Introduction Illuminating neurobiological mechanisms underlying the protective effect of recently discovered common genetic resilience variants for schizophrenia is crucial for more effective prevention efforts. Current models implicate adaptive neuroplastic changes in the visual system and their pro-cognitive effects as a schizophrenia resilience mechanism. We investigated whether common genetic resilience variants might affect brain structure in similar neural circuits. Method Using structural magnetic resonance imaging, we measured the impact of an established schizophrenia polygenic resilience score (PRSResilience) on cortical volume, thickness, and surface area in 101 healthy subjects and in a replication sample of 33 224 healthy subjects (UK Biobank). Finding We observed a significant positive whole-brain correlation between PRSResilience and cortical volume in the right fusiform gyrus (FFG) (r = 0.35; P = .0004). Post-hoc analyses in this cluster revealed an impact of PRSResilience on cortical surface area. The replication sample showed a positive correlation between PRSResilience and global cortical volume and surface area in the left FFG. Conclusion Our findings represent the first evidence of a neurobiological correlate of a genetic resilience factor for schizophrenia. They support the view that schizophrenia resilience emerges from strengthening neural circuits in the ventral visual pathway and an increased capacity for the disambiguation of social and nonsocial visual information. This may aid psychosocial functioning, ameliorate the detrimental effects of subtle perceptual and cognitive disturbances in at-risk individuals, and facilitate coping with the cognitive and psychosocial consequences of stressors. Our results thus provide a novel link between visual cognition, the vulnerability-stress concept, and schizophrenia resilience models.

Abstract Background N-methyl-D-aspartate receptor (NMDAR) hypofunction is an important pathophysiological mechanism in schizophrenia. At the postsynapse the NMDAR interacts with the post-synaptic density (PSD). Neuronal nitric oxide synthase 1 (NOS1) binds to the PSD scaffolding proteins PSD-93 and PSD-95, enabling NMDAR-mediated release of nitric oxide via NOS1. NOS1AP (adaptor of NOS1) is capable of disrupting the interactions between NOS1, PSD-93, and PSD95. Therefore, NOS1AP is closely involved in both glutamatergic and nitrinergic neurotransmission. NOS1AP has been implicated as a risk gene for schizophrenia and cognitive dysfunction. Its increased expression has been observed in dorsolateral prefrontal post-mortem brain tissue of patients with schizophrenia, and NOS1AP SNPs have been associated with established schizophrenia endophenotypes. These findings suggest that the influence of NOS1AP variants should be observable in neural systems implicated in schizophrenia. In the present study, we investigate the impact of NOS1AP and its interaction partners at the glutamatergic synapse on the cortical working memory (WM) networks using fMRI and a gene set analysis approach. Methods 97 right-handed individuals with no personal or family history of psychiatric disorders underwent fMRI in a 3T Siemens Trio scanner during the performance of a visuospatial change detection WM task. Data analysis in Brain Voyager QX 2.8 included standard data preprocessing. Additionally, a multiscale curvature driven cortex based alignment procedure was used to minimize macro-anatomical variability between subjects. Subsequently, data were analyzed using a random-effects multi-subject general linear model. We investigated 19 regions of interest (ROIs) within the core fronto-parietal WM network. We studied all phases of our WM paradigm (encoding, maintenance, retrieval), which were modeled by a total of 5 regressors (encoding, delays 1–3, retrieval). Genetic data was quality controlled and imputed using the RICOPILI pipeline. Gene-set analyses of the 19 ROIs were performed using MAGMA. Two gene sets were selected: 1) NOS1AP/NOS1; 2) NOS1AP/glutamatergic synapse. We applied a Bonferroni correction for the total of 19 ROIs and 5 regressors (95 tests) to both analyses. Results Both gene set analyses revealed multiple associations between brain activation in core fronto-parietal WM areas. For the NOS1/NOS1AP set, most associations were observed during the late maintenance phase (Delay 3) of our WM paradigm. One association was significant Bonferroni correction: a cluster in the left intraparietal sulcus during the late maintenance phase (Delay 3; β=2.2459, SD=0.0239, SE=0.6451, p=0,00025). For NOS1AP / glutamatergic synapse interaction partners, two associations were significant after Bonferroni correction: a cluster in the right IPS during the early maintenance phase (Delay 1; β=0.8525, SD=0.0257, SE=0.2127, p=0.0000308) and a cluster in a different part of the right IPS during the late maintenance phase (Delay 3; β=0.7186, SD=0.0216, SE=0.2119, p=0,000348). Discussion In our gene set analyses we observed multiple associations between brain activation during WM and NOS1AP and its interaction partners, which were most pronounced during the late maintenance phase of our WM task in bilateral areas within the IPS. Both the more constrained NOS1AP / NOS1 gene set and the NOS1AP / glutamatergic synapse gene set showed similar association patterns. Our results implicate the NOS1AP interactome and the glutamatergic system in information processing and brain function in a cognitive domain strongly impaired in schizophrenia. They also indicate that altered activation of parietal WM areas during the maintenance phase is most strongly affected.

