The interaction between early life complications and a polygenic risk score for schizophrenia is associated with brain activity during emotion processing in healthy participants.

BACKGROUND: Previous evidence suggests that early life complications (ELCs) interact with polygenic risk for schizophrenia (SCZ) in increasing risk for the disease. However, no studies have investigated this interaction on neurobiological phenotypes. Among those, anomalous emotion-related brain activity has been reported in SCZ, even if evidence of its link with SCZ-related genetic risk is not solid. Indeed, it is possible this relationship is influenced by non-genetic risk factors. Thus, this study investigated the interaction between SCZ-related polygenic risk and ELCs on emotion-related brain activity. METHODS: 169 healthy participants (HP) in a discovery and 113 HP in a replication sample underwent functional magnetic resonance imaging (fMRI) during emotion processing, were categorized for history of ELCs and genome-wide genotyped. Polygenic risk scores (PRSs) were computed using SCZ-associated variants considering the most recent genome-wide association study. Furthermore, 75 patients with SCZ also underwent fMRI during emotion processing to verify consistency of their brain activity patterns with those associated with risk factors for SCZ in HP. RESULTS: Results in the discovery and replication samples indicated no effect of PRSs, but an interaction between PRS and ELCs in left ventrolateral prefrontal cortex (VLPFC), where the greater the activity, the greater PRS only in presence of ELCs. Moreover, SCZ had greater VLPFC response than HP. CONCLUSIONS: These results suggest that emotion-related VLPFC response lies in the path from genetic and non-genetic risk factors to the clinical presentation of SCZ, and may implicate an updated concept of intermediate phenotype considering early non-genetic factors of risk for SCZ.

Effect of anticholinergic burden on brain activity during Working Memory and real-world functioning in patients with schizophrenia.

Cognitive impairment has been associated with poor real-world functioning in patients with Schizophrenia. Previous studies have shown that pharmacological treatment with anticholinergic properties may contribute to cognitive impairment in Schizophrenia. We investigated the effect of the anticholinergic burden (ACB) on brain activity, cognition, and real-world functioning in Schizophrenia. We hypothesized that greater ACB would be associated with altered brain activity along with poorer cognitive performance and lower real-world functioning. A sample of 100 patients with a diagnosis of schizophrenia or schizoaffective disorder was recruited in the naturalistic multicenter study of the Italian Network for Research on Psychoses (NIRP) across 7 centres. For each participant, ACB was evaluated using the Anticholinergic Cognitive Burden scale. The association of ACB with brain function was assessed using BOLD fMRI during the N-Back Working Memory (WM) task in a nested cohort (N = 31). Real-world functioning was assessed using the Specific Level of Functioning (SLOF) scale. Patients with high ACB scores (≥3) showed lower brain activity in the WM frontoparietal network (TFCE corrected alpha <0.05) and poorer cognitive performance (p = 0.05) than patients with low ACB scores (<3). Both effects were unaffected by demographic characteristics, clinical severity, and antipsychotic dosage. Moreover, patients with high ACB showed poorer real-world functioning than patients with lower ACB (p = 0.03). Our results suggest that ACB in Schizophrenia is associated with impaired WM and abnormal underlying brain function along with reduced real-world functioning. Clinical practice should consider the potential adverse cognitive effects of ACB in the treatment decision-making process.