Reactive Astrocytes and Network Functional Connectivity Underlying Cognitive Symptoms in Schizophrenia: A Positron...

Cognitive symptoms are among the core features of schizophrenia, but their underlying mechanisms remain unclear. Current hypotheses suggest that alterations in the frontal cortex cause network dysfunction, thereby contributing to cognitive symptoms. Growing evidence links reactive astrocytes with cognitive function and the pathophysiology of schizophrenia. We aimed to investigate in vivo reactive astrocyte signals in the dysconnected networks underlying cognitive symptoms in patients with schizophrenia.

[¹⁸F]THK5351 positron emission tomography (PET) and resting-state functional magnetic resonance imaging data were obtained from 32 patients with schizophrenia and 32 age- and sex-matched healthy control participants. [¹⁸F]THK5351 PET was used to measure monoamine oxidase B, a marker of reactive astrocytes. We performed network analysis to identify dysconnected subnetworks related to cognitive symptoms and examined reactive astrocyte signals in these subnetwork regions.

Patients showed impaired verbal learning (F_1,61 = 18.97, p < .001) and memory (F_1,61 = 24.31, p < .001). In patients, reduced left medial orbitofrontal cortex (mOFC)-left dorsolateral prefrontal cortex and left mOFC-right dorsal anterior cingulate cortex connectivity predicted impaired verbal learning (β = 0.45, p = .011) and memory (β = 0.56, p = .001), respectively. The PET standardized uptake value ratio was greater in the left mOFC in patients than in controls (t₆₂ = -2.61, p = .011).

We found evidence of increased reactive astrocyte activity in the key region of the dysconnected network underlying cognitive impairments in schizophrenia. These results suggest a potential link between reactive astrocytes in the mOFC and the pathophysiology underlying cognitive symptoms in schizophrenia.