Widespread cortical thinning, excessive glutamate and impaired linguistic functioning in schizophrenia: A cluster analytic approach

Abstract

IntroductionSymptoms of schizophrenia are closely related to aberrant language comprehension and production. Macroscopic brain changes seen in some patients with schizophrenia are suspected to relate to impaired language production, but this is yet to be reliably characterized. Since heterogeneity in language dysfunctions, as well as brain structure, is suspected in schizophrenia, we aimed to first seek patient subgroups with different neurobiological signatures and then quantify linguistic indices that capture the symptoms of “negative formal thought disorder” (i.e., fluency, cohesion, and complexity of language production).MethodsAtlas-based cortical thickness values (obtained with a 7T MRI scanner) of 66 patients with first-episode psychosis and 36 healthy controls were analyzed with hierarchical clustering algorithms to produce neuroanatomical subtypes. We then examined the generated subtypes and investigated the quantitative differences in MRS-based glutamate levels [in the dorsal anterior cingulate cortex (dACC)] as well as in three aspects of language production features: fluency, syntactic complexity, and lexical cohesion.ResultsTwo neuroanatomical subtypes among patients were observed, one with near-normal cortical thickness patterns while the other with widespread cortical thinning. Compared to the subgroup of patients with relatively normal cortical thickness patterns, the subgroup with widespread cortical thinning was older, with higher glutamate concentration in dACC and produced speech with reduced mean length of T-units (complexity) and lower repeats of content words (lexical cohesion), despite being equally fluent (number of words).ConclusionWe characterized a patient subgroup with thinner cortex in first-episode psychosis. This subgroup, identifiable through macroscopic changes, is also distinguishable in terms of neurochemistry (frontal glutamate) and language behavior (complexity and cohesion of speech). This study supports the hypothesis that glutamate-mediated cortical thinning may contribute to a phenotype that is detectable using the tools of computational linguistics in schizophrenia.

Glutamatergic basis of antipsychotic response in first-episode psychosis: a dual voxel study of the anterior cingulate cortex

“…More recent work in treatmentresistant subjects indicate that ACC glutamate could in uence subcortical substrates of reward learning, thus providing further mechanistic link to negative symptoms [40]. This is also consistent with several other observations based on genetic [41] and structural imaging data [42] linking glutamate aberrations to the broader construct of negative symptoms.…”

Language abnormalities in schizophrenia: binding core symptoms through contemporary empirical evidence

“…Moreover, ketamine, when administered to patients with prior experience of psychosis, results in the reemergence of AVHs and FTD features in particular 149 . More direct examinations of the glutamate dynamics and FTD in patients are needed 150 , since pharmaco-fMRI studies in healthy participants only provide indirect evidence of the involvement of glutamate in the occurrence of FTD.…”

Dissociation between neuroanatomical and symptomatic subtypes in schizophrenia

“…We also found that the CPZ equivalent of neuroanatomical subtype 2 (widespread GMV loss) was higher than that of neuroanatomical subtype 1 (focal GMV increase). Previous in vivo and ex vivo MRI and postmortem histological studies suggested that exposure to antipsychotic treatment causes significantly reduced whole brain volume, especially gray matter [ 51 – 53 ]. Thus, antipsychotic drugs could partially explain the wider brain atrophy in neuroanatomical subtype-2 chronic patients [ 54 ].…”