Professor Ulli Schall

© 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. White matter abnormalities associated with schizophrenia have been widely reported, although the consistency of findings across studies is moderate. In this study, neuroimaging was used to investigate white matter pathology and its impact on whole-brain white matter connectivity in one of the largest samples of patients with schizophrenia. Fractional anisotropy (FA) and mean diffusivity (MD) were compared between patients with schizophrenia or schizoaffective disorder (n = 326) and age-matched healthy controls (n = 197). Between-group differences in FA and MD were assessed using voxel-based analysis and permutation testing. Automated whole-brain white matter fiber tracking and the network-based statistic were used to characterize the impact of white matter pathology on the connectome and its rich club. Significant reductions in FA associated with schizophrenia were widespread, encompassing more than 40% (234ml) of cerebral white matter by volume and involving all cerebral lobes. Significant increases in MD were also widespread and distributed similarly. The corpus callosum, cingulum, and thalamic radiations exhibited the most extensive pathology according to effect size. More than 50% of cortico-cortical and cortico-subcortical white matter fiber bundles comprising the connectome were disrupted in schizophrenia. Connections between hub regions comprising the rich club were disproportionately affected. Pathology did not differ between patients with schizophrenia and schizoaffective disorder and was not mediated by medication. In conclusion, although connectivity between cerebral hubs is most extensively disturbed in schizophrenia, white matter pathology is widespread, affecting all cerebral lobes and the cerebellum, leading to disruptions in the majority of the brain's fiber bundles.

© 2016 The application of microarray technology in schizophrenia research was heralded as paradigm-shifting, as it allowed for high-throughput assessment of cell and tissue function. This technology was widely adopted, initially in studies of postmortem brain tissue, and later in studies of peripheral blood. The collective body of schizophrenia microarray literature contains apparent inconsistencies between studies, with failures to replicate top hits, in part due to small sample sizes, cohort-specific effects, differences in array types, and other confounders. In an attempt to summarize existing studies of schizophrenia cases and non-related comparison subjects, we performed two mega-analyses of a combined set of microarray data from postmortem prefrontal cortices (n = 315) and from ex-vivo blood tissues (n = 578). We adjusted regression models per gene to remove non-significant covariates, providing best-estimates of transcripts dysregulated in schizophrenia. We also examined dysregulation of functionally related gene sets and gene co-expression modules, and assessed enrichment of cell types and genetic risk factors. The identities of the most significantly dysregulated genes were largely distinct for each tissue, but the findings indicated common emergent biological functions (e.g. immunity) and regulatory factors (e.g., predicted targets of transcription factors and miRNA species across tissues). Our network-based analyses converged upon similar patterns of heightened innate immune gene expression in both brain and blood in schizophrenia. We also constructed generalizable machine-learning classifiers using the blood-based microarray data. Our study provides an informative atlas for future pathophysiologic and biomarker studies of schizophrenia.

© 2016 Elsevier B.V. Background Intervention trials for young people at ultra high risk (UHR) for psychosis have shown cognitive behaviour therapy (CBT) to have promising effects on treating psychotic symptoms but have not focused on functional outcomes. We hypothesized that compared to an active control, CBT would: (i) reduce the likelihood of, and/or delay, transition to psychosis; (ii) reduce symptom severity while improving social functioning and quality of life, whether or not transition occurred. Method This was a single-blind randomised controlled trial for young people at UHR for psychosis comparing CBT to an active control condition, Non Directive Reflective Listening (NDRL), both in addition to standard care, with a 6 month treatment phase and 12 months of follow-up. Statistical analysis is based on intention-to-treat and used random effect models to estimate treatment effects common to all time-points. Results Fifty-seven young people (mean age = 16.5 years) were randomised to CBT (n = 30) or NDRL (n = 27). Rate of transition to psychosis was 5%; the 3 transitions occurred in the CBT condition (baseline, 2 months, 5 months respectively). The NDRL condition resulted in a significantly greater reduction in distress associated with psychotic symptoms compared to CBT (treatment effect = 36.71, standard error = 16.84, p = 0.029). There were no significant treatment effects on frequency and intensity of psychotic symptoms, global, social or role functioning. Conclusion Our sample was higher functioning, younger and experiencing lower levels of psychotic like experiences than other trials. The significantly better treatment effect of NDRL on distress associated with psychotic symptoms supports the recommendations for a stepped-care model of service delivery. This treatment approach would accommodate the younger UHR population and facilitate timely intervention. Trial registration: ANZCTR 12606000101583

