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 ( ; ).

Proposed mechanisms: How does TMS work?

In TMS, an electric charge is stored in a capacitor and discharged through a wire that is wound around a coil ( ). The current is discharged in an intermittent manner, causing a pulsed magnetic field in the local area around the coil. This magnetic field is time varying, resulting in the induction of an electrical field with a magnitude proportional to the rate of change of the magnetic field (in accordance with Faraday’s law) ( ). When applied transcranially, the coil is placed near the scalp, and the electromagnetic field it generates passes through the intervening skin and bone, inducing an electrical current in the brain, which when delivered with a sufficient intensity leads to action potentials in cortical neurons.

If TMS is applied over the motor cortex, the induced action potentials can produce movements in muscles. By targeting specific muscles, such as those of the fingers or hand, and systematically varying the intensity of the coil output, a motor threshold (MT) can be established. In this manner, the “dose” of stimulation can be individualized to each person. The most important variables in determining how TMS affects the brain are the shape of the coil, placement of the coil, frequency of the pulsation, and the intensity of the magnetic field ( ; ). The nomenclature describes several different ways to deliver TMS: one stimulus at a time (single-pulse), pairs of pulses (paired-pulse), and repeated pulses called trains (repetitive TMS) ( ). The former two are usually used in experimental neurophysiology (cortical mapping, conduction time, cortico-cortical interactions). rTMS can be divided into conventional rTMS, characterized by the application of regularly repetitive single TMS pulses in a fixed frequency (i.e., 10 Hz, 1 Hz), and burst patterns of rTMS. This latter form of rTMS is composed of high frequency trains (bursts) interleaved with short pauses. Theta burst is the most widely known patterned form of rTMS and refers to bursts of 50 Hz rTMS repeated at a rate of 5 Hz, either in a continuous (cTBS) or intermittent (iTBS) trains. The effects of rTMS on brain excitability can also be measured in the human motor system via electromyography (EMG). A substantial literature supports the generalization that HF (≥ 5 Hz)/iTBS rTMS tends to increase brain excitability, while low-frequency (LF) (~ 1 Hz)/cTBS rTMS tends to inhibit it ( ).

Despite the clear evidence of behavioral, system and network plasticity induced by rTMS, one of the major limitations in the field is that we do not yet have a clear understanding of how rTMS alters neuronal plasticity. Existing research supports the view that HF-rTMS increases the efficiency of communication between neurons, a type of synaptic plasticity known as long-term potentiation (LTP). The most specific evidence for this hypothesis comes from animal studies. Using the same experimental approach as with classical LTP experiments (which use electrical stimulation), Vlachos and colleagues found that 10 Hz repetitive magnetic stimulation (rMS) over mouse hippocampal slices produced LTP-like potentiation ( ). More specifically, hallmark characteristics of LTP, including prolonged (over several hours) potentiation mediated by GluA1-containing AMPA receptors, were accompanied by dendritic spine growth, and required activation of NMDA receptors, sodium, and calcium channels. The same group also reported that 10 Hz rMS “cuts” the metaphorical “brakes”; that is, it reduces GABAergic tone by reducing expression of GABA _A receptor alpha-2 subunits through destabilization of its major scaffolding protein, gephyrin ( ).

How these animal studies translate to humans is less clear; however, several studies have tested the effects of blocking various key steps in the synaptic plasticity pathway in humans (most often using pharmacologic approaches at the NMDA receptor). The NMDA receptor is well-known to be important for LTP ( ; ). Using nonclinical protocols designed to enhance potentiation (i.e., pairing an rTMS pulse with a pulse on the median nerve, and pairing rTMS with an ischemic nerve block), several studies have found that NMDA receptor antagonists blocked LTP-like enhancement ( ; ; ). Of greater clinical relevance, TBS protocols which produced robust bidirectional plasticity changes were blocked by the NMDA receptor antagonist, memantine ( ). Whether the dependence of rTMS-induced plasticity on NMDA receptor activity is specific to LTP is less clear. The NMDA receptor partial agonist, d-cycloserine (DCS) was not by itself sufficient to enhance TBS-induced potentiation ( ; ). On the other hand, NMDA receptor activity increased by DCS was sufficient to enhance potentiation with 10 Hz rTMS, hinting that these two clinical forms of TMS may work through different mechanisms ( ).

