Transcranial magnetic stimulation (TMS) allows for direct modulation of the central nervous system (CNS) neuronal activity by magnetic field-induced electrical stimulation and subsequent depolarization of neurons through the mechanism described by Faraday’s law. When given in a series of pulse sequences, it is referred to as repetitive transcranial magnetic stimulation (rTMS). This is a noninvasive, office-based technique that is generally regarded as well tolerated and safe.1
The first TMS device, NeuroStar® TMS Therapy (Neuronetics, Malvern, PA), was cleared by the U.S. Food and Drug Administration (FDA) in 2008 for treatment of patients with depression who have not benefited from one prior antidepressant medication. This labeling was expanded in April 2014 to include treatment of adult patients with major depressive disorder who have failed to benefit from any number of antidepressant medications. A second device, Brainsway Deep TMS System (Brainsway, Jerusalem, Israel), received FDA clearance in 2013, also with an indication as is described for the April 2014 expanded labeling for NeuroStar TMS Therapy. Even before commercial availability, there had been an interest in using rTMS for the treatment of psychiatric conditions other than depression.2
With a selection of variables to manipulate and the potential for differing long-term effects on neuronal potentiation, rTMS has flexibility in its delivery and effects that are amenable to addressing underlying pathophysiology of differing diseases. The science of rTMS is not reviewed here but is covered in this issue in the article by Sauvé and Crowther. We only briefly mention diagnostic assessment using TMS, as this is beyond the scope of this article; however, coupling diagnostic TMS techniques to treatment delivery could theoretically enhance treatment specificity.
The complexity of the human brain limits accuracy of any magnetic stimulation. The network connectivity will lead to downstream effects from any pulse sequence delivery. Superficial targets on the cortex are likely to have distal impact that may not intuitively respond as predicted. Efforts to potentiate an area of cortical activity may decrease activity in a downstream structure.3 This connectivity requires providers to envision impact on a biological system, rather than a singular cause and effect of local stimulation.
Treatments are delivered at differing frequencies, with ≤1 Hz considered to be low frequency and ≥5 Hz considered to be high frequency, with varying impact on brain neuronal function.4 When evaluating clinical trials involving rTMS, multiple variables should be noted when interpreting results, beyond just the frequency of stimulation. Variations in stimulation time, intervals, total pulses, threshold stimulation intensity, frequency of treatment delivery, and total duration of treatments are some of the variables that can affect the ultimate impact on neuronal function and thus affect clinical outcome.
In the following sections, we present an update on clinical evidence for a variety of psychiatric conditions for rTMS other than the FDA-cleared indication of depression. This review is not meant to suggest treatment approaches and is not an endorsement of a clinical practice technique. Even with an attention to detail to replicate a treatment used in a clinical trial, providers must exercise sound clinical judgment. Providers must weigh the risks and benefits as well as alternate treatment options. There should be extensive informed consent counseling before deciding to pursue a treatment course that has not received clearance from the FDA. As with all novel medical therapies, the potential exists for unknown short- and long-term consequences that are not elucidated in small clinical trials or in trials without longitudinal assessment.
We describe clinical evidence for seven psychiatric conditions (posttraumatic stress disorder [PTSD], schizophrenia, dementia, bipolar disorder, obsessive-compulsive disorder [OCD], autism spectrum disorder [ASD], and attention-deficit/hyperactivity disorder [ADHD]) based on prevalence, current treatment options, theoretical neurobiological pathophysiology, and societal interest. Emphasis has been placed on clinical trials with specificity for treatment paradigms.
rTMS in Posttraumatic Stress Disorder
rTMS treatment of PTSD has appeal because it avoids issues of polypharmacy or patient intolerance that can occur with medication administration and exposure-based therapies, respectively. Studies of rTMS for treatment of PTSD have utilized various treatment frequencies and threshold intensities, making consensus analysis difficult.
In 2009, Rossi et al.5 clinically evaluated 20 patients with PTSD, treated with multiple approaches, and compared results with those of 16 healthy control subjects. The researchers investigated a wide set of TMS variables with intent to identify patterns of neurophysiological changes. The PTSD patients showed reversal toward facilitation of short-latency intracortical inhibition, which is where a conditioning subthreshold pulse (80% of resting motor threshold [RMT]) precedes the test pulse by 3 milliseconds, and is reflective of gamma-aminobutyric acid (GABA) A-ergic impairment. There was also a marked increase in intracortical facilitation in the right hemisphere, which is where a conditioning subthreshold pulse (80% of RMT) precedes the test pulse by 12 milliseconds, and suggests a predominance of glutamatergic activity. These results support the theoretical presence of bilaterally decreased GABA A-ergic tone and increase glutamatergic tone of the right hemisphere, and have helped suggest treatment pulse sequences for the disorder.
