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MicroRNAs have been linked to synaptic plasticity and memory function and are emerging as potential biomarkers and therapeutic targets for cognitive diseases. Most of these data stem from the analysis of model systems or postmortem tissue from patients which mainly represents an advanced stage of pathology. Due to the in-accessibility of human brain tissue upon experimental manipulation, it is still challenging to identify microRNAs relevant to human cognition, which is however a key step for future translational studies. Here, we employ exercise as an experimental model for memory enhancement in healthy humans with the aim to identify microRNAs linked to memory function. By analyzing the circulating smallRNAome we find a cluster of 18 microRNAs that are highly correlated to cognition. MicroRNA-409-5p and microRNA-501-3p were the most significantly regulated candidates. Functional analysis revealed that the two microRNAs are important for neuronal integrity, synaptic plasticity, and morphology. In conclusion, we provide a novel approach to identify microRNAs linked to human memory function., (© 2021. The Author(s).)

Background: Repetitive transcranial magnetic stimulation (rTMS) is a safe non-invasive neuromodulation technique used for the treatment of various neuropsychiatric disorders. The effect of rTMS applied to the cortex on autonomic functions has not been studied in detail in patient cohorts, yet patients who receive rTMS may have disease-associated impairments in the autonomic system and may receive medication that may pronounce autonomic dysfunctions., Methods: Using data from the 'rTMS for the Treatment of Negative Symptoms in Schizophrenia' (RESIS) trial we evaluated the effect of rTMS applied to the left dorsolateral prefrontal cortex (DLPFC) on autonomic nervous system-related parameters such as blood pressure (BP) and heart rate (HR) in both reclining and standing postures from screening up to 105 days after intervention among patients with schizophrenia., Results: 157 patients received either active (n = 76) or sham (n = 81) rTMS treatment. Apart from gender no significant group differences were observed. During intervention, Linear Mixed Model (LMM) analyses showed no significant time × group interactions nor time effects for any of the variables (all p > 0.055). During the whole trial beside a significant time × group interaction for diastolic BP (p = 0.017) in the standing posture, no significant time × group interactions for other variables (all p > 0.140) were found., Conclusion: These secondary analyses of the largest available rTMS trial on the treatment of negative symptoms in schizophrenia did not show a significant effect of active rTMS compared to sham rTMS on heart rate or blood pressure, neither during the intervention period nor during the follow-up period., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Studies show that psychiatric symptoms in adults and children are sometimes associated with serum neural autoantibodies. The significance of serum neural autoantibodies associated with psychiatric symptoms in children remains often unclear, but might be relevant for the extent and occurrence of psychiatric disease manifestation in later life, as well as therapy and outcome. For this narrative review, we sought articles listed in PubMed and published between 1988 and 2020 addressing the maternal-fetal transfer of neural autoantibodies and psychiatric disorders associated with serum neural autoantibodies. We identified six major subgroups of psychiatric disorders in children that are associated with serum neural autoantibodies: patients with attentional deficit hyperactivity disorder, autism spectrum disorder, obsessive compulsive disorder, Gilles de la Tourette syndrome, psychosis and catatonia. Furthermore, we summarized study findings from maternal-fetal transfer of Contactin-associated protein-like 2, N-methyl-D-aspartate receptor and fetal brain autoantibodies associated with behavioral effects in animals and humans. We hypothesize that the maternal transfer of serum neuronal autoantibodies during or after birth could result (1) in the ignition of an autoimmune-mediated inflammation having neurodevelopmental consequences for their children (autoimmune-priming-attack hypothesis) and (2) has a potential impact on the later manifestation of psychiatric disorders. Through this narrative review, we propose a diagnostic pathway for the clinical diagnosis of a potentially autoimmune origin of psychiatric symptoms in children while considering recent guidelines.

Autoantibody-associated cognitive impairment is an expanding field in geriatric psychiatry. We aim to assess the association between the presence of specific neural autoantibodies and cognitive performance in a memory clinic cohort. 154 patients with cognitive impairment were included between 2019 and 2020 presenting initially in a memory clinic. We evaluated their patient files retrospectively applying epidemiologic parameters, psychopathology, neuropsychology, intracellular and membrane-surface autoantibodies in serum and cerebrospinal fluid (CSF) and markers of neurodegeneration in CSF. In 26 of 154 patients, we searched for neural autoantibodies due to indicators for autoimmunity. In 15/26 (58%) of patients we detected serum and/or CSF autoantibodies. We identified autoantibodies against intracellular or cell-surface antigens in 7 of all 26 (27%) patients with cognitive dysfunction, although we cannot exclude patients with potential specific autoantibodies lacking autoimmune indicators. There were no significant differences between psychopathological and neuropsychological profiles in groups of patients with cognitive impairment comprising patients with autoantibodies (ABS + COG), no autoantibodies (ABS - COG), and Alzheimer's disease (ADCOG). Concerning our CSF parameters, we detected intrathecal IgG synthesis in 14% of ABS + COG and in 13% of ABS - COG patients, whereas no intrathecal IgG synthesis was found in ADCOG patients. Furthermore, CSF Aß42 was significantly diminished in the ADCOG compared to the ABS + COG group (p < 0.05). In addition, the Aß42/40 ratio was lower in ADCOG patients than in the ABS + COG or ABS - COG group (p < 0.05). Our findings reveal the underestimated occurrence and autoantibodies' potential role in patients presenting cognitive impairment. Furthermore, the patients with possible Alzheimer's disease might be differentiated from autoantibody-positive patients via a reduced Aß42 and Aß42/40 ratio in the CSF. The antibody-type varies between patients to a relevant degree, thus demonstrating the need for more research to identify subgroup-specific phenotypes. These pilot study results open an avenue for improving diagnosis and treatment in a memory clinic.

Even today, patients with schizophrenia often have an unfavorable outcome. Negative symptoms and cognitive deficits are common features in many patients and prevent recovery. In recent years, aerobic endurance training has emerged as a therapeutic approach with positive effects on several domains of patients' health. However, appropriately sized, multicenter randomized controlled trials that would allow better generalization of results are lacking. The exercise study presented here is a multicenter, rater-blind, two-armed, parallel-group randomized clinical trial in patients with clinically stable schizophrenia being conducted at five German tertiary hospitals. The intervention group performs aerobic endurance training on bicycle ergometers three times per week for 40-50 min/session (depending on the intervention week) for a total of 26 weeks, and the control group performs balance and tone training for the same amount of time. Participants are subsequently followed up for 26 weeks. The primary endpoint is all-cause discontinuation; secondary endpoints include psychopathology, cognition, daily functioning, cardiovascular risk factors, and explorative biological measures regarding the underlying mechanisms of exercise. A total of 180 patients will be randomized. With currently 162 randomized participants, our study is the largest trial to date to investigate endurance training in patients with schizophrenia. We hypothesize that aerobic endurance training has beneficial effects on patients' mental and physical health, leading to lower treatment discontinuation rates and improving disease outcomes. The study results will provide a basis for recommending exercise interventions as an add-on therapy in patients with schizophrenia.The study is registered in the International Clinical Trials Database (ClinicalTrials.gov identifier [NCT number]: NCT03466112) and in the German Clinical Trials Register (DRKS-ID: DRKS00009804).