In summary, TMS causes bidirectional local and distant circuit-level changes in the brain, but the cellular mechanisms remain unknown.

Parameters, response and remission rates, and durability

The US Food and Drug Administration (FDA) first approved the use of rTMS for treatment-resistant depression in 2008. The original approval included the use of 3000 pulses at 10 Hz stimulation sessions, in 4-s pulse trains with 26-s intertrain intervals for figure of 8 coils and the use of 1980 pulses at 18 Hz stimulation sessions, in 2-s pulse trains with 20-s intertrain intervals for the H-coil ( ; ; ). Treatment utilizing both coils is applied to the left dorsolateral prefrontal cortex (DLPFC) at 120% of a person’s resting motor threshold for a total of 20–30 sessions spanning 4–6 weeks ( ).

There have been three multisite randomized controlled trials assessing the efficacy of rTMS for treatment-resistant depression ( ). In these trials, remission was defined as no longer meeting criteria for a clinical diagnosis of depression and response was defined as decreasing depressive symptoms by at least 50% from baseline. The reported response rates ranged from 18.1% to 38.4% and remission rates ranged from 7.1% to 32.6% for active rTMS compared to response rates ranging from 11% to 21.4% and remission rates ranging from 5.1% to 14.6% for sham rTMS ( ; ; ). Both the treatment resistance level of the patients enrolled in these studies as well as the response and remission rates are similar to those treated in the level 2 with next step psychopharmacology in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial ( ; ; ). However, it should be noted that these findings were reported after 15–30 rTMS treatment sessions, while it has been suggested to be more effective with more treatment sessions ( ; ; ; ). Follow-up clinical effectiveness research has further suggested higher rates of response and remission in real world settings ( ; ; ).

Also, some works have addressed the question of whether it is possible to increase the efficacy of rTMS by increasing the number of pulses per session or by increasing the number of sessions delivered each day. A recent randomized controlled trial compared standard and high dose rTMS (including both high and low frequency protocols) in 300 patients and concluded that increasing the number of pulses in individual sessions does not appear to result in increased antidepressant efficacy ( ). Studies looking at number of sessions delivered each day, however, have suggested that increasing the number of sessions in a day may result in a greater and faster antidepressant effect ( ; ; ; ). A recent study compared standard and accelerated HF-rTMS protocols. Whereas there was no difference of efficacy between both protocols, accelerated form of HF-rTMS has been suggested to achieve a faster antidepressant action ( ). In addition, a recent metaanalysis reported that accelerated HF-TMS protocols were not superior to traditional rTMS but more studies may be needed to draw definitive conclusions ( ).

About a decade of research has led to the development of TBS in the treatment of depression ( ). The seminal randomized, multicenter study by Blumberger and colleagues demonstrated that just 3 min of TBS is noninferior to 37.5 min of traditional 10 Hz rTMS ( ). This trial compared the effectiveness of the traditional rTMS protocol to the newer iTBS protocol in a noninferiority study. In this study, traditional rTMS achieved a response rate of 49% and remission rate of 32%, whereas patients that received iTBS treatment achieved a response rate of 47% and a remission rate of 27%, showing that this accelerated form of rTMS treatment was statistically noninferior to traditional treatment ( ). The evidence from this study led to FDA clearance to use the iTBS protocol for the treatment of depression in 2018. Since then, there are a number of groups working to optimize different TBS parameters in hopes of improving remission and response rates in depressed individuals.