Boggio et al.6 indicated in their 2010 article that high-frequency stimulation (20 Hz) at the right dorsolateral prefrontal cortex (DLPFC) was successful for the treatment of PTSD. Additionally, no significant clinical worsening or discomfort occurred at this higher frequency. In a similar study that used rTMS at a lower frequency, Cohen et al.’s7 2004 double-blind, placebo-controlled study showed treatment using 10-Hz rTMS stimulation to right DLPFC had greater therapeutic effect on PTSD when compared with 1 Hz rTMS or sham. Watts et al.8 demonstrated statistically significant improvement in core PTSD and depressive symptoms with 1 Hz applied to the right DLPFC compared with sham.
Karsen et al.9 completed a recent meta-analysis using eight published studies. Their conclusion favored a benefit with rTMS treatment on PTSD symptoms, with right DLPFC stimulation possibly favored over left. Right-sided treatment frequencies of 1 Hz and 20 Hz did not distinguish themselves in efficacy, which was further complicated by varying threshold treatment levels between 80% and 120%.
Although the right DLPFC appears to be a viable target for rTMS treatment, frequency and threshold stimulation levels have yet to consolidate around agreed-on parameters. A significantly powered trial would help bring clarity to this debate. The use of TMS for assessment of cortical function has potential implications for both diagnosis and treatment, and further description of these parameters with clinical trials would be welcome.
rTMS in Schizophrenia
rTMS has been studied for a variety of symptoms associated with schizophrenia, including negative symptoms, hallucinations, and cognitive dysfunction. The potential benefit of a modality that is free from systemic side effects and does not require unsupervised treatment compliance is appealing. Several recent meta-analyses help interpret existing studies of this patient population.
The negative symptoms of schizophrenia contribute greatly to the social and occupational dysfunction inherent to this disorder and are often less favorably impacted by current pharmacological options than the companion positive symptoms. Shi et al.10 performed a meta-analysis assessing the effects of rTMS on negative symptoms of schizophrenia. Sixteen prospective studies published between 1999 through 2013, with a total subject population of 342 individuals, were included. The meta-analysis concluded there is a moderate effect size with high-frequency stimulation to the left DLPFC when rTMS is given daily for at least 3 weeks. Those patients with a longer duration of illness received less benefit from rTMS therapy. An older review and meta-analysis by Dlabac-de Lange et al.11 is also consistent with the conclusions of Shi et al.10
The impact of rTMS on auditory hallucinations is mixed. Slotema et al.12 completed a meta-analysis of 17 trials, including the addition of more recently published negative results. Despite a lessening of an effect size compared with prior meta-analysis, there appeared to be an acute small effect size that failed to differentiate 1 month after treatment when low-frequency stimulation is administered over the left primary auditory cortex. Older meta-analyses offer mixed conclusions regarding effectiveness of rTMS for auditory hallucinations.13–15
Although data currently exist supporting the use of rTMS in alleviating positive and negative symptoms via low-frequency and high-frequency stimulation of respective cortical regions, the totality of the evidence does not yet strongly support its use over traditional treatments of medication and electroconvulsive therapy (ECT).16
rTMS in Dementia
Diagnostic uncertainty can complicate the diagnosis and treatment of neurodegenerative conditions. Using analysis of the CNS response to various pulse sequences, TMS may have a role in demonstrating the physiology of cortical stimulation, connectivity, and plasticity, and thus assist with diagnostic clarity.17 This has allowed for the study of subtypes of dementia syndromes.18,19 As further characterization of differing dementia syndromes occurs with regard to cortical response with magnetic stimulation, this technology may offer a noninvasive method of facilitating diagnostic certainty in patients with cognitive decline.
Current treatments for dementia syndromes often have a suboptimal effect size. The geriatric population is vulnerable to medication side effects, and patients with memory disorders are often required to manage their own polypharmaceutical regimens. The allure of a method for direct brain stimulation to assist with memory impairment that avoids these clinical drawbacks is self-evident.
