INTRODUCTION — Many patients with unipolar major depression do not respond to standard treatment with pharmacotherapy and psychotherapy [1,2] and are thus candidates for noninvasive neuromodulation procedures, including repetitive transcranial magnetic stimulation (TMS) and electroconvulsive therapy (ECT) [3-7]. Although ECT is more efficacious than repetitive TMS [8,9], patients may prefer repetitive TMS because it is better tolerated and unlike ECT, TMS does not require general anesthesia and induction of seizures.
This topic reviews the technique for performing TMS to treat unipolar major depression in adults; the indications, efficacy, and safety of TMS are discussed elsewhere. Other neuromodulation procedures, including ECT, magnetic seizure therapy, focal electrically administered seizure therapy, transcranial direct current stimulation, transcranial low voltage pulsed electromagnetic fields, cranial electrical stimulation, vagus nerve stimulation, deep brain stimulation, direct cortical stimulation, and ablative neurosurgery, are also discussed separately, as is choosing treatment for treatment resistant depression and treatment refractory depression:
●(See "Unipolar depression in adults: Overview of neuromodulation procedures".)
●(See "Overview of electroconvulsive therapy (ECT) for adults".)
●(See "Unipolar depression in adults: Treatment with surgical approaches".)
●(See "Unipolar depression in adults: Choosing treatment for resistant depression".)
●(See "Unipolar depression in adults: Management of highly resistant (refractory) depression".)
OVERVIEW — Repetitive transcranial magnetic stimulation (TMS) treats major depression by modulating activity in cortical regions and associated neural circuits [10]. The intervention uses an alternating current passed through a metal coil placed against the scalp to generate rapidly alternating magnetic fields, which pass through the skull nearly unimpeded and induce electric currents that depolarize neurons in a focal area of the surface cortex; some TMS devices may also stimulate deeper brain structures [11-13]. The magnetic field generated by repetitive TMS is comparable to that of a standard magnetic resonance imaging (MRI) device (approximately 1.5 to 3 Tesla); however, the TMS field is focal (beneath the coil), whereas the MRI field is large and fills the room housing the MRI device [12,14]. Repetitive TMS is comparable to electroconvulsive therapy in that both are noninvasive neuromodulation therapies. (See "Unipolar depression in adults: Overview of neuromodulation procedures", section on 'Noninvasive neuromodulation therapies'.)
SETTING — Repetitive transcranial magnetic stimulation is generally an outpatient procedure, with patients awake and seated in a reclining chair during treatment. Anesthesia is not used and patients can thus drive themselves to and from sessions, which typically last about 30 to 40 minutes [15]. The equipment used to administer transcranial magnetic stimulation is displayed in the graphic (picture 1).
SURFACE CORTICAL TMS — Repetitive transcranial magnetic stimulation (TMS) that stimulates the surface cortex is called surface cortical TMS or superficial TMS. Surface cortical TMS is the most widely used and studied form of TMS. Other forms of TMS include deep TMS, accelerated TMS, high dose TMS, theta burst TMS, and bilateral TMS. (See 'Deep TMS' below and 'Experimental techniques' below.)
The efficacy of surface cortical TMS is discussed separately. (See "Unipolar depression in adults: Indications, efficacy, and safety of transcranial magnetic stimulation (TMS)", section on 'Efficacy'.)
Treatment parameters — TMS can be delivered either as a single pulse (stimulus) or as a series of pulses called a train; stimulation with a train is called repetitive TMS [12,14]. The depth of stimulation is approximately 2 to 3 cm beneath the coil, and most repetitive TMS devices depolarize cortical neurons in a circular area with a diameter of about 2 to 3 cm. Parameters of repetitive TMS include [12,16]:
●Frequency – number of magnetic pulses per second (hertz).