© 2015 Elsevier B.V. Since its inception in the 1970s, the mismatch negativity (MMN) event-related potential has improved our understanding of pre-attentive detection of rule violations, which is a fundamental cognitive process considered by some a form of "primitive intelligence". The body of research to date ranges from animal studies (i.e. when investigating the neural mechanisms and pharmacological properties of MMN generation) to researching the psychophysiological nature of human consciousness. MMN therefore offers the possibility to detect abnormal functioning in the neural system involved in MMN generation, such as it occurs in some neurodevelopmental disorders or patients in vegetative state. While the clinical research data holds considerable promise for translation into clinical practice, standardization and normative data of an optimized (i.e. disorder-specific) MMN recording algorithm is needed in order for MMN to become a valuable clinical investigation tool.

© 2015 Elsevier B.V. The early detection of young people at-risk of developing a severe mental illness like schizophrenia offers the opportunity of introducing treatment earlier than currently possible. There is some evidence that early intervention improves prognosis and functional outcome, or even prevents the full clinical manifestation of the condition in some individuals. A key prerequisite to facilitate early intervention would be a biomarker that can reliably predict a transition to schizophrenia. A smaller event-related mismatch negativity (MMN) potential has emerged as one of the most robust psychophysiological finding in schizophrenia akin of a biomarker of the condition. More recent research further demonstrates that MMN, but also P3a amplitudes, are already reduced in the prodromal phase of illness. Several lines of pre-clinical and clinical research support this notion and are reviewed in this article together with current obstacles, which are still limiting the translation of MMN as a biomarker into clinical practice.

© 2015 John Wiley & Sons, Ltd. Background: Social difficulties are often noted among people with intellectual disabilities. Children and adults with 22q.11.2 deletion syndrome (22q11DS) often have poorer social competence as well as poorer performance on measures of executive and social-cognitive skills compared with typically developing young people. However, the relationship between social functioning and more basic processes of social cognition and executive functioning are not well understood in 22q11DS. The present study examined the relationship between social-cognitive measures of emotion attribution and theory of mind with executive functioning and their contribution to social competence in 22q11DS. Method: The present cross-sectional study measured social cognition and executive performance of 24 adolescents with 22q11DS compared with 27 age-matched typically developing controls. Social cognition was tested using the emotion attribution task (EAT) and a picture sequencing task (PST), which tested mentalising (false-belief), sequencing, cause and effect, and inhibition. Executive functioning was assessed using computerised versions of the Tower of London task and working memory measures of spatial and non-spatial ability. Social competence was also assessed using the parent-reported Strengths and Difficulties Questionnaire. Results: Adolescents with 22q11DS showed impaired false-belief, emotion attribution and executive functioning compared with typically developing control participants. Poorer performance was reported on all story types in the PST, although, patterns of errors and response times across story types were similar in both groups. General sequencing ability was the strongest predictor of false-belief, and performance on the false-belief task predicted emotion attribution accuracy. Intellectual functioning, rather than theory of mind or executive functioning, predicted social competence in 22q11DS. Conclusions: Performance on social-cognitive tasks of theory of mind indicate evidence of a general underlying dysfunction in 22q11DS that includes executive ability to understand cause and effect, to logically reason about social scenarios and also to inhibit responses to salient, but misleading cues. However, general intellectual ability is closely related to actual social competence suggesting that a generalised intellectual deficit coupled with more specific executive impairments may best explain poor social cognition in 22q11DS.

© 2015, Springer Science+Business Media New York. This study investigated neurodevelopmental changes in sound processing by recording mismatch negativity (MMN) in response to various degrees of sound complexity in 18 mildly to moderately autistic versus 15 healthy boys aged between 6 and 15¿years. Autistic boys presented with lower IQ and poor performance on a range of executive and social function measures when compared to their healthy counterparts. We found that MMN in response to duration deviants was less lateralized in the clinical group whereas larger amplitudes correlated with advanced age, thus capturing neurodevelopmental changes. Larger MMN in response to speech-like sound deviants was associated with better verbal fluency and executive function performance, respectively, but did not reliably discriminate the two groups.

