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With new data about different aspects of schizophrenia being continually generated, it becomes necessary to periodically revisit exactly what we know. Along with a need to review what we currently know about schizophrenia, there is an equal imperative to evaluate the construct itself. With these objectives, we undertook an iterative, multi-phase process involving fifty international experts in the field, with each step building on learnings from the prior one. This review assembles currently established findings about schizophrenia (construct, etiology, pathophysiology, clinical expression, treatment) and posits what they reveal about its nature. Schizophrenia is a heritable, complex, multi-dimensional syndrome with varying degrees of psychotic, negative, cognitive, mood, and motor manifestations. The illness exhibits a remitting and relapsing course, with varying degrees of recovery among affected individuals with most experiencing significant social and functional impairment. Genetic risk factors likely include thousands of common genetic variants that each have a small impact on an individual's risk and a plethora of rare gene variants that have a larger individual impact on risk. Their biological effects are concentrated in the brain and many of the same variants also increase the risk of other psychiatric disorders such as bipolar disorder, autism, and other neurodevelopmental conditions. Environmental risk factors include but are not limited to urban residence in childhood, migration, older paternal age at birth, cannabis use, childhood trauma, antenatal maternal infection, and perinatal hypoxia. Structural, functional, and neurochemical brain alterations implicate multiple regions and functional circuits. Dopamine D-2 receptor antagonists and partial agonists improve psychotic symptoms and reduce risk of relapse. Certain psychological and psychosocial interventions are beneficial. Early intervention can reduce treatment delay and improve outcomes. Schizophrenia is increasingly considered to be a heterogeneous syndrome and not a singular disease entity. There is no necessary or sufficient etiology, pathology, set of clinical features, or treatment that fully circumscribes this syndrome. A single, common pathophysiological pathway appears unlikely. The boundaries of schizophrenia remain fuzzy, suggesting the absence of a categorical fit and need to reconceptualize it as a broader, multi-dimensional and/or spectrum construct. [ABSTRACT FROM AUTHOR]

In the last two decades, much neuroscientific research has been done on the pathomechanisms of catatonia. However, catatonic symptoms have mainly been assessed with clinical rating scales based on observer ratings. Although catatonia is often associated with strong affective reactions, the subjective domain of catatonia has simply been neglected in scientific research. The main objective of this study was to modify, extend and translate the original German version of the Northoff Scale for Subjective Experience in Catatonia (NSSC) and to examine its preliminary validity and reliability. Data were collected from 28 patients diagnosed with catatonia associated with another mental disorder (6A40) according to ICD-11. Descriptive statistics, correlation coefficients, internal consistency and principal component analysis were employed to address preliminary validity and reliability of the NSSC. NSSC showed high internal consistency (Cronbach's alpha = 0.92). NSSC total scores were significantly associated with Northoff Catatonia Rating Scale (r = 0.50, p <.01) and Bush Francis Catatonia Rating Scale (r = 0.41, p <.05) thus supporting its concurrent validity. There was no significant association between NSSC total score and Positive and Negative Symptoms Scale total (r = 0.26, p =.09), Brief Psychiatric Rating Scale (r = 0.29, p =.07) and GAF (r = 0.03, p =.43) scores. The extended version of the NSSC consists of 26 items and was developed to assess the subjective experience of catatonia patients. Preliminary validation of the NSSC revealed good psychometric properties. NSSC is a useful tool for everyday clinical work to assess the subjective experience of catatonia patients. [ABSTRACT FROM AUTHOR]

