High frequency repetitive transcranial magnetic stimulation of dorsomedial prefrontal cortex for negative symptoms in patients with schizophrenia: A double-blind, randomized controlled trial

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Highlights

ABSTRACT

Negative symptoms are the major challenge in clinical management of schizophrenia. Dorsomedial prefrontal cortex (DMPFC) has been suggested to be highly involved in the mechanisms of negative symptoms of schizophrenia. However, the effect of repetitive Transcranial Magnetic Stimulation (rTMS) over DMPFC has not yet been well studied. In this double-blind, randomized controlled rTMS clinical trial, thirty-three participants (17 in active group and 16 in sham group) were enrolled. This study includes the rTMS treatment phase (lasts for 4 weeks) and a subsequently naturalistic follow-up phase (lasts for another 4 weeks). Schizophrenia patients with prominently negative symptoms were randomly assigned to receive 10 Hz or sham rTMS intervention. The score change in Scale of Negative Symptoms (SANS) was defined as the primary outcome measure. There was a significant decrease in negative symptoms, especially affective flattening and anhedonia in schizophrenia patients after DMPFC-rTMS intervention. Moreover, the negative symptoms improvement could maintain at least another 4 weeks. In addition, no memory impairment or serious adverse reaction of rTMS emerged. Our results suggest that high frequency rTMS over DMPF may represent a safe and effective treatment for negative symptoms in patients with schizophrenia.

Introduction

Negative symptom is one of core symptoms in patients with schizophrenia, which predicts a range of poor clinical outcomes, such as reduced rates of recovery (Strauss et al., 2010), lower subjective well-being (Strauss et al., 2012) and less social interaction (Lieberman et al., 2019). It was assumed that the severity of negative symptoms is the best predictor for functional outcomes and quality of life in schizophrenia patients (Robertson et al., 2014). First-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs) are the most commonly used treatment for schizophrenia, however the negative symptoms in schizophrenia are often treatment-resistant (Fusar-Poli et al., 2015; Moller and Czobor, 2015). Negative symptoms are still the major challenge in clinical management of schizophrenia.

Repetitive Transcranial Magnetic Stimulation (rTMS), a relatively safe and non-invasive neuromodulation method, could modulate cortical excitability and neurotransmitter release in certain brain areas (Brady et al., 2019; Eldaief et al., 2011; Halko et al., 2014; Iwabuchi et al., 2017; Pell et al., 2011; Strafella et al., 2001; Wang et al., 2014). Some evidences indicated that high frequency rTMS could improve negative symptoms in schizophrenia patients (Hasan et al., 2017; Quan et al., 2015; Wang et al., 2017; Zhuo et al., 2019), and the left dorsolateral prefrontal cortex (DLPFC) is the most often used target for negative symptoms in schizophrenia (Shi et al., 2014); however, some other researches revealed that the effect of rTMS on negative symptoms in schizophrenia was disputed and ambiguous (Hansbauer et al., 2018; Li et al., 2016; Wobrock et al., 2015). More recently, the evidence-based guidelines on the rTMS therapeutic use have reduced the level of evidence from B to C for negative symptoms of schizophrenia, which means just a possible efficacy of high frequency rTMS on left DLPFC for negative symptoms of schizophrenia (Lefaucheur et al., 2020); and the rTMS patterns and parameters on negative symptoms in schizophrenia need to be further investigated and clarified.

As we known, the stimulation target of rTMS is one of key parameters affecting the curative effect. Besides the left DLPFC, some studies indicated that the dorsomedial prefrontal cortex (DMPFC) also has a close relationship with the negative symptoms in schizophrenia (Ferrari et al., 2014; Harvey and Lepage, 2014; Lieberman et al., 2019; Yamazaki et al., 2018). DMPFC is an important joint of the mesencephalic-limbic dopaminergic system, which known as reward circuit (Volkow et al., 2011), some evidences revealed that an aberrant reward pathway might contribute to the negative symptoms in patients with schizophrenia, such as anhedonia, social amotivation and voluntary impairments (Dodell-Feder et al., 2014; Fulford et al., 2018; Strauss et al., 2019; Strauss et al., 2018). However, the conventional TMS coils such as the 8-figure coil is limited by the penetration depth. The butterfly coil was designed to reach deeper targets. Although DMPFC could be effectively stimulated by the butterfly coil (Deng et al., 2014), it is difficult to stimulate other deeper regions of reward circuit such as the nucleus accumbens or ventral tegmental area. So, the DMPFC might be a promising rTMS target for the negative symptoms of schizophrenia. Recently some studies found that the DMPFC-rTMS could improve the depressive symptom in patients with depression (Downar et al., 2014; Dunlop et al., 2015; Miron et al., 2019), which specially help to relieve anhedonia by improving the connectivity of reward pathway (Downar et al., 2014). However, the effect of DMPFC-rTMS has not yet been well studied.

In the present study, schizophrenia patients with prominently negative symptoms were recruited and high frequency/sham rTMS protocol was employed on the DMPFC of the participants. We hypothesized that high frequency rTMS on DMPFC could improve the reward circuit integrity; thereby improve the negative symptoms in patients with schizophrenia.

Section snippets

Study design

This study is a double blind, randomized controlled clinical trial, which has been registered on the ClinicalTrials.gov with ID NCT02842034. This study is a two-phase clinical trial, which includes the rTMS treatment phase (lasts for 4 weeks) and a subsequently naturalistic follow-up phase (lasts for another 4 weeks). After enrollment, all participants were randomized to receive the add-on therapy with active rTMS or sham rTMS on the DMPFC, and promised to maintain the currently medications for

Demographic characteristics and clinical variables

Fig. 1.indicated the flowchart of this study. Forty schizophrenia patients with prominently negative symptoms were enrolled in this study, 33 patients were randomized to receive active rTMS or sham rTMS on the DMPFC, finally 15 patients in the active rTMS group and 14 patients in the sham rTMS group fulfilled the naturalistic follow-up phase. The numbers of patients on different drugs for the active treatment group versus sham groups are as follows: amisulpride 7/5, clozapine 5/3, aripiprazole

Discussion

Although many studies have been performed on the efficacy of rTMS in patients with schizophrenia, studies on the efficacy of DMPFC-rTMS are scarce. To our knowledge, this is the first report of the application of DMPFC-rTMS for the negative symptoms in schizophrenia patients. The SANS scores of the high frequency rTMS group decreased significantly without any adverse events in this study. In addition, the efficacy maintained at least 4 weeks even after the end of rTMS intervention.

DLPFC is the

Author Statement

We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us.

We confirm that this is an original paper which has neither previously nor simultaneously in whole or in part been submitted anywhere else.

We further confirm that any aspect of the work covered in this manuscript that has

Funding

The authors would like to acknowledge those patients taking part in this study and the support of the funding sources. This work was supported by National Natural Science Foundation of China (81871047), Key Program of Multidisciplinary Cross Research Foundation of Shanghai Jiao Tong University (YG2017ZD13), Shanghai Municipal Health Commission Clinical Research Project (20194Y0037), Key Program of Shanghai Mental Health Center Clinical Research Center (CRC2017ZD03), Shanghai Mental Health

Declaration of Competing Interest

There are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.

Acknowledgment

HG, JuZ, JijW, and DL were responsible for study design, statistical analysis, and manuscript preparation. KZ, JiZ, YT, ZQ, QX, XL, and YZ were responsible for recruiting the patients, and collecting the clinical data. JinW, JijW, and DLwere involved in evolving the ideas and editing the manuscript. All authors gave final approval of the version to be published and agree to be accountable for all aspects of the work.

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