit, or suppress, the "voices" once they occur. Future research should pin down the neuronal basis of both the origination and the attentional and cognitive control aspects of AVHs., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Inattention in people with schizophrenia is common. However, there has been little research on the association between inattention and auditory hallucinations. The aim of the study was to investigate how inattention is affected by beliefs about voices as benevolent and malevolent and perceived control of voices. A total of 31 patients who experienced auditory hallucinations and who met the criteria for schizophrenia or other psychosis completed the attention subscale of the Scale for the Assessment of Negative Symptoms (SANS) and the Connors' Continuous Performance Test II (CCPT-II). The revised Beliefs About Voices Questionnaire (BAVQ-R) was used to assess malevolent and benevolent beliefs about voices, and severity of auditory hallucinations (the Psychotic Symptom Rating Scales; PSYRATS) was used to assess perceived control of voices and frequency of voices. Levels of depression (the Beck Depression Inventory; BDI), anxiety (the Beck Anxiety Inventory; BAI), severity of overall psychiatric symptoms (the Brief Psychiatric Rating Scale; BPRS), and severity of negative symptoms (SANS) were assessed to control for their potential confounding effects. The relations between the variables were explored with correlations and multiple hierarchical regression analyses. The results indicated that more malevolent, but not more benevolent, beliefs about voices predicted lower levels of attention, independently of general psychiatric symptoms and various other psychotic symptoms such as frequency of and perceived control of voices. These findings suggest an important relationship between malevolent beliefs about voices and levels of inattention. The possible impact of changing beliefs about voices to improve attentional functioning is discussed., (© 2013 The Authors. Scandinavian Journal of Psychology © 2013 The Scandinavian Psychological Associations.)

Reduced left-hemispheric language lateralization has been proposed to be a trait marker for schizophrenia, but the empirical evidence is ambiguous. Recent studies suggest that auditory hallucinations are critical for whether a patient shows reduced language lateralization. Therefore, the aim of the study was to statistically integrate studies investigating language lateralization in schizophrenia patients using dichotic listening. To this end, two meta-analyses were conducted, one comparing schizophrenia patients with healthy controls (n = 1407), the other comparing schizophrenia patients experiencing auditory hallucinations with non-hallucinating controls (n = 407). Schizophrenia patients showed weaker language lateralization than healthy controls but the effect size was small (g = -0.26). When patients with auditory hallucinations were compared to non-hallucinating controls, the effect size was substantially larger (g = -0.45). These effect sizes suggest that reduced language lateralization is a weak trait marker for schizophrenia as such and a strong trait marker for the experience of auditory hallucinations within the schizophrenia population.

In schizophrenia research executive functions have been frequently reported to be impaired on a global level, largely ignoring the fact that the term executive functions refers to a collection of cognitive functions, which may be affected independently of each other. In the present meta-analysis we were able to show that an aspect of interference control, the ability to resist to distracting information, is not substantially affected in schizophrenia. Summarizing the results of 21 studies using a flanker task, we did not find an increased incompatibility slowing (relative to a compatible flanker condition). The mean effect size, integrating the data of 1029 schizophrenia and 848 controls, was with M(g) = 0.037 (95% confidence interval: -0.05 to 0.13) small and the test power was with 1-β = 0.991 sufficiently high to exclude even small population effects. A similar result was obtained when analyzing the incompatibility slowing relative to a neutral flanker condition (8 studies, M(g) = -0.032, 95% confidence interval: -0.16 to 0.09). In not being substantially affected in schizophrenia, the ability to resist distractor interference could serve as "scaffold function", which used by cognitive remediation programs, would allow to build up general functions, such as vigilance and attention, before the affected executive abilities would be addressed., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

