Psychiatric Annals

CME Article 

Treating Neuropsychiatric Disorders Other than Depression: Using Transcranial Magnetic Stimulation

Khurshid A. Khurshid, MD; Philip G. Janicak, MD

Abstract

Transcranial magnetic stimulation (TMS) involves the passage of pulsed electrical current through a ferromagnetic coil placed on the scalp. When stimulations are delivered in a rapid repetitive fashion (rTMS), this creates an intermittent magnetic field that passes painlessly through the tissues of the head, causing depolarization of neurons in the underlying cortex.1

While the primary therapeutic application of rTMS has been for depression, there are also positive controlled trials for several other neuropsychiatric disorders. These are complemented by open studies and case reports, many of which demonstrate benefit.

In this article, we review the existing evidence base, emphasizing data from controlled therapeutic trials of rTMS for disorders other than depression. These include neurological conditions such as pain disorders, Parkinson's disease, dystonia and tics, seizure disorders, and idiopathic tinnitus. Psychiatric conditions studied other than major depression have included obsessive-compulsive disorder (OCD), schizophrenia, catatonia, bipolar mania, posttraumatic stress disorder (PTSD), and nicotine dependence.

TMS has demonstrated benefit for acute and chronic pain syndromes (Table 1, see page 148). The use of rTMS was based in part on the observation that epidural electrodes provided relief from chronic pain.2–6 Following up on this observation, Tsubokawa et al.6 reported that symptoms faded for a maximum of 6 hours with rTMS stimulation over the motor cortex in 11 patients with thalamic pain. An anti-nocioceptive effect of rTMS over the primary motor cortex was also described by Migita et al.,7 who reported benefit in a 52-year-old man with left putaminal hemorrhage. A second patient (a 43-year old man with left thalamotomy for congenital cerebral palsy), however, did not respond to either rTMS or electrical stimulation over the motor cortex.

Table 1:

Controlled Trials of rTMS for Pain Management

Subsequently, seven controlled trials, three open trials, and several case reports used rTMS for the treatment of pain. Six of the seven controlled trials were double-blind, randomized designs, and all except one found rTMS effective in relieving pain.

Lefaucheur et al.8 studied 18 patients ages 28 to 75 (mean age 57.4) with drug-resistant, chronic neurogenic pain (11 men and seven women). The etiology was a thalamic stroke in six patients, a brain stem lesion in 6 paitnes, and a brachial plexus lesion in 6 paients. The study used rTMS over the motor cortex at 10 hertz or 0.5 hertz with 20 5-second trains, a 55-second intertrain interval (ITI), an 80% motor threshold (MT), and 20 minutes of total treatment. Treatment was compared with sham stimulation in a randomized, double-blind design. Significant differences in preand post-stimulation Visual Analog Scale (VAS) pain scores occurred only with the 10-hertz stimulation: 7.0 ±0.4 pre-stimulation versus 5.6 ±0.6 post-stimulation at 10 hertz (P = .001), compared with 6.8 ±0.4 pre-stimulation versus 6.5 ±0.4 post-stimulation for 0.5 hertz (P = .23) and 6.7 ±0.5 pre-stimulation versus 6.2 ±0.5 post-stimulation for sham stimulation (P = .19).

Rollnik et al.9 studied 12 patients with treatment-resistant, chronic pain syndromes (mean age 51.3 ±12.6; six men and six women). The investigators compared real rTMS over the corresponding motor cortex area (20 hertz; 20 2-second trains at 80% MT; 20-minute treament) to sham stimulation in a sequence-controlled, crossover design. They reported no significant difference between active and sham stimulation (mean VAS reduction: real rTMS, −4.0 ±14.1%; sham rTMS, −2.3 ±8.8%). All the patients, however, had an analgesic effect, and one patient with cervical myelopathy reported persistent pain relief for several days with active treatment.

Canavero et al.10 studied nine patients with central pain using rTMS over the motor cortex contralateral to the side of pain. Their stimulation parameters were 0.2 hertz, 2 trains of 10 stimuli, ITI 10 seconds, and…

Transcranial magnetic stimulation (TMS) involves the passage of pulsed electrical current through a ferromagnetic coil placed on the scalp. When stimulations are delivered in a rapid repetitive fashion (rTMS), this creates an intermittent magnetic field that passes painlessly through the tissues of the head, causing depolarization of neurons in the underlying cortex.1

While the primary therapeutic application of rTMS has been for depression, there are also positive controlled trials for several other neuropsychiatric disorders. These are complemented by open studies and case reports, many of which demonstrate benefit.

In this article, we review the existing evidence base, emphasizing data from controlled therapeutic trials of rTMS for disorders other than depression. These include neurological conditions such as pain disorders, Parkinson's disease, dystonia and tics, seizure disorders, and idiopathic tinnitus. Psychiatric conditions studied other than major depression have included obsessive-compulsive disorder (OCD), schizophrenia, catatonia, bipolar mania, posttraumatic stress disorder (PTSD), and nicotine dependence.

TMS for Pain Disorders

TMS has demonstrated benefit for acute and chronic pain syndromes (Table 1, see page 148). The use of rTMS was based in part on the observation that epidural electrodes provided relief from chronic pain.2–6 Following up on this observation, Tsubokawa et al.6 reported that symptoms faded for a maximum of 6 hours with rTMS stimulation over the motor cortex in 11 patients with thalamic pain. An anti-nocioceptive effect of rTMS over the primary motor cortex was also described by Migita et al.,7 who reported benefit in a 52-year-old man with left putaminal hemorrhage. A second patient (a 43-year old man with left thalamotomy for congenital cerebral palsy), however, did not respond to either rTMS or electrical stimulation over the motor cortex.

