Executive control of language in schizophrenia patients with history of auditory verbal hallucinations: A neuropsychological and resting-state fMRI study.

BACKGROUND: As demonstrated by a plethora of studies, compromised executive functions (EF) and language are implicated in mechanisms of auditory verbal hallucinations (AVH), but the contribution of their interaction to AVH remains unclear. We hypothesized that schizophrenia patients with history of AVH (AVHh+) vs. without history of AVH (AVHh-) have a specific deficit of executive control of language and alterations in functional connectivity (FC) between the brain regions involved in EF and language, and these neuropsychological and neurophysiological traits are associated with each other. METHODS: To explore the executive control of language and its contribution to AVH, we used an integrative approach involving analysis of neuropsychological and resting-state fMRI data of 34 AVHh+, 16 AVHh-, and 40 healthy controls. We identified the neuropsychological and FC measures that differentiated between AVHh+, AVHh-, and HC, and tested the associations between them. RESULTS: AVHh+ were characterized by decreased category and phonological verbal fluency, utterance length, productivity in the planning tasks, and poorer retelling. AVHh+ had decreased FC between the left inferior frontal gyrus and the anterior cingulate cortex. Productivity in category verbal fluency was associated with the FC between these regions. CONCLUSIONS: Poor executive control of word retrieval and deficient programming of sentence and narrative related to more general deficits of planning may be the neuropsychological traits specific for AVHh+. A neurophysiological trait specific for AVHh+ may be a decreased FC between regions involved in language production and differentiation between alien- vs. self-generated speech and between language production vs. comprehension.

De novo mutations identified by exome sequencing implicate rare missense variants in SLC6A1 in schizophrenia.

Schizophrenia is a highly polygenic disorder with important contributions from both common and rare risk alleles. We analyzed exome sequencing data for de novo variants (DNVs) in a new sample of 613 schizophrenia trios and combined this with published data to give a total of 3,444 trios. In this new data, loss-of-function (LoF) DNVs were significantly enriched among 3,471 LoF-intolerant genes, which supports previous findings. In the full dataset, genes associated with neurodevelopmental disorders (n = 159) were significantly enriched for LoF DNVs. Within these neurodevelopmental disorder genes, SLC6A1, which encodes a γ-aminobutyric acid transporter, was associated with missense-damaging DNVs. In 1,122 trios for which genome-wide common variant data were available, schizophrenia and bipolar disorder polygenic risk were significantly overtransmitted to probands. Probands carrying LoF or deletion DNVs in LoF-intolerant or neurodevelopmental disorder genes had significantly less overtransmission of schizophrenia polygenic risk than did non-carriers, which provides a second robust line of evidence that these DNVs increase liability to schizophrenia.