•High (fast) frequency refers to stimulation delivered at >1 pulse per second (typically 10 to 20 pulses per second)
•Low (slow) frequency denotes stimulation delivered at ≤1 pulse per second
●Intensity – expressed as a percentage of the resting motor threshold, which is established by stimulating the motor cortex and determining the minimum amount of energy that is required to evoke a motor response in a specific muscle group (generally the contralateral small hand muscles). The motor response is assessed visually or with electromyography. Intensity is generally set at 100 to 120 percent of resting motor threshold.
●Train duration (on time; eg, 4 seconds).
●Intertrain interval – time between successive trains (off time, eg, 26 seconds).
●Number of trains per session (eg, 75).
Most studies report the number of pulses per session (eg, 3000), which is calculated from the frequency, train duration, and number of trains per session.
Stimulation site — Most clinical trials of repetitive TMS for unipolar major depression have stimulated a single cortical site [10]. Generally, the left dorsal lateral prefrontal cortex is targeted, and neuroimaging of depressed patients has found hypoactivity in the dorsal lateral prefrontal cortex [17]. However, some trials have stimulated the right dorsal lateral prefrontal cortex, and other trials have sequentially or simultaneously stimulated two cortical sites [18]. TMS of the dorsomedial prefrontal cortex has also been studied [19].
Acute treatment — For acute treatment of unipolar major depression, repetitive TMS is usually administered by stimulating the left dorsal lateral prefrontal cortex daily (Monday through Friday) over four to six weeks, using the following parameters (see 'Overview' above) [5,10,12,13,20]:
●10 magnetic pulses per second (hertz)
●3000 pulses per session
●100 to 120 percent of motor threshold (ie, the magnetic field intensity relative to the patient’s resting motor threshold)
However, the stimulation parameters required to optimize efficacy are not known, and administration of repetitive TMS is thus not standardized. As an example, meta-analyses have found that either low frequency (≤1 pulse per second) [21,22] or high frequency (≥5 pulses per second) [23] repetitive TMS is more effective than sham treatment, and that the benefits of low frequency and high frequency repetitive TMS are comparable [24]. Low frequency repetitive TMS is administered over the right dorsolateral prefrontal cortex and inhibits cortical activity, whereas high frequency repetitive TMS is administered over the left dorsolateral prefrontal cortex and enhances cortical activity.
The number of treatments necessary for patients with acute major depression is not clear. Some authorities suggest that a trial of repetitive TMS should last a minimum of three to four weeks before determining whether the treatment is beneficial [16]. In addition, it is reasonable to extend treatment beyond six weeks for an additional two to six weeks for patients who have achieved a partial response that has not plateaued and for patients with a prior history of late response (eg, after 10 weeks) to antidepressant medications [12]. Evidence supporting treatment beyond six weeks includes the following:
●In an observational study, 73 patients with unipolar major depression who did not respond to daily repetitive TMS for four to six weeks were treated for an additional six weeks; response (improvement from baseline on the depression rating scale ≥ 50 percent) occurred in 26 percent [25].
●Another observational study enrolled 61 patients who did not initially respond satisfactorily to acute TMS and then administered additional acute TMS, such that patients received a total of up to 12 weeks of acute TMS; remission occurred in 31 percent [26].
Treatments can be spaced rather than administered on a daily basis [27]. In a randomized trial, repetitive TMS given three days per week for six weeks (18 sessions) was compared with repetitive TMS given five days per week for four weeks (20 sessions) in 77 patients with major depression; improvement and tolerability were similar [28].
Positioning the magnetic coil to stimulate the left dorsal lateral prefrontal cortex is typically performed by first identifying the optimal spot on the scalp for evoking a motor evoked potential in the hand muscles, and then advancing the coil 5 cm anteriorly in a parasagittal plane along the skull surface (some authorities measure 6 to 7 cm) [12,16,29]. However, the utility of this approach is limited because patients have varying brain sizes and morphology. Thus, neuronavigation guided by magnetic resonance imaging scans has been used in some research protocols to localize the prefrontal cortex [13,30].