Controlled Trials of rTMS for Pain Management

Table 1:

Controlled Trials of rTMS for Pain Management

Subsequently, seven controlled trials, three open trials, and several case reports used rTMS for the treatment of pain. Six of the seven controlled trials were double-blind, randomized designs, and all except one found rTMS effective in relieving pain.

Lefaucheur et al.8 studied 18 patients ages 28 to 75 (mean age 57.4) with drug-resistant, chronic neurogenic pain (11 men and seven women). The etiology was a thalamic stroke in six patients, a brain stem lesion in 6 paitnes, and a brachial plexus lesion in 6 paients. The study used rTMS over the motor cortex at 10 hertz or 0.5 hertz with 20 5-second trains, a 55-second intertrain interval (ITI), an 80% motor threshold (MT), and 20 minutes of total treatment. Treatment was compared with sham stimulation in a randomized, double-blind design. Significant differences in preand post-stimulation Visual Analog Scale (VAS) pain scores occurred only with the 10-hertz stimulation: 7.0 ±0.4 pre-stimulation versus 5.6 ±0.6 post-stimulation at 10 hertz (P = .001), compared with 6.8 ±0.4 pre-stimulation versus 6.5 ±0.4 post-stimulation for 0.5 hertz (P = .23) and 6.7 ±0.5 pre-stimulation versus 6.2 ±0.5 post-stimulation for sham stimulation (P = .19).

Rollnik et al.9 studied 12 patients with treatment-resistant, chronic pain syndromes (mean age 51.3 ±12.6; six men and six women). The investigators compared real rTMS over the corresponding motor cortex area (20 hertz; 20 2-second trains at 80% MT; 20-minute treament) to sham stimulation in a sequence-controlled, crossover design. They reported no significant difference between active and sham stimulation (mean VAS reduction: real rTMS, −4.0 ±14.1%; sham rTMS, −2.3 ±8.8%). All the patients, however, had an analgesic effect, and one patient with cervical myelopathy reported persistent pain relief for several days with active treatment.

Canavero et al.10 studied nine patients with central pain using rTMS over the motor cortex contralateral to the side of pain. Their stimulation parameters were 0.2 hertz, 2 trains of 10 stimuli, ITI 10 seconds, and 100% machine capacity. They compared rTMS, a subhypnotic propofol test, and sham stimulation. Both rTMS and propofol stimulation relieved pain partially for up to 16 hours. The results were correlated between rTMS and the propofol test, which predicts short-term benefits with extradural cortical stimulation (ECS), known to allay central pain in some patients. Thus, the authors suggested that rTMS may be useful in patients selected for ECS.

In another trial, Lefaucheur et al.11 found that motor cortex stimulation with rTMS resulted in significant but transient pain relief in 60 patients suffering from intractable pain due to thalamic stroke, brainstem stroke, spinal cord lesion, brachial plexus lesion, or trigeminal nerve lesion. The authors used 20-minute active sessions versus sham stimulation at 10 hertz over the motor cortex corresponding to the hand on the painful side. Rating pain on the VAS before and after stimulation, the percent reduction was significantly greater following active versus sham stimulation (ie, −22.9% versus −7.8%, P = .0002).

Tamura et al.12 studied the efficacy of rTMS over the primary motor cortex for acute pain induced by intradermal capsaicin injections. To further clarify its potential mechanism of action, they also employed single photon emission computed tomography (SPECT) in seven normal participants under three different conditions — rTMS over the motor cortex, sham stimulation, and a control condition (natural course of acute pain without any stimulation). They also studied regional cerebral blood flow (rCBF) after capsaicin injection in ten normal participants under two conditions, rTMS over the motor cortex and a control condition. rTMS over the motor cortex induced earlier recovery from acute pain compared with the sham procedure or the control condition. When rTMS over the right motor cortex was compared with a control condition, SPECT demonstrated a significant rCBF decrease in the right medial pre-frontal cortex (mPFC) corresponding to Brodmann area (BA) 9, and a significant increase in the caudal part of the right anterior cingulate cortex (ACC), corresponding to BA 24, and the left premotor area, corresponding to BA 6. Further, there was a significant correlation between pain reduction and rCBF changes in both BA 9 and BA 24. The authors concluded that rTMS over the right motor cortex had beneficial effects for acute pain, which appeared to be mediated by functional changes in the mPFC and caudal ACC. The duration of pain relief in this study, however, was markedly shorter compared to other studies. This raises the question of whether a larger number of stimuli, a higher frequency, or both could induce a longer-lasting effect on pain perception.

Pleger et al.13 demonstrated relief in seven of 10 patients with complex regional pain syndrome type I (CPRS I). While some relief occurred 30 seconds after a stimulation, the maximum effect occurred at 15 minutes. The pain re-intensified, however, 45 minutes after the rTMS treatment. By contrast, sham rTMS did not alter pain perception. These findings provided evidence that CPRS I can be modulated by motor cortex stimulation with rTMS, offering an opportunity to stimulate the precentral gyrus in a noninvasive manner with limited side effects.

Summers et al.14 studied 40 healthy adults to compare the effects of low-frequency (1 hertz), high-frequency (20 hertz) and sham stimulation