Polygenic risk for schizophrenia and the language network: Putative compensatory reorganization in unaffected siblings

Chen, Xudong; Tan, Wenjian; Cheng, Yong; Huang, Dingming; Liu, Dayi; Zhang, Jiamei; Li, Jinyue; Liu, Zhening; Pan, Yunzhi; Palaniyappan, Lena

doi:10.1016/j.psychres.2023.115319

Cited by 1 publication

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“…Unlike the symptoms of reality distortion that are episodic and emerge later in the course, disorganized thinking is seen many years before the first psychotic episode in those at risk (by mid-childhood/adolescence (18), often in conjunction with impoverished mental activity (together called 'Bleulerian factor' by Dominguez et al (19) and the core of classical schizophrenia by Liddle et al (20)). The genetic diathesis to schizophrenia, reflected in the continuous polygenic risk scores of this illness, map on to the burden of disorganization symptoms more than any other symptom domain (including negative symptoms) (21). Several studies have found that the cognitive deficits that are pervasive and influential in determining overall outcomes of schizophrenia track the severity of disorganization more closely than other symptom domains (22)(23)(24)(25)(26).…”

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confidence: 99%

A multistage, dual voxel study of glutamate in the anterior cingulate cortex in schizophrenia supports a primary pyramidal dysfunction model of disorganization

Fan,

Zhang,

et al. 2023

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BackgroundSchizophrenia is an illness where glutamatergic dysfunction in the anterior cingulate cortex (ACC) has been long suspected; Recent in vivo evidence (Adams et al. 2022) has implicated pyramidal dysfunction (reduced glutamate tone) as the primary pathophysiology contributing to subtle features, with a secondary disinhibition effect (higher glutamate tone) resulting in the later emergence of prominent clinical symptoms. We investigate if genetic high risk (GHR) for schizophrenia reduces glutamatergic tone in ACC when compared to the states of clinical high risk (CHR) and first episode schizophrenia (FES) where symptoms are already prominent.MethodsWe recruited 302 individuals across multiple stages of psychosis (CHR, n=63; GHR, n=76; FES, n=96) and healthy controls (n=67) and obtained proton magnetic resonance spectroscopy of glutamate from perigenual ACC (pACC) and dorsal ACC (dACC) using 3-Tesla scanner.ResultsGHR had lower Glu compared to CHR while CHR had higher Glu compared to FES and HC. Higher disorganization burden, but not any other symptom domain, was predicted by lower levels of Glu in the GHR group (dACC and pACC) and in the CHR group (pACC only).ConclusionsThe reduction in glutamatergic tone in GHR supports the case for a pyramidal dysfunction contributing to higher disorganization, indicating disorganization to be the core domain in the pathophysiology of schizophrenia. Higher glutamate (likely due to disinhibition) is apparent when psychotic symptoms are raising to be prominent (CHR), though at the full-blown stage of psychosis, the relationship between glutamate and symptoms ceases to be a simple linear one.

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