Considering the high relapse rate for major depressive disorder, it is necessary to understand the durability of the antidepressant response following a successful course of rTMS. Despite the fact that current FDA-approved rTMS treatment protocols do not recommend it yet, maintenance protocols for other antidepressant treatments have been shown to significantly extend the duration of remission and reduce the rate of relapse for ECT ( ; ; ; ), psychotherapy ( ; ; ), and antidepressant medication ( ; ). Maintenance rTMS therapy has been shown beneficial for prolonging the antidepressant effects of acute rTMS treatment as well ( ; ; ). Initial studies investigating the impact of maintenance rTMS treatment have used various types of maintenance protocols ranging from 3 weeks of tapering after the acute treatment phase ( ) to 6 years of 1–2 sessions per week ( ). As well as these differences in maintenance course duration, the maintenance protocols have differed in the frequency at which maintenance sessions are delivered ( ; ; ; ). Maintenance rTMS can be provided in a prospective, scheduled regimen or on an as needed basis. Pharmacotherapy, psychotherapy, exercise, or a combination of these treatments have also been used to maintain the antidepressant effects of an acute course of rTMS treatment ( ). To date, although promising, only a few studies have reported the potential benefit of the combination of antidepressants and rTMS and have resulted in mixed results ( ; ). Nevertheless, consensus recommendations converge toward the use of these medications after a successful course of rTMS ( ). Also, the combined use of mindfulness-based cognitive behavioral therapy could be beneficial ( ; ) as well as the combination of aerobic exercise and rTMS ( ).

In conclusion, maintenance rTMS trials show great promise in prolonging the antidepressant response in some individuals with major depression, albeit more trials are needed to determine the optimal dose and duration of maintenance rTMS treatments to prolong durability.

Effect on treatment-resistant bipolar depression

Due to the significant challenges in the treatment and management of bipolar disorder (BD), novel treatments are needed ( ). As HF-rTMS has shown efficacy in the treatment of depressive episodes among individuals with MDD, clinical trials and “real world,” naturalistic reports have found a similar antidepressant response during episodes of depression in BD ( ; ; ). Similar to the potential side-effects of antidepressant medications in individuals with BD, some have reported hypomanic or manic “affective switching” during or after a course of rTMS ( ). In a recent review compiling 10 cases of affective switching, no clear risk factors were identified ( ). Others have explored the use of HF- and LF-rTMS in the treatment of mania and mixed states, with varying results ( ; ; ). In addition to mood-related outcomes, HF-rTMS has also shown to improve neurocognitive function in BD ( ). recently reviewed original trials highlighting the use of rTMS, including iTBS and bilateral simulation paradigms, across all phases of BD. A recent RCT, testing the superiority of active versus sham daily L-DLPFC iTBS over 4 weeks in bipolar depression, was stopped due to futility. This study randomized 37 participants (18 active/19 sham). No difference has been shown between groups on the primary outcome (MADRS total score) and two manic episodes has been reported, one in the active group and one during the open label phase ( ). This negative result raised few questions specifically the need to better understand the pathophysiology of this particular depressive phenotype (i.e., bipolar depression) that could inform a disorder-specific targeting ( ). Further trials including larger samples, sham controlled trials, and targeted stimulation parameters are needed.

Potential biomarkers

Given the response and remission rates, and durability, rTMS is a validated treatment for TRD. Nevertheless, no established biomarker is yet available on this condition.

Three main large scale networks appear to be involved in the pathophysiology of depression, including the: (1) central executive network (CEN); (2) default mode network (DMN); and (3) salience network (SN) ( ; ; ; ). Previous studies showed the hyperconnectivity of DMN in depression, which may be normalized with effective treatments ( ; ). Also, an increased connectivity between DMN and sgACC has been suggested in depression ( ; ; ; ). Reduced activity of the dorsolateral prefrontal cortex (DLPFC), which is included in the CEN, has been reported in depression ( ; ). This abnormal activity may potentially be changed by effective treatments ( ; ; ). Another study demonstrated the increased connectivity of DLPFC-amygdala ( ). Furthermore, the activity of sgACC has reportedly been increased in depression ( ), which is correlated with the reduced activity of the DLPFC ( ; ). Improvements of depression are associated with the reduction of sgACC activity ( ; ; ; ).

HF-rTMS increases cortical excitability over a cortical target ( ; ). HF-left DLPFC (L-DLPFC) rTMS has been hypothesized to improve depression by upregulating the CEN ( ; ; ). Also, the upregulation of CEN may be related to the downregulation of DMN ( ). These effects may be correlated with the accuracy of targeting ( ; ). The hypoactivity in LDPFC and hyperactivity in sgACC in depression are normalized by rTMS, which are indeed consistent with clinical effects.

A recent study employed functional MRI to individually target the L-DLPFC most anticorrelated with sgACC and induced remission in 90% of patients with severe TRD ( ), which may confirm the importance of connectivity between these regions. These interventions also decreased the connectivity of sgACC-DMN after intervention ( ). Another group used a novel approach classifying patients with depression based on functional connectivity ( ). In this study, hierarchical clustering was used, i.e., patients were classified into biotypes of similar functional connectivity. A specific biotype was demonstrated to predict the effect of dorsomedial prefrontal cortex (DMPFC) rTMS on depression. Also, responders and nonresponders were distinguished by baseline functional connectivity that involved DMPFC, left amygdala, L-DLPFC, bilateral orbitofrontal cortex and posterior cingulate cortex. The combination of biotype and functional connectivity best predicted the treatment effect of rTMS on depression.

Optimal stimulation parameters

As discussed earlier in this chapter, stimulation parameters are suggested to be important for the effect of rTMS. Several different parameters can be set to optimize the neural and clinical response, such as the number of pulses per session, number of pulses per course, the way these pulses are delivered (traditional-fixed frequency rTMS, or patterned burst TBS), the number of sessions per day, the spacing between sessions, and the intensity of the stimulation. First, studies have hypothesized that delivering a higher dose (i.e., number of pulses) may result in improved clinical outcome ( ; ). Despite that a recent trial has failed to show any benefit from increasing the number of pulses per session with traditional rTMS ( ), it seems that some evidence supports this assumption for iTBS. Indeed, a study reported a dose-dependent response of iTBS with a greater enhancement of motor cortical excitability with 1800 pulses protocol compared with 600 and 1200 pulses ( ). In addition, basic science works have shown that the administration of 1800 iTBS pulses resulted in modulating brain activity in the intended direction with either increased motor cortex excitability ( ) or decreased DMN-ACC functional connectivity ( ). Note that this optimal 1800 pulses iTBS dose has been successfully tested in blinded trials in depression ( ). Second, from works in human neurophysiology ( ; ), the pattern of the stimulation session (iTBS) has been indirectly demonstrated to be more effective than HF-rTMS in modulating motor cortex excitability ( ). The above-mentioned depression trial THREE-D concluded that patterned iTBS stimulation protocol, using less number of pulses for a shorter duration of session, was as effective as a traditional 10 Hz rTMS course ( ). Third, the pattern of the stimulation course (intersession interval—ISI) had also shown benefits on both clinical and neurophysiological response to stimulation. Inspired by neurophysiology theory of learning, spaced training has more robust effects at the cellular and molecular level ( ). Basic science works have reported that a 50–90 min ISI resulted in a cumulative effect on dendritic spine enlargement whereas ISI ≤ 40 min didn’t ( ). These properties have been reproduced in the human motor cortex with an increase of cortical excitability induced by iTBS with ISI > 30 min ( ; ). Moreover, the number of daily TBS sessions may also be of importance. Compared to a single one, two spaced stimulation sessions have greater and long-lasting effects ( ) with beneficial clinical effects in depressed patients ( ). Nevertheless, this last finding remains controversial as reported by a metaanalytic work on accelerated traditional rTMS protocols ( ). Interestingly, contrary to traditional rTMS, high-dose and accelerated forms of iTBS, when combined, seem to provide a strong and fast antidepressant effect ( ; ). Fourth, the stimulation intensity is another important parameter. The distance between the targeted area and the coil may influence the brain response of the motor cortex and justify adjusting the intensity to the depth ( ). Using TBS stimulation, the optimal intensity for prefrontal regions seems to respond to an inverse U-shape relationship with best effect using subthreshold level (75%–90% of resting motor threshold) of stimulation on neurophysiological response ( ; ), while it doesn’t seem to be the case with traditional rTMS ( ).

Recently, one study used these optimized parameters combining a high-dose (90,000 pulses in total) patterned iTBS and functional MRI targeted rTMS course in 22 treatment-resistant depressed participants ( ). In this open-label study, participants achieved a remission rate of up to 90% with a significant and rapid reduction in depression scores and suicidality. These preliminary results are very promising given the evidence of a robust and rapid effect of network-based and optimized rTMS technique. These open label data were confirmed by a randomized controlled trial enrolling 29 TRD participants (14 in active group/15 in sham group) with an overall remission rate of 78.6% in the active group across the 4 weeks follow-up. This study reported strong effect sizes on the main outcome (MADRS score) were 1.7, 1.4, 1.8, 1.5, and 1.4, at immediate, week 1, week 2, week 3, and week 4 posttreatment, respectively ( ). These results suggest that the future of TMS leads into a personalized, biomarker-based, and optimized stimulation approach.

Future directions and perspectives

Thirty-five years of rTMS research have led to a standardized and effective rTMS treatment course for TRD but further personalization, higher doses, and the development of a standardized maintenance treatment schedule may increase efficacy and durability further. Improved efficacy, alongside the minimal side effects ( ) and data showing the cost-effectiveness of rTMS compared to other treatments for TRD ( ; ; ) will likely result in rTMS becoming more widely used; perhaps becoming a first-line treatment for depression ( ).

The future of rTMS, as many areas of medicine, is likely to be come increasingly personalized. The stimulation intensity of rTMS is already personalized in the current FDA-approved rTMS treatment course for TRD by measuring an individual’s MT. Other stimulation parameters such as the frequency of stimulation, location of stimulation, number of pulses per session, intersession and interpulse interval are all kept constant across patients. Motor physiology studies have consistently shown high interindividual variability in response to rTMS protocols ( ; ; ; ; ), suggesting optimal stimulation parameters differ across individuals. Individualizing stimulation frequency based on peak neural oscillatory activity in each individual has been shown to be more effective than standard stimulation protocols in schizophrenia ( ) but initial studies in TRD show mixed results ( ; ). Retrospective studies suggest that the functional connectivity of the stimulated location predicts clinical outcome ( ; ) implying that individualizing stimulation location using functional MRI-guided targeting may increase efficacy. Studies using individualized functional MRI-guided targeting have shown high efficacy ( ; ) but trials directly comparing different targeting methods need to be conducted. Motor physiology studies have provided evidence to support personalization of other stimulation parameters such as number of pulses per session ( ; ; ) and intersession interval ( ; ), but no clinical trials to date have investigated the clinical benefit of individualizing these parameters.

Development of a standardized tapering and maintenance rTMS treatment schedules may improve durability and cost effectiveness of rTMS treatment for TRD. Despite the high interindividual variability in clinical response to rTMS, predictors of response have not been widely studied and therefore no reliable predictors of response duration have been found ( ; ). Once reliable clinical, genetic or neuroimaging biomarkers of response duration have been identified, it may be possible to add maintenance protocols for those individuals who are likely to have a shorter duration of response, e.g., patients with poor durability.

Eligibility criteria and accessibility of rTMS treatment for TRD are currently variable based on insurance coverage in the United States. Currently, nonresponse to three or more antidepressant medication trials is typically required for insurance coverage. Some insurance companies require higher numbers of failed medication trials and even an ECT trial before approving rTMS. Unlike antidepressant medications and ECT, rTMS has minimal side effects, the most common being discomfort at the stimulation site and headache, with incidence rates ranging from 39% to 65% ( ; ; ; ; ). Longitudinal rTMS studies have demonstrated lower relapse rates for TRD patients 12 months after treatment without maintenance treatment compared to relapse rates reported for those who received ECT ( ; ; ; ; ) which is currently the gold-standard treatment for TRD. Analyses into the cost-effectiveness of rTMS have shown this treatment is more cost-effective than antidepressant medications ( ; ) due to the lower rates of retreatment and hospitalization. rTMS has particular utility for cases in which medication cannot be effectively metabolized or absorbed, when a patient is pregnant or when side effects of medications or ECT can be particularly damaging, e.g., heart disease. The utility of rTMS for these conditions, the durability of response, minimal side effects and superior cost-effectiveness, collectively suggest that rTMS should be accessible to patients earlier in their course of depression.

In conclusion, increased personalization of stimulation parameters and the addition of maintenance rTMS treatment in conjunction with the higher-pulse doses and individualized targeting already discussed in this book may increase the efficacy of rTMS treatment for TRD. The benefits of minimal side effects, superior durability, and cost-effectiveness compared to other available treatments for TRD suggest rTMS should be more readily available for TRD patients.