Transcranial magnetic stimulation for treatment-resistant depression

Introduction

Although diverse treatments are currently available for depression, one class of treatments that holds significant promise, especially for treatment-resistant depression (TRD) in the near future, is neuromodulation. This growing category of treatment techniques includes interventions, either electrical, chemical, or mechanical in nature, that directly modify the function of the nervous system ( ). The oldest form of neuromodulation, electroconvulsive therapy (ECT), is still the most effective treatment available for depression ( ; ), and has been joined by a variety of newer techniques. The possibility of directly modifying activity in discrete brain areas or systems has a number of advantages over traditional first-line treatments for depression, not least among these being the focal nature of neuromodulatory treatments, their speed of action, and their potentially lower cost (compared to the cost of untreated or undertreated depression in treatment-resistant individuals) ( ; ; ).

Neuromodulatory treatments for depression can be divided into two broad categories: invasive and noninvasive. Invasive treatments include procedures such as vagus nerve stimulation (VNS) and deep brain stimulation (DBS), and are typically reserved for the most severe cases, given the risks involved with surgery. The noninvasive techniques, such as ECT, repetitive transcranial magnetic stimulation (rTMS), and transcranial electrical stimulation (TES), have a potentially broader clinical application than the invasive techniques given the significantly lower risks and costs associated with them. This chapter will focus in particular on the application of rTMS for TRD.

Compared to ECT, rTMS has several advantages. It does not require general anesthesia, which is perhaps the most dangerous aspect of administering ECT ( ). It also does not require seizure induction, meaning that it is substantially less disruptive to the lives of patients undergoing this treatment (e.g., does not impair daily activities, does not prevent driving during the recovery period). Because of the more focal nature of rTMS, it is free of the cognitive and memory impairments that are associated with ECT ( ). Finally, rTMS does not come with the cultural stigma that has long been attached to ECT ( ) and has likely prevented more widespread use of the technique ( ).

Several large randomized controlled studies have investigated the efficacy of rTMS for depression and have repeatedly found active stimulation to be more effective than sham stimulation ( ; ; ). Although it is not as effective as ECT in its current conventional form ( ), rTMS is significantly more tolerable than ECT ( ), and for many, this is an acceptable tradeoff. In this chapter, we first introduce the theoretical basis of rTMS. Then, we present a state of the art of rTMS practice in the indication of TRD. Finally, we open the discussion on the perspectives of development of this technique through the use of biomarkers and the optimization of stimulation parameters.

Historical overview

Since the development of magnetic stimulators as a clinical tool ( ), it was known that electromagnetic stimulation could stimulate neurons ( ). The first formal work in the area combined TMS with electromyography, to measure neural conduction time ( ), and to compare the brain electrophysiological response in different psychiatric disorders ( ). These early works focused on the motor system, and TMS, used here as a probe, utilized a single-pulse format and was able to induce a motor response ( ). Contemporary to these studies, further work has confirmed that “patterned, or repetitive” simulation of the motor cortex is able to predictably alter motor function ( ; ). Utilizing this knowledge, this work initiated on the motor cortex was extended to the prefrontal cortex in healthy volunteers and was found to have an effect on mood and emotions ( ; ).

One of the first reports of rTMS being used to treat depression was a study in which daily rTMS was applied to the left prefrontal cortex of six patients with TRD ( ), resulting in significant reduction in depressive symptoms and an increase in brain metabolic demand, as measured by positron emission tomography. Large-scale controlled studies ( ; ) later led to FDA approval of high frequency (HF) rTMS for treatment-resistant forms of depression. Additionally, through functional magnetic resonance imaging (fMRI) and electroencephalography (EEG), researchers have observed secondary effects from rTMS on brain regions that are connected to but distant from the site of stimulation ( ; ). This secondary activation of connected regions is hypothesized to be essential for the antidepressant effects of rTMS ( ; ).