High-frequency rTMS may have utility in improving symptoms associated with Alzheimer’s disease (AD). In a trial of 45 patients, Ahmed et al.20 randomized subjects into one of three groups: high-frequency (20 Hz) bilateral DLPFC stimulation, low-frequency (1 Hz) bilateral DLPFC stimulation, or sham treatment over the same areas. Treatments delivered 2000 pulses daily for 5 days. Patients with mild to moderate dementia who received high-frequency stimulation demonstrated sustained improvement in Mini-Mental State Examination, Geriatric Depression Scale, and Instrumental Activities of Daily Living scales up to 3 months after treatment.20
Given the diffuse neurotoxicity seen with AD and the focal stimulation inherent in many TMS coils, global improvement may require treatment at multiple sites. Bentwich et al.21 enrolled eight patients in a case series where high-frequency treatment was delivered using magnetic resonance imaging navigation to six different cortical areas (bilateral dorsolateral prefrontal cortices, Wernicke’s and Broca’s areas, and bilateral parietal somatosensory association cortices) daily for 6 weeks and then twice weekly for 3 months. Alzheimer Disease Assessment Scale-Cognitive and Clinical Global Impression Scale scores improved significantly at 6 weeks and 4.5 months, respectively.21
Overall, rTMS has showed initial promise as a nonpharmacological adjunct to the treatment of dementia.22 However, most studies to date have been limited in size, and treatment locations and pulse sequences have been variable.23 Given the initial success of diagnostic assessment and treatment, TMS may have an expanding role in this patient population as further research is presented to guide clinical delivery.
rTMS in Bipolar Disorder
Despite the defined role of ECT in the treatment of bipolar disorder, the use of rTMS has been less clear for this condition. Differing pulse sequences are likely required for the various mood states inherent to this disorder, specifically depression, mania, and mixed. Further complicating study are the potential confounders of adjunctive medication versus rTMS monotherapy.
The majority of current efforts in the use of rTMS in bipolar spectrum disorders have focused on bipolar depression. A sham-controlled trial that randomized 23 patients (12 bipolar I, 9 bipolar II, 2 bipolar I mixed) to receive sham or daily left pre-frontal rTMS (5 Hz, 110% MT, 8 seconds on, 22 seconds off, over 20 minutes) for 2 weeks showed no statistically significant difference in the antidepressant effect of the active treatment.24
Other open-label studies and case reports using rTMS as an adjunct to standard care have shown positive outcomes when targeting bipolar depression. Harel et al.25 used an H1 coil to stimulate the left prefrontal cortex (20 Hz, 120% MT, 2 seconds on, 20 seconds off, totaling 1680 stimuli) in 19 patients for 4 weeks, showing a statistically significant decrease in Hamilton Depression Rating Scale (HDRS) scores. Dell’Osso et al.26 reported a case series of 11 patients with bipolar depression treated for 3 weeks at 1 Hz, 110% MT, 300 stimuli per day, over the right DLPFC, with improvement across a variety of metrics.
When treating bipolar depression, concerns in this patient population include treatment-emergent mania and hypomania (TEM).27 A meta-analysis offers some reassurance, showing no statistically significant difference in pooled data from 10 studies, with rates of TEM of 0.84% for the active treatment groups and 0.73% for the sham groups.28 Ultimately, the balance of safety and efficacy with differing frequencies over the left or right DLPFC remains poorly defined and further study is needed.
No randomized controlled trials (RCTs) have been conducted in bipolar mixed patients. A single prospective open-label study with 40 patients with bipolar mixed episode underwent adjunct 1 Hz rTMS applied to the right DLPFC as treatment for 3 weeks.29 Using the HDRS, there was a 46.6% responder rate, of which 28.6% remitted, whereas for the Young Mania Rating Scale (YMRS) there was a 15% responder rate. Although these results have methodological limitations, they suggest that low-frequency stimulation of the right DLPFC might be a target for treatment of bipolar mixed states.
A single RCT of 41 patients with bipolar mania showed statistically significant change in YMRS and Clinical Global Impression-Symptoms (CGI-S) following treatment with 20 Hz rTMS over the right DLPFC for 10 days.30 There are two case series also suggesting benefit to high-frequency stimulation of the right DLPFC.31,32 Although limited, these data suggest possible benefit to high-frequency stimulation of the right DLPFC in bipolar mania.
Overall, there is currently a lack of robust evidence for the efficacy of rTMS in bipolar depression, mixed state, and mania. More RCTs are needed prior to wider recommendation of rTMS in bipolar spectrum disorders.
rTMS in Obsessive-Compulsive Disorder
OCD has been theorized to be associated with dysfunction of frontal cortical-striatal connectivity.33 Dysfunction of these neurophysiological constructs would seem amenable to rTMS manipulation, although consistent efficacy with defined treatment locations and pulse sequences has been elusive.
