Abstract
Schizophrenia is a neurocognitive illness of synaptic and brain network-level dysconnectivity that often reaches a persistent chronic stage in many patients. Subtle language deficits are a core feature even in the early stages of schizophrenia. However, the primacy of language network dysconnectivity and language-related genetic variants in the observed phenotype in early stages of illness remains unclear. This study used two independent schizophrenia dataset consisting of 138 and 53 drug-naïve first-episode schizophrenia (FES) patients, and 112 and 56 healthy controls, respectively. A brain-wide voxel-level functional connectivity analysis was conducted to investigate functional dysconnectivity and its relationship with illness duration. We also explored the association between critical language-related genetic (such as FOXP2) mutations and the altered functional connectivity in patients. We found elevated functional connectivity involving Broca’s area, thalamus and temporal cortex that were replicated in two FES datasets. In particular, Broca’s area - anterior cingulate cortex dysconnectivity was more pronounced for patients with shorter illness duration, while thalamic dysconnectivity was predominant in those with longer illness duration. Polygenic risk scores obtained from FOXP2-related genes were strongly associated with functional dysconnectivity identified in patients with shorter illness duration. Our results highlight the criticality of language network dysconnectivity, involving the Broca’s area in early stages of schizophrenia, and the role of language-related genes in this aberration, providing both imaging and genetic evidence for the association between schizophrenia and the determinants of language.
Highlights
Schizophrenia is one of the most costly and disabling neuropsychiatric disorders
We found that FC clusters between thalamus and superior/middle functional connectivity abnormalities seen in our untreated temporal gyrus, and between left inferior frontal gyrus (i.e., Broca’s schizophrenia samples, we reanalyzed genetic area) and right anterior cingulate cortex were significantly association using SNPs from all 20 genes that are not filtered by correlated with positive and negative syndrome scale (PANSS) negative total score, see Table 1
In a large sample of drug-naïve first-episode schizophrenia (FES) patients with a broad range of illness duration (1 to 100 weeks), we report that increased restingstate functional connectivity involving thalamus and Broca’s area as the predominant aberration in functional connectivity
Summary
Schizophrenia is one of the most costly and disabling neuropsychiatric disorders. Despite the large number of neuroimaging studies investigating this illness, the origins and the mechanism of schizophrenia has remained largely elusive. While progressive nature of brain changes has been demonstrated in this illness[1,2,3], especially in patients with poor prognosis[4,5], a number of patients recover after the first psychotic episode, and cognitive functioning does not appear to deteriorate over time[6]. It has been suggested that prognostically critical abnormalities in functional connectivity are evident during the first two years of illness[8,9,10], highlighting the critical importance of studying patients with drug-naïve first-episode schizophrenia (FES). The brain regions critical for the variable prognostic trajectories are likely to be captured by studying the early stages of the illness[2,11,12]
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