We report evidence that auditory verbal hallucinations (AVH) in schizophrenia patients are perceptual distortions lateralized to the left hemisphere. We used a dichotic listening task with repeated presentations of consonant-vowel syllables, a different syllable in the right and left ear. This task produces more correct reports for the right ear syllable in healthy individuals, indicative of left hemisphere speech processing focus. If AVHs are lateralized to the left hemisphere language receptive areas, then this should interfere with correct right ear reports in the dichotic task, which would result in significant negative correlations with severity of AVHs. We correlated the right and left ear correct reports with the PANSS hallucination symptom, and a randomly selected negative symptom, in addition to the sum total of the positive and negative symptoms, in 160 patients with schizophrenia. The results confirmed the predictions with significant negative correlations for the right ear scores with the PANSS hallucination item, and for the sum total of positive symptoms, while all other correlations were close to zero. The results are unambiguous evidence for AVHs as aberrant speech perceptions originating in the left hemisphere., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Despite a growing interest in auditory verbal hallucinations (AVHs) in different clinical and nonclinical groups, the phenomenological characteristics of such experiences have not yet been reviewed and contrasted, limiting our understanding of these phenomena on multiple empirical, theoretical, and clinical levels. We look at some of the most prominent descriptive features of AVHs in schizophrenia (SZ). These are then examined in clinical conditions including substance abuse, Parkinson's disease, epilepsy, dementia, late-onset SZ, mood disorders, borderline personality disorder, hearing impairment, and dissociative disorders. The phenomenological changes linked to AVHs in prepsychotic stages are also outlined, together with a review of AVHs in healthy persons. A discussion of key issues and future research directions concludes the review.

Schizophrenia has been consistently shown to be associated with impairment in executive functioning. However, although frequently treated as such, the term executive functioning does not refer to a unitary cognitive function; it rather represents a set of basic, lower-level cognitive sub-components, e.g. updating, shifting, and cognitive inhibition. This specification into sub-components allows for a further differentiation of the executive deficits found in schizophrenia. Focusing on the sub-component of cognitive inhibition, we here present a meta-analysis of interference effect as assessed with the Stroop Color-Word Interference paradigm. Including the results of 36 studies with 1081 schizophrenia patients and 1026 healthy control subjects, it was shown that schizophrenia patients exhibit an increased Stroop interference effect both in response time (mean effect size: M(g) = 0.43; 95% confidence interval, CI95%: 0.35-0.52) and accuracy (M(g) = 0.62; CI95%: 0.47-0.77) measures of interference. However, a meta-regression analysis revealed that the size of the effect varies depending on the version of the Stroop paradigm used. Regarding the response time measures of interference, studies using the classical card version of the paradigm showed a significantly larger effect size than studies using a single-trial computerized version of the paradigm (M(g) = 0.60 vs. M(g) = 0.19). Despite of the dissociation between the two versions of the paradigm, the results of the present meta-analysis indicate that the reported global deficits in executive functioning found to be associated with schizophrenia are at least partly due to a reduced ability of cognitive inhibition., (Copyright © 2011. Published by Elsevier B.V.)

The n-back task is frequently used as an experimental paradigm in imaging studies of working memory. This study aimed to investigate whether the Bergen 2-back task is suitable for use in desktop assessment of patients with schizophrenia. Looking at the psychometric properties of the task, including the newly added measure of discriminability, d prime (d '), our analyses confirmed that the 2-back d ' is the preferred measure of working memory dysfunction in desktop assessment compared to the Digit Span Backward and the Letter-Number Sequencing subtests from the Wechsler Adult Intelligence Scale-Third Edition (WAIS-III). d ' has the advantage of capturing executive skills needed to perform mental operations in patients with schizophrenia, without being influenced by demographic variables or IQ.

Auditory hallucination is a key characteristic of schizophrenia that seriously debilitates the patient, with consequences for social engagement with others. Hallucinatory experiences are also observed in healthy individuals in the general population who report "hearing voices" in the absence of an external acoustic input. A view on auditory hallucinations and "hearing voices" is presented that regards such phenomena as perceptual processes, originating from speech perception areas in the left temporal lobe. Healthy individuals "hearing voices" are, however, often aware that the experience comes from inner thought processes, which is not reported by hallucinating patients. A perceptual model can therefore, not alone explain the difference in the phenomenology of how the "voices heard" are attributed to either an inner or outer cause. An expanded model is thus presented which takes into account top-down cognitive control, localized to prefrontal cortical areas, to inhibit and re-attribute the perceptual mis-representations. The expanded model is suggested to be empirically validated using a dichotic listening speech perception paradigm with instructions for top-down control of attention focus to either the right or left side in auditory space. It is furthermore suggested to use fMRI to validate the temporal and frontal lobe neuronal correlates of the cognitive processes involved in auditory hallucinations.

