Treatment options for treatment-resistant depression are currently limited. More than 20 randomized controlled trials of prefrontal repetitive transcranial magnetic stimulation have been published. Knowledge of the risks and benefits of this unique treatment option is imperative for clinicians who treat these patients.
• Describe how repetitive transcranial magnetic stimulation is administered.
• Describe the acute efficacy data of prefrontal in treatment-resistant depression.
• Be familiar with the most common side effects of repetitive transcranial magnetic stimulation.
Primary care physicians and psychiatrists.
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Read this article and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME quiz. To obtain credits, you should score 70% or better. Termination date: October 31, 2007. The estimated time to complete all three articles and the quiz is 3 hours.
Primary Psychiatry. 2005;12(10):51-58
Dr. George is distinguished professor of psychiatry, radiology and neuroscience, director of the Center for Advanced Imaging Research, and director of the Brain Stimulation Laboratory (BSL); Dr. Nahas is the BSL medical director and assistant professor of psychiatry; Dr. Li is BSL research scientist at the Center for Advanced Imaging; Dr. Anderson is postdoctoral research nurse at the IOP; Dr. Molnar is postdoctoral research fellow at the Institute of Psychiatry (IOP); Dr. Kose is post-doctoral research fellow; Dr. Borckardt is postdoctoral fellow in the Department of Psychiatry and Behavioral Sciences; Dr. Ricci is visiting scientist at the IOP; and Dr. Mu is is research scientist, all at the Medical University of South Carolina in Charleston.
Disclosure: Dr. George is consultant to Cyberonics, Mindcare Centres, and Neuronetics; and receives research support from Mecta Corporation and Neuronetics. Dr. Nahas is a consultant to Mindcare Centres. Dr. George, Dr. Nahas, and Dr. Li receive grant support from the Borderline Personality Disorders Foundation, the Defense Advanced Research Projects Agency, the National Alliance for Research on Schizophrenia and Depression, National Institute of Mental Health grants R01-MH069887 and R01-MH069896, National Institute of Neurological Disorders and Stroke grant R01-AG40956, and the Stanley Foundation. Dr. Anderson, Dr. Molnar, Dr. Kose, Dr. Borckardt, Dr. Ricci, and Dr. Mu report no affiliations with or financial interests in any organization that may pose a conflict of interest.
Acknowledgments: The authors would like to thank Minnie Dobbins and Jerusha Wilson for administrative support.
Please direct all correspondence to Mark S. George, MD, Distinguished Professor of Psychiatry, Radiology and Neurosciences, Medical University of South Carolina, Charleston, SC 29425; Tel: 843-876-5142; Fax: 843-792-5702; E-mail: firstname.lastname@example.org.
Repetitive transcranial magnetic stimulation (rTMS) is a new brain intervention that modulates neuronal activity in discrete cortical regions and associated neural circuits by the noninvasive induction of intracerebral currents. Single pulse transcranial magnetic stimulation (TMS) is a unique method for mapping brain-behavior relations and functional connectivity, and probing cortical excitability. Repeated pulses are used in rTMS as a potential therapy. rTMS modulates activity in discrete cortical areas that, in turn, impact on specific pathways or brain networks. This spatial specificity may provide advantages by producing clinical improvement with reduced or minimal side effects. Standard pharmacologic interventions are limited by the inability to restrict their action to discrete brain regions. In addition to the spatial specificity, rTMS differs from pharmacologic interventions in the temporal domain. Medications act continuously in altering the physiology of brain and other organs, especially when steady-state levels are reached. In contrast, rTMS is delivered in a punctate fashion, akin to electroconvulsive therapy. The remarkable brevity of the TMS pulse (-200 μs) results in a total exposure to a time-varying magnetic field of only a few seconds over an entire rTMS treatment course, despite weeks of daily treatment sessions. This article focuses on the therapeutic potential of TMS for the acute treatment of depression, a domain that has been the subject of a large number of single site, small sample studies. Virtually all reviewers of this preliminary work have concluded that rTMS has antidepressant properties, with all meta-analyses indicating that there is a large effect size for symptom change when compared to sham treatment. Across the literature using active TMS, the median level of symptom change on the Hamilton Rating Scale for Depression has been on the order of 30%; approximately 10% of those receiving sham rTMS responded. Recent effectiveness data suggest that rTMS in clinical settings has similar effects as in the published controlled trails. Drastically improving on prior studies, an industry-sponsored multisite TMS trial designed for Food and Drug Administration submission is near completion, and a rigorous four-site National Institute of Mental Health-sponsored treatment trial is underway.
