The genetic determinants of language network dysconnectivity in drug-naïve early stage schizophrenia

Schizophrenia, a debilitating neuropsychiatric disorder, is characterized by synaptic and brain network dysconnectivity. While the progressive nature of brain changes in schizophrenia is well-documented, many patients recover after the first psychotic episode, suggesting that early stages are crucial for determining long-term trajectory. Studying drug-naïve first-episode schizophrenia (FES) patients is essential to understand the origins and mechanisms of the illness, minimizing confounding effects of treatment. Functional dysconnectivity patterns are known to change with illness progression and treatment, implying that early-stage dysconnectivity is more closely tied to genetic factors. Language dysfunction is a core feature of schizophrenia, but the role of language-related genetic markers in early-stage dysconnectivity remains unknown. This study aimed to investigate progressive functional connectivity changes in FES patients with varying illness durations and to determine whether variations in dysconnectivity are linked to genetic mutations in language-readiness genes. The researchers hypothesized that genetic determinants would play a more significant role in the dysconnectivity patterns observed in the early stages of the illness.

The introduction provides a review of the literature supporting the importance of studying early-stage schizophrenia, the impact of treatment on brain connectivity, and the link between schizophrenia and language dysfunction. The researchers cite studies demonstrating the progressive nature of brain changes in schizophrenia, as well as studies showing that some patients recover after a first episode. The significant role of familial history as a risk factor is also mentioned. Several studies highlighting the importance of studying drug-naïve FES patients and the prognostic value of early-stage dysconnectivity are referenced. Prior research indicating a close relationship between schizophrenia and language dysfunction, as suggested by Crow's hypothesis, is also reviewed, highlighting the gap in knowledge regarding language-related genetic markers in early-stage dysconnectivity.

This study used two independent datasets of drug-naïve FES patients and healthy controls. The primary dataset consisted of 138 patients and 112 controls, while the validation dataset included 53 patients and 56 controls. Resting-state fMRI and whole-exome sequencing data were collected. Voxel-level whole-brain functional connectivity analysis was performed to identify altered functional connectivity clusters in FES patients compared to healthy controls. A cluster-based brain-wide association study (BWAS) method was used, employing a general linear model to compare functional connectivity between groups, controlling for age, gender, education level, and mean framewise displacement. A cluster-defining threshold (CDT) was applied, and cluster-level inference was used to correct for multiple comparisons. The analysis included an examination of correlations between altered functional connectivity clusters and PANSS scores (positive and negative symptom scales), also controlling for age, gender, and education level. To study the impact of illness duration, FES patients were divided into short-duration and long-duration groups based on the median illness duration. The analysis was repeated for each subgroup. Genetic association analysis was conducted using pathway-specific polygenic risk scores obtained from a gene cluster involving FOXP2, implicated in language and schizophrenia. The correlation between polygenic risk scores and altered functional connectivity clusters was assessed separately for short-duration and long-duration groups.

The study found that increased resting-state functional connectivity involving the thalamus and Broca's area was a predominant aberration in FES patients. These findings were replicated across two independent datasets. Specifically, 33 significantly altered functional connectivity clusters were identified in the primary dataset, many involving the thalamus, temporal cortex, inferior frontal cortex, and precuneus. Sixteen of these clusters were replicated in the validation dataset. The connectivity between the thalamus and superior/middle temporal gyrus, and between the left inferior frontal gyrus (Broca's area) and the right anterior cingulate cortex, showed significant correlations with PANSS negative scores. Further analysis linked Broca's area-anterior cingulate cortex dysconnectivity to negative symptoms, especially in patients with shorter illness durations. In contrast, thalamic dysconnectivity was more prevalent in patients with longer illness durations. Polygenic risk scores from FOXP2-related genes showed a strong association with functional dysconnectivity in the short-duration group, indicating a role of language-related genes in the early stages of the illness. This association was not significant in the long-duration group. The study also found that the degree of anterior cingulate cortex dysconnectivity with language-related areas correlated with the severity of core negative symptoms.

This study provides strong evidence for the critical role of language network dysconnectivity, particularly involving Broca's area, in the early stages of schizophrenia. The findings support Crow's hypothesis of schizophrenia as a consequence of the evolutionary pressures of language. The results suggest that Broca's area might be the origin of functional connectivity changes in schizophrenia, with subsequent changes involving the thalamus and temporal cortex as the illness progresses. The observed association between FOXP2-related genes and dysconnectivity in early stages of the illness provides direct neuroimaging and genetic evidence supporting this hypothesis. The study also highlights the importance of considering illness duration in imaging genetics studies of psychosis, as genetic factors may have a stronger impact in the early stages before compensatory brain changes occur. Future research is needed to investigate how linguistic interventions might influence these pathophysiological processes.

This study provides compelling evidence for the critical role of language network dysconnectivity, specifically involving Broca's area, in the early stages of schizophrenia. Genetic factors, particularly those related to language, seem to significantly influence these early dysconnectivity patterns. These findings support the "linguistic primacy hypothesis" of schizophrenia and highlight the potential for linguistic interventions in early-stage treatment. Further longitudinal studies are warranted to clarify the temporal dynamics of these connections and their relationship with symptoms.

The study is limited by the lack of symptom scores or task parameters specifically related to linguistic deficits, making it impossible to directly assess how language network dysconnectivity influences core features of schizophrenia, such as conceptual disorganization. The findings should not be generalized to verbal performance and abilities, as these were not explicitly evaluated. The study population was specifically Mandarin-speaking Han Chinese individuals from the Shanghai metropolitan area, limiting the generalizability of findings to other populations.