The number of magnetic resonance imaging (MRI) studies on neuronal correlates of catatonia has dramatically increased in the last 10 years, but conclusive findings on white matter (WM) tracts alterations underlying catatonic symptoms are still lacking. Therefore, we conduct an interdisciplinary longitudinal MRI study (whiteCAT) with two main objectives: First, we aim to enroll 100 psychiatric patients with and 50 psychiatric patients without catatonia according to ICD-11 who will undergo a deep phenotyping approach with an extensive battery of demographic, psychopathological, psychometric, neuropsychological, instrumental and diffusion MRI assessments at baseline and 12 weeks follow-up. So far, 28 catatonia patients and 40 patients with schizophrenia or other primary psychotic disorders or mood disorders without catatonia have been studied cross-sectionally. 49 out of 68 patients have completed longitudinal assessment, so far. Second, we seek to develop and implement a new method for semi-automatic fiber tract delineation using active learning. By training supportive machine learning algorithms on the fly that are custom tailored to the respective analysis pipeline used to obtain the tractogram as well as the WM tract of interest, we plan to streamline and speed up this tedious and error-prone task while at the same time increasing reproducibility and robustness of the extraction process. The goal is to develop robust neuroimaging biomarkers of symptom severity and therapy outcome based on WM tracts underlying catatonia. If our MRI study is successful, it will be the largest longitudinal study to date that has investigated WM tracts in catatonia patients. [ABSTRACT FROM AUTHOR]

At present, current diagnostic criteria and systems neglect affective symptom expression in catatonia. This potentially serious omission could explain why putative contributions of limbic system structures, such as amygdala, hippocampus or hypothalamus, to catatonia in schizophrenia spectrum disorders (SSD) have been scarcely investigated so far. To determine whether topographical alterations of the amygdala, hippocampus and hypothalamus contribute to catatonia in SSD patients, we conducted structural magnetic resonance imaging (MRI) of SSD patients with (SSD-Cat, n = 30) and without (SSD-nonCat, n = 28) catatonia as defined by a Northoff Catatonia Rating Scale (NCRS) total score of ≥3 and =0, respectively, in comparison with healthy controls (n = 20). FreeSurfer v7.2 was used for automated segmentation of the amygdala and its 9 nuclei, hippocampus and its 21 subfields and hypothalamus and its associated 5 subunits. SSD-Cat had significantly smaller anterior inferior hypothalamus, cortical nucleus of amygdala, and hippocampal fimbria volumes when compared to SSD-nonCat. SSD-Cat had significantly smaller amygdala, hippocampus and hypothalamus whole and subunit volumes when compared to healthy controls. In SSD-Cat according to DSM-IV-TR (n = 44), we identified positive correlations between Brief Psychiatric Rating Scale (BPRS) item #2 (reflecting anxiety) and respective amygdala nuclei as well as negative correlation between NCRS behavioral score and hippocampus subiculum head. The lower volumes of respective limbic structures involved in affect regulation may point towards central affective pathomechanisms in catatonia. [ABSTRACT FROM AUTHOR]

Mentalizing impairment in schizophrenia has been linked to altered neural responses. This study aimed to replicate previous findings of altered activation of the mentalizing network in schizophrenia and investigate its possible association with impaired domain-general cognition. We analyzed imaging data from two large multi-centric German studies including 64 patients, 64 matched controls and a separate cohort of 300 healthy subjects, as well as an independent Australian study including 46 patients and 61 controls. All subjects underwent functional magnetic resonance imaging while performing the same affective mentalizing task and completed a cognitive assessment battery. Group differences in activation of the mentalizing network were assessed by classical as well as Bayesian two-sample t -tests. Multiple regression analysis was performed to investigate effects of neurocognitive measures on activation of the mentalizing network. We found no significant group differences in activation of the mentalizing network. Bayes factors indicate that these results provide genuine evidence for the null hypothesis. We found a positive association between verbal intelligence and activation of the medial prefrontal cortex, a key region of the mentalizing network, in three independent samples. Finally, individuals with low verbal intelligence showed altered activation in areas previously implicated in mentalizing dysfunction in schizophrenia. Mentalizing activation in patients with schizophrenia might not differ compared to large well-matched groups of healthy controls. Verbal intelligence is an important confounding variable in group comparisons, which should be considered in future studies of the neural correlates of mentalizing dysfunction in schizophrenia. [ABSTRACT FROM AUTHOR]

