Transcranial magnetic stimulation (TMS) is a US Food and Drug Administration (FDA)-approved treatment for major depressive disorder (MDD). The FDA cleared the first TMS machine (NeuroStar; Neuronetics, Malvern, PA) in 2008 for patients with MDD who have failed one adequate medication trial during a current episode of depression. TMS is a neuromodulation technique that works by creating a focal magnetic field that induces a small electric current. To create a prescribed dose, the machine creates these currents using pulses of varying strength frequency (defined in Hz), and an interval rest period without stimulation. This is modified by the total amount of time the magnet is placed over a targeted brain region. By doing this, the magnetic field stimulus can alter the firing patterns of the brain regions located underneath the magnet. Because of the success of TMS in treating depression, there has been interest in applications for its use in other neuropsychiatric diseases. This article provides a brief background on the current use of TMS in clinical practice and reviews the current data on the use of TMS in the treatment of depression and other psychiatric illnesses.
TMS for Depression
The standard TMS protocol to treat depression targets the left dorsolateral prefrontal cortex (DLPFC). The left DLPFC was chosen because brain imaging research demonstrated decreased activity of this area in patients with depression as well as an association of this area with the behavioral dysregulation seen in depression (decreased energy, disruption of sleep-wake cycle, appetite changes).1 The standard approach to this target uses a stimulus delivered at 120% above the patient motor threshold (strength), 10 pulses per second (10 Hz) for 4 seconds with a 26-second interval period, for 37.5 minutes.2 During that time, the patient receives a total of 3,000 pulses. The repetitive stimulation pattern in this dosing is defined as repetitive high-frequency (>1 Hz) TMS (HF-rTMS). The proposed mechanism of action is that HF-rTMS increases neuronal firing in this region, thus increasing its activity to modulate the neural circuit.2 In contrast, low-frequency (LF) rTMS (<1 Hz) decreases neuronal firing with resultant decreased regional brain activity.3
TMS appears quite effective for MDD when using this target. In 2016, the Clinical TMS Society published a review of the effectiveness of this TMS approach for MDD.4 The review included more than 100 studies and also polled clinicians actively using TMS. The authors concluded that TMS is an effective treatment for MDD that should be considered for patients who are both moderately to severely treatment refractory and who are moderately to severely ill. A group of European experts reached a similar conclusion in 2014 when commissioned to establish guidelines on the therapeutic uses of TMS.5 In that review, the authors gave left DLPFC-targeted TMS for depression a level “A” recommendation (ie, supporting proven efficacy with convincing evidence).5 A recent meta-analysis supported these recommendations, reporting an overall response rate of 29.3% and a remission rate of 18.6% for patients receiving rTMS versus 10.4% and 5%, respectively, for patients receiving sham TMS.6
In 2013, a new TMS device, the Brainsway Deep TMS machine (Brainsway; Jerusalem, Israel), was approved by the FDA for the treatment of depression. This device uses a different type of magnetic coil (an “H” coil), which the manufacturer claims that it stimulates a deeper and wider brain region compared with the “figure 8” coil used on older devices. The dosing schedule and left DLFPC target using deep TMS (dTMS) is similar to the older devices. In the pivotal study used to gain FDA approval, the authors reported a response rate of 38.4% compared to 21.4% for placebo, and remission rates of 32.6% for dTMS compared with 14.6% for sham treatment.7 However, there was a concern about one report of a seizure, an adverse event not observed in studies using a figure 8 coil.
One disadvantage to the conventional approach of HF-rTMS is discomfort, which can lead to patient withdrawal. There is also the potential of adverse events at higher-intensity stimulation. The most common side effect in clinical practice is headache. To address these concerns, research has examined LF-rTMS (1 Hz) over the right DLPFC. The hypothesis is that this region is overactive in depression and that LF-rTMS will inhibit this overactivity.7 A meta-analysis examined LF-rTMS in treatment-refractory depression (defined as failure of ≥2 antidepressants) and reported a response rate of 38.2% for patients receiving TMS versus 15% for sham, with remission rates of 34.6% for active and 9.7% for sham treatments.8 The authors also noted that in the Sequenced Treatment Alternatives to Relieve Depression study9 remission rates in patients taking lithium or triiodothyronine after a failed second antidepressant were 20.4%. This shows that there are alternative approaches to deliver TMS (other than the standard FDA-approved HF-rTMS delivered over the left DLPFC) that may be both better tolerated and potentially more effective.
To improve current response and remission rates and to address practical issues of the time-intensive nature of the treatments (37.5 minutes per day, 5 days a week, for 6 weeks), interest has developed in finding new dosing parameters that may be more effective and require less time per session. One such design showing promise uses theta-burst stimulation.10 Theta burst delivers pulses at 50 Hz, which is much higher than traditional HF-rTMS. This is done with a 200-ms interval at 80% of the motor threshold.10 Although the data are limited at this time, there is hope that this method will be more effective while taking much less time to deliver in a clinical setting.
