Recent Advances in Noninvasive Brain Stimulation for Schizophrenia

Jérôme Brunelin; Ondine Adam; Marine Mondino

Disclosures

Curr Opin Psychiatry. 2022;35(5):338-344. 

In This Article

Abstract and Introduction

Abstract

Purpose of Review: Noninvasive brain stimulation has emerged in the last three decades as a promising treatment for patients with antipsychotic-resistant symptoms of schizophrenia. This review updates the latest progress in the use of noninvasive brain stimulation to treat schizophrenia symptoms.

Recent Findings: Several recently published randomized-controlled trials support a long-lasting clinical effect of stimulation techniques on schizophrenia symptoms. In addition, efforts have been made in recent months to improve efficacy through several optimization strategies. Studies have tested new parameters of stimulation, such as theta burst stimulation, and alternative cortical or subcortical targets and have reported encouraging results. New forms of electrical stimulations such as alternating and random noise stimulation, have also been studied and have shown clinical and cognitive usefulness for patients. Accelerated stimulation protocols, and prospects could arise with deeper stimulation strategies.

Summary: Using brain stimulation to treat symptoms of schizophrenia seems promising and the great flexibility of the stimulation parameters leaves much room for developing optimization strategies and improving its effectiveness. Further studies need to identify the optimal parameters to maximize response rate.

Introduction

Schizophrenia is a severe chronic mental disorder with a median lifetime risk of around 0.7% and accounting for a substantial part of the global burden of diseases (for a recent review, see).[1] Its clinical expression involves several symptoms that have been commonly clustered into positive symptoms, such as delusions and hallucinations, and negative symptoms, which include apathy, lack of motivation, social withdrawal, and speech poverty. First line treatments of schizophrenia rely on the use of antipsychotic medications. However, approximately 10–30% of patients show a poor or partial response to these treatments, emphasizing the need for a renewal in the therapeutic armamentarium of schizophrenia.

Noninvasive brain stimulation techniques have emerged in the last three decades as promising tools in the treatment of psychiatric disorders.[2] Among them, transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) are the most widely used. TMS consists of applying a magnetic field with an electromagnetic coil placed over the scalp with respect to a targeted cortical brain region. The magnetic field leads to a modulation of neuronal firing rate of the targeted area. The most common protocols propose to deliver multiple pulses repeated at a defined frequency (repetitive TMS – rTMS). The effects of rTMS on the neuronal excitability of the brain region located under the coil depend on frequency: rTMS delivered at low frequency (≤1 Hz – LF-rTMS) can decrease cortical excitability,[3] whereas rTMS delivered at high frequency (≥5 Hz – HF-rTMS) can increase cortical excitability in the targeted brain areas.[4]

tDCS consists of applying a low intensity direct current (from 1 to 3 mA) to the brain through at least two electrodes placed on the scalp. The current that flows from the anode to the cathode is supposed to reach the brain and induce polarity-dependent effects on cortical excitability. Namely, currents entering the brain at the anode site (i.e., anodal stimulation) are assumed to increase cortical excitability beneath the electrode by depolarizing neuronal resting membrane potentials, whereas currents exiting the brain at the cathode site (i.e., cathodal stimulation) are believed to decrease it by hyperpolarizing resting membrane potentials.[5,6] Local effects on cortical excitability last beyond the stimulation period for both rTMS[3,4] and tDCS.[7] In addition, acute and long-term local effects are not only observed on the excitability of the targeted cortical regions but also on the activity and connectivity of brain regions that are functionally connected to the area located under the stimulation site (long-scale effects).[8,9] The effects can also reach deeper structure as revealed by an induced subcortical dopamine release following stimulation of the dorsolateral prefrontal cortex (DLPFC).[10,11]

Since neuroimaging studies have repeatedly reported dysregulation of brain activity in specific regions or functional networks, alteration of dopamine transmission and oscillations associated with symptoms of schizophrenia, noninvasive brain stimulation has thus been proposed as alternative therapeutic interventions in schizophrenia to normalize brain dysfunctions. Two main applications have been proposed: decreasing the hyperactivity of the temporo-parietal junction (TPJ) associated with auditory–verbal hallucinations; increasing the hypoactivity of the prefrontal cortex associated with negative symptoms, especially the left DLPFC (Figure 1). Usually, noninvasive brain stimulation strategies have been proposed for patients with treatment-resistant or persistent symptoms, even those under antipsychotic medication at an adequate dose and duration.

Figure 1.

Illustration of common placements of rTMS coils (panel A for auditory verbal hallucinations and panel B for negative symptoms) and placements of tDCS electrodes (panel C for symptoms of schizophrenia, including auditory verbal hallucinations) to target symptoms of schizophrenia based on the 10/20 EEG electrode placement system. Panel c: dark grey electrode, anode; light grey, cathode. rTMS, repetitive transcranial magnetic stimulation; tDCS, transcranial direct current stimulation.

Since the first publication of rTMS as a treatment for hallucinations in 1999,[12] there has been an exponential increase in the number of articles published on the interest of noninvasive brain stimulation for schizophrenia, both for clinical and fundamental purposes. In April 2022, the search equation [('rTMS OR tDCS') AND (schizophrenia)] yielded 299 hits in the PubMed database. Half of these have been published in the last 6 years, indicating the increased interest of the scientific community in these techniques. A recent meta-analysis including 208 randomized-controlled trials examined the efficacy of both rTMS and tDCS across all mental disorders and observed significant effect size for both techniques in various mental pathologies, including schizophrenia,[13] further emphasizing the relevance of investigating the effectiveness of these techniques in the treatment of psychiatric diseases. Given the extensive literature on this topic, evidence-based guidelines have been published on the therapeutic use of rTMS and tDCS by groups of European and international experts in the field. These regularly updated guidelines are useful to help clinicians make decisions and avoid inappropriate applications.

This review presents the state of the literature and the latest advances in the development of noninvasive brain stimulation interventions for the management of symptoms of schizophrenia, with a focus on rTMS and tDCS techniques.

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