Background: Autoimmune-mediated encephalitis is a disease that often encompasses psychiatric symptoms as its first clinical manifestation's predominant and isolated characteristic. Novel guidelines even distinguish autoimmune psychosis from autoimmune encephalitis. The aim of this review is thus to explore whether a wide range of psychiatric symptoms and syndromes are associated or correlate with autoantibodies., Methods: We conducted a PubMed search to identify appropriate articles concerning serum and/or cerebrospinal fluid (CSF) autoantibodies associated with psychiatric symptoms and syndromes between 2000 and 2020. Relying on this data, we developed a diagnostic approach to optimize the detection of autoantibodies in psychiatric patients, potentially leading to the approval of an immunotherapy., Results: We detected 10 major psychiatric symptoms and syndromes often reported to be associated with serum and/or CSF autoantibodies comprising altered consciousness, disorientation, memory impairment, obsessive-compulsive behavior, psychosis, catatonia, mood dysfunction, anxiety, behavioral abnormalities (autism, hyperkinetic), and sleeping dysfunction. The following psychiatric diagnoses were associated with serum and/or CSF autoantibodies: psychosis and schizophrenia spectrum disorders, mood disorders, minor and major neurocognitive impairment, obsessive-compulsive disorder, autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), anxiety disorders, eating disorders and addiction. By relying on these symptom clusters and diagnoses in terms of onset and their duration, we classified a subacute or subchronic psychiatric syndrome in patients that should be screened for autoantibodies. We propose further diagnostics entailing CSF analysis, electroencephalography and magnetic resonance imaging of the brain. Exploiting these technologies enables standardized and accurate diagnosis of autoantibody-associated psychiatric symptoms and syndromes to deliver early immunotherapy., Conclusions: We have developed a clinical diagnostic pathway for classifying subgroups of psychiatric patients whose psychiatric symptoms indicate a suspected autoimmune origin., Competing Interests: The authors declare no conflict of interest., (© 2020 The Author(s).)

Exercise therapy has proven to be effective in the treatment of multiple mental illnesses. As mental disorders result in tremendous costs for the healthcare system as well as a huge burden for the affected individuals, improving treatment strategies according to latest scientific evidence should be of highest priority. In 2016 a first study provided indications that only a minority of patients are treated with exercise therapy during their stay in hospital. Hence, the aim of this study was to assess the actual extent of exercise therapy usage in psychiatric inpatients in Germany, thereby giving a scientific foundation to the call for a better standard of care. To achieve this, a retrospective analysis was performed on pre-existing data from 2693 patients who were treated in 1 of 4 participating university hospitals. Only 23% of these patients participated in exercise therapy with a mean training duration of 36 min per week. Patients with the diagnosis of schizophrenia or patients with multiple comorbidities were even less likely to participate in exercise therapy. With these findings it becomes evident that the healthcare situation concerning exercise therapy is insufficient. Solid evidence for the effectiveness of exercise therapy, the current treatment guidelines as well as the positive side effects, especially when compared to side effects of pharmacotherapy (i.e. weight gain) should motivate healthcare officials to make an effort to improve this situation.

In schizophrenia, decreased hippocampal volume, reduced oligodendrocyte numbers in hippocampal cornu ammonis (CA) subregions and reduced neuron number in the dentate gyrus have been reported; reduced oligodendrocyte numbers were significantly related to cognitive deficits. The hippocampus is involved in cognitive functions and connected to the hypothalamus, anterior thalamus, and cingulate cortex, forming the Papez circuit, and to the mediodorsal thalamus. The relationship between the volume of these interconnected regions and oligodendrocyte and neuron numbers in schizophrenia is unknown. Therefore, we used stepwise logistic regression with subsequent multivariate stepwise linear regression and bivariate correlation to analyze oligodendrocyte and neuron numbers in the posterior hippocampal subregions CA1, CA2/3, CA4, dentate gyrus, and subiculum and volumes of the hippocampal CA region, cingulum, anterior and mediodorsal thalamus and hypothalamus in postmortem brains of 10 schizophrenia patients and 11 age- and gender-matched healthy controls. Stepwise logistic regression identified the following predictors for diagnosis, in order of inclusion: (1) oligodendrocyte number in CA4, (2) hypothalamus volume, (3) oligodendrocyte number in CA2/3, and (4) mediodorsal thalamus volume. Subsequent stepwise linear regression analyses identified the following predictors: (1) for oligodendrocyte number in CA4: (a) oligodendrocyte number in CA2/3, (b) diagnostic group, (c) hypothalamus volume, and (d) neurons in posterior subiculum; (2) for hypothalamus volume: (a) mediodorsal thalamus volume; (3) for oligodendrocyte number in CA2/3: oligodendrocyte number (a) in posterior CA4 and (b) in posterior subiculum; (4) for mediodorsal thalamus volume: volumes of (a) anterior thalamus and (b) hippocampal CA. In conclusion, we found a positive relationship between hippocampal oligodendrocyte number and the volume of the hypothalamus, a brain region connected to the hippocampus, which is important for cognition.

This is a data article from the original publication "Effect of aerobic exercise combined with cognitive remediation on cortical thickness and prediction of social adaptation in patients with schizophrenia" [1]. Twenty-one patients with schizophrenia and 23 healthy controls underwent aerobic exercise. Another 21 patients with schizophrenia played table soccer instead. The 12-week exercise intervention was combined with computer-assisted cognitive remediation training from week 6 to week 12. Clinical assessments were conducted at baseline and after the 12-week intervention. Magnetic resonance imaging (MRI) scans were acquired at baseline then in weeks 6, 12, and 24. The thickness of the entorhinal, parahippocampal, and lateral and medial prefrontal cortices was assessed with FreeSurfer 6.0. Data are publicy available via https://osf.io/sfgxk/., (© 2020 The Author(s). Published by Elsevier Inc.)

Higher glutamate and glutamine (together: Glx) and lower N-acetyl-aspartate (NAA) levels were reported in schizophrenia. Endurance training normalizes NAA in the hippocampus, but its effects on other metabolites in the brain and the relationship of metabolites to clinical symptoms remain unknown. For 12 weeks, 20 schizophrenia inpatients (14 men, 6 women) and 23 healthy controls (16 men, 7 women) performed endurance training and a control group of 21 schizophrenia inpatients (15 men, 6 women) played table soccer. A computer-assisted cognitive performance training program was introduced after 6 weeks. We assessed cognitive performance, psychopathological symptoms, and everyday functioning at baseline and after 6 and 12 weeks and performed single voxel magnetic resonance spectroscopy of the hippocampus, left dorsolateral prefrontal cortex (DLPFC), and thalamus. We quantified NAA, Glx, total creatine (tCr), calculated NAA/tCr and Glx/tCr and correlated these ratios with physical fitness, clinical and neurocognitive scores, and everyday functioning. At baseline, in both schizophrenia groups NAA/tCr was lower in the left DLPFC and left hippocampus and Glx/tCr was lower in the hippocampus than in the healthy controls. After 6 weeks, NAA/tCr increased in the left DLPFC in both schizophrenia groups. Brain metabolites did not change significantly in the hippocampus or thalamus, but the correlation between NAA/tCr and Glx/tCr normalized in the left DLPFC. Global Assessment of Functioning improvements correlated with NAA/tCr changes in the left DLPFC. In our study, endurance training and table soccer induced normalization of brain metabolite ratios in the brain circuitry associated with neuronal and synaptic elements, including metabolites of the glutamatergic system.