Working memory and attention are fundamental and closely linked cognitive domains. This close link is exemplified by the crucial role of selective attention for the selection of information to be encoded into working memory. Patients with schizophrenia are markedly impaired in many aspects of both domains. However, the interplay between these cognitive deficits on both the cognitive and neurophysiological level remains poorly understood. Based on our previous findings regarding the central role of impaired working memory encoding to working memory dysfunction in schizophrenia, we hypothesize, that impaired attentional processes contribute to working memory dysfunction specifically during the encoding stage. This hypothesis was tested in both a behavioral experiment and in an fMRI imaging genetics study. For the behavioral study, we investigated 35 patients with schizophrenia and 35 matched healthy controls. In a change detection task, participants were simultaneously presented with both highly salient and non-salient spatial information. They were instructed to encode either the highly salient or the non-salient information. In half of the conditions, they were aided by a cue pointing them towards the relevant information. Our goal was to test, whether patients with schizophrenia were biased toward a particular type of information and whether a top-down cue would influence such a bias. In the imaging genetics study, we investigated 100 right-handed individuals without personal or family history of psychiatric disorders, who performed a visuospatial change detection task. The fMRI data were preprocessed and analyzed using Brain Voyager QX 20. For genotyping we used a custom Illumina HumanCoreExome-24 BeadChip array. We calculated polygenic scores (PGS) for schizophrenia based on 108 loci associated with schizophrenia in a recent mega-analysis of the Psychiatric Genetic Consortium (PGC2). We computed whole brain correlations between BOLD activation and PGS to elucidate the relationship between genetic risk for schizophrenia and abnormal brain function. In the behavioral study, patients were significantly more impaired when required to encode non-salient compared to salient information. However, this impairment was specific to conditions without a top-down cue. This demonstrates, that patients could use top-down attention to overcome a bottom-up bias towards highly salient information during working memory encoding. In the fMRI data, we observed a significant negative correlation between BOLD activation in the right temporo-parietal junction (TPJ) during working memory encoding and PGS for schizophrenia. Across all subjects, this area showed robust deactivation during encoding. The TPJ is a crucial region of the ventral attention network and is closely involved in bottom-up attentional processes. Previous fMRI studies observed stronger deactivation of the TPJ during working memory encoding with increasing cognitive demand. Therefore, our results indicate that participants with a higher genetic risk for schizophrenia had to commit more cognitive resources by downregulating their ventral attention network. Taken together, the results of both studies point toward specific disturbance of bottom-up attention during working memory encoding, which might be linked to genetic risk for schizophrenia. Conversely, top-down attention appears to be relatively spared. These findings provide new constraints for cognitive and neurophysiological models of impaired working memory encoding in schizophrenia.

Background: Schizophrenia is a complex genetic disorder, whose genetic architecture remains poorly understood. Recent genome-wide association studies (GWAS) have provided evidence for a growing number of common genetic risk variants. In the current imaging genetics study we aimed to investigate the correlation between brain activation during a visual working memory task and genetic risk for schizophrenia. Methods: 98 right-handed individuals without personal or family history of psychiatric disorders underwent fMRI during the performance of a visuospatial change detection task. During encoding, an array of 3 red rectangular bars, which varied in orientation, was presented for 33 ms. After a delay period, a second array was presented for 3000 ms (retrieval). This array was identical to the first array in 50% of trials. Data analysis in Brain Voyager QX 2.8 included standard data preprocessing. Additionally, a multiscale curvature driven cortex based alignment procedure was used to minimize macro-anatomical variability between subjects. Subsequently, functional data were analyzed using a random-effects multi-subject general linear model. Participants were genotyped using a custom Illumina HumanCoreExome-24 BeadChip array. Polygenic scores (PGS) for schizophrenia were calculated based on Psychiatric Genetic Consortium data (PGC2). Results: We observed a significant negative correlation between BOLD activation in the right temporo-parietal junction (TPJ)—part of the ventral attention network—and PGS for schizophrenia during the encoding phase. During the delay phase, we observed a significant positive correlation between BOLD activation in the left superior parietal lobule and PGS for schizophrenia. Conclusion: Previous studies reported stronger deactivation of the TPJ during working memory encoding with increasing cognitive demand. Therefore, our results might indicate that participants with a higher genetic risk for schizophrenia had to commit more cognitive resources during working memory encoding. This finding is also in line with growing evidence for disturbances of working memory encoding in schizophrenia.