Effects of polygenic risk of schizophrenia on interhemispheric callosal white matter integrity and frontotemporal functional connectivity in first-episode schizophrenia

Background Schizophrenia is a severely debilitating psychiatric disorder with high heritability and polygenic architecture. A higher polygenic risk score for schizophrenia (SzPRS) has been associated with smaller gray matter volume, lower activation, and decreased functional connectivity (FC). However, the effect of polygenic inheritance on the brain white matter microstructure has only been sparsely reported. Methods Eighty-four patients with first-episode schizophrenia (FES) patients and ninety-three healthy controls (HC) with genetics, diffusion tensor imaging (DTI), and resting-state functional magnetic resonance imaging (rs-fMRI) data were included in our study. We investigated impaired white matter integrity as measured by fractional anisotropy (FA) in the FES group, further examined the effect of SzPRS on white matter FA and FC in the regions connected by SzPRS-related white matter tracts. Results Decreased FA was observed in FES in many commonly identified regions. Among these regions, we observed that in the FES group, but not the HC group, SzPRS was negatively associated with the mean FA in the genu and body of corpus callosum, right anterior corona radiata, and right superior corona radiata. Higher SzPRS was also associated with lower FCs between the left inferior frontal gyrus (IFG)–left inferior temporal gyrus (ITG), right IFG–left ITG, right IFG–left middle frontal gyrus (MFG), and right IFG–right MFG in the FES group. Conclusion Higher polygenic risks are linked with disrupted white matter integrity and FC in patients with schizophrenia. These correlations are strongly driven by the interhemispheric callosal fibers and the connections between frontotemporal regions.

A Diffusion Tensor Imaging Study on the Phonology-related Pathways in Cantonese-mandarin Bilinguals.

Cantonese and Mandarin are logographic languages, and the phonology is the main difference between the two languages. It is unclear whether long-term experience of Cantonese-Mandarin bilingualism will shape different brain white matter structures of pathways related to phonological processing. 30 Cantonese-Mandarin bilinguals and 30 Mandarin monolinguals completed diffusion-weighted imaging (DWI) scans and phonological processing tasks. The tractography and TBSS were used to investigate the structural differences in the bilateral superior longitudinal fasciculus (SLF), inferior longitudinal fasciculus (ILF) and inferior fronto-occipital fasciculus (IFOF) between Cantonese-Mandarin bilinguals and Mandarin monolinguals. Post-hoc correlation analysis was conducted to investigate the relationship between the different structures with phonological processing skills. Compared to the Mandarin monolinguals, the Cantonese-Mandarin bilinguals had higher fractional anisotropy (FA) along the left ILF, higher mean diffusivity (MD) in the clusters along the temporoparietal segment of SLF (tSLF), as well as higher axial diffusivity (AD) in the right tSLF, IFOF, bilateral ILF. The mean AD of the different voxels in the right IFOF and the mean FA of the different voxels in the left ILF were positively correlated with the inverse efficiency score (IES) of the Cantonese auditory and Mandarin visual rhyming judgment tasks respectively within the bilingual group. Long-term experience of Cantonese-Mandarin bilinguals shape different brain white matter structures including right tSLF, IFOF, bilateral ILF. The bilinguals’ white matter showed higher diffusivity, especially in the axonal direction, than the monolinguals. These changes were related to bilinguals’ phonological processing.

SYT1 Gene-Wide Analysis on White Matter Microstructure in Adulthood ADHD

The Synaptotagmin-1 encoding gene (SYT1) is a key regulator of neurotransmitter release and is associated with cognitive and psychiatric phenotypes in GWAS, and with ADHD in single-gene studies, raising the need for dissecting possible cross-trait effects on clinical and brain phenotypes. Inferences about white matter microstructure can be made by diffusion-tensor imaging (DTI), which makes this method a promising tool in the understanding of biological changes that underpin cognitive functions and brain disorders. Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that affects multiple functioning domains, highly overlapping with other psychiatric disorders, and known to involve white matter abnormalities and neurotransmission dysfunction. Using a set-based analysis, the present study investigates how genetic variants within SYT1 might affect brain white matter at a cellular level using DTI in adults with ADHD (n = 85). The combined effect of all measured variations in the gene (i.e., 468 variants) was evaluated concerning specific white matter tracts. Set-based analysis was performed in PLINK software and followed by in silico analysis of all variants included in the study. SYT1 gene was nominally associated with white matter changes in two important tracts: forceps major and inferior fronto-occipital fasciculus. In addition, two regions within the SYT1 have more consistent associations with different white matter tracts. These findings endorse the involvement of SYT1 on psychiatric phenotypes and suggest that white matter tracts underlie this complex relationship.