Aerobic exercise is a promising intervention for patients with schizophrenia, but structural neuroplastic effects on brain regions relevant to the pathophysiology of the disease remain unclear. This study aimed to elucidate longitudinal changes in cortical thickness after aerobic exercise intervention in schizophrenia patients and the relationship of these changes to clinical correlates. We investigated 21 schizophrenia patients and 23 healthy controls who performed aerobic exercise and 21 schizophrenia patients who played table soccer. The 12-week exercise intervention was combined with computer-assisted cognitive remediation training from week 6 to week 12. Magnetic resonance imaging (MRI) scans were acquired at baseline and weeks 6, 12, and 24. The thickness of the entorhinal, parahippocampal, and lateral and medial prefrontal cortices was assessed with FreeSurfer 6.0. The schizophrenia aerobic exercise group showed a significant increase of cortical thickness in the right entorhinal cortex at week 6, and we found a significant correlation between the cortical thickness of the right lateral prefrontal cortex at baseline and improvement of social adaptation at week 12. In the schizophrenia table soccer and healthy control groups, we found no significant longitudinal change in cortical thickness through the intervention and follow-up period and no correlation of cortical thickness at baseline with clinical measures. Our results suggest that aerobic exercise in schizophrenia modulates the thickness of the entorhinal cortex, a structure adjacent to the hippocampus. Greater cortical thickness of the right lateral prefrontal cortex appears to predict better clinical response to an aerobic exercise intervention in patients with schizophrenia., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Hippocampal volume decrease is a structural hallmark of schizophrenia (SCZ), and convergent evidence from postmortem and imaging studies suggests that it may be explained by changes in the cytoarchitecture of the cornu ammonis 4 (CA4) and dentate gyrus (DG) subfields. Increasing evidence indicates that aerobic exercise increases hippocampal volume in CA subfields and improves cognition in SCZ patients. Previous studies showed that the effects of exercise on the hippocampus might be connected to the polygenic burden of SCZ risk variants. However, little is known about cell type-specific genetic contributions to these structural changes. In this secondary analysis, we evaluated the modulatory role of cell type-specific SCZ polygenic risk scores (PRS) on volume changes in the CA1, CA2/3, and CA4/DG subfields over time. We studied 20 multi-episode SCZ patients and 23 healthy controls who performed aerobic exercise, and 21 multi-episode SCZ patients allocated to a control intervention (table soccer) for 3 months. Magnetic resonance imaging-based assessments were performed with FreeSurfer at baseline and after 3 months. The analyses showed that the polygenic burden associated with oligodendrocyte precursor cells (OPC) and radial glia (RG) significantly influenced the volume changes between baseline and 3 months in the CA4/DG subfield in SCZ patients performing aerobic exercise. A higher OPC- or RG-associated genetic risk burden was associated with a less pronounced volume increase or even a decrease in CA4/DG during the exercise intervention. We hypothesize that SCZ cell type-specific polygenic risk modulates the aerobic exercise-induced neuroplastic processes in the hippocampus.

Cognitive symptoms are a core feature of schizophrenia and are related to an unfavorable disease outcome. So far, there are no satisfactory pharmacological approaches to address cognitive symptoms. For some time now, aerobic exercise has been demonstrated in various trials to be a promising candidate for this indication. The aim of this brief qualitative review was to present the most recent meta-analyses regarding the capacity of exercise to improve cognition in schizophrenia patients. Additionally, we give a short overview of the effects in other conditions, like healthy subjects and patients with major depression. We conducted a focused literature search using the PubMed database, concentrating on meta-analyses which are based on a systematic search. The most recent meta-analysis investigating the efficacy of aerobic exercise on cognitive impairments in schizophrenia patients provides evidence that exercise has positive effects on cognitive functioning in this population. However, the effect seems not to be specific; there were positive findings regarding healthy subjects and patients with depressive disorders as well, even if they were less consistent. As most available trials have a small to modest sample size and have no consensus with regard to the intervention regime, nor to the assessment of cognition, the findings are difficult to generalize. In the future, standardized clinical trials focusing on the long-term effects of exercise are needed to evaluate whether the improvements in cognition are sustainable.
., (© 2019, AICH – Servier GroupCopyright © 2019 AICH – Servier Group. All rights reserved.)

Schizophrenia is a severe neuropsychiatric disease that is associated with neurobiological alterations in multiple brain regions and peripheral organs. Negative symptoms and cognitive deficits are present in about half of patients and are difficult to treat, leading to an unfavorable functional outcome. To investigate the impact of aerobic exercise on various neurobiological parameters, we conducted a narrative review. Add-on aerobic exercise was shown to be effective in improving negative and general symptoms, cognition, global functioning, and quality of life in schizophrenia patients. Based on findings in healthy individuals and animal models, this qualitative review gives an overview of different lines of evidence on how aerobic exercise impacts brain structure and function and molecular mechanisms in patients with schizophrenia and how its effects could be related to clinical and functional outcomes. Structural magnetic resonance imaging studies showed a volume increase in the hippocampus and cortical regions in schizophrenia patients and healthy controls after endurance training. However, results are inconsistent and individual risk factors may influence neuroplastic processes. Animal studies indicate that alterations in epigenetic mechanisms and synaptic plasticity are possible underlying mechanisms, but that differentiation of glial cells, angiogenesis, and possibly neurogenesis may also be involved. Clinical and animal studies also revealed effects of aerobic exercise on the hypothalamus-pituitary-adrenal axis, growth factors, and immune-related mechanisms. Some findings indicate effects on neurotransmitters and the endocannabinoid system. Further research is required to clarify how individual risk factors in schizophrenia patients mediate or moderate the neurobiological effects of exercise on brain and cognition. Altogether, aerobic exercise is a promising candidate in the search for pathophysiology-based add-on interventions in schizophrenia.

Background: Repetitive transcranial magnetic stimulation (rTMS) is a promising augmentation treatment for schizophrenia, however there are few controlled studies of rTMS augmentation of clozapine., Methods: Using data from the 'rTMS for the Treatment of Negative Symptoms in Schizophrenia' (RESIS) trial we examined the impact of rTMS on PANSS total, general, positive and negative symptoms among participants on clozapine. rTMS was applied to the left dorsolateral prefrontal cortex (DLPFC) for five treatment sessions/week for 3-weeks as augmentation for patients with a predominant negative syndrome of schizophrenia, as rated on PANSS., Results: 26 participants from the RESIS trial were on clozapine, receiving active (N=12) or sham (N=14) rTMS treatment. In our Linear Mixed Model (LMM) analysis, time×group interactions were significant in the PANSS positive subscale (p=0.003) (not being the corresponding behavioral output for DLPFC stimulation), the PANSS general subscale (p<0.001), the PANSS total scale (p=0.015), but not the PANSS negative subscale (p=0.301) (primary endpoint of the RESIS trial), when all PANSS measurements from screening to day 105 were included. Descriptive data suggests that in the active group the improvement was more pronounced compared to the sham rTMS group., Conclusions: In this largest available clozapine cohort, active rTMS may be more effective than sham rTMS when added to clozapine for positive and total psychotic symptoms. These findings should be interpreted with caution given this is a secondary analysis with a limited number of participants., (Copyright © 2019. Published by Elsevier B.V.)

