Disrupted pathways from limbic areas to thalamus in schizophrenia highlighted by whole-brain resting-state effective connectivity analysis.

BACKGROUND: Numerous neuroimaging studies have revealed that schizophrenia was characterized by wide-spread dysconnection among brain regions during rest measured by functional connectivity (FC). In contrast with FC, effective connectivity (EC) provides information about directionality of brain connections and is thus valuable in mechanistic investigation of schizophrenic brain. However, a systematic characterization of whole-brain resting-state EC (rsEC) and how it captures different information compared with resting-state FC (rsFC) in schizophrenia are still lacking. AIMS: To systematically characterize the abnormalities of rsEC, compared with rsFC, in schizophrenia, and to test its discriminative power as a neuroimaging marker for schizophrenia diagnosis. METHOD: Whole-brain rsEC and rsFC networks were constructed using resting-state fMRI data and compared between 103 patients with schizophrenia and 110 healthy participants. Pattern classifications between patients and controls based on whole-brain rsEC and rsFC were further performed using multivariate pattern analysis. RESULTS: We identified 17 rsEC significantly disrupted (mostly decreased) in patients, among which all were associated with the thalamus and 15 were from limbic areas (including hippocampus, parahippocampus and cingulate cortex) to the thalamus. In contrast, abnormal rsFC were widely distributed in the whole brain. The classification accuracies for distinguishing patients and controls using whole-brain rsEC and rsFC patterns were 78.6% and 82.7%, respectively, and was further improved to 84.5% when combining rsEC and rsFC. CONCLUSIONS: Schizophrenia is featured by disrupted 'limbic areas-to-thalamus' rsEC, in contrast with diffusively altered rsFC. Moreover, both rsEC and rsFC contain valuable and complementary information which may be used as diagnostic markers for schizophrenia.

Macrophage migration inhibitory factor mediates metabolic dysfunction induced by atypical antipsychotic therapy.

Atypical antipsychotics are highly effective antischizophrenic medications but their clinical utility is limited by adverse metabolic sequelae. We investigated whether upregulation of macrophage migration inhibitory factor (MIF) underlies the insulin resistance that develops during treatment with the most commonly prescribed atypical antipsychotic, olanzapine. Olanzapine monotherapy increased BMI and circulating insulin, triglyceride, and MIF concentrations in drug-naive schizophrenic patients with normal MIF expression, but not in genotypic low MIF expressers. Olanzapine administration to mice increased their food intake and hypothalamic MIF expression, which led to activation of the appetite-related AMP-activated protein kinase and Agouti-related protein pathway. Olanzapine also upregulated MIF expression in adipose tissue, which reduced lipolysis and increased lipogenic pathways. Increased plasma lipid concentrations were associated with abnormal fat deposition in liver and skeletal muscle, which are important determinants of insulin resistance. Global MIF-gene deletion protected mice from olanzapine-induced insulin resistance, as did intracerebroventricular injection of neutralizing anti-MIF antibody, supporting the role of increased hypothalamic MIF expression in metabolic dysfunction. These findings uphold the potential pharmacogenomic value of MIF genotype determination and suggest that MIF may be a tractable target for reducing the metabolic side effects of atypical antipsychotic therapy.