Developmental expression of Neuregulin-3 in the rat central nervous system

Neuregulin-3 (Nrg3) is a member of the Nrg family of growth factors identified as risk factors for schizophrenia. There are three Nrgs expressed in the nervous system (Nrg1-3) and of these Nrg1 has been the best characterized. To set the groundwork for elucidating neural roles for Nrg3, we studied its expression in the rat brain at both the RNA and protein levels. Using an antibody developed against Nrg3, we observed a developmental increase of Nrg3 protein expression from embryonic stages to adulthood and determined that it carries O-linked carbohydrates. In cortical neuronal cultures, transfected Neuro2a cells, and brain tissue sections Nrg3 protein was localized to the soma, neurites, and to the Golgi apparatus, where it is prominently expressed. Nrg3 was detected in excitatory, GABAergic and parvalbumin-expressing inhibitory neurons while expression in glia was limited. Nrg3 mRNA and protein were widely expressed during both embryonic and postnatal ages. At E17, Nrg3 was detected within the cortical plate and ventricular zone suggesting possible roles in cell proliferation or migration. At postnatal ages, Nrg3 was abundantly expressed throughout the cerebral cortex and hippocampus. Multiple thalamic nuclei expressed Nrg3, while detection in the striatum was limited. In the cerebellum, Nrg3 was found in both Purkinje cells and granule neurons. In the rodent brain, Nrg3 is the most abundantly expressed of the Nrgs and its patterns of expression differ both temporally and spatially from that of Nrg1 and Nrg2. These findings suggest that Nrg3 plays roles that are distinct from the other Nrg family members.     

Alterations in intrinsic fronto‐thalamo‐parietal connectivity are associated with cognitive control deficits in psychotic disorders

Despite a growing number of reports about alterations in intrinsic/resting brain activity observed in patients with psychotic disorders, their relevance to well‐established cognitive control deficits in this patient group is not well understood. Totally 88 clinically stabilized patients with a psychotic disorder and 50 healthy controls participated in a resting‐state magnetic resonance imaging study (rs‐MRI) and performed an antisaccade task in the laboratory to assess voluntary inhibitory control ability. Deficits on this task are a well‐established biomarker across psychotic disorders as we found in the present patient sample. First, regional cerebral function was evaluated by measuring the amplitude of low frequency fluctuations (ALFF) in rs‐MRI BOLD signals. We found reduced ALFF in patients in regions known to be relevant to antisaccade task performance including bilateral frontal eye fields (FEF), supplementary eye fields (SEF) and thalamus. Second, areas with ALFF alterations were used as seed areas in whole‐brain functional connectivity (FC) analysis. Altered FC was observed in a fronto‐thalamo‐parietal network that was associated with inhibition error rate in patients but not in controls. In contrast, faster time to generate a correct antisaccade was associated with FC in FEF and SEF in controls but this effect was not seen in patients. These findings establish a behavioral relevance of resting‐state fMRI findings in psychotic disorders, and extend previous reports of alterations in fronto‐thalamo‐parietal network activation during antisaccade performance seen in task‐based fMRI studies.     

Impaired Sensorimotor Gating Using the Acoustic Prepulse Inhibition Paradigm in Individuals at a Clinical High Risk for Psychosis

