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Schizophrenia is conceptualized as a neurodevelopmental disorder and pre-morbid differences in social function and cognition have been well-established. Less is known about pre-morbid temperament and personality. Inhibited temperament-the predisposition to respond to novelty with wariness, fear, or caution-is a premorbid risk factor for anxiety, depression, and substance use but is understudied in schizophrenia. Participants were patients with schizophrenia spectrum disorders (n = 166) and healthy controls (n = 180). Patients completed measures of childhood inhibited temperament, clinical symptoms (anxiety, depression, PANSS factors), and quality of life. Patients had significantly higher levels of inhibited temperament relative to healthy controls. In patients with schizophrenia, higher inhibited temperament was significantly associated with co-morbid anxiety disorders, greater anxiety and depression symptoms, higher PANSS Distress scores, lower PANSS Excitement scores, and lower quality of life. The current findings replicate and extend previous research with a larger sample and are consistent with vulnerability in an affective path to psychosis. In schizophrenia, higher inhibited temperament was associated with a cluster of mood and anxiety symptoms. Inhibited temperament was not associated with psychosis symptoms. Patients with high inhibited temperament may especially benefit from treatments that specifically target anxiety and depression.
Copyright © 2019. Published by Elsevier B.V.

Transcriptomic imputation approaches combine eQTL reference panels with large-scale genotype data in order to test associations between disease and gene expression. These genic associations could elucidate signals in complex genome-wide association study (GWAS) loci and may disentangle the role of different tissues in disease development. We used the largest eQTL reference panel for the dorso-lateral prefrontal cortex (DLPFC) to create a set of gene expression predictors and demonstrate their utility. We applied DLPFC and 12 GTEx-brain predictors to 40,299 schizophrenia cases and 65,264 matched controls for a large transcriptomic imputation study of schizophrenia. We identified 413 genic associations across 13 brain regions. Stepwise conditioning identified 67 non-MHC genes, of which 14 did not fall within previous GWAS loci. We identified 36 significantly enriched pathways, including hexosaminidase-A deficiency, and multiple porphyric disorder pathways. We investigated developmental expression patterns among the 67 non-MHC genes and identified specific groups of pre- and postnatal expression.

Contrary to the notion that neurology but not psychiatry is the domain of disorders evincing structural brain alterations, it is now clear that there are subtle but consistent neuropathological changes in schizophrenia. These range from increases in ventricular size to dystrophic changes in dendritic spines. A decrease in dendritic spine density in the prefrontal cortex (PFC) is among the most replicated of postmortem structural findings in schizophrenia. Examination of the mechanisms that account for the loss of dendritic spines has in large part focused on genes and molecules that regulate neuronal structure. But the simple question of what is the effector of spine loss, ie, where do the lost spines go, is unanswered. Recent data on glial cells suggest that microglia (MG), and perhaps astrocytes, play an important physiological role in synaptic remodeling of neurons during development. Synapses are added to the dendrites of pyramidal cells during the maturation of these neurons; excess synapses are subsequently phagocytosed by MG. In the PFC, this occurs during adolescence, when certain symptoms of schizophrenia emerge. This brief review discusses recent advances in our understanding of MG function and how these non-neuronal cells lead to structural changes in neurons in schizophrenia.

Substance use may confound the study of brain structure in schizophrenia. We used voxel-based morphometry (VBM) to examine whether differences in regional gray matter volumes exist between schizophrenia patients with (n = 92) and without (n = 66) clinically significant cannabis and/or alcohol use histories compared to 88 healthy control subjects. Relative to controls, patients with schizophrenia had reduced gray matter volume in the bilateral precentral gyrus, right medial frontal cortex, right visual cortex, right occipital pole, right thalamus, bilateral amygdala, and bilateral cerebellum regardless of substance use history. Within these regions, we found no volume differences between patients with schizophrenia and a history of cannabis and/or alcohol compared to patients with schizophrenia without a clinically significant substance use history. Our data support the idea that a clinically meaningful history of alcohol or cannabis use does not significantly compound the gray matter deficits associated with schizophrenia.
Copyright © 2018. Published by Elsevier B.V.