The rs1625579 variant near the microRNA-137 (MIR137) gene is one of the best-supported schizophrenia variants in genome-wide association studies (GWAS), and microRNA-137 functionally regulates other GWAS identified schizophrenia risk variants. Schizophrenia patients with the MIR137 rs1625579 risk genotype (homozygous for the schizophrenia risk variant) also have aberrant brain structure. It is unclear if the effect of MIR137 among schizophrenia patients is due to potential epistasis with genetic risk for schizophrenia or other factors of the disorder. Here, we investigated the effect of MIR137 genotype on white matter fractional anisotropy (FA), cortical thickness (CT), and surface area (SA) in a sample comprising healthy control subjects, and individuals with familial risk for psychosis (first-degree relatives of patients with schizophrenia or bipolar disorder; N=426). In voxel-wise analyses of FA, we observed a significant genotype-by-group interaction (PFWE<0.05). The familial risk group with risk genotype had lower FA (PFWE<0.05), but there was no genetic association in controls. In vertex-wise analyses of SA, we also observed a significant genotype-by-group interaction (PFWE<0.05). Relatives with MIR137 risk genotype had lower SA, however the risk genotype was associated with higher SA in the controls (all PFWE<0.05). These results show that MIR137 risk genotype is associated with lower FA in psychosis relatives that is similar to previous imaging-genetics findings in patients with schizophrenia. Furthermore, MIR137 genotype may also be a risk factor in a subclinical population with wide reductions in white matter FA and cortical SA. [ABSTRACT FROM AUTHOR]

Abstract: Patients with schizophrenia suffer from deficits in monitoring and controlling their own thoughts. Within these so-called metacognitive impairments, alterations in probabilistic reasoning might be one cognitive phenomenon disposing to delusions. However, so far little is known about alterations in associated brain functionality. A previously established task for functional magnetic resonance imaging (fMRI), which requires a probabilistic decision after a variable amount of stimuli, was applied to 23 schizophrenia patients and 28 healthy controls matched for age, gender and educational levels. We compared activation patterns during decision-making under conditions of certainty versus uncertainty and evaluated the process of final decision-making in ventral striatum (VS) and ventral tegmental area (VTA). We replicated a pre-described extended cortical activation pattern during probabilistic reasoning. During final decision-making, activations in several fronto- and parietocortical areas, as well as in VS and VTA became apparent. In both of these regions schizophrenia patients showed a significantly reduced activation. These results further define the network underlying probabilistic decision-making. The observed hypo-activation in regions commonly associated with dopaminergic neurotransmission fits into current concepts of disrupted prediction error signaling in schizophrenia and suggests functional links to reward anticipation. Forthcoming studies with patients at risk for psychosis and drug-naive first episode patients are necessary to elucidate the development of these findings over time and the interplay with associated clinical symptoms. [Copyright &y& Elsevier]

Abstract: Patients with schizophrenia show deficits in motivation, reward anticipation and salience attribution. Several functional magnetic resonance imaging (fMRI) investigations revealed neurobiological correlates of these deficits, raising the hypothesis of a common basis in midbrain dopaminergic signaling. However, investigations of drug-naïve first-episode patients with comprehensive fMRI tasks are still missing. We recruited unmedicated schizophrenia spectrum patients (N=27) and healthy control subjects (N=27) matched for sex, age and educational levels. An established monetary reward anticipation task in combination with a novel task aiming at implicit salience attribution without the confound of monetary incentive was applied. Patients showed reduced right ventral striatal activation during reward anticipation. Furthermore, patients with a more pronounced hypoactivation attributed more salience to neutral stimuli, had more positive symptoms and better executive functioning. In the patient group, a more differentially active striatum during reward anticipation was correlated positively to differential ventral striatal activation in the implicit salience attribution task. In conclusion, a deficit in ventral striatal activation during reward anticipation can already be seen in drug-naïve, first episode schizophrenia patients. The data suggest that rather a deficit in differential ventral striatal activation than a generally reduced activation underlies motivational deficits in schizophrenia and that this deficit is related to the aberrant salience attribution. [Copyright &y& Elsevier]