Many robust studies have investigated prepulse inhibition (PPI) in patients with schizophrenia. Recent evidence indicates that PPI may help identify individuals who are at clinical high risk for psychosis (CHR). Selective attention to prepulse stimulus can specifically enhance PPI in healthy subjects; however, this enhancement effect is not observed in patients with schizophrenia. Modified PPI measurement with selective attentional modulation using perceived spatial separation (PSS) condition may be a more robust and sensitive index of PPI impairment in CHR individuals. The current study investigated an improved PSSPPI condition in CHR individuals compared with patients with first-episode schizophrenia (FES) and healthy controls (HC) and evaluated the accuracy of PPI in predicting CHR from HC. We included 53 FESs, 55 CHR individuals, and 53 HCs. CHRs were rated on the Structured Interview for Prodromal Syndromes. The measures of perceived spatial co-location PPI (PSCPPI) and PSSPPI conditions were applied using 60- and 120-ms lead intervals. Compared with HC, the CHR group had lower PSSPPI level (Inter-stimulus interval [ISI] = 60 ms, P < .001; ISI = 120 ms, P < .001). PSSPPI showed an effect size (ES) between CHR and HC (ISI = 60 ms, Cohen’s d = 0.91; ISI = 120 ms, Cohen’s d = 0.98); on PSSPPI using 60-ms lead interval, ES grade increased from CHR to FES. The area under the receiver operating characteristic curve for PSSPPI was greater than that for PSCPPI. CHR individuals showed a PSSPPI deficit similar to FES, with greater ES and sensitivity. PSSPPI appears a promising objective approach for preliminary identification of CHR individuals.     

Development and Validation of a Computerized Adaptive Assessment Tool for Discrimination and Measurement of Psychotic Symptoms

ObjectiveTime constraints limit the use of measurement-based approaches in research and routine clinical management of psychosis. Computerized adaptive testing (CAT) can reduce administration time, thus increasing measurement efficiency. This study aimed to develop and test the capacity of the CAT-Psychosis battery, both self-administered and rater-administered, to measure the severity of psychotic symptoms and discriminate psychosis from healthy controls.MethodsAn item bank was developed and calibrated. Two raters administered CAT-Psychosis for inter-rater reliability (IRR). Subjects rated themselves and were retested within 7 days for test-retest reliability. The Brief Psychiatric Rating Scale (BPRS) was administered for convergent validity and chart diagnosis, and the Structured Clinical Interview (SCID) was used to test psychosis discriminant validity.ResultsDevelopment and calibration study included 649 psychotic patients. Simulations revealed a correlation of r = .92 with the total 73-item bank score, using an average of 12 items. Validation study included 160 additional patients and 40 healthy controls. CAT-Psychosis showed convergent validity (clinician: r = 0.690; 95% confidence interval [95% CI]: 0.610–0.757; self-report: r = .690; 95% CI: 0.609–0.756), IRR (intraclass correlation coefficient [ICC] = 0.733; 95% CI: 0.611–0.828), and test-retest reliability (clinician ICC = 0.862; 95% CI: 0.767–0.922; self-report ICC = 0.815; 95%CI: 0.741–0.871). CAT-Psychosis could discriminate psychosis from healthy controls (clinician: area under the receiver operating characteristic curve [AUC] = 0.965, 95% CI: 0.945–0.984; self-report AUC = 0.850, 95% CI: 0.807–0.894). The median length of the clinician-administered assessment was 5 minutes (interquartile range [IQR]: 3:23–8:29 min) and 1 minute, 20 seconds (IQR: 0:57–2:09 min) for the self-report.ConclusionCAT-Psychosis can quickly and reliably assess the severity of psychosis and discriminate psychotic patients from healthy controls, creating an opportunity for frequent remote assessment and patient/population-level follow-up.     

Glutamate hypothesis in schizophrenia

Schizophrenia is a chronic and severe psychiatric disorder that has profound impact on an individual’s life and on society. Thus, developing more effective therapeutic interventions is essential. Over the past quarter‐century, an abundance of evidence from pharmacologic challenges, post‐mortem studies, brain imaging, and genetic studies supports the role of glutamatergic dysregulation in the pathophysiology of schizophrenia, and the results of recent randomized clinical trials based on this evidence have yielded promising results. In this article, we review the evidence that alterations in glutamatergic neurotransmission, especially focusing on the N‐methyl‐d ‐aspartate receptor (NMDAR) function, may be a critical causative feature of schizophrenia, how this contributes to pathologic circuit function in the brain, and how these insights are revealing whole new avenues for treatment development that could reduce treatment‐resistant symptoms, which account for persistent disability.