If one were to design the perfect antidepressant treatment, it would achieve complete symptom remission and complete restoration of day-to-day function, prevent relapse (return of the index episode) and recurrence (ie, new episodes), and have a minimal side-effect burden.1-8 We are a long way from that ideal. In fact, generally speaking, in randomized controlled trials of nonresistant, uncomplicated major depressive disorder (MDD), only 50% to 60% respond to any one medication; of this group, only two thirds (or 35% of the initial group) attain remission.7 The need to frequently augment or switch treatments is well recognized.9 While the therapeutic armamentarium developed over the past few decades has transformed the treatment of MDD, treatment-resistant depression (TRD) remains a common clinical problem, with ≤30% of patients not even partially responding and only a modest percentage remitting with antidepressant treatment.3,4,10,11 A conservative estimate is that 10% to 15% of patients remain chronically depressed with significant psychosocial morbidity despite aggressive pharmacotherapy.9,11
Failure to respond to an antidepressant treatment may arise either from intolerance of the medication or from resistance to the antidepressant effects. Treatment resistance is a major public health concern.12-15 Ideally, a new treatment would be as or more effective and have fewer side-effect burdens than our most powerful therapy, electroconvulsive therapy (ECT). Alternatively, the ideal is that a new treatment be as or more effective and as or better tolerated than medications, with minimal symptom breakthrough in the longer term; this option would reduce the need for ECT and would address the problem of high relapse rates following discontinuation of ECT. In short, a new treatment that fits into the treatment algorithm for depression,10 after several unsuccessful attempts at medication and psychotherapy treatment, would likely have a major impact on the public health and clinical practice.
What is Transcranial Magnetic Stimulation?
Transcranial magnetic stimulation (TMS) stimulates cortical neurons by creating a time-varying magnetic field generated by brief but powerful electrical currents.16 High-intensity current is rapidly turned on and off in the electromagnetic coil through the discharge of capacitors.17-27 The end result of TMS is thus electrical stimulation of the brain; some refer to TMS as “electrodeless electrical stimulation”.17-27 The electrical energy stored in a capacitor discharges and creates about 3,000 Amps. Through Maxwell’s equations and Faraday’s law, this creates a powerful magnetic field, on the order of 2 Tesla. This rapidly changing magnetic field (~30 KT/second) then travels across the scalp and skull and induces an electric field within the brain (~30 V/meter). This induces current to flow in the brain by creating a transmembrane potential.28 This localized pulsed magnetic field over the surface of the head depolarizes underlying superficial neurons,29,30 which then induces electrical currents in the brain.18 TMS, therefore, differs from techniques where direct electrical or magnetic energy is applied to the brain (such as ECT). TMS also radically differs from the use of low-level static magnetic fields as alternative therapies. Constant exposure to static magnetic fields can have biological effects.31 However, TMS does not produce magnetic fields for very long (microseconds), and they are relatively weak except directly under the TMS coil. It is thus assumed by most TMS researchers that TMS produces its behavioral effects solely through the production of electrical currents in brain cortex. The magnetic field induced by TMS declines rapidly with distance away from the coil. Thus, with current technology, TMS coils are only able to directly electrically stimulate the superficial cortex, and are not able to produce direct electrical stimulation deep in the brain.27,28,32 Although this shallow depth of penetration is a limitation of present technology, deeper brain structures can be influenced by cortical TMS, due to the cortex’s massive interconnections and redundant cortical-subcortical loops.33
An rTMS procedure is non-invasive and anesthesia is not required. TMS subjects are awake and alert; a hand-held electromagnetic coil is placed next to the head (Figure 1). In most laboratories, TMS patients sit upright or in a slight recliner, have their heads passively restrained, wear earplugs, and close their eyes and rest during the procedure. The TMS coil is initially positioned by the researcher and is held in place against the scalp using a coilholder. For most clinical trials in depression, the TMS device fires for short intervals (1–5 seconds), at a frequency of 1–20 Hz (times/second). Most depression studies have treated over the left prefrontal cortex, although there are some studies showing efficacy over the right prefrontal cortex as well.