Safety measures for repetitive TMS include use of hearing protection (eg, ear plugs) and keeping oxygen and anticonvulsant medications available for treatment of seizures, which are consistent with repetitive TMS safety guidelines [31,32]. The risk of hearing loss and seizures is discussed elsewhere. (See "Unipolar depression in adults: Indications, efficacy, and safety of transcranial magnetic stimulation (TMS)", section on 'Safety and adverse effects'.)
Acute repetitive TMS can be used with or without concurrent medications [12]. Concomitant psychotropic (eg, antidepressants) and nonpsychotropic medications are generally safe to use during a course of repetitive TMS for major depression [33,34], and most clinicians continue currently prescribed antidepressant drugs [12]. Some clinicians taper and discontinue proconvulsant medications (eg, bupropion, tricyclics, and theophylline). However, given the potential benefit of maintaining even partially effective medications, continuation of these medications is reasonable, provided that clinicians carefully monitor the motor threshold to ensure that stimulation intensity does not exceed the recommended safety range [35]. Intensity is discussed elsewhere in this topic. (See "Unipolar depression in adults: Indications, efficacy, and safety of transcranial magnetic stimulation (TMS)", section on 'Overview'.)
A psychiatrist should prescribe and supervise treatment of major depression with repetitive TMS, although individual treatments are often provided by a nurse, physician assistant, or medical assistant [12,14,32]. For most practice settings in which someone other than the psychiatrist is operating the TMS device, the psychiatrist is immediately available [12]. We recommend that all providers receive training through a formal university affiliated or industry independent certification course, or through peer to peer training, as well as industry sponsored training on the specific repetitive TMS system to be used. In addition, all personnel should be trained to recognize and initially manage generalized seizures:
●Immediately terminate the procedure
●Assess airway breathing and circulation
●Turn patients onto one side after convulsions cease to help clear the airway and prevent aspiration
For patients who complete acute treatment with repetitive TMS and are not receiving maintenance TMS (see 'Maintenance treatment' below), we typically discontinue TMS without a taper. However, it is reasonable for clinicians to taper TMS over two to three weeks before stopping it [12]. As an example, during a three-week taper, clinicians can administer three sessions in week 1, two sessions in week 2, and one session in the final week.
Maintenance treatment — For patients with unipolar major depression who respond to acute repetitive TMS and are at risk for recurrence, it is reasonable to use TMS for maintenance treatment; TMS is usually given in conjunction with antidepressant medications but can be used as the sole treatment [12]. Maintenance TMS typically uses the same stimulation parameters that were used during acute treatment, unless side effects necessitate changes [31,36,37]. However, the frequency of sessions for maintenance TMS has not been standardized, and it is not known whether any specific schedule is superior to another [5].
The most common maintenance TMS schedule appears to be one in which the number of sessions is gradually tapered over several months [36], and many clinicians determine the schedule based upon patient response [12]. Examples of specific, reasonable maintenance schedules that have been studied include the following:
●In a retrospective study of 42 patients, daily treatments were reduced to three sessions in week 1 of maintenance treatment, two sessions in week 2, and one in week 3 [31]. After one session per week for four weeks, the schedule was tapered further to two sessions per month for two months and then to one session per month. The frequency of sessions was intermittently increased or decreased depending upon the patient’s clinical status.
●A prospective observational study enrolled 35 patients who initially responded to acute TMS, then relapsed, and subsequently responded to a second course of acute TMS [37]. The maintenance TMS schedule was such that every month, patients received five sessions administered over three days.
It is not known how long patients should receive maintenance TMS. Across different studies, the duration has ranged from approximately six months to six years [31,36-38]. Based upon indirect evidence from studies of maintenance pharmacotherapy, patients with unipolar major depression who are at risk for recurrence of major depressive episodes are candidates for maintenance TMS lasting at least one year to three years. (See "Unipolar depression in adults: Continuation and maintenance treatment", section on 'Duration'.)