© 2014 Elsevier GmbH. All rights reserved. Converging evidence from epidemiological, clinical and neuropsychological research suggests a link between cannabis use and increased risk of psychosis. Long-term cannabis use has also been related to deficit-like "negative" symptoms and cognitive impairment that resemble some of the clinical and cognitive features of schizophrenia. The current functional brain imaging study investigated the impact of a history of heavy cannabis use on impaired executive function in first-episode schizophrenia patients. Whilst performing the Tower of London task in a magnetic resonance imaging scanner, event-related blood oxygenation level-dependent (BOLD) brain activation was compared between four age and gender-matched groups: 12 first-episode schizophrenia patients; 17 long-term cannabis users; seven cannabis using first-episode schizophrenia patients; and 17 healthy control subjects. BOLD activation was assessed as a function of increasing task difficulty within and between groups as well as the main effects of cannabis use and the diagnosis of schizophrenia. Cannabis users and non-drug using first-episode schizophrenia patients exhibited equivalently reduced dorsolateral prefrontal activation in response to task difficulty. A trend towards additional prefrontal and left superior parietal cortical activation deficits was observed in cannabis-using first-episode schizophrenia patients while a history of cannabis use accounted for increased activation in the visual cortex. Cannabis users and schizophrenia patients fail to adequately activate the dorsolateral prefrontal cortex, thus pointing to a common working memory impairment which is particularly evident in cannabis-using first-episode schizophrenia patients. A history of heavy cannabis use, on the other hand, accounted for increased primary visual processing, suggesting compensatory imagery processing of the task.

Both polygenicity (many small genetic effects) and confounding biases, such as cryptic relatedness and population stratification, can yield an inflated distribution of test statistics in genome-wide association studies (GWAS). However, current methods cannot distinguish between inflation from a true polygenic signal and bias. We have developed an approach, LD Score regression, that quantifies the contribution of each by examining the relationship between test statistics and linkage disequilibrium (LD). The LD Score regression intercept can be used to estimate a more powerful and accurate correction factor than genomic control. We find strong evidence that polygenicity accounts for the majority of the inflation in test statistics in many GWAS of large sample size.

© 2015 Elsevier B.V. The molecular mechanisms underlying schizophrenia remain largely unknown. Although schizophrenia is a mental disorder, there is increasing evidence to indicate that inflammatory processes driven by diverse environmental factors play a significant role in its development. With gene expression studies having been conducted across a variety of sample types, e.g., blood and postmortem brain, it is possible to investigate convergent signatures that may reveal interactions between the immune and nervous systems in schizophrenia pathophysiology. We conducted two meta-analyses of schizophrenia microarray gene expression data (N= 474) and non-psychiatric control (N= 485) data from postmortem brain and blood. Then, we assessed whether significantly dysregulated genes in schizophrenia could be shared between blood and brain. To validate our findings, we selected a top gene candidate and analyzed its expression by RT-qPCR in a cohort of schizophrenia subjects stabilized by atypical antipsychotic monotherapy (N= 29) and matched controls (N= 31). Meta-analyses highlighted inflammation as the major biological process associated with schizophrenia and that the chemokine receptor CX3CR1 was significantly down-regulated in schizophrenia. This differential expression was also confirmed in our validation cohort. Given both the recent data demonstrating selective CX3CR1 expression in subsets of neuroimmune cells, as well as behavioral and neuropathological observations of CX3CR1 deficiency in mouse models, our results of reduced CX3CR1 expression adds further support for a role played by monocyte/microglia in the neurodevelopment of schizophrenia.

© 2015 The American Society of Human Genetics. All rights reserved. Polygenic risk scores have shown great promise in predicting complex disease risk and will become more accurate as training sample sizes increase. The standard approach for calculating risk scores involves linkage disequilibrium (LD)-based marker pruning and applying a p value threshold to association statistics, but this discards information and can reduce predictive accuracy. We introduce LDpred, a method that infers the posterior mean effect size of each marker by using a prior on effect sizes and LD information from an external reference panel. Theory and simulations show that LDpred outperforms the approach of pruning followed by thresholding, particularly at large sample sizes. Accordingly, predicted R 2 increased from 20.1% to 25.3% in a large schizophrenia dataset and from 9.8% to 12.0% in a large multiple sclerosis dataset. A similar relative improvement in accuracy was observed for three additional large disease datasets and for non-European schizophrenia samples. The advantage of LDpred over existing methods will grow as sample sizes increase.

The neural response to occasional variations in acoustic stimuli in a regular sequence of sounds generates an N-methyl-D-aspartate receptor-modulated event-related potential in primates and rodents in the primary auditory cortex known as mismatch negativity (MMN). The current study investigated MMN in pigeons (Columba livia L) through intracranial recordings from Field L of the caudomedial nidopallium, the avian functional equivalent of the mammalian primary auditory cortex. Auditory evoked field potentials were recorded from awake birds using a low-frequency (800 Hz) and high-frequency (1400 Hz) deviant auditory oddball procedure with deviant-as-standard (flip-flop design) and multiple-standard control conditions. An MMN-like field potential was recorded and blocked with systemic 5 mg/kg ketamine administration. Our results are similar to human and rodent findings of an MMN-like event-related potential in birds suggestive of similar auditory sensory memory mechanisms in birds and mammals that are homologue from a common ancestor 300 million years ago or resulted from convergent evolution.