Introduction: We propose that auditory hallucinations are internally generated speech misrepresentations that are lateralised to the left temporal lobe. If hallucinations are misrepresentations involving the speech perception area of the left temporal lobe, then hallucinating patients should have problems identifying a simultaneously presented external speech sound, especially when the sound is lateralised to the left hemisphere. Lateralisation of speech perception can be experimentally studied with the dichotic listening task with consonant-vowel syllables. We predicted a negative relation between frequency of auditory hallucinations and performance on the dichotic listening task., Method: We studied 87 right-handed patients with schizophrenia. Hallucination scores were taken from the BPRS symptom scale. Right and left ear scores in the dichotic listening task were recorded. A right ear advantage is expected in healthy individuals, indicating left temporal lobe processing superiority. The patients were compared with 36 right-handed healthy reference subjects., Results: A gradual decrease in the ability to process and report the right ear stimulus with increasing frequency of hallucinations was seen in the schizophrenia patients. No such relationship was found for processing and reporting of the left ear stimulus. There were no significant correlations with negative symptoms. Thus, the results were not the consequence of illness severity. There was however a significant correlation with unusual thought content symptom, pointing to a relationship also between delusions and auditory hallucinations., Conclusion: The results support that auditory hallucinations may be internally generated speech misrepresentations, originating in the left temporal lobe.

The fractal dimension (FD) was used to reveal brain structure irregularities in patients with schizophrenia. FD provides a unique way of quantifying the shape complexity of cortical folding of the human brain. MR images were obtained from seven patients with schizophrenia that were compared with six healthy control subjects. The MR images were first segmented, and the FD was calculated for the grey/white matter boundary for the whole brain and the hemispheres separately, using the box-counting and Minkowski-Bouligand methods. The results showed that the patients had larger FD values than the controls, for the whole brain volume and right hemisphere.

The authors used voxel-based morphometry (VBM) to study GM volume differences in the whole brain volume between a group of patients with schizophrenia and a healthy control group. There were 12 patients and 12 control subjects. The subjects were scanned in a 1.5 T MR scanner. The patients had all been evaluated by a senior psychiatrist on the brief psychiatric rating scale (BPRS). The VBM data was correlated with reports of rate and frequency of hallucinations based on their scores on the BPRS hallucination item. There were significant grey matter volume reductions in the schizophrenia patient group in the left superior (transverse) temporal gyrus, the left middle frontal gyrus, and in the right cuneus. Areas of grey matter volume reduction that correlated negatively with hallucinations were found in the left superior (transverse) temporal gyrus, left thalamus, and left and right cerebellum. This article proposes that significant reductions in grey matter volume may be instrumental in generating spontaneous neuronal activity that is associated with speech perception experiences in the absence of an external acoustic stimulus that may cause hallucinations.

Auditory hallucinations (AH) in schizophrenia have been found to be related to both functional and structural brain abnormalities of left temporal lobe language areas. We do not know if these rain abnormalities are state or trait markers for AH. This study tested these alternatives by contrasting schizophrenic patients with ongoing AH and with a previous history of AH. A heterogeneous group of 26 schizophrenic patients was compared with a healthy control group matched for education and age. We used a verbal dichotic listening (DL) test with consonant-vowel syllables to study hemispheric asymmetry and the functional integrity of the left temporal lobe language areas. All subjects were tested during a divided and two focused attention conditions. Our data suggest that abnormal DL asymmetry for language stimuli is a state marker for AH, seen during the perception of AH. In contrast, problems of modulating DL performance by means of attentional control are a trait marker, seen both in patients with ongoing AH and only a history of AH.

The Judgment of Line Orientation Test, a visuospatial processing task, was administered to normal subjects, to schizophrenic patients and to patients with delusional disorder. Significantly better performance was seen in the normal subjects than in the schizophrenic and delusional patients. Delusional patients, in turn, showed better performance than the schizophrenic patients., (Copyright 2004 Elsevier Ireland Ltd.)

Patients with schizophrenia have repeatedly shown deficits in early visual processing using backward masking (VBM) tasks. Whether this represents a specific dysfunction in schizophrenia is an unsolved question. Patients with recurrent unipolar depression represent an interesting comparison group to examine the question of specificity, but have never previously been assessed on VBM. In addition to comparing VBM performance in patients with schizophrenia and patients with depression, we wanted to examine the relations between VBM and clinical symptoms. Fifty-one patients with schizophrenia were compared to 49 patients with recurrent unipolar depression and 47 healthy controls. All subjects were administered a two-digit identification task in a no-masking and four masking conditions. Patients with schizophrenia performed significantly worse than normal controls on four of the five conditions. No significant difference was found between depression patients and normal controls. The effect of masking stimuli had no differential effects on the three groups. VBM correlated strongly with positive symptoms in the schizophrenia group.