TMS or rTMS over most cortical regions produces no easily observable response, so the only thing a subject notices is the noise (a loud clicking) and a sensation on the scalp. The scalp sensation results from the mild percussive effect of the electricity coursing through the TMS coil, and the stimulation of superficial nerves and scalp muscles. This is sometimes described as a “drawing” tight of the scalp muscles. TMS over certain nerves can be painful. However, for almost all regions except near the eyes, TMS is well-tolerated, with few dropouts in clinical trials or healthy volunteer research subjects. The amount of electricity needed to cause changes in the cortex varies from person to person, and from one brain region to the next.34 One commonly used method for standardizing and adjusting the amount of electricity delivered and induced by TMS across different individuals is to determine each person’s motor threshold (MT).35,36 The MT is commonly defined as the minimum amount of electricity needed to produce movement in the contralateral thumb, when the coil is placed optimally over the primary motor cortex.37
Overview of Published Depression Studies
Although there is controversy, and much more work is needed, certain brain regions have consistently been implicated in the pathogenesis of depression and mood regulation.38-45 These include the medial and dorsolateral prefrontal cortex, the cingulate gyrus, and other regions commonly referred to as limbic (amygdala, hippocampus, parahippocampus, septum, hypothalamus, limbic thalamus, insula) and paralimbic (anterior temporal pole, orbitofrontal cortex). A widely-held theory over the last decade has been that depression results from a dyregulation of prefrontal cortical and limbic regions.42,45-47 Daily prefrontal rTMS was developed as a potential treatment to manipulate these dysfunctional circuits.39,48
One way of evaluating TMS as an antidepressant is to perform meta-analyses on the published trials.48-69 There are five published independent meta-analyses of the published or public TMS antidepressant literature, each differing in the articles included and the statistics used.70-74 By and large, most depressed patients in these trials have not responded adequately to one or more medication trials prior to trying TMS. Thus, they represent a more treatment-resistant cohort than patients typically entering trials for a new antidepressant medication. The results of the five meta-analyses are the same—daily prefrontal TMS delivered over several weeks has antidepressant effects greater than sham treatment. For example, Burt and colleagues71 examined 23 published comparisons for controlled TMS prefrontal antidepressant trials, and found that TMS had a combined effect size of 0.67, indicating a moderate to large antidepressant effect. The meta-analysis conducted by Kozel and George72 was confined to published double-masked studies with individual data using TMS over the left prefrontal cortex. The summary analysis using all 10 studies that met criteria revealed a cumulative effect size of 0.53 (Cohen’s d) (0.31–0.97) with 220 patients. The most critical meta-analysis of the TMS antidepressant field was recently conducted using the guidelines put forth in the Cochrane library.73 However, even this stringent meta-analysis included 14 trials suitable for their analysis and found that left prefrontal TMS at 2 weeks produced significantly greater improvements in the Hamilton Rating Scale for Depression than did sham.73 They were critical about the size of the clinical effect. In summary, all
five meta-analyses of the TMS published literature concur that repeated daily prefrontal TMS for at least 2 weeks has antidepressant effects greater than sham.