RATIONALE - Metabotropic glutamate receptors and muscarinic M receptors have been proposed as novel targets for various brain disorders, including schizophrenia. Both receptors are coupled to G proteins and are expressed in brain circuits that are important in schizophrenia. Therefore, their mutual activation may be an effective treatment and allow minimizing the doses of ligands required for optimal activity.
OBJECTIVES - In the present studies, subactive doses of mGlu and M activators (LSP4-2022 and VU152100, respectively) were administered to investigate the mutual interaction between mGlu and M receptors in animal models of schizophrenia.
METHODS - The behavioral tests used were MK-801-induced hyperactivity, (±)-2.5-dimethoxy-4-iodoamphetamine hydrochloride (DOI)-induced head twitches, the modified forced swim test, and MK-801-induced disruptions of social interactions and novel object recognition. DOI-induced spontaneous excitatory postsynaptic currents (sEPSCs) in brain slices and positron emission tomography (PET) in were used to establish the ability of these compounds to modulate the glutamatergic and dopaminergic systems. Rotarod was used to assess putative adverse effects.
RESULTS - The mutual administration of subactive doses of LSP4-2022 and VU152100 exerted similar antipsychotic-like efficacy in animals as observed for active doses of both compounds, indicating their additive actions. VU152100 inhibited the DOI-induced frequency (but not amplitude) of sEPSCs in the frontal cortex, confirming presynaptic regulation of glutamate release. Both compounds reversed amphetamine-induced decrease in D receptor levels in the striatum, as measured with [F]fallypride. The compounds did not induce any motor impartments when measured in rotarod test.
CONCLUSIONS - Based on our results, the simultaneous activation of M and mGlu receptors is beneficial in reversing MK-801- and amphetamine-induced schizophrenia-related changes in animals.

The latent structure of schizotypy and psychosis-spectrum symptoms remains poorly understood. Furthermore, molecular genetic substrates are poorly defined, largely due to the substantial resources required to collect rich phenotypic data across diverse populations. Sample sizes of phenotypic studies are often insufficient for advanced structural equation modeling approaches. In the last 50 years, efforts in both psychiatry and psychological science have moved toward (1) a dimensional model of psychopathology (eg, the current Hierarchical Taxonomy of Psychopathology [HiTOP] initiative), (2) an integration of methods and measures across traits and units of analysis (eg, the RDoC initiative), and (3) powerful, impactful study designs maximizing sample size to detect subtle genomic variation relating to complex traits (the Psychiatric Genomics Consortium [PGC]). These movements are important to the future study of the psychosis spectrum, and to resolving heterogeneity with respect to instrument and population. The International Consortium of Schizotypy Research is composed of over 40 laboratories in 12 countries, and to date, members have compiled a body of schizotypy- and psychosis-related phenotype data from more than 30000 individuals. It has become apparent that compiling data into a protected, relational database and crowdsourcing analytic and data science expertise will result in significant enhancement of current research on the structure and biological substrates of the psychosis spectrum. The authors present a data-sharing infrastructure similar to that of the PGC, and a resource-sharing infrastructure similar to that of HiTOP. This report details the rationale and benefits of the phenotypic data collective and presents an open invitation for participation.