Currently, the clinical diagnosis of schizophrenia relies solely on self-reporting and clinical interview, and likely comprises heterogeneous biological subsets. Such subsets may be defined by an underlying biology leading to solid biomarkers. A transgenic rat model modestly overexpressing the full-length, non-mutant Disrupted-in-Schizophrenia 1 (DISC1) protein (tgDISC1 rat) was generated that defines such a subset, inspired by our previous identification of insoluble DISC1 protein in post mortem brains from patients with chronic mental illness. Besides specific phenotypes such as DISC1 protein pathology, abnormal dopamine homeostasis, and changes in neuroanatomy and behavior, this animal model also shows subtle disturbances in overarching signaling pathways relevant for schizophrenia. In a reverse-translational approach, assuming that both the animal model and a patient subset share common disturbed signaling pathways, we identified differentially expressed transcripts from peripheral blood mononuclear cells of tgDISC1 rats that revealed an interconnected set of dysregulated genes, led by decreased expression of regulator of G-protein signaling 1 (RGS1), chemokine (C-C) ligand 4 (CCL4), and other immune-related transcripts enriched in T-cell and macrophage signaling and converging in one module after weighted gene correlation network analysis. Testing expression of this gene network in two independent cohorts of patients with schizophrenia versus healthy controls (n = 16/50 and n = 54/45) demonstrated similar expression changes. The two top markers RGS1 and CCL4 defined a subset of 27% of patients with 97% specificity. Thus, analogous aberrant signaling pathways can be identified by a blood test in an animal model and a corresponding schizophrenia patient subset, suggesting that in this animal model tailored pharmacotherapies for this patient subset could be achieved.

Schizophrenia is a severe neuropsychiatric disorder with persistence of symptoms throughout adult life in most of the affected patients. This unfavorable course is associated with multiple episodes and residual symptoms, mainly negative symptoms and cognitive deficits. The neural diathesis-stress model proposes that psychosocial stress acts on a pre-existing vulnerability and thus triggers the symptoms of schizophrenia. Childhood trauma is a severe form of stress that renders individuals more vulnerable to developing schizophrenia; neurobiological effects of such trauma on the endocrine system and epigenetic mechanisms are discussed. Childhood trauma is associated with impaired working memory, executive function, verbal learning, and attention in schizophrenia patients, including those at ultra-high risk to develop psychosis. In these patients, higher levels of childhood trauma were correlated with higher levels of attenuated positive symptoms, general symptoms, and depressive symptoms; lower levels of global functioning; and poorer cognitive performance in visual episodic memory end executive functions. In this review, we discuss effects of specific gene variants that interact with childhood trauma in patients with schizophrenia and describe new findings on the brain structural and functional level. Additive effects between childhood trauma and brain-derived neurotrophic factor methionine carriers on volume loss of the hippocampal subregions cornu ammonis (CA)4/dentate gyrus and CA2/3 have been reported in schizophrenia patients. A functional magnetic resonance imaging study showed that childhood trauma exposure resulted in aberrant function of parietal areas involved in working memory and of visual cortical areas involved in attention. In a theory of mind task reflecting social cognition, childhood trauma was associated with activation of the posterior cingulate gyrus, precuneus, and dorsomedial prefrontal cortex in patients with schizophrenia. In addition, decreased connectivity was shown between the posterior cingulate/precuneus region and the amygdala in patients with high levels of physical neglect and sexual abuse during childhood, suggesting that disturbances in specific brain networks underlie cognitive abilities. Finally, we discuss some of the questionnaires that are commonly used to assess childhood trauma and outline possibilities to use recent biostatistical methods, such as machine learning, to analyze the resulting datasets.

People with schizophrenia die on average 15-20 years earlier than age and gender matched controls in the general population. An essential part of this excess mortality in people with schizophrenia is caused by physical illnesses. Among the physical illnesses, cardiovascular disease (CVD) has been identified as the most common natural cause of death in up to 40-45% of the cases. Chronotropic incompetence (CI) is defined as the inability of the heart to increase its beating frequency in proportion to increased physical activity or higher metabolic demand. It is an established independent cardiovascular risk factor for major cardiac events and overall mortality and might explain adaptation intolerance of the cardiovascular system to even minor exercise courses. CI needs objective exercise testing for definitive diagnosis and therefore represents a biological marker indicating the integrity of the cardiovascular system. It was recently described in patients with schizophrenia and might help explain the reduced physical fitness in these patients and the inability of a subgroup of patients to benefit from exercise interventions. In this study, we tried to replicate the occurrence of CI in an independent sample of patients with schizophrenia and evaluated whether CI can be influenced by a continuous endurance training of 12 weeks. Therefore, we re-analyzed the fitness testing data of 43 patients with schizophrenia and 22 aged and gender matched healthy controls. Parameters of aerobic fitness and chronotropic response to exercise were calculated. Patients with schizophrenia were less physically fit than the healthy controls and displayed a significantly higher heart rate at rest. 10 of 43 patients with schizophrenia and no healthy control subject were classified as chronotropically incompetent. Chronotropic response to exercise did not change significantly after 12 weeks of continuous aerobic exercise training. No differences were observed for baseline heart rate and peak heart rate in both subgroups of schizophrenia patients. Aerobic fitness did not improve significantly in the patients with schizophrenia classified as chronotropically incompetent. Our results confirm the occurrence of CI in patients with multi-episode schizophrenia. This should be taken into account when planning an exercise or lifestyle intervention studies in this population. Schizophrenia patients with CI do not seem to benefit as well as schizophrenia patients without CI from aerobic exercise training interventions. Larger, prospective randomized controlled clinical trials with different training interventions are urgently needed to address the topic of schizophrenia patients not responding to exercise and the relationship to the illness itself.

Purpose: Development of a warp-based automated brain segmentation approach of 3D fluid-attenuated inversion recovery (FLAIR) images and comparison to 3D T1-based segmentation., Methods: 3D FLAIR and 3D T1-weighted sequences of 30 healthy subjects (mean age 29.9 ± 8.3 years, 8 female) were acquired on the same 3T MR scanner. Warp-based segmentation was applied for volumetry of total gray matter (GM), white matter (WM), and 116 atlas regions. Segmentation results of both sequences were compared using Pearson correlation (r)., Results: Correlation of GM segmentation results based on FLAIR and T1 was overall good for cortical structures (mean r across all cortical structures = 0.76). Comparatively weaker results were found in the occipital lobe (r = 0.77), central region (mean r = 0.58), basal ganglia (mean r = 0.59), thalamus (r = 0.30), and cerebellum (r = 0.73). FLAIR segmentation underestimated volume of the central region compared to T1, but showed a better anatomic concordance with the occipital lobe on visual review and subcortical structures, when also compared to manual segmentation. Visual analysis of FLAIR-based WM segmentation revealed frequent misclassification of regions of high signal intensity as GM., Conclusion: Warp-based FLAIR segmentation yields comparable results to T1 segmentation for most cortical GM structures and may provide anatomically more congruent segmentation of subcortical GM structures. Selected cortical regions, especially the central region and total WM, seem to be underestimated on FLAIR segmentation.