An intrinsic endothelial dysfunction causes cerebral small vessel disease

Small Vessel Disease (SVD) is the leading cause of vascular dementia, causes a quarter of strokes, and worsens stroke outcomes(1, 2). The disease is characterised by cerebral small vessel and white matter pathology, but the underlying mechanisms are poorly understood. Classically, the microvascular and tissue damage has been considered secondary to extrinsic factors, such as hypertension, consisting of microvessel stiffening, impaired vasoreactivity and blood-brain barrier dysfunction identified in human sporadic SVDs. However, increasing evidence points to an underlying vulnerability to SVD-related brain damage, not just extrinsic factors. Here, in a novel normotensive transgenic rat model where the phospholipase flippase Atp11b is deleted, we show pathological, imaging and behavioural changes typical of those in human sporadic SVD, but that occur without hypertension. These changes are due to an intrinsic endothelial cell dysfunction, identified in vessels of the brain white matter and the retina, with pathological evidence of vasoreactivity and blood-brain barrier deficits, which precipitate a secondary maturation block in oligodendroglia and myelin disruption around the small vessels. This highlights that an intrinsic endothelial dysfunction may underlie vulnerability to human sporadic SVD, providing alternative therapeutic targets to prevent a major cause of stroke and dementia.

DNA Methylation Basis in the Effect of White Matter Integrity Deficits on Cognitive Impairments and Psychopathological Symptoms in Drug-Naive First-Episode Schizophrenia

Background: Mounting evidence from diffusion tensor imaging (DTI) and epigenetic studies, respectively, confirmed the abnormal alterations of brain white matter integrity and DNA methylation (DNAm) in schizophrenia. However, few studies have been carried out in the same sample to simultaneously explore the WM pathology relating to clinical behaviors, as well as the DNA methylation basis underlying the WM deficits.Methods: We performed DTI scans in 42 treatment-naïve first-episode schizophrenia patients and 38 healthy controls. Voxel-based method of fractional anisotropy (FA) derived from DTI was used to assess WM integrity. Participants' peripheral blood genomic DNAm status, quantified by using Infinium® Human Methylation 450K BeadChip, was examined in parallel with DTI scanning. Participants completed Digit Span test and Trail Making test, as well as Positive and Negative Syndrome Scale measurement. We acquired genes that are differentially expressed in the brain regions with abnormal FA values according to the Allen anatomically comprehensive atlas, obtained DNAm levels of the corresponding genes, and then performed Z-test to compare the differential epigenetic-imaging associations (DEIAs) between the two groups.Results: Significant decreases of FA values in the patient group were in the right middle temporal lobe WM, right cuneus WM, right anterior cingulate WM, and right inferior parietal lobe WM, while the significant increases were in the bilateral middle cingulate WM (Ps < 0.01, GRF correction). Abnormal FA values were correlated with patients' clinical symptoms and cognitive impairments. In the DEIAs, patients showed abnormal couple patterns between altered FA and DNAm components, for which the enriched biological processes and pathways could be largely grouped into three biological procedures: the neurocognition, immune, and nervous system.Conclusion: Schizophrenia may not cause widespread neuropathological changes, but subtle alterations affecting local cingulum WM, which may play a critical role in positive symptoms and cognitive impairments. This imaging-epigenetics study revealed for the first time that DNAm of genes enriched in neuronal, immunologic, and cognitive processes may serve as the basis in the effect of WM deficits on clinical behaviors in schizophrenia.

Transcriptomic and macroscopic architectures of intersubject functional variability in human brain white-matter

Intersubject variability is a fundamental characteristic of brain organizations, and not just “noise”. Although intrinsic functional connectivity (FC) is unique to each individual and varies across brain gray-matter, the underlying mechanisms of intersubject functional variability in white-matter (WM) remain unknown. This study identified WMFC variabilities and determined the genetic basis and macroscale imaging in 45 healthy subjects. The functional localization pattern of intersubject variability across WM is heterogeneous, with most variability observed in the heteromodal cortex. The variabilities of heteromodal regions in expression profiles of genes are related to neuronal cells, involved in synapse-related and glutamic pathways, and associated with psychiatric disorders. In contrast, genes overexpressed in unimodal regions are mostly expressed in glial cells and were related to neurological diseases. Macroscopic variability recapitulates the functional and structural specializations and behavioral phenotypes. Together, our results provide clues to intersubject variabilities of the WMFC with convergent transcriptomic and cellular signatures, which relate to macroscale brain specialization.