Objective: The authors used functional magnetic resonance imaging (fMRI) to investigate brain activation in patients with schizophrenia and major depression while they performed two tasks-a vigilance task and a mental arithmetic task-that differed in cognitive complexity., Method: In the vigilance task, the participants had to press a response button whenever a specific number was seen on a screen inside the MR scanner. In the mental arithmetic task, the participants had to add two consecutive numbers and press the response button whenever the sum was 10. fMRI was performed with a 1.5-T MR scanner. Twelve patients with recurrent nonpsychotic unipolar major depression, 12 patients with schizophrenia, and 12 healthy comparison subjects were included in the study., Results: Performance data showed that the patients were impaired relative to the comparison subjects and showed no difference in performance between the patient groups. The patients with schizophrenia, but not those with major depression, had less activation in prefrontal brain regions, relative to the comparison participants. However, subtracting brain activation during the vigilance task from activation during the mental arithmetic task showed that the schizophrenia patients had activation in parietal areas., Conclusions: A double dissociation of parietal and frontal lobe activation was found for the schizophrenia patients and the depression patients. The greater parietal lobe activation in the patients with schizophrenia may reflect a compensatory strategy for the failure to recruit cognitive processes that involve frontal lobe areas when solving a mental arithmetic task.

Background: We compared performance on a dichotic listening (DL) task between schizophrenic, depressed, and healthy control subjects. A variant of the traditional DL paradigm was used in which the subjects were required to focus attention either on the left (forced-left condition) or right (forced-right condition) ear stimulus., Methods: The subjects were 51 patients with a DSM-IV diagnosis of schizophrenia, 49 patients with recurrent unipolar major depression, and 49 healthy control subjects. They were tested with a consonant-vowel syllables dichotic listening task under three attentional instructions., Results: There was a significant overall right ear advantage during the nonforced condition, which increased dramatically during the forced-right condition and was eliminated during the forced-left condition. The depressed patients showed no signs of impairments compared with the healthy control group. Thus, they showed a right ear advantage during the nonforced and forced-right conditions, which was shifted to a left ear advantage during the forced left condition. The schizophrenic patients, however, were impaired on the forced-left condition compared with the healthy control and depressed subjects., Conclusions: The results are discussed in terms of separating attentional and inhibitory executive impairments in schizophrenia and depression, taking into consideration illness duration and information-processing demands.

Fifty-three schizophrenic subjects were compared to 50 patients with major depression and 50 normal controls on measures of working memory, declarative memory and malingering. The schizophrenic group scored 1-2 SDs below controls on all measures, while depressive patients exposed only lesser deficits in working memory and free recall. The memory deficit of the schizophrenic subjects was disproportionately greater than their intellectual decline. Differences between clinical groups could not be explained by differences in IQ, clinical symptom load or demographic characteristics. This indicates that impaired memory is a particular sensitive symptom of schizophrenia and that the impairment is specific to the illness. Working memory failure was prominent in both clinical groups. The schizophrenic subjects displayed primarily an acquisition failure, while the depressed group showed retrieval difficulties.

Impaired functional brain asymmetry has been shown in schizophrenic patients, in addition to attentional deficits related to this laterality impairment. However, it has usually been shown in older patients with frequent positive symptoms. This is a matter of concern because previous studies have suggested that such deficits interact with subgroup characteristics, especially positive symptoms like hallucinations and age/duration of the illness. Thus, in this study, we tested a homogeneous group of young and stabilised schizophrenic patients. We used a verbal dichotic listening test with consonant-vowel syllables to study brain asymmetry and attentional modulation. Nineteen patients were compared with healthy subjects with the same age, handedness and gender distribution. All subjects were tested during a divided and two focused attention conditions. The patient and reference group showed the same performance pattern. This indicates that young and stabilised patients show normal functional brain asymmetry and normal ability to modulate attention. It is suggested that impairments in functional asymmetry and attentional modulation may follow a continuum related to symptomatology and age/duration of illness.