Schizophrenia Bulletin最新文献

Background and hypothesis: Corollary discharge mechanism suppresses the conscious auditory sensory perception of self-generated speech and attenuates electrophysiological markers such as the auditory N1 Event-Related Potential (ERP) during Electroencephalographic (EEG) recordings. This phenomenon contributes to self-identification and seems to be altered in people with schizophrenia. Therefore, its alteration could be related to the anomalous self-experiences (ASEs) frequently found in these patients.

Study design: To analyze corollary discharge dysfunction as a possible substrate of ASEs, we recorded EEG ERP from 43 participants with schizophrenia and 43 healthy controls and scored ASEs with the 'Inventory of Psychotic-Like Anomalous Self-Experiences' (IPASE). Positive and negative symptoms were also scored with the 'Positive and Negative Syndrome Scale for Schizophrenia' (PANSS) and with the 'Brief Negative Symptom Scale' (BNSS) respectively. The N1 components were elicited by two task conditions: (1) concurrent listening to self-pronounced vowels (talk condition) and (2) subsequent non-concurrent listening to the same previously self-uttered vowels (listen condition).

Study results: The amplitude of the N1 component elicited by the talk condition was lower compared to the listen condition in people with schizophrenia and healthy controls. However, the difference in N1 amplitude between both conditions was significantly higher in controls than in schizophrenia patients. The values of these differences in patients correlated significantly and negatively with the IPASE, PANSS, and BNSS scores.

Conclusions: These results corroborate previous data relating auditory N1 ERP amplitude with altered corollary discharge mechanisms in schizophrenia and support corollary discharge dysfunction as a possible underpinning of ASEs in this illness.

In our previous paper on the Future of Cognitive Remediation published more than 10 years ago, we envisaged an imminent and wide implementation of cognitive remediation therapies into mental health services. This optimism was misplaced. Despite evidence of the benefits, costs, and savings of this intervention, access is still sparse. The therapy has made its way into some treatment guidance, but these documents weight the same evidence very differently, causing confusion, and do not consider barriers to implementation. This paper revisits our previous agenda and describes how some challenges were overcome but some remain. The scientific community, with its commitment to Open Science, has produced promising sets of empirical data to explore the mechanisms of treatment action. This same community needs to understand the specific and nonspecific effects of cognitive remediation if we are to provide a formulation-based approach that can be widely implemented. In the last 10 years we have learned that cognitive remediation is not "brain training" but is a holistic therapy that involves an active therapist providing motivation support, and who helps to mitigate the impact of cognitive difficulties through metacognition to develop awareness of cognitive approaches to problems. We conclude that, of course, more research is needed but, in addition and perhaps more importantly at this stage, we need more public and health professionals' understanding of the benefits of this therapy to inform and include this approach as part of treatment regimens.

Background and hypothesis: Schizophrenia (SCZ) and anorexia nervosa (AN) are 2 severe and highly heterogeneous disorders showing substantial familial co-aggregation. Genetic factors play a significant role in both disorders, but the shared genetic etiology between them is yet to be investigated.

Study design: Using summary statistics from recent large genome-wide association studies on SCZ (Ncases = 53 386) and AN (Ncases = 16 992), a 2-sample Mendelian randomization analysis was conducted to explore the causal relationship between SCZ and AN. MiXeR was employed to quantify their polygenic overlap. A conditional/conjunctional false discovery rate (condFDR/conjFDR) framework was adopted to identify loci jointly associated with both disorders. Functional annotation and enrichment analyses were performed on the shared loci.

Study results: We observed a cross-trait genetic enrichment, a suggestive bidirectional causal relationship, and a considerable polygenic overlap (Dice coefficient = 62.2%) between SCZ and AN. The proportion of variants with concordant effect directions among all shared variants was 69.9%. Leveraging overlapping genetic associations, we identified 6 novel loci for AN and 33 novel loci for SCZ at condFDR <0.01. At conjFDR <0.05, we identified 10 loci jointly associated with both disorders, implicating multiple genes highly expressed in the cerebellum and pituitary and involved in synapse organization. Particularly, high expression of the shared genes was observed in the hippocampus in adolescence and orbitofrontal cortex during infancy.

Conclusions: This study provides novel insights into the relationship between SCZ and AN by revealing a shared genetic component and offers a window into their complex etiology.

Background: The ganglionic eminences (GE) are fetal-specific structures that give rise to gamma-aminobutyric acid (GABA)- and acetylcholine-releasing neurons of the forebrain. Given the evidence for GABAergic, cholinergic, and neurodevelopmental disturbances in schizophrenia, we tested the potential involvement of GE neuron development in mediating genetic risk for the condition.