Although there is general consensus that TMS has statistically significant antidepressant effects, a more important question is whether these effects are clinically significant. The meta-analyses above have on average an effect size of Cohen’s d of approximately 0.65, which is a moderate effect, in the same range as the effects of antidepressant medications. For example, small to medium effect sizes (0.31–0.40) are common in randomized controlled trials of novel antidepressants.75 Thus, with respect to whether or not TMS has clinical significance, an important clinical issue is whether TMS would be clinically effective in patients referred for ECT. This question has been addressed in a series of studies in which ECT referrals were randomized to receive either ECT or rTMS. In an initial study, Grunhaus and colleagues76 compared 40 patients who presented for ECT treatment and were randomized to receive either ECT or TMS. ECT was superior to TMS in patients with psychotic depression, but the two treatments were not statistically different in patients without psychotic depression. This same group recently replicated this finding in a larger and independent cohort with an improved design.77 Recently, Janicak and colleagues66 reported a similar small series, finding near equivalence between TMS and ECT, with a 55% reduction of symptoms with TMS and 65% with ECT. While relatively small sample studies have not established clinical equivalence between TMS and ECT,78 they do reveal similar effect sizes. The major differences between these studies and the rest of the controlled studies of TMS efficacy are patient selection (suitable for ECT), the length of treatment (3–4 weeks), the lack of a mask, and the lack of a sham control. Unfortunately, no studies have explicitly measured differences in cognitive side effects, although presumably TMS has no measurable cognitive side effects, while ECT has several. In a similar but slightly modified design, Pridmore79 recently reported a study in 22 subjects comparing the antidepressant effects of standard ECT (3 times/week), and one ECT session per week followed by TMS on the other 4 weekdays. At 3 weeks, both regimens produced similar antidepressant effects. Finally, Dannon and colleagues80 recently found that relapse rates in the 6 months following ECT or rTMS were similar (20% for either treatment). In summary, the studies to date suggest that TMS clinical antidepressant effects are in the range of other antidepressants, and persist as long as the clinical effects following ECT.
Are There Dose-Response Relationships?
Most of the rTMS studies on depression have followed the initial clinical studies and have explored only a small amount of the possible combinations of scalp location, frequency, intensity, daily dose, and time needed for response. Even with this limitation, some relationships have emerged.
TMS shows dose-response relationships in many of the domains where it is used. For example, each time a researcher determines a subject’s motor threshold, they are in fact determining a dose response relationship between the TMS dose and a behavior (thumb movement). In addition to the numerous electrophysiological studies showing TMS dose-response relationships,25,26,81-94 TMS intensity of stimulation has been shown to be important in blood oxygen level dependant (BOLD) functional magnetic resonance imaging (fMRI) (with higher intensity of stimulation producing more localized and distributed blood flow changes),95 as well as radiotracer studies,96 using TMS to create “virtual lesions”,92 and to influence the visual system.93,97 It seems natural, therefore, to wonder whether and to what degree the intensity of stimulation, or length of treatment, might be a factor in TMS antidepressant effects. For political and safety concerns, early TMS studies were short in duration (maximum 2 weeks), and employed doses that were sub-motor threshold.48,53,61 Kozel and colleagues98 at the Medical University of South Carolina (MUSC) initially found that TMS intensity affects clinical outcome.62 Another TMS depression study in elderly patients confirmed that TMS antidepressant response inversely correlated with prefrontal cortex distance.99 In related work at MUSC, Kozel and colleagues initially found and then confirmed in an independent healthy sample study conducted by McConnell and colleagues,100 that the TMS motor threshold increases with increased motor cortex to scalp distance. The TMS magnetic field and the ability to induce electrical currents in tissue decline exponentially with distance from the coil.28,101,102 Most recently, Padberg and colleagues67 have tested and found that higher intensity TMS has superior antidepressant effects than TMS at lower intensities.
Thus, it appears that there is a critical amount of TMS intensity needed to reach the cortex and treat depression. There is also a suggestion of a more complete intensity-response relationship.
The early clinical trials of TMS were brief (≤10 sessions), and were short due to the limited literature and concerns about safety and exposure of vulnerable populations to an unproven technique.48,53,61 However, more recent studies with longer treatment durations (>10 sessions) have produced higher rates of response, and even remission.103 As noted above, the studies directly comparing TMS with ECT have shown the highest TMS antidepressant effects. These studies have delivered TMS for at least 3 weeks (15 sessions), using a clinical response-driven algorithm to determine when to stop TMS.66,76,77,104 These clinical studies suggest, but do not prove, that treating for longer periods of time and with higher doses improves response and remission rates with TMS.
