Prefronto‐thalamic hypoconnectivity in schizophrenia: Monkey to human translation of critical pathways for symptom‐related functions

Aim Recent advances in genetic neuromodulation technology have enabled circuit‐specific interventions in nonhuman primates (NHPs), thereby revealing the causal functions of specific neural circuits. Using this technology, we recently identified in NHPs the causal roles of the dorsolateral prefrontal cortex (DLPFC) to the lateral part of the mediodorsal thalamic nucleus (MDl) pathway in working memory, a core deficit in schizophrenia (SCZ) patients. Here, we aimed to examine if this alteration was translational to the human patients with SCZ. Methods Using the publicly available, multisite, multi‐disorder magnetic resonance imaging (MRI) dataset, we evaluated the resting‐state functional connectivity in this DLPFC–MDl pathway and examined whether the alteration was, if any, specific to SCZ ( N = 91) and not to healthy controls (HCs, N = 511), patients with major depressive disorder (MDD, N = 133), and autism spectrum disorders (ASDs, N = 120). Results We found that the DLPFC–MDl connectivity was significantly reduced in the SCZ group compared to HCs, whereas no such hypoconnectivity was observed in the ASD or MDD groups, suggesting a disease‐dependent profile of altered connectivity at rest. This hypoconnectivity was not observed between the DLPFC and other neighboring thalamic nuclei, suggesting a focal thalamic anomaly underlying the altered connectivity in SCZ. Conclusion These results support the potential of translating pathway‐specific causal insights from NHP studies to identify disease‐specific connectivity alterations in neuropsychiatric disorders with related symptoms in humans.