Another unknown in clinical practice is how long the benefit from TMS persists, as few studies have examined the duration of TMS response. Kedzior et al.11 conducted a meta-analysis of 16 randomized controlled trials with 495 patients to help answer this question. Although informative, this meta-analysis has limited applicability for clinical practice, as most of the included studies used a brief, acute course of 5 to 15 TMS treatments with lower dosing parameters than those currently used in clinical practice. Additionally, most of the included studies only had a follow-up period of 1 to 4 weeks, although one study did at 3 months. They concluded that the effect of TMS was small but stable throughout the follow-up period. Similarly, a review recently published by the Clinical TMS Society quoted a 64% to 90% durability for TMS response/remission over a 3- to 12-month period.4 The studies they reviewed employed either antidepressant maintenance or a repeat course of TMS for patients who began to worsen clinically to maintain the effect. The society's recommendation was that TMS can be used as maintenance for patients who have responded or re-introduced for patients beginning to relapse.4 However, the guidelines for how many sessions over what period of time remain undefined.
Compared with other neuromodulation techniques (eg, electroconvulsive therapy, deep brain stimulation, vagus nerve stimulation), TMS is a noninvasive procedure that is generally well-tolerated. The most serious potential side effect is seizure, although in a review of more than 10,000 treatments using the figure 8 coil (the most common coil used in clinical practice), there were no reported seizures.12 Given the ability of TMS to modulate neuronal firing in both excitatory and inhibitory ways in a clinically safe manner, interest has grown in TMS as a useful tool for treatment of a variety of neuropsychiatric illnesses, such as obsessive-compulsive disorder (OCD), schizophrenia, Parkinson's disease, posttraumatic stress disorder (PTSD), substance use disorders, and chronic pain.
TMS for Obsessive-Compulsive Disorder
In comparison to some other psychiatric illnesses, there is a better understanding of the neural cortico-striatal-thalamic-coritcal circuits involved in the pathogenesis of OCD. Consequently, clinical interest has developed in using rTMS for refractory OCD. The supplementary motor area (SMA) and orbitofrontal cortex (OFC) exhibit hyperexcitability in OCD, which has led to the application of LF-rTMS to reverse this hyperactivity.13 Berlim et al.14 conducted a meta-analysis of rTMS for OCD consisting of 10 studies and 282 participants. They found that LF-rTMS over the SMA or OFC demonstrated promising results, and reported a 35% response rate for active treatment versus a 13% response rate for sham treatment, resulting in a number needed to treat of 5.14 Treatment of the left DLPFC with HF-rTMS showed no effect. These results were similar to those in a review of neuromodulation in OCD by Bais et al.15 One key concern raised in this review was that the effect may not be sustained after rTMS is stopped. Despite the promising initial results of studies included in these two reviews, a more recent randomized, double-blind, sham-controlled trial of LF-rTMS over the SMA failed to show a significant difference between the two groups.16 Taking all of this into consideration, the long-term usefulness and ideal treatment protocol for rTMS in OCD remain to be determined.
TMS for Schizophrenia
In their 2005 review article, Khurshid and Janicak17 examined a number of trials that assessed the utility of TMS for schizophrenia and related disorders. At that time, although some studies supported the efficacy of TMS for psychotic symptoms, the majority of the evidence was conflicting and no single study provided unequivocal evidence for TMS as a primary treatment for this spectrum of disorders.
Since that report by Khurshid and Janicak,17 research has continued to examine the role for TMS in the treatment of schizophrenia spectrum disorders. Much of this work has examined global symptomatology, but recent work has focused more specifically on positive and negative symptoms of the disorders.18–25 Positive symptoms, which include hallucinations, have been theorized to occur due to hyperactivation of the temporal lobe.26 Negative symptoms, which include avolition, apathy, and cognitive dulling, may be related to hypoactivity of the prefrontal cortex.27 Accordingly, research into the treatment of each has focused on low-frequency stimulation of the temporoparietal cortex for positive symptoms, and high-frequency stimulation of the prefrontal cortex for negative symptoms.28
In 2015, Dougall et al.18 examined 41 studies that included a total of 1,473 participants. Although some data suggested that temporoparietal TMS showed improvement in global state measures on the Clinical Global Impression scale and positive symptom measures on the Positive and Negative Syndrome scale (PANSS), the evidence was assessed as low quality. They similarly concluded that only low-quality evidence supported the use of prefrontal TMS on global measures or prefrontal theta-burst stimulation.18 TMS was also compared to sham TMS for mental state on the PANNS scale. The overall conclusions were equivocal, with no strong evidence to “support or refute the use of TMS in the treatment of schizophrenia.”18 Another recent review reached similar conclusions, proposing that although isolated studies have shown promise, the majority of data do not support a significant overall effect when TMS is compared with sham treatment;19 however, TMS may still provide benefit for specific symptoms.