Schizophrenia is a severe psychiatric disorder with a lifetime prevalence of about 1%. People with schizophrenia have a 4-fold higher prevalence of metabolic syndrome than the general population, mainly because of antipsychotic treatment but perhaps also because of decreased physical activity. Metabolic syndrome is a risk factor for cardiovascular diseases, and the risk of these diseases is 2- to 3-fold higher in schizophrenia patients than in the general population. The suicide risk is also higher in schizophrenia, partly as a result of depression, positive, and cognitive symptoms of the disease. The higher suicide rate and higher rate of cardiac mortality, a consequence of the increased prevalance of cardiovascular diseases, contribute to the reduced life expectancy, which is up to 20 years lower than in the general population. Regular physical activity, especially in combination with psychosocial and dietary interventions, can improve parameters of the metabolic syndrome and cardiorespiratory fitness. Furthermore, aerobic exercise has been shown to improve cognitive deficits; total symptom severity, including positive and negative symptoms; depression; quality of life; and global functioning. High-intensity interval endurance training is a feasible and effective way to improve cardiorespiratory fitness and metabolic parameters and has been established as such in somatic disorders. It may have more beneficial effects on the metabolic state than more moderate and continuous endurance training methods, but to date it has not been investigated in schizophrenia patients in controlled, randomized trials. This review discusses physical training methods to improve cardiorespiratory fitness and reduce metabolic syndrome risk factors and symptoms in schizophrenia patients. The results of studies and future high-quality clinical trials are expected to lead to the development of an evidence-based physical training program for patients that includes practical recommendations, such as the optimal length and type of aerobic exercise programs and the ideal combination of exercise, psychoeducation, and individual weight management sessions.

Physical activity (PA) may be therapeutic for people with severe mental illness (SMI) who generally have low PA and experience numerous life style-related medical complications. We conducted a meta-review of PA interventions and their impact on health outcomes for people with SMI, including schizophrenia-spectrum disorders, major depressive disorder (MDD) and bipolar disorder. We searched major electronic databases until January 2018 for systematic reviews with/without meta-analysis that investigated PA for any SMI. We rated the quality of studies with the AMSTAR tool, grading the quality of evidence, and identifying gaps, future research needs and clinical practice recommendations. For MDD, consistent evidence indicated that PA can improve depressive symptoms versus control conditions, with effects comparable to those of antidepressants and psychotherapy. PA can also improve cardiorespiratory fitness and quality of life in people with MDD, although the impact on physical health outcomes was limited. There were no differences in adverse events versus control conditions. For MDD, larger effect sizes were seen when PA was delivered at moderate-vigorous intensity and supervised by an exercise specialist. For schizophrenia-spectrum disorders, evidence indicates that aerobic PA can reduce psychiatric symptoms, improves cognition and various subdomains, cardiorespiratory fitness, whilst evidence for the impact on anthropometric measures was inconsistent. There was a paucity of studies investigating PA in bipolar disorder, precluding any definitive recommendations. No cost effectiveness analyses in any SMI condition were identified. We make multiple recommendations to fill existing research gaps and increase the use of PA in routine clinical care aimed at improving psychiatric and medical outcomes., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Background: The variability of responses to plasticity-inducing repetitive transcranial magnetic stimulation (rTMS) challenges its successful application in psychiatric care. No objective means currently exists to individually predict the patients' response to rTMS., Methods: We used machine learning to develop and validate such tools using the pre-treatment structural Magnetic Resonance Images (sMRI) of 92 patients with schizophrenia enrolled in the multisite RESIS trial (http://clinicaltrials.gov, NCT00783120): patients were randomized to either active (N = 45) or sham (N = 47) 10-Hz rTMS applied to the left dorsolateral prefrontal cortex 5 days per week for 21 days. The prediction target was nonresponse vs response defined by a ≥20% pre-post Positive and Negative Syndrome Scale (PANSS) negative score reduction., Results: Our models predicted this endpoint with a cross-validated balanced accuracy (BAC) of 85% (nonresponse/response: 79%/90%) in patients receiving active rTMS, but only with 51% (48%/55%) in the sham-treated sample. Leave-site-out cross-validation demonstrated cross-site generalizability of the active rTMS predictor despite smaller training samples (BAC: 71%). The predictive pre-treatment pattern involved gray matter density reductions in prefrontal, insular, medio-temporal, and cerebellar cortices, and increments in parietal and thalamic structures. The low BAC of 58% produced by the active rTMS predictor in sham-treated patients, as well as its poor performance in predicting positive symptom courses supported the therapeutic specificity of this brain pattern., Conclusions: Individual responses to active rTMS in patients with predominant negative schizophrenia may be accurately predicted using structural neuromarkers. Further multisite studies are needed to externally validate the proposed treatment stratifier and develop more personalized and biologically informed rTMS interventions.

Background: Aerobic endurance training has been discussed to induce brain plasticity and improve cognitive functions in healthy subjects and patients with neuropsychiatric disorders. For schizophrenia, a motor cortical inhibitory deficit has been established as one aspect of impaired plasticity, especially involving impairments in GABAergic interneuron networks, but the possibility to restore these deficits via exercise-induced plasticity has not been evaluated yet., Methods: 17 schizophrenia patients and 16 matched healthy controls underwent 3 months of aerobic endurance training (30 min, 3 times a week) on bicycle ergometers. After 6 weeks, computer-assisted cognitive remediation training (30 min, 2 times a week) was added. Transcranial magnetic stimulation of the left and right hemispheres was performed at baseline and at the end of the intervention. We evaluated the intensity to induce a motor-evoked potential of 1 mV (S1mV), the resting motor threshold (RMT), the cortical silent period (CSP) at an intensity of 120 and 150% of the individual RMT, short-latency interval intracortical inhibition (3 ms), and intracortical facilitation (7 and 15 ms). Depending on the variable and hemisphere, follow-up data was available for 7-15 schizophrenia patients and for 10-12 healthy controls., Results: Repeated measures ANOVA revealed no significant time × group interactions for any of the analyzed variables. A significant increase in S1mV and CSP duration at 150% RMT of the left hemisphere could be observed in both groups over time., Conclusion: Regular ergometer training over 3 months increases motor cortical inhibition as displayed by an increase in CSP. The increase in S1mV may also indicate a higher degree of inhibition after the intervention. We could not establish a difference between schizophrenia patients and healthy controls. Due to the limited sample size, our results have to be considered as preliminary and need to be replicated in future trials., (© 2018 S. Karger AG, Basel.)

