Abstract
The aim of the current resting-state functional magnetic resonance imaging (fMRI) study was to investigate the potential mechanism of schizophrenia through the posterior–anterior cerebrum imbalance in methylazoxymethanol acetate (MAM) rats and to evaluate the effectiveness of repetitive transcranial magnetic stimulation (rTMS) as an early-stage intervention. The rats were divided into four groups: the MAM-sham group, vehicle-sham group, MAM-rTMS group, and vehicle-rTMS group. The rTMS treatment was targeted in the visual cortex (VC) in adolescent rats. Granger Causality Analysis (GCA) was used to evaluate the effective connectivity between regions of interest. Results demonstrated a critical right VC–nucleus accumbens (Acb)–orbitofrontal cortex (OFC) pathway in MAM rats; significant differences of effective connectivity (EC) were found between MAM-sham and vehicle-sham groups (from Acb shell to OFC: t = −2.553, p = 0.021), MAM-rTMS and MAM-sham groups (from VC to Acb core: t = −2.206, p = 0.043; from Acb core to OFC: t = 4.861, p < 0.001; from Acb shell to OFC: t = 4.025, p = 0.001), and MAM-rTMS and vehicle-rTMS groups (from VC to Acb core: t = −2.482, p = 0.025; from VC to Acb shell: t = −2.872, p = 0.012; from Acb core to OFC: t = 4.066, p = 0.001; from Acb shell to OFC: t = 3.458, p = 0.004) in the right hemisphere. Results of the early-stage rTMS intervention revealed that right nucleus accumbens played the role as a central hub, and VC was a potentially novel rTMS target region during adolescent schizophrenia. Moreover, the EC of right nucleus accumbens shell and orbitofrontal cortex was demonstrated to be a potential biomarker. To our knowledge, this was the first resting-state fMRI study using GCA to assess the deficits of a visual-reward neural pathway and the effectiveness of rTMS treatment in MAM rats. More randomized controlled trials in both animal models and schizophrenia patients are needed to further elucidate the disease characteristics.
Highlights
The mechanisms of schizophrenia remain unclear, altered brain maturational processes can be found in schizophrenia patients, suggesting schizophrenia as a potential neurodevelopmental disease (Armenteros and Davies, 2006; Brent et al, 2013)
We found an alteration of effective connectivity (EC) in the right visual cortex (VC)–Acb–orbitofrontal cortex (OFC) pathway, which characterized both the potential mechanism of schizophrenia and the effectiveness of a novel Repetitive transcranial magnetic stimulation (rTMS) treatment through the methylazoxymethanol acetate (MAM) rat model; right accumbens shell (AcbSh)-OFC EC was suggested as a potential biomarker for both diagnosis and early-stage intervention of schizophrenia
The right AcbSh-OFC EC showed significant difference between both MAM-sham and vehicle-sham groups and MAM-rTMS and MAM-sham groups; according to our results, we suggest that schizophrenia decreased the causal link from AcbSh to OFC, and early-stage rTMS treatment increased it compensately
Summary
The mechanisms of schizophrenia remain unclear, altered brain maturational processes can be found in schizophrenia patients, suggesting schizophrenia as a potential neurodevelopmental disease (Armenteros and Davies, 2006; Brent et al, 2013). An earlier onset age often predicts poorer outcomes (Rotstein et al, 2018); on the other hand, both human and animal models indicate that the symptoms of schizophrenia can be improved in young patients through intervention (Nordentoft et al, 2009; Gomes et al, 2016; Hashimoto, 2019). These models suggest that studying AOS carries a significant clinical value. It is generally acknowledged that the mechanism of schizophrenia is tightly related to deficit
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