Study design: We combined data from a recent large-scale genome-wide association study of schizophrenia with single-cell RNA sequencing data from the human GE to test the enrichment of schizophrenia risk variation in genes with high expression specificity for developing GE cell populations. We additionally performed the single nuclei Assay for Transposase-Accessible Chromatin with Sequencing (snATAC-Seq) to map potential regulatory genomic regions operating in individual cell populations of the human GE, using these to test for enrichment of schizophrenia common genetic variant liability and to functionally annotate non-coding variants-associated with the disorder.

Study results: Schizophrenia common variant liability was enriched in genes with high expression specificity for developing neuron populations that are predicted to form dopamine D1 and D2 receptor-expressing GABAergic medium spiny neurons of the striatum, cortical somatostatin-positive GABAergic interneurons, calretinin-positive GABAergic neurons, and cholinergic neurons. Consistent with these findings, schizophrenia genetic risk was concentrated in predicted regulatory genomic sequence mapped in developing neuronal populations of the GE.

Conclusions: Our study implicates prenatal development of specific populations of GABAergic and cholinergic neurons in later susceptibility to schizophrenia, and provides a map of predicted regulatory genomic elements operating in cells of the GE.

Background and hypothesis: N-Methyl-d-aspartate receptor (NMDA-R) hypofunctioning has been hypothesized to be involved in circuit dysfunctions in schizophrenia (ScZ). Yet, it remains to be determined whether the physiological changes observed following NMDA-R antagonist administration are consistent with auditory gamma-band activity in ScZ which is dependent on NMDA-R activity.

Study design: This systematic review investigated the effects of NMDA-R antagonists on auditory gamma-band activity in preclinical (n = 15) and human (n = 3) studies and compared these data to electro/magneto-encephalographic measurements in ScZ patients (n = 37) and 9 studies in early-stage psychosis. The following gamma-band parameters were examined: (1) evoked spectral power, (2) intertrial phase coherence (ITPC), (3) induced spectral power, and (4) baseline power.

Study results: Animal and human pharmacological data reported a reduction, especially for evoked gamma-band power and ITPC, as well as an increase and biphasic effects of gamma-band activity following NMDA-R antagonist administration. In addition, NMDA-R antagonists increased baseline gamma-band activity in preclinical studies. Reductions in ITPC and evoked gamma-band power were broadly compatible with findings observed in ScZ and early-stage psychosis patients where the majority of studies observed decreased gamma-band spectral power and ITPC. In regard to baseline gamma-band power, there were inconsistent findings. Finally, a publication bias was observed in studies investigating auditory gamma-band activity in ScZ patients.

Conclusions: Our systematic review indicates that NMDA-R antagonists may partially recreate reductions in gamma-band spectral power and ITPC during auditory stimulation in ScZ. These findings are discussed in the context of current theories involving alteration in E/I balance and the role of NMDA hypofunction in the pathophysiology of ScZ.

Background and hypothesis: Brain development/aging is not uniform across individuals, spawning efforts to characterize brain age from a biological perspective to model the effects of disease and maladaptive life processes on the brain. The brain age gap represents the discrepancy between estimated brain biological age and chronological age (in this case, based on structural magnetic resonance imaging, MRI). Structural MRI studies report an increased brain age gap (biological age > chronological age) in schizophrenia, with a greater brain age gap related to greater negative symptom severity. Less is known regarding the nature of this gap early in schizophrenia (ESZ), if this gap represents a psychosis conversion biomarker in clinical high-risk (CHR-P) individuals, and how altered brain development and/or aging map onto specific symptom facets.

Study design: Using structural MRI, we compared the brain age gap among CHR-P (n = 51), ESZ (n = 78), and unaffected comparison participants (UCP; n = 90), and examined associations with CHR-P psychosis conversion (CHR-P converters n = 10; CHR-P non-converters; n = 23) and positive and negative symptoms.

Study results: ESZ showed a greater brain age gap relative to UCP and CHR-P (Ps < .010). CHR-P individuals who converted to psychosis showed a greater brain age gap (P = .043) relative to CHR-P non-converters. A larger brain age gap in ESZ was associated with increased experiential (P = .008), but not expressive negative symptom severity.

Conclusions: Consistent with schizophrenia pathophysiological models positing abnormal brain maturation, results suggest abnormal brain development is present early in psychosis. An increased brain age gap may be especially relevant to motivational and functional deficits in schizophrenia.