The elevated cardiovascular risk of patients with schizophrenia contributes to a reduced life expectancy of 15-20years. This study investigated whether cardiac autonomic dysfunction (CADF) in schizophrenia is related to chronotropic incompetence, an established cardiovascular risk marker. We investigated thirty-two patients suffering from paranoid schizophrenia and thirty-two control subjects matched for age, sex, body mass index and fat free mass. A cardiopulmonary exercise test (CPET) was performed to study heart rate responses to exercise as well as submaximal (ventilatory threshold 1, VT 1 ) and maximal endurance capacities (peak oxygen consumption, VO 2peak ; peak power output, P peak ). In addition, epinephrine and norepinephrine levels were assessed in a subset of patients. Fitness parameters were significantly reduced in all patients. Most investigated physiological parameters were significantly different at rest as well as during peak exercise being in line with previously described CADF in schizophrenia. In particular, 14 out of 32 patients were classified as chronotropically incompetent whereas no control subject was below the cut-off value. In addition, a positive correlation of a slope reflecting chronotropic incompetence with peak oxygen uptake (p<0.001) was observed in patients only indicating a close correlation to the lack of physical fitness. The catecholamine increase was reduced in patients after exercise. This study identified a novel cardiac risk factor in patients with schizophrenia. Moreover, it seems to be associated with reduced physical fitness and indicates targets for exercise intervention studies. Future studies are warranted to elucidate pathophysiological mechanisms of this cardiac condition., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Repetitive transcranial magnetic stimulation (rTMS) applied to the left frontal lobe is discussed to be a promising add-on treatment for negative symptoms in schizophrenia. The Positive and Negative Syndrome Scale (PANSS) has been used as outcome parameter in several previous rTMS trials, but studies focusing on PANSS factor analyses are lacking. For this purpose, we used the available PANSS data of the 'rTMS for the Treatment of Negative Symptoms in Schizophrenia' (RESIS) trial to calculate different literature-based PANSS factors and to re-evaluate the impact of rTMS on negative symptoms in this trial. In an exploratory re-analysis of published data from the RESIS study (Wobrock et al. 2015), we tested the impact of rTMS applied to the left dorsolateral prefrontal cortex on two PANSS factors for negative symptoms in psychotic disorders as well as on a PANSS five-factor consensus model intending to show that active rTMS treatment improves PANSS negative symptom subscores. In accordance to the original analysis, all PANSS factors showed an improvement over time in the active and, to a considerable extent, also in the sham rTMS group. However, comparing the data before and directly after the rTMS intervention, the PANSS excitement factor improved in the active rTMS group significantly more than in the sham group, but this finding did not persist if follow-up data were taken into account. These additional analyses extend the previously reported RESIS trial results showing unspecific improvements in the PANSS positive subscale in the active rTMS group. Our PANSS factor-based approach to investigate the impact of prefrontal rTMS on different negative symptom domains confirmed no overall beneficial effect of the active compared to sham rTMS., (Copyright © 2018 Elsevier B.V. All rights reserved.)

This systematic review analyzed strength training (ST) in patients with schizophrenia. Two independent reviewers searched PubMed and CENTRAL. Only two studies reported on the effects of isolated ST. ST with a single exercise did not improve psychopathology but walking performance. ST for several large muscle groups significantly improved muscle strength and psychopathology. To date, no treatment recommendations can be made for ST. Consistent with recommendations for healthy people combined strength and endurance training can be recommended for schizophrenia. For higher transparency regarding trainings aspects, we recommend for future studies to use the sport science checklist proposed in this paper., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objectives: Despite progress in identifying molecular pathophysiological processes in schizophrenia, valid biomarkers are lacking for both the disease and treatment response., Methods: This comprehensive review summarises recent efforts to identify molecular mechanisms on the level of protein and gene expression and epigenetics, including DNA methylation, histone modifications and micro RNA expression. Furthermore, it summarises recent findings of alterations in lipid mediators and highlights inflammatory processes. The potential that this research will identify biomarkers of schizophrenia is discussed., Results: Recent studies have not identified clear biomarkers for schizophrenia. Although several molecular pathways have emerged as potential candidates for future research, a complete understanding of these metabolic pathways is required to reveal better treatment modalities for this disabling condition., Conclusions: Large longitudinal cohort studies are essential that pair a thorough phenotypic and clinical evaluation for example with gene expression and proteome analysis in blood at multiple time points. This approach might identify biomarkers that allow patients to be stratified according to treatment response and ideally also allow treatment response to be predicted. Improved knowledge of molecular pathways and epigenetic mechanisms, including their potential association with environmental influences, will facilitate the discovery of biomarkers that could ultimately be effective tools in clinical practice.

Cognitive deficits are pervasive among people with schizophrenia and treatment options are limited. There has been an increased interest in the neurocognitive benefits of exercise, but a comprehensive evaluation of studies to date is lacking. We therefore conducted a meta-analysis of all controlled trials investigating the cognitive outcomes of exercise interventions in schizophrenia. Studies were identified from a systematic search across major electronic databases from inception to April 2016. Meta-analyses were used to calculate pooled effect sizes (Hedges g) and 95% CIs. We identified 10 eligible trials with cognitive outcome data for 385 patients with schizophrenia. Exercise significantly improved global cognition (g = 0.33, 95% CI = 0.13-0.53, P = .001) with no statistical heterogeneity (I2 = 0%). The effect size in the 7 studies which were randomized controlled trials was g = 0.43 (P < .001). Meta-regression analyses indicated that greater amounts of exercise are associated with larger improvements in global cognition (β = .005, P = .065). Interventions which were supervised by physical activity professionals were also more effective (g = 0.47, P < .001). Exercise significantly improved the cognitive domains of working memory (g = 0.39, P = .024, N = 7, n = 282), social cognition (g = 0.71, P = .002, N = 3, n = 81), and attention/vigilance (g = 0.66, P = .005, N = 3, n = 104). Effects on processing speed, verbal memory, visual memory and reasoning and problem solving were not significant. This meta-analysis provides evidence that exercise can improve cognitive functioning among people with schizophrenia, particularly from interventions using higher dosages of exercise. Given the challenges in improving cognition, and the wider health benefits of exercise, a greater focus on providing supervised exercise to people with schizophrenia is needed., (© The Author 2016. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Purpose of Review: Schizophrenia is a severe neuropsychiatric disorder with incomplete remission because of negative and cognitive symptoms in a large proportion of patients. Antipsychotic medication is successful in modulating positive symptoms, but only to a lower extent negative symptoms including cognitive dysfunction. Therefore, development of innovative add-on treatment is highly needed. In this review, recent evidence from clinical studies reveals effects of aerobic exercise on cognitive deficits in schizophrenia patients., Recent Findings: First studies and meta-analyses on aerobic exercise in schizophrenia patients have shown effects on positive, negative, and global symptoms and cognitive domains such as global cognition, working memory, and attention. Underlying neurobiological mechanisms such as neuroplasticity-related synaptogenesis and neurogenesis have been identified in animal studies and possibly mediate effects of aerobic exercise on brain structure and function., Summary: Different aspects of methods (e.g., endurance training versus yoga and Tai Chi), length and dose of the intervention, supervision of patients by sports therapists as well as maintenance of cognitive improvement after cessation of training have been raised by previous studies. However, minimal and most effective dosage of the intervention and mechanisms underlying changes in neuroplasticity need to be answered in future basic and large-scale randomized clinical trials.

Background: It is unknown whether health related quality of life measured in German patients one year after mechanical ventilation in the intensive care unit is impaired or not., Objectives: The aim of this study was to assess health related quality of life one year after inclusion into a randomized controlled trial for weaning from mechanical ventilation with the help of a questionnaire that has never been used in critically ill patients and to investigate whether health related quality of life scores differ between the study population and a general German population., Methods: We followed up with patients one year after inclusion into a randomized control trial investigating the effect of SmartCare/PS on total ventilation time compared to protocol-driven weaning (ASOPI trial, clinicaltrials.gov ID00445289). Health related quality of life was measured using the quality of life questionnaire C‑30 version 3.0 from the European Organization of Research and Treatment of Cancer (EORTC). Mean differences of at least 10 score points in the quality of life scales were considered clinically significant., Results: Of the 232 patients who were alive 90 days after study inclusion, 24 patients died one year after study inclusion and 64 patients were lost to follow-up. Of the remaining145 patients who were successfully contacted, 126 patients agreed to fill out the questionnaire. Questionnaires were sent back to the study site by 83 patients and these were analyzed. Health-related quality of life was significantly lower in five of the six functional scales (physical functioning, role functioning, cognitive functioning, social functioning, global health status) and in eight of the nine symptom scales (fatigue, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, financial difficulties) compared to the reference values of a German normal population., Conclusions: The EORTC QLQ-C30 questionnaire is suitable for the acquisition of the health-related quality of life in formerly critically ill patients. Health-related quality of life is severely impaired after mechanical ventilation in the intensive care unit. Future studies should consider health related quality of life as a possible study endpoint.