Studies Currently Underway
Although the design and sophistication of prefrontal rTMS trials have continued to improve,105 single-site studies are inherently limited in sample size and concerns about specific site confounds. Thus, two studies currently underway will be crucial in the development of prefrontal rTMS as a potential antidepressant treatment. Neuronetics, a TMS manufacturer based in Malvern, Pennsylvania, has launched a 21-site randomized controlled clinical trial (N=286) of daily prefrontal rTMS for depression. This study, if positive, will be submitted for potential Food and Drug Administration approval of the device for treating depression. This study completed enrollment in August 2005 and incorporates many innovations and improvements over previous studies, including a headholder for repositioning patients, a sham TMS coil, a high dose for 4–6 weeks, and follow-up to determine the durability of response.
An additional important ongoing study, funded by the National Institute of Mental Health, involves four US sites (Atlanta, Charleston, New York City, and Seattle). This randomized, controlled trial involves a variable dose design to determine the methods to optimize the delivery of TMS for the treatment of depression (Figure 2). This study also involves extensive brain imaging, electroencephalogram recording, and neuropsychological testing to potentially identify responders and markers of response. Additionally, this trial makes use of a new sham TMS system developed by Sackeim and the James Long Company where subjects and TMS administrators wear noise-cancelling earphones, and subjects receive either active TMS or, for those randomized to sham, a mild electrical surface stimulation that mimics the TMS skin sensation (Figure 1).
Safety and Tolerability
TMS is generally regarded as safe and without lasting side effects. There have been no significant cognitive,106,107 neurological,108 or cardiovascular sequelae reported as a result of rTMS. Patients treated with TMS may experience discomfort at the site of stimulation due to depolarization of sensory and motor neurons in the scalp under the point of stimulation. A muscle tension headache may result in some patients (generally estimated at <10% of sessions), and can persist for 1–2 hours poststimulation. These headaches are never disabling and always respond to aspirin or acetaminophen.
The primary safety concern with rTMS has been the risk of an accidental seizure induction. Eight seizures have been reported secondary to rTMS.109 These have occurred in a sample size estimated to be more than several thousand TMS treatment sessions. The TMS community has adopted and widely used the guidelines prescribing a safe interval between pulse trains110 and the safety guidelines from a National Institute of Neurological Disorders and Stroke workshop on TMS. To our knowledge, there have been only two publications since 1997 describing events during TMS that might be considered seizures. Conca and colleagues111 reported a patient who experienced a “pseudoabsence seizure.” It is unclear if this was a true seizure. Bernabeu and colleagues112 reported on a patient who had a seizure during rTMS. In this case, there was a brief interstimulus interval.
Subjects have been tested immediately following a TMS session, and have shown no significant neurocognitive side effects. They are thus free to return to work or drive themselves home after treatment. One report found evidence of short-term hearing loss in subjects who had been exposed to rTMS.37 A study of single pulse TMS in humans did not find any hearing loss.113 To our knowledge, there has been only one study of TMS effects on hearing in rats.114 Further animal research is needed. Of more importance to the field, Loo and colleagues115 found mild changes in auditory threshold in two depressed patients following a 2–4-week treatment regimen. This was mild and transient, and further safety testing appears warranted. In general, subjects in TMS studies should wear earplugs to minimize potential ear damage.
Several other case reports have been published with unclear significance. Zwanzger and colleagues116 reported one patient who developed new delusions during a 13-day treatment course with TMS. The patient had never suffered from psychotic depression in prior episodes. Holtzheimer and colleagues70 reported two bilingual patients who developed differences in the use of their preferred language during a course of rTMS treatment for depression. Researchers do not know the upper limit of safety regarding the total number of treatments to be delivered within a day or week. Previous rTMS studies as a treatment for depression consisted of 800–3,000 magnetic pulses per day, with 8,000–30,000 magnetic pulses over 2–3 weeks. In a study examining the effects of TMS on cognition following sleep deprivation, researchers at MUSC safely administered 12,960 magnetic pulses a day for up to 3 days to healthy young men. This equals 38,880 magnetic pulses over a 1 week period, which is likely one of the largest exposures of TMS to date. Despite this intense treatment regiment, no significant side effects were produced.