© 2014 Harms et al. Mismatch negativity (MMN) is a scalp-recorded electrical potential that occurs in humans in response to an auditory stimulus that defies previously established patterns of regularity. MMN amplitude is reduced in people with schizophrenia. In this study, we aimed to develop a robust and replicable rat model of MMN, as a platform for a more thorough understanding of the neurobiology underlying MMN. One of the major concerns for animal models of MMN is whether the rodent brain is capable of producing a human-like MMN, which is not a consequence of neural adaptation to repetitive stimuli. We therefore tested several methods that have been used to control for adaptation and differential exogenous responses to stimuli within the oddball paradigm. Epidural electroencephalographic electrodes were surgically implanted over different cortical locations in adult rats. Encephalographic data were recorded using wireless telemetry while the freely-moving rats were presented with auditory oddball stimuli to assess mismatch responses. Three control sequences were utilized: the flip-flop control was used to control for differential responses to the physical characteristics of standards and deviants; the many standards control was used to control for differential adaptation, as was the cascade control. Both adaptation and adaptation-independent deviance detection were observed for high frequency (pitch), but not low frequency deviants. In addition, the many standards control method was found to be the optimal method for observing both adaptation effects and adaptation-independent mismatch responses in rats. Inconclusive results arose from the cascade control design as it is not yet clear whether rats can encode the complex pattern present in the control sequence. These data contribute to a growing body of evidence supporting the hypothesis that rat brain is indeed capable of exhibiting human-like MMN, and that the rat model is a viable platform for the further investigation of the MMN and its associated neurobiology.

Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia. © 2014 Macmillan Publishers Limited. All rights reserved.

Repetitive patterning facilitates inferences about likely properties of sound to follow. Mismatch negativity (MMN) occurs when sound fails to match an inference. Smaller MMN in schizophrenia indexes deficient gain control (difference in utilizing a limited dynamic range). Although it is clear that this group has a lower limit to MMN size, this study addressed whether smaller MMN indicates impaired perceptual inference. MMN was elicited to four deviants in two sequences: one in which occurrence was random and one in which it was paired. Despite smaller MMN, persons with schizophrenia are equally able to reduce MMN size evoked by a deviant when its occurrence is cued. Results also expose alterations in the evoked response to repeated sounds that appear to be exacerbations of age-related amplitude decline. Since these anomalies impact the computed MMN, they highlight the need to identify all contributions to limits in gain control in schizophrenia. © 2014 Society for Psychophysiological Research.

Transcranial direct current stimulation (tDCS) is a non-invasive intervention altering neural plasticity by modulating neuronal excitability of pre- and postsynaptic neuron populations, which has been shown to improve depression symptoms and cognition. We investigated the effects of a single session of 20 min of 2 mA left-prefrontal anodal versus sham stimulation on auditory event-related potentials (ERPs) in 11 male and 5 female healthy subjects (mean age of 28.6 [SD 6.2] years) by employing a randomized single-blind crossover design. Stimulation effects on cortical glutamate (Glu) and glutamine (Glx) levels were subsequently measured in 12 of the 16 healthy subjects in a 3 T proton magnetic resonance spectroscopy scan. tDCS was associated with a significant increase of N1 amplitudes while smaller P3b amplitudes correlated with higher cortical Glu and Glx levels in the stimulated brain area when performing an auditory go/no-go discrimination task. tDCS did not change mismatch negativity, nor task performance or cortical Glu/Glx levels which, together with N1 amplitudes, depended on stimulation order ("sham" versus "active"). Increased N1 amplitudes are consistent with higher levels of cortical excitability following prefrontal anodal tDCS. The failure to replicate Glu/Glx changes with tDCS may have been masked by between-session carry-over effects while ceiling effects may have masked tDCS effects on task performance. © 2014 Elsevier GmbH. All rights reserved.