DEEP TMS — Commercially available repetitive transcranial magnetic stimulation (TMS) devices have been developed that theoretically stimulate brain structures beneath the superficial prefrontal cortex using magnetic coils (H coils); these H coils can induce a magnetic field with a deeper and wider distribution than the standard (figure eight) coils used for surface cortical TMS [39,40]. The H coils also stimulate surface cortical structures. It is not clear that stimulation of deeper brain structures with the H coils results in clinically or physiologically meaningful effects.
Several studies suggest that deep repetitive TMS may perhaps be safe and beneficial [12,41,42]:
●A four-week randomized trial compared daily deep TMS with sham TMS in 212 patients with treatment resistant depression, and found that remission occurred in more patients treated with active TMS (30 versus 16 percent) [43]. However, following daily treatment for four weeks, patients received additional study treatments two days per week for 12 weeks; remission at week 16 was comparable for deep TMS and sham TMS (29 and 22 percent of patients).
●A network meta-analysis (81 randomized trials, n >4000 patients) found that deep TMS was no more effective than sham TMS. The network meta-analysis included randomized trials that studied different modalities of TMS and thus relied upon indirect evidence of the efficacy of deep TMS compared with sham, as well as direct evidence [44].
The efficacy of deep TMS appears to be similar to that for surface cortical TMS; however, no head-to-head randomized trials have compared the two modalities.
EXPERIMENTAL TECHNIQUES — Investigators are studying several variations of administering repetitive transcranial magnetic stimulation (TMS) to patients with major depression [45]:
Accelerated TMS — To address the logistical constraint of standard repetitive TMS protocols that call for one session per day for four to six weeks, investigators have administered multiple sessions per day for less than four weeks in small studies. The results suggest that the benefit of accelerated protocols may be comparable to standard protocols, if not superior:
●A two-week randomized trial (n = 38 patients with major depression) compared active TMS (1500 pulses per session) with sham TMS administered twice per weekday [46]. Improvement was greater with active TMS on only one of the several outcome measures; following the two-week study, active TMS was provided once per day on an open-label basis for four weeks, and further improvement was observed during the four weeks.
●A three-week randomized trial compared active TMS delivered either twice per day or once per day (1600 pulses per session) in 52 patients with treatment resistant depression [47]. The study found a trend towards greater efficacy with twice daily TMS.
●An observational study administered 15 repetitive TMS sessions over two days (15,000 pulses in total) in an inpatient setting in 14 patients [48]. Response (reduction of baseline symptoms ≥50 percent) occurred in 6 patients (43 percent), and discontinuation of treatment due to adverse events in 2 (14 percent).
High dose TMS — Delivering more pulses than usual over the same treatment time frame (eg, 6000 pulses per session rather than 3000 pulses) has been tested as a means of improving response. An observational study of high dose repetitive TMS (6800 pulses per session) in 19 patients found that remission occurred in 12 (63 percent) and discontinuation of treatment due to adverse events in 2 (11 percent) [49].
Theta burst TMS — Theta burst repetitive TMS involves magnetic pulses that are administered at 50 hertz five times per second and are intended to mimic endogenous theta rhythms [50]; this approach appears to exert longer lasting effects upon motor cortex excitability than conventional repetitive TMS and requires less stimulation time (eg, 6 minutes per session rather than 30 to 40 minutes) [51]. Multiple randomized trials indicate that theta burst stimulation may be safe and beneficial:
●A conventional meta-analysis that used direct evidence from four randomized trials (n = 155 patients with major depression) found that response (reduction of baseline symptoms ≥50 percent) was more likely to occur with theta burst TMS than sham TMS (odds ratio 2.6, 95% CI 1.2-5.6) [44]. In addition, a network meta-analysis, which included both direct and indirect evidence, also found that theta burst TMS was efficacious [44]. In both meta-analyses, discontinuation of treatment for any reason was comparable for the active and sham treatment.
●A pooled analysis of five randomized trials compared theta burst TMS with sham TMS in patients with major depression (n = 221; primarily treatment resistant depression), and found that response occurred in more patients who received active treatment (36 versus 17 percent) [51]. In addition, discontinuation of treatment for any reason was comparable for active and sham theta burst TMS (4 and 8 percent).