BACKGROUND - Functional dysconnectivity has been proposed as a major pathophysiological mechanism for cognitive dysfunction in schizophrenia. The hippocampus is a focal point of dysconnectivity in schizophrenia, with decreased hippocampal functional connectivity contributing to the marked memory deficits observed in patients. Normal memory function relies on the interaction of complex corticohippocampal networks. However, only recent technological advances have enabled the large-scale exploration of functional networks with accuracy and precision.
METHODS - We investigated the modularity of hippocampal resting-state functional networks in a sample of 45 patients with schizophrenia spectrum disorders and 38 healthy control subjects. Modularity was calculated for two distinct functional networks: a core hippocampal-medial temporal lobe cortex network and an extended hippocampal-cortical network. As hippocampal function differs along its longitudinal axis, follow-up analyses examined anterior and posterior networks separately. To explore effects of resting network function on behavior, we tested associations between modularity and relational memory ability. Age, sex, handedness, and parental education were similar between groups.
RESULTS - Network modularity was lower in schizophrenia patients, especially in the posterior hippocampal network. Schizophrenia patients also showed markedly lower relational memory ability compared with control subjects. We found a distinct brain-behavior relationship in schizophrenia that differed from control subjects by network and anterior/posterior division-while relational memory in control subjects was associated with anterior hippocampal-cortical modularity, schizophrenia patients showed an association with posterior hippocampal-medial temporal lobe cortex network modularity.
CONCLUSIONS - Our findings support a model of abnormal resting-state corticohippocampal network coherence in schizophrenia, which may contribute to relational memory deficits.
Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Impairments in cognitive control-the ability to exert control over thoughts and actions and respond flexibly to the environment-are well-documented in schizophrenia. However, the degree to which experimental task performance reflects true cognitive control impairments or more general alterations in effort, arousal and/or task preparedness is unclear. Pupillary responses can provide insight into these latter factors, as the pupil dilates with degree of cognitive effort and response preparation. In the current study, 16 medicated outpatients with schizophrenia (SZP) and 18 healthy controls performed a task that measures the ability to reactively inhibit and modify a planned action-the double-step task. In this task, participants were required to make a saccade to a visual target. Infrequently, the target jumped to a new location and participants were instructed to rapidly inhibit and change their eye movement plan. Applying a race model of performance, we have previously shown that SZP require more time to inhibit a planned action. In the current analysis, we measured pupil dilation associated with task preparation and found that SZP had a shallower increase in pupil size prior to the onset of the trial. Additionally, reduced magnitude of the pupil response was associated with negative symptom severity in patients. Based on primate neurophysiology and cognitive neuroscience work, we suggest that this blunted pupillary response may reflect abnormalities in a general orienting response or reduced motivational significance of a cue signifying the onset of a preparatory period and that these abnormalities might share an autonomic basis with negative symptoms.
Copyright © 2018 Elsevier B.V. All rights reserved.

BACKGROUND - Executive cognitive functions, including working memory, cognitive flexibility, and inhibition, are impaired in schizophrenia. Executive functions rely on coordinated information processing between the prefrontal cortex (PFC) and thalamus, particularly the mediodorsal nucleus. This raises the possibility that anatomical connectivity between the PFC and mediodorsal thalamus may be 1) reduced in schizophrenia and 2) related to deficits in executive function. The current investigation tested these hypotheses.
METHODS - Forty-five healthy subjects and 62 patients with a schizophrenia spectrum disorder completed a battery of tests of executive function and underwent diffusion-weighted imaging. Probabilistic tractography was used to quantify anatomical connectivity between six cortical regions, including PFC, and the thalamus. Thalamocortical anatomical connectivity was compared between healthy subjects and patients with schizophrenia using region-of-interest and voxelwise approaches, and the association between PFC-thalamic anatomical connectivity and severity of executive function impairment was examined in patients.
RESULTS - Anatomical connectivity between the thalamus and PFC was reduced in schizophrenia. Voxelwise analysis localized the reduction to areas of the mediodorsal thalamus connected to lateral PFC. Reduced PFC-thalamic connectivity in schizophrenia correlated with impaired working memory but not cognitive flexibility and inhibition. In contrast to reduced PFC-thalamic connectivity, thalamic connectivity with somatosensory and occipital cortices was increased in schizophrenia.
CONCLUSIONS - The results are consistent with models implicating disrupted PFC-thalamic connectivity in the pathophysiology of schizophrenia and mechanisms of cognitive impairment. PFC-thalamic anatomical connectivity may be an important target for procognitive interventions. Further work is needed to determine the implications of increased thalamic connectivity with sensory cortex.
Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.