Schizophrenia is a severe neuropsychiatric disorder with impairments in social cognition. Several brain regions have been implicated in social cognition, including the nucleus caudatus, prefrontal and temporal cortex, and cerebellum. Oxytocin is a critical modulator of social cognition and the formation and maintenance of social relationships and was shown to improve symptoms and social cognition in schizophrenia patients. However, it is unknown whether the oxytocin receptor is altered in the brain. Therefore, we used qRT-PCR and Ornithine Vasotocin Analog ([ 125 I]OVTA)-based receptor autoradiography to investigate oxytocin receptor expression at both the mRNA and protein level in the left prefrontal and middle temporal cortex, left nucleus caudatus, and right posterior superior vermis in 10 schizophrenia patients and 6 healthy controls. Furthermore, to investigate confounding effects of long-term antipsychotic medication we treated rats with clozapine or haloperidol for 12weeks and assessed expression of the oxytocin receptor in cortical and subcortical brain regions. In schizophrenia patients, we found a downregulation of oxytocin receptor mRNA in the temporal cortex and a decrease in receptor binding in the vermis. In the other regions, the results showed trends in the same direction, without reaching statistical significance. We found no differences between antipsychotic-treated rats and controls. Downregulated expression and binding of the oxytocin receptor in brain regions involved in social cognition may lead to a dysfunction of oxytocin signaling. Our results support a dysfunction of the oxytocin receptor in schizophrenia, which may contribute to deficits of social cognition., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objectives: Schizophrenia is a group of severe psychiatric disorders with high heritability but only low odds ratios of risk genes. Despite progress in the identification of pathophysiological processes, valid biomarkers of the disease are still lacking., Methods: This comprehensive review summarises recent efforts to identify genetic underpinnings, clinical and cognitive endophenotypes and symptom dimensions of schizophrenia and presents findings from neuroimaging studies with structural, functional and spectroscopy magnetic resonance imaging and positron emission tomography. The potential of findings to be biomarkers of schizophrenia is discussed., Results: Recent findings have not resulted in clear biomarkers for schizophrenia. However, we identified several biomarkers that are potential candidates for future research. Among them, copy number variations and links between genetic polymorphisms derived from genome-wide analysis studies, clinical or cognitive phenotypes, multimodal neuroimaging findings including positron emission tomography and magnetic resonance imaging, and the application of multivariate pattern analyses are promising., Conclusions: Future studies should address the effects of treatment and stage of the disease more precisely and apply combinations of biomarker candidates. Although biomarkers for schizophrenia await validation, knowledge on candidate genomic and neuroimaging biomarkers is growing rapidly and research on this topic has the potential to identify psychiatric endophenotypes and in the future increase insight on individual treatment response in schizophrenia.

The aims were to examine the feasibility of and adaptations to endurance training in persons diagnosed with schizophrenia and to address the question whether the principles and beneficial effects of endurance training established in the healthy population apply also to patients with schizophrenia. In this controlled interventional study, 22 patients with schizophrenia and 22 healthy controls performed a standardized aerobic endurance training on bicycle ergometers over 12 weeks. Another group of 21 patients with schizophrenia played table soccer. Endurance capacity was measured with incremental cycle ergometry before and after the intervention and 3 months later. A specific set of outcome parameters was defined. The training stimuli can be assumed to be similar in both endurance groups. Endurance capacity improved significantly in the endurance groups, but not in the table soccer group. Patients and healthy controls showed comparable adaptations to endurance training, as assessed by physical working capacity and maximal achieved power. Differences were found in changes of performance at a lactate concentration of 3 mmol/l. Endurance training was feasible and effective in both groups. The principles and types of training that are usually applied to healthy controls need to be verified in patients with schizophrenia. Nevertheless, patients benefited from endurance training in terms of improvement of endurance capacity and reduction in the baseline deficit in comparison with healthy controls. Therefore, endurance training should be implemented in future therapy programs. These programs need to pay special attention to the differences between patients with schizophrenia and healthy controls.

Findings from multiple lines of research provide evidence of aberrant functional brain connectivity in schizophrenia. By using graph-analytical measures, recent studies indicate that patients with schizophrenia exhibit changes in the organizational principles of whole-brain networks and that these changes relate to cognitive symptoms. However, there has not been a systematic investigation of functional brain network changes in schizophrenia to test the consistency of these changes across multiple studies. A comprehensive literature search was conducted to identify all available functional graph-analytical studies in patients with schizophrenia. Effect size measures were derived from each study and entered in a random-effects meta-analytical model. All models were tested for effects of potential moderator variables as well as for the presence of publication bias. The results of a total of n = 13 functional neuroimaging studies indicated that brain networks in patients with schizophrenia exhibit significant decreases in measures of local organization (g = -0.56, P = .02) and significant decreases in small-worldness (g = -0.65, P = .01) whereas global short communication paths seemed to be preserved (g = 0.26, P = .32). There was no evidence for a publication bias or moderator effects. The present meta- analysis demonstrates significant changes in whole brain network architecture associated with schizophrenia across studies., (© 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.)

The hippocampus is involved in cognition as well as emotion, with deficits in both domains consistently described in schizophrenia. Moreover, the whole volumes of both the anterior and posterior region have been reported to be decreased in schizophrenia patients. While fewer oligodendrocyte numbers in the left and right cornu ammonis CA4 subregion of the posterior part of the hippocampus have been reported, the aim of this stereological study was to investigate cell numbers in either the dentate gyrus (DG) or subregions of the anterior hippocampus. In this design-based stereological study of the anterior part of the hippocampus comparing 10 patients with schizophrenia to 10 age- and gender-matched healthy controls were examined. Patients showed a decreased number of oligodendrocytes in the left CA4, fewer neurons in the left DG and smaller volumes in both the left CA4 and DG, which correlated with oligodendrocyte and neuron numbers, respectively. When exploring the total hippocampus, keeping previously published own results from the posterior part of the same brains in mind, both decreased oligodendrocyte numbers in the left CA4 and reduced volume remained significant. The decreased oligodendrocyte number speaks for a deficit in myelination and connectivity in schizophrenia which may originate from disturbed maturational processes. The reduced neuron number of the DG in the anterior hippocampus may well point to a reduced capacity of this region to produce new neurons up to adulthood. Both mechanisms may be involved in cognitive dysfunction in schizophrenia patients., (© 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.)