●A subsequent four-week randomized trial compared add-on theta burst TMS with conventional TMS in 414 patients with unipolar major depression that did not respond to an antidepressant (which continued during the study) [50]. With conventional TMS, 3000 pulses per session were delivered over 37.5 minutes; with theta burst TMS, 600 pulses per session were delivered over 3 minutes. All participants received up to 30 daily sessions. Both treatments targeted the left dorsolateral prefrontal cortex with a stimulus intensity of 120 percent of resting motor threshold (see 'Treatment parameters' above). The trial was open-label, but outcome assessors were masked to treatment. The completer analysis showed that remission with theta burst and conventional TMS was comparable (32 and 27 percent). The most common adverse event was headache, which occurred in approximately 65 percent of patients in each group. Although average pain scores were modestly greater with theta burst TMS, all-cause discontinuation of treatment in each group was comparable (roughly 7 percent).
Bilateral TMS — Studies have combined high frequency stimulation of the left dorsolateral prefrontal cortex with low frequency stimulation of the right dorsolateral prefrontal cortex (either simultaneously or sequentially) during each session to test the hypothesis that stimulation of each side may activate complementary mechanisms that enhance efficacy. Although bilateral repetitive TMS is more efficacious than sham treatment [44,52], a meta-analysis of seven randomized trials (n >500 patients) found no advantage for bilateral repetitive TMS over unilateral repetitive TMS with regard to efficacy or discontinuation of treatment [53].
SUMMARY
●Patients with unipolar major depression who do not respond to standard treatment with pharmacotherapy and psychotherapy are candidates for noninvasive neuromodulation procedures, including repetitive transcranial magnetic stimulation (TMS). (See "Unipolar depression in adults: Indications, efficacy, and safety of transcranial magnetic stimulation (TMS)".)
●TMS modulates activity in cortical regions and associated neural circuits by passing an alternating current through a metal coil placed against the scalp to generate rapidly alternating magnetic fields, which pass through the skull and induce electric currents that depolarize neurons in a focal area of the surface cortex. TMS is delivered as a series of pulses called a train; stimulation parameters include frequency, intensity, train duration, intertrain interval, and number of trains per session. (See 'Overview' above and 'Treatment parameters' above.)
●TMS that stimulates the surface cortex is called surface cortical TMS, and is the most widely used and studied form of TMS. (See 'Surface cortical TMS' above.)
•Surface cortical TMS generally targets the left dorsal lateral prefrontal cortex, but some studies have stimulated the right dorsal lateral prefrontal cortex. (See 'Stimulation site' above.)
•For treating unipolar major depression, acute TMS is usually administered daily over four to six weeks, using 10 magnetic pulses per second; 3000 pulses per session; and 100 to 120 percent of motor threshold. (See 'Acute treatment' above.)
•However, the stimulation parameters, number of treatments, and position of the magnetic coil required to optimize efficacy for major depression are not known and administration is thus not standardized. It is reasonable to extend treatment beyond six weeks for an additional two to six weeks for patients who have achieved a partial response that has not plateaued and for patients with a prior history of late response (eg, after 10 weeks) to antidepressant medications. (See 'Acute treatment' above.)
•A psychiatrist should supervise the procedure, and safety measures include ear plugs and keeping oxygen and anticonvulsant medications available for treatment of seizures. Proconvulsant medications should generally be discontinued prior to administering repetitive TMS. (See 'Acute treatment' above.)
●Maintenance TMS typically uses the same stimulation parameters that were used during acute treatment, unless side effects intervene. The most common maintenance TMS schedule appears to be one in which the number of sessions is gradually tapered over several months, and many clinicians determine the schedule based upon patient response. (See 'Maintenance treatment' above.)
●TMS devices have been developed that theoretically stimulate brain structures beneath the superficial prefrontal cortex. (See 'Deep TMS' above.)
●Investigational techniques for administering TMS include an accelerated schedule as well as high dose, theta burst, and bilateral stimulation. (See 'Experimental techniques' above.)