Greenberg et al.34 reported modest success with 20-Hz stimulation at 80% of the MT over the right prefrontal cortical area, after rotating treatment sites in a group of eight patients with OCD. Alonso et al.35 followed this study with a randomized, sham-controlled trial using 1-Hz stimulation of the right prefrontal cortex, but was unable to show any benefit over sham treatment. Low-frequency stimulation of the left DLP-FC has failed to show consistent benefit in several trials since this initial work.36 There is growing evidence that low-frequency stimulation of bilateral supplementary motor areas may offer more convincing benefit for core OCD symptoms.37,38
Treatment of OCD symptoms with rTMS needs further study to confirm treatment location and pulse sequences that offer the greatest likelihood of benefit. Low-frequency stimulation of the right DLPFC does not appear to be a viable treatment option. Low-frequency stimulation of the supplementary motor areas holds promise, but larger powered studies are needed to confirm initial results.
rTMS in Autism Spectrum Disorder
Autism spectrum disorder (ASD) has few medical interventions available to improve core symptoms. Given a neurobiologic basis to the disorder, modalities such as rTMS that directly impact central nervous system activity are of interest. Despite a theoretical promise, scant data to date support the use of rTMS for this disorder, and optimal treatment location is uncertain.
Enticott et al.39 reported a recent, single randomized clinical trial with predominantly male Asperger’s syndrome or high-functioning autism patients. Sixteen patients received treatments to bilateral dorsomedial prefrontal cortices (5 Hz, with total of 1500 pulses per session) using a HAUT-coil, and 14 received treatment with a sham coil system for 10 sessions over 2 weeks. Those patients who received active rTMS had significantly reduced social relating impairments as measured by the Ritvo Autism-Asperger’s Diagnostic Scale, and decreased self-oriented anxiety in difficult social environments as measured by the Interpersonal Reactivity Index.
Further investigation is needed to determine what role rTMS may have in the treatment of ASD. The use of functional neuroimaging, to confirm hypothesis for mechanism of action and to better refine pulse sequences that impact target areas, is needed.
rTMS in Attention-Deficit/Hyperactivity Disorder
The use of rTMS in understanding ADHD pathophysiology has been undertaken in multiple studies.40–42 However, studies of treatment efficacy with rTMS in either inattention or hyperactivity are lacking. Complementing case reports is a single pilot study conducted with 13 patients using a crossover, double-blind, randomized, sham-controlled design with application of a single session of high-frequency rTMS directed to the right prefrontal cortex.43 The end-outcome measured attention at 10 minutes post-rTMS treatment, showing significant improvement in attention scores compared with sham treatment. The clinical significance of improved attention at 10 minutes post-rTMS treatment is unclear and further studies are needed.
rTMS is a noninvasive neuromodulation procedure approved by the FDA for the treatment of depression that has failed to respond to any number of antidepressant trials. There is interest in its utility for other conditions beyond that included in its FDA clearance. Overall, most trials for other psychiatric conditions are not highly powered, and definitive interpretation is not possible. Within a specific psychiatric condition, several different types of pulse sequences and treatment locations may be reported, further clouding interpretation.
For PTSD, the data suggest the right DLPFC is a viable target for rTMS stimulation, but there is debate as to which frequency and threshold stimulation levels are most efficacious. rTMS in schizophrenia suggests high-frequency stimulation of the left DLPFC may have some benefit in negative symptom relief, and low-frequency stimulation of the primary auditory cortex may assist with auditory hallucinations. Neither of these treatments have proven benefit over more traditional treatment modalities. The role of rTMS in the diagnosis and treatment of dementia is promising, but further studies are needed, and focal treatment administration for a disease that affects larger areas of the brain remains an issue to be resolved. Data for bipolar disorder was inconsistent across the spectrum of mood states inherent to this disorder, and further clarity needs to be achieved to determine possible treatment location and pulse sequences. Data suggest that treatment of OCD with low-frequency stimulation of the right DLPFC is ineffective, but early data suggest a possible benefit with the supplementary motor areas as a target. Both ASD and ADHD lack enough data to draw definitive conclusions, and both conditions require further study.
In the years to come, it is likely that rTMS will have an expanding role in the treatment of psychiatric illnesses. Differing coil designs and pulse sequence parameters serve to increase the flexibility of this tool in its application to a variety of conditions. Although rTMS is believed to be safe and well tolerated, the total number of patients treated for conditions other than depression is so small that having such a reassurance is premature. The desire for clinical altruism should not outpace cautious advancement of this field through careful clinical study with protections and oversight afforded through the scientific process.
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