The objective of this longitudinal magnetic resonance (MR) imaging study was to examine the effects of endurance training on hippocampal and grey matter volumes in schizophrenia patients and healthy controls. 20 chronic schizophrenia patients and 21 age- and gender-matched healthy controls underwent 3months of endurance training (30min, 3 times per week). 19 additionally recruited schizophrenia patients played table soccer ("foosball" in the USA) over the same period. MR imaging with 3D-volumetric T1-weighted sequences was performed on a 3T MR scanner at baseline, after 6weeks and after the 3-month intervention and 3 additional training-free months. In addition to voxel-based morphometry (VBM), we performed manual and automatic delineation of the hippocampus and its substructures. Endurance capacity and psychopathological symptoms were measured as secondary endpoints. No significant increases in the volumes of the hippocampus or hippocampal substructures were observed in schizophrenia patients or healthy controls. However, VBM analyses displayed an increased volume of the left superior, middle and inferior anterior temporal gyri compared to baseline in schizophrenia patients after the endurance training, whereas patients playing table soccer showed increased volumes in the motor and anterior cingulate cortices. After the additional training-free period, the differences were no longer present. While endurance capacity improved in exercising patients and healthy controls, psychopathological symptoms did not significantly change. The subtle changes in the left temporal cortex indicate an impact of exercise on brain volumes in schizophrenia. Subsequent studies in larger cohorts are warranted to address the question of response variability of endurance training., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Cognitive impairments are one of the main contributors to disability and poor long-term outcome in schizophrenia. Proof-of-concept trials indicate that repetitive transcranial magnetic stimulation (rTMS) applied to the left dorsolateral prefrontal cortex (DLPFC) has the potential to improve cognitive functioning. We analyzed the effects of 10-Hz rTMS to the left DLPFC on cognitive deficits in schizophrenia in a large-scale and multicenter, sham-controlled study. A total of 156 schizophrenia patients with predominant negative symptoms were randomly assigned to a 3-week intervention (10-Hz rTMS, 15 sessions, 1000 stimuli per session) with either active or sham rTMS. The Rey Auditory Verbal Learning Test, Trail Making Test A and B, Wisconsin Card Sorting Test, Digit Span Test, and the Regensburg Word Fluency Test were administered before intervention and at day 21, 45, and 105 follow-up. From the test results, a neuropsychological composite score was computed. Both groups showed no differences in any of the outcome variables before and after intervention. Both groups improved markedly over time, but effect sizes indicate a numeric, but nonsignificant superiority of active rTMS in certain cognitive tests. Active 10-Hz rTMS applied to the left DLPFC for 3 weeks was not superior to sham rTMS in the improvement of various cognitive domains in schizophrenia patients with predominant negative symptoms. This is in contrast to previous preliminary proof-of-concept trials, but highlights the need for more multicenter randomized controlled trials in the field of noninvasive brain stimulation., (© 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.)

In schizophrenia, previous stereological post-mortem investigations of anterior, posterior, and total hippocampal subfields showed no alterations in total neuron number but did show decreased oligodendrocyte numbers in CA4, an area that corresponds to the polymorph layer of the dentate gyrus (DG). However, these investigations identified oligodendrocytes only on the basis of morphological criteria in Nissl staining and did not assess alterations of interneurons with immunohistochemical markers. Moreover, the association of findings in the posterior hippocampus with cognitive deficits remains unknown. On the basis of the available clinical records, we compared patients with definite and possible cognitive dysfunction; nine patients had evidence in their records of either definite (n = 4) or possible (n = 5) cognitive dysfunction. Additionally, we assessed the density of two oligodendrocyte subpopulations immunostained by the oligodendrocyte transcription factors Olig1 and Olig2 and of interneurons immunolabeled by parvalbumin. We investigated posterior hippocampal subregions in the post-mortem brains of the same schizophrenia patients (SZ; n = 10) and healthy controls (n = 10) we examined in our previously published stereological studies. Our stereological studies found that patients with definite cognitive deficits had decreased total/Nissl-stained oligodendrocyte numbers in the left (p = 0.014) and right (p = 0.050) CA4, left CA2/3 (p = 0.050), left CA1 (p = 0.027), and left (p = 0.050) and right (p = 0.014) subiculum of the anterior part of the hippocampus compared to patients with possible cognitive deficits. In the present study, we found no significant influence of definite cognitive deficits in the posterior part of the hippocampus, whereas in the entire hippocampus SZ with definite cognitive deficits showed decreased oligodendrocyte numbers in the left (p = 0.050) and right (p = 0.050) DG and left CA2/3 (p = 0.050). We did not find significant differences in Olig1-, Olig2-, or parvalbumin-positive cell density between SZ and controls in any of the subregions of the posterior hippocampus. Based on the results from our stereological study we hypothesize that a decreased number of oligodendrocytes in the anterior and entire hippocampus may be involved in cognitive deficits by impairing the connectivity of this structure in schizophrenia. In the posterior hippocampus, we could not replicate previously reported findings of decreased interneurons from the entire hippocampus.

Substitution of a histidine, comprising part of the catalytic base group in the ent-copalyl diphosphate synthases found in all seed plants for gibberellin phytohormone metabolism, by a larger aromatic residue leads to rearrangements. Through a series of 1,2-hydride and methyl shifts of the initially formed bicycle predominant formation of (-)-kolavenyl diphosphate is observed. Further mutational analysis and quantum chemical calculations provide mechanistic insight into the basis for this profound effect on product outcome., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Despite many pharmacological and psychosocial treatment options, schizophrenia remains a debilitating disorder. Thus, new treatment strategies rooted in the pathophysiology of the disorder are needed. Recently, vagus nerve stimulation (VNS) has been proposed as a potential treatment option for various neuropsychiatric disorders including schizophrenia. The objective of this study was to investigate for the first time the feasibility, safety and efficacy of transcutaneous VNS in stable schizophrenia. A bicentric randomized, sham-controlled, double-blind trial was conducted from 2010 to 2012. Twenty schizophrenia patients were randomly assigned to one of two treatment groups. The first group (active tVNS) received daily active stimulation of the left auricle for 26 weeks. The second group (sham tVNS) received daily sham stimulation for 12 weeks followed by 14 weeks of active stimulation. Primary outcome was defined as change in the Positive and Negative Symptom Scale total score between baseline and week 12. Various other secondary measures were assessed to investigate safety and efficacy. The intervention was well tolerated with no relevant adverse effects. We could not observe a statistically significant difference in the improvement of schizophrenia psychopathology during the observation period. Neither psychopathological and neurocognitive measures nor safety measures showed significant differences between study groups. Application of tVNS was well tolerated, but did not improve schizophrenia symptoms in our 26-week trial. While unsatisfactory compliance questions the feasibility of patient-controlled neurostimulation in schizophrenia, the overall pattern of symptom change might warrant further investigations in this population.

Background: Health-related Quality of life (HRQoL) is a major goal of clinical management after liver transplantation (LTx). There is still disagreement on the effects of social-demographic factors and changes in the allocation system on HRQoL. The aim of this study was to evaluate the impact of social-demographic factors, mode of organ-allocation, waiting time and hepatocellular carcinoma (HCC) on HRQoL after LTx., Methods: HRQoL was assessed using the EORTC-QLQ-C30 questionnaire, which was sent to 238 recipients. Investigated parameters included age, sex, distance to transplant center, follow-up at hospital, size of hometown, highest education, marital status, having children, background liver disease, waiting time, mode of allocation, HCC, hospitalization after LTx and diagnosis of malignancy after LTx. All evaluated parameters were entered into multivariate linear regression analysis., Results: Completed questionnaire were returned by 73% of the recipients. After LTx, the HRQoL-function scales increased over time. Age, marital status, highest education, completed professional training, working status, job position, duration of waiting time to LTx, distance to transplant center, place offollow, HU-statuts, mode of organ allocation and duration of hospitalization were associated with significantly worse function- and significantly lower symptom scales. HCC as a primary disease did not affect HRQoL., Conclusions: Low HRQoL correlated significantly with MELD-based organ allocation, more than 28-day hospitalization, divorced status, lower education- and non-working status, higher distance to transplant center, follow up at transplant center, HU-status, shorter waiting time to LTx and younger age. Improvement of HRQoL after LTx may require clinical management of pain, psychotherapy and financial support.