© 2014 McCabe et al.; licensee BioMed Central Ltd. Background: 22q11.2 deletion syndrome (22q11DS) is associated with a number of physical anomalies and neuropsychological deficits including impairments in executive and sensorimotor function. It is estimated that 25% of children with 22q11DS will develop schizophrenia and other psychotic disorders later in life. Evidence of genetic transmission of information processing deficits in schizophrenia suggests performance in 22q11DS individuals will enhance understanding of the neurobiological and genetic substrates associated with information processing. In this report, we examine information processing in 22q11DS using measures of startle eyeblink modification and antisaccade inhibition to explore similarities with schizophrenia and associations with neurocognitive performance. Methods: Startle modification (passive and active tasks; 120- and 480-ms pre-pulse intervals) and antisaccade inhibition were measured in 25 individuals with genetically confirmed 22q11DS and 30 healthy control subjects. Results: Individuals with 22q1 1DS exhibited increased antisaccade error as well as some evidence (trend-level effect) of impaired sensorimotor gating during the active condition, suggesting a dysfunction in controlled attentional processing, rather than a pre-attentive dysfunction using this paradigm. Conclusions: The findings from the present study show similarities with previous studies in clinical populations associated with 22q11DS such as schizophrenia that may indicate shared dysfunction of inhibition pathways in these groups.

© 2014 Elsevier GmbH. All rights reserved. Cognitive impairment is one of the most significant factors determining the long-term rehabilitation prospects of schizophrenia patients. Cognitive training has been shown to be beneficial; however, effect sizes of cognitive remediation remain relatively low. Anodal transcranial direct current stimulation (tDCS) increases cortical excitability along with larger N1 auditory event-related potentials (ERPs), thus providing a non-invasive physiological mechanism that is potentially capable of facilitating cognitive training of schizophrenia patients. The current study investigated the effects of left-prefrontal anodal tDCS on auditory discrimination performance and N1, Mismatch Negativity (MMN), and P3b ERPs, which have been linked to cognitive and global function deficits in schizophrenia. We compared 20 min of 2 mA tDCS versus sham stimulation in 14 schizophrenia patients by employing a randomised crossover design. Patients performed equally well in a go/no-go auditory discrimination task when compared to healthy subjects but presented with significantly smaller N1, MMN and P3b amplitudes, which did not change with tDCS. Auditory discrimination performance and reaction times also remained unaffected by tDCS. Our findings suggest that a single application of tDCS has no acute effects on ERPs and associated auditory information processing in schizophrenia patients.

Objective The present study was undertaken to evaluate the effect of cognitive training in improving trained and untrained cognitive processes in schizophrenia. Methods A simple pre- and post experimental study with a three month follow-up was conducted to determine the efficacy of cognitive training in speed of processing and executive functions improving cognition in 22 schizophrenia patients. Results Significant improvement was found in those cognitive domains specifically targeted in the training protocol, but also to a limited extent on verbal memory and social cognition. There was also evidence of improvements in symptoms and social functioning. The training effects failed to transfer to community functioning skills however. Except for social cognition, these improvements were maintained at 3 month follow-up. Conclusion The study highlights the importance of understanding the mechanisms that contribute to the transfer of skills as well as the maintenance of cognitive changes in individuals with schizophrenia. © 2013 Elsevier Inc. All rights reserved.

Background Schizophrenia is associated with lower pre-morbid intelligence (IQ) in addition to (pre-morbid) cognitive decline. Both schizophrenia and IQ are highly heritable traits. Therefore, we hypothesized that genetic variants associated with schizophrenia, including copy number variants (CNVs) and a polygenic schizophrenia (risk) score (PSS), may influence intelligence. Method IQ was estimated with the Wechsler Adult Intelligence Scale (WAIS). CNVs were determined from single nucleotide polymorphism (SNP) data using the QuantiSNP and PennCNV algorithms. For the PSS, odds ratios for genome-wide SNP data were calculated in a sample collected by the Psychiatric Genome-Wide Association Study (GWAS) Consortium (8690 schizophrenia patients and 11 831 controls). These were used to calculate individual PSSs in our independent sample of 350 schizophrenia patients and 322 healthy controls. Results Although significantly more genes were disrupted by deletions in schizophrenia patients compared to controls (p = 0.009), there was no effect of CNV measures on IQ. The PSS was associated with disease status (R 2 = 0.055, p = 2.1 × 10 -7 ) and with IQ in the entire sample (R 2 = 0.018, p = 0.0008) but the effect on IQ disappeared after correction for disease status. Conclusions Our data suggest that rare and common schizophrenia-associated variants do not explain the variation in IQ in healthy subjects or in schizophrenia patients. Thus, reductions in IQ in schizophrenia patients may be secondary to other processes related to schizophrenia risk. © Cambridge University Press 2013.