A Primer on the Treatment of Schizophrenia Through Repetitive Transcranial Magnetic Stimulation

Daphne Voineskos; Zafiris J Daskalakis


Expert Rev Neurother. 2013;13(10):1079-1082. 

In This Article

Negative & Cognitive Symptoms

The neuroanatomical basis of pervasive negative symptoms in schizophrenia has been localized, in part, to the medial frontal areas,[19] anterior cingulate[20] and medial temporal lobe.[21] The correlation of reduced frontal activation with more severe negative schizophrenia symptoms has been corroborated by several functional neuroimaging studies.[22–24] Given the excitatory effects of high frequency rTMS (5–20 Hz),[25] several studies have explored targeting the dorsolateral prefrontal cortex (DLPFC) to reduce negative symptoms. The common hypothesis has been that high-frequency rTMS would decrease negative schizophrenia symptoms by modulating perfusion, cerebral metabolism and neuronal excitability in the prefrontal cortex.[26–28] A statistically significant, albeit small, clinical decrease in negative symptom intensity was reported by Cohen et al. in a study of six subjects.[29] Neuroimaging studies demonstrated disrupted activation of the right PFC that correlated with negative schizophrenia results,[30] with similar results in bilateral prefrontal cortices.[31] Fitzgerald et al. designed a study to verify the efficacy of bilateral stimulation of the PFC in treatment of negative symptoms.[32] The results reported that there was no statistically significant difference between real and placebo stimulations. A further study, by Barr et al. focused on stable, medicated schizophrenia patients with prominent negative symptoms.[33] The efficacy of 4 weeks of daily 20 Hz bilateral stimulation targeted to the DLPFC was determined by examining changes in the scale for the assessment of negative symptoms (SANS) and positive and negative syndrome scale (PANSS). There was no difference in negative symptoms with either measure with either active or sham rTMS.[33] While the most effective rTMS parameters for the treatment of negative symptoms have yet to be defined, several studies have explored different stimulation parameters in an effort to explore treatment of negative symptoms with rTMS. With respect to stimulation frequency, 10 Hz has shown evidence to be optimal in minimizing negative symptoms of schizophrenia,[34,35] and the DLPFC appears to be an effective target.

Researchers have also targeted the DLPFC in rTMS treatment studies in hopes of treating the cognitive deficits of schizophrenia. Like negative symptoms, cognitive deficits in schizophrenia are not effectively treated with antipsychotic medication.[36–38] As one of the identified cognitive deficits of schizophrenia, working memory[39] has been connected with altered DLPFC activity in schizophrenia[40–42] in neuroimaging and neurophysiological studies. Targeted rTMS to DLPFC has been found to improve working memory function in healthy subjects when applied bilaterally[43] and to the right DLPFC.[44] Through a combination of working memory tasks and neurophysiological measures, Barr et al. published a pilot study assessing the effects of high-frequency rTMS to bilateral DLPFC regions, as targeted by MRI, on working memory performance.[45] They compared 27 subjects with schizophrenia with 13 age- and sex-matched controls in a 4-week randomized double-blind sham-controlled treatment trial. Barr et al. were able to demonstrate that bilateral 20-Hz rTMS targeted to DLPFC significantly improved working memory compared with sham.[45] Statistical analysis revealed that subjects with schizophrenia performed significantly worse on working memory tasks than healthy subjects prior to rTMS administration, although this improved to a similar level as the healthy subjects after the rTMS course.[45] These results provided compelling evidence of an improvement in working memory performance in schizophrenia patients after rTMS.