Frontal–striatal connectivity and positive symptoms of schizophrenia: implications for the mechanistic basis of prefrontal rTMS

Abstract

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 of resting state fMRI in a sample of 19 first episode psychosis subjects. We found that the total score of positive symptoms of schizophrenia is strongly associated with the frontostriatal circuitry. Stronger intrinsic inhibitory tone of LDLPFC and LSTR, as well as decreased bidirectional excitatory influence between the LDLPFC and the LSTR is related to the severity of positive symptoms, especially delusions. We interpret that an increase in striatal dopaminergic tone that underlies positive 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 (1 Hz) rTMS of the prefrontal area.

Effects of High-Frequency rTMS on Negative Symptoms and Cognitive Function in Hospitalized Patients With Chronic Schizophrenia: A Double-Blind, Sham-Controlled Pilot Trial

“…In the present study, there was no significant difference in the improvement in positive symptoms between the active rTMS and sham groups, which is in agreement with most previous studies (39,(61)(62)(63). The most important reasons underlying the lack of improvement in positive symptoms may be the frequencies and sites of stimulation.…”

Neuromodulation to Treat Substance Use Disorders in People With Schizophrenia and Other Psychoses: A Systematic Review

“…Evidence of alleviation of depression or positive and negative SCZ symptoms was mixed. However, given that neuromodulation has also been used to ameliorate positive and negative symptoms ( 67 , 68 ) and meta-analyses have shown rTMS to be effective in the treatment of both major depression and schizophrenia ( 69 ). Thus, future studies should continue to investigate the possibility of neuromodulation as an integrated treatment, as well as potential pathways to efficacy via reductions in negative symptoms, while controlling for symptom changes that are associated with reductions in substance use.…”

Progressive Changes in Glutamate Concentration in Early Stages of Schizophrenia: A Longitudinal 7-Tesla MRS Study

“…Glutamatergic disruption is implicated in the wide range of symptoms observed in schizophrenia. 1–3 Specifically, disinhibition of the excitatory glutamatergic outputs of the prefrontal cortex is thought to disrupt dopaminergic signaling in the striatum 4 , 5 resulting in acute psychotic symptoms. However, sustained disinhibition of prefrontal glutamatergic neurons might lead to excitotoxic damage with subsequent reduction in glutamate, with greater reductions occurring in patients with more severe forms of schizophrenia.…”