Understanding the Effect of Left Prefrontal Stimulation on Positive Symptoms of Schizophrenia: A Dynamic Causal Modeling Study of Ultra-high field (7-Tesla) Resting-state fMRI

Repetitive transcranial magnetic stimulation (rTMS), when applied to left dorsolateral prefrontal cortex (LDLPFC), reduces negative symptoms of schizophrenia, but has no effect on positive symptoms. In a small number of cases, it appears to worsen the severity of positive symptoms. It has been hypothesized that high frequency rTMS of the LDLPFC might increase the dopaminergic neurotransmission by driving the activity of the left striatum in the basal ganglia (LSTR), increasing striatal dopaminergic activity. This hypothesis relies on the assumption that either the frontal-striatal connection or the intrinsic frontal and/or striatal connections covary with the severity of positive symptoms. The current work aimed to evaluate this assumption by studying the association between positive and negative symptoms severity and the effective connectivity within the frontal and striatal network using dynamic causal modeling (DCM) of ultra-high field (7 Tesla) resting state fMRI in a sample of 19 first episode psychosis (FEP) subjects. We found that of all core symptoms of schizophrenia, only delusions are strongly associated with the fronto striatal circuitry. Stronger intrinsic inhibitory tone of LDLPFC and LSTR, as well as a pronounced backward inhibition of the LDLPFC on the LSTR related to the severity of delusions. We interpret that an increase in striatal dopaminergic tone that underlies delusional symptoms, is likely associated with increased prefrontal inhibitory tone, strengthening the frontostriatal "brake". Furthermore, based on our model, we propose that lessening of positive symptoms could be achieved by means of continuous theta-burst or low frequency (1Hz) rTMS of the prefrontal area.