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.
Highlights
Neuromodulatory interventions such as repetitive transcranial magnetic stimulation are appropriate when antipsychotic treatment fails to control psychotic symptoms [40]
Bayesian model comparison revealed that the model representing the effect of total positive scores on the network’s effective connectivity outperformed all other models, posterior probability (PP) > 0.95 (Fig. 2), followed by delusions
We aimed to elucidate the mechanism of exacerbation of positive symptoms of schizophrenia upon applying HF-repetitive transcranial magnetic stimulation (rTMS) to the left dorsolateral prefrontal cortex (LDLPFC)
Summary
Neuromodulatory interventions such as repetitive transcranial magnetic stimulation (rTMS) are appropriate when antipsychotic treatment fails to control psychotic symptoms [40]. While rTMS applied to left dorsolateral prefrontal cortex (LDLPFC) reduces the burden of negative symptoms. The effect of rTMS strongly varies with the site of stimulation. Auditory hallucinations decrease upon high-frequency stimulation (HF-rTMS) of the left temporo-parietal junction [30], while left prefrontal HFrTMS appears effective to treat negative symptoms. While HF-rTMS of TPJ has no effect on negative symptoms, stimulating the LDLPFC appears to worsen positive symptoms in some patients [20]. Though individual studies reporting worsening of positive symptoms [12] have not identified if this effect is specific to certain positive symptoms, the earliest anecdotes indicated a specific but brief detrimental effect on delusions [44, 56]. More recent trials indicate that some positive symptoms such as excitement may
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