In sum, the short-term adverse events are mild discomfort at the site of stimulation, transient tension-type headaches on the day of stimulation, and concerns about high-frequency hearing loss. There is very little long-term (more than several weeks following treatment) safety data on subjects who have undergone TMS studies. The non-invasiveness and favorable safety profile of rTMS contribute to its promise as a potential new treatment.
How Might Repetitive Transcranial Magnetic Stimulation Work?
A thorough review of the imaging studies of TMS is beyond this review; however, combining TMS with functional and structural brain imaging is evolving as an important neuroscience tool for researching brain connectivity.117-124 Combining TMS with functional imaging can also inform using TMS as an antidepressant. In contrast to imaging studies with ECT which have found that ECT decreases global and regional activity,125 most studies using serial scans in depressed patients undergoing TMS have found increased activity in the cingulate and other limbic regions.126,127 Several recent studies combining TMS with other neurophysiological and neuroimaging techniques have helped to elucidate how TMS achieves its effects. Bohning and colleagues,28 at MUSC, have pioneered and perfected the technique of interleaving TMS with BOLD fMRI, allowing for direct imaging of TMS effects with high spatial (1–2 mm) and temporal (2–3 seconds) resolution.121,128-131 Another group in Germany has now succeeded in interleaving TMS and fMRI in this manner, replicating the earlier MUSC work.132 Work with this technology has shown that prefrontal TMS at 80% MT produces much less local and remote blood flow changes than does 120% MT TMS.95 Strafella and Paus133 used positron emission tomography to show that prefrontal cortex TMS causes dopamine release in the caudate nucleus and has reciprocal activity with the anterior cingulate gyrus.81 George and colleagues134 at MUSC, as well as researchers in Scotland126 and Australia,135 have all shown that lateral prefrontal TMS can cause changes in the anterior cingulate gyrus and other limbic regions in depressed patients. Recent work at MUSC has shown that left prefrontal TMS produces immediate blood flow increases in orbitofrontal cortex, hippocampus, and left prefrontal cortex.136 The brain imaging studies to date thus suggest that TMS delivered over the prefrontal cortex has immediate effects in important subcortical limbic regions, which are involved in mood and anxiety regulation.
Numerous animal studies have been important in trying to understand the modes of action of TMS. TMS studies with intracranial electrodes in rhesus monkeys have provided information about the nature and spatial extent of the rTMS-induced electric field.137 Corticospinal tract development, aspects of motor control, and medication effects on corticospinal excitability have been studied fairly extensively in non-human primates using single pulse TMS.138-143 Such work has yielded information about TMS neurophysiological effects, such as the observation that TMS-evoked motor responses result from direct excitation of corticospinal neurons at or close to the axon hillock.143
rTMS studies in rodents have reported antidepressant-like behavioral and neurochemical effects. In particular, rTMS enhances apomorphine-induced stereotypy and reduces immobility in the Porsolt swim test.144 rTMS has been reported to induce electroconvulsive shock-like changes in rodent brain monoamines, β-adrenergic receptor binding, and immediate early gene induction.145 The effects of rTMS on seizure threshold are variable and may depend upon the parameters and chronicity of stimulation.146 Pope and Keck147 have completed a series of studies using more focal TMS in rat models replicating and extending earlier TMS animal studies using less-focal coils. Most recently, Zangen and Hyodo,82 a Japanese group, has shown that prefrontal TMS in the rat induces increased levels of dopamine and glutamate in the nucleus accumbens.
In summary, recent pilot human, brain imaging, and animal data provide strong support that TMS has neurobiological effects similar to other somatic and pharmacologic antidepressant treatments. Although the exact mechanisms of action by which TMS improves mood are unknown, evidence to date shows that rTMS has the ability to affect most brain regions and neurotransmitter systems involved in regulating mood.
A growing body of data from clinical trials, human brain imaging, and animal studies, suggest that daily prefrontal rTMS for several weeks is an acute antidepressant treatment. However, further work is needed. In the clinical arena, the field awaits the results from ongoing multi-site trials. Additional studies are needed concerning optimizing the dose of rTMS, and predicting who responds. Finally, more human brain imaging studies and animal studies are needed to understand the neurobiological mechanisms of action of this most important neuroscience tool and potential therapy. PP
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