Negative symptoms and cognitive impairments are two core features of schizophrenia, that contribute mainly to the treatment-refractory symptoms observed in this clinical group. Repetitive transcranial magnetic stimulation (rTMS) is considered to be a promising non-medical intervention for treating the negative and cognitive symptoms in schizophrenia because of its noninvasive nature and fewer side effects. The current dissertation aimed to explore the therapeutic effects of rTMS on negative and cognitive symptoms. Moreover, it also aimed to explore if this observed behavioral changes would be associated with the corresponding changes in the brain structural and functional connectivity.
The dissertation consists of two main parts. In part 1, we conducted a meta-analysis of the effects of rTMS on negative symptoms. We found a moderate effect size (Cohen’s d 0.53) when sham-control was taken into account, also we found a 10 Hz setting, at least three consecutive weeks of treatment, treatment site at the left dorsolateral prefrontal cortex (DLPFC) and a 110% motor threshold (MT) were found to be the best rTMS parameters for the treatment of negative symptoms. In part 2, a double-blind randomized controlled trial study was conducted to examine the clinical (behavioural) changes in negative symptoms and cognitive functions.. Firstly,, we investigated the effects of rTMS on negative symptoms. The results showed that the treatment efficacy in the rTMS was significant for the patients with schizophrenia who were younger, with a shorter duration of illness and duration of untreated psychosis, and had predominant negative symptoms at baseline, especially in the subdomains of affective flattening and avolition. However, the placebo effect was also observed in the sham control group. The functioning outcome was influenced by the negative symptoms, especially by anhedonia and avolition. We should take into account the confounders of dosage of medication, depression and cognition when we evaluate the negative symptom in clinic. Then, we explored the effects of rTMS on cognitive function improvement. The therapeutic effects of rTMS on cognitive function were also significant, especially in the speed of information processing, verbal learning, visual learning and executive function. However, similar effects were also observed in the sham-control group, After controlling for the placebo effect observed in the sham-control group, we still found a significant improvement in Maze Test in the rTMS experimental group. Finally, we further explored whether these observed changes in clinical symptoms and cognitive performances were associated with a corresponding change in the underlying neural mechanism. The results showed that the patients with predominant negative symptoms demonstrated a significant reduction in gray matter volume, especially in the frontal lobes and limbic system. However, no significant changes were observed in white matter integrity by diffusion tensor imaging (DTI). . Resting-state analysis indicated that the small world property in the patients with predominant negative symptom was reduced. However, such a small world property was not changed by the rTMS treatment. The improvement of negative symptoms by the rTMS in our study was probably due to the activations of the left DLPFC, an increased connectivity between the left DLPFC and the anterior cingulate gyrus and the putamen, a decreased connectivity between the central executive network and insula of the salience network. The improvement of Maze performance by rTMS in our study might be due to the activations of left DLPFC, an increased connectivity between the parahippocampus,the superior temporal gyrus,and the anterior cingulate gyrus.
In summary, rTMS could improve the negative symptoms and cognitive impairments in patients with schizophrenia, especially in affective flattening, avolition and problem solving ability. The improvement of negative symptoms was likely related to the changes of the connectivity within the central executive network and the changes of the connectivity between the central executive network and salience network. The improvement of problem solving ability (as observed in the Maze Test) might be due to the activations of brain area related topographical and planning.