Most of the studies specifically examining positive symptoms have targeted the left temporoparietal cortex (TPC), with only one targeting the right temporoparietal cortex. In their 2010 study, Slotema et al.20 reported a moderate effect of TMS on auditory verbal hallucinations with an effect size of 0.54, although the overall study numbers were small. A subsequent study by this group21 confirmed that left TPC stimulation at a frequency of 1 Hz was superior to other TMS approaches, including low-frequency TMS targeting the right TPC. These findings are consistent with conclusions made by Freitas et al.,22 who reported that across 12 studies LF-rTMS administered to the TPC yielded a significant improvement in positive symptoms. Subsequent examination proposed that TMS administered to the left TPC had efficacy specifically for the treatment of auditory hallucinations.22
Studies examining the utility of TMS for negative symptoms of schizophrenia are more numerous, with the most common approach targeting the DLPFC. Slotema et al.20 found a trend for TMS applied to the DLPFC to improve negative symptoms compared to sham treatment, but that this result was not statistically significant. These findings are consistent with those made by Freitas et al.22 A meta-analysis of studies examining negative symptoms conducted by Dlabac-de Lange et al.23 examined nine trials including 213 patients. They reported an overall benefit to negative symptoms, but effect sizes were influenced by TMS frequency (10 Hz) and duration of treatment (>3 weeks being the line of demarcation).23 These findings were replicated in subsequent meta-analyses.24,25
Summary of TMS for Schizophrenia
Although initial studies suggested some efficacy for TMS in the treatment of schizophrenia spectrum disorders, the preponderance of the evidence does not support TMS as a first-line treatment for the illness. However, TMS using different treatment paradigms targeting specific symptom clusters may provide benefit. Positive findings appear to be most pronounced for TMS applied to the left TPC to address auditory hallucinations. Similarly, DLPFC stimulation may provide benefit for negative symptoms. Additional trials are needed to ultimately determine which patients with schizophrenia would be most likely to respond to TMS treatment.
TMS for Parkinson's Disease
Chung and Mak29 conducted a meta-analysis and systematic review examining 22 trials and 555 patients with Parkinson's disease. They found improvements in short-term upper limb function, short- and long-term walking performance, and short- and long-term unified Parkinson's Disease Rating Scale section III score. The data also suggested that stimulating the primary motor cortex may be more effective than the DLPFC or SMA.
TMS for Posttraumatic Stress Disorder
In 2015, Clark et al.30 published a review of the literature (10 primary studies, 1 systematic review, and 2 meta-analyses) examining the use of rTMS to treat PTSD. Primary outcomes and results varied among the studies; however, it appears promising that targeting the right DLPFC and the medial prefrontal cortex may reduce some symptoms of PTSD either directly or indirectly by modulating affective symptoms, most often anxiety and avoidance.
TMS for Substance Use Disorders
In 2014, a review of the current literature regarding the use of rTMS in substance use disorders was written by Gorelick et al.31 Each of the studies that were reviewed examined the impact of rTMS on the use or craving of the specific substance in persons without a comorbid psychiatric disorder. In the tobacco use studies, the DLPFC was stimulated. Three studies demonstrated a decrease in spontaneous craving or cue-induced craving, three studies demonstrated a decrease in smoking, and one study showed an increase in cue craving but a decrease in spontaneous craving. In the studies examining treatment of stimulant use (cocaine or methamphetamine), the DLPFC was stimulated. Patients in two of the four studies demonstrated decreased spontaneous craving, one study showed no change, and one study showed an increase in spontaneous craving. Studies examining effects of rTMS on alcohol use disorder also stimulated the DLPFC. There were mixed results with the alcohol use studies, as some showed a reduction in alcohol craving whereas others showed no change in craving.
TMS for Chronic Pain
The most recent meta-analysis and systematic review examined 43 studies including several types of chronic pain, mostly migraines or headaches and forms of neuropathic pain, but also rheumatoid arthritis, complex regional pain syndrome, osteoarthritis, and myofascial pain.32 The studies in the meta-analysis examined cortical excitability in relation to treating chronic pain with rTMS, using the primary motor cortex as the stimulation target. In about 50% of the studies reviewed, the short-interval intracortical inhibition was decreased; however, many of the other studies showed mixed results. In those studies examining resting motor threshold, corticospinal excitability, and long-interval intracortical facilitation, the majority of patients showed no difference, whereas patients in the remaining studies showed mixed results. Neuropathic pain was the only subgroup of pain that showed a significant effect, although migraine neared significance.32
TMS is indicated by the FDA for treatment of depression, and good data support its use. However, there are potential advancements in how TMS is administered that could lead to better outcomes or reduced administration times. Clinicians could also benefit from further research to establish guidelines for treatment if the patient relapses after successful treatment with TMS. TMS has potential for use in other neuropsychiatric disorders, although these areas require further study before it can be approved for widespread clinical use. Research in schizophrenia demonstrates that a single TMS target may not produce sufficient clinical response in disorders with broad symptoms; therefore, we may need to identify discrete treatment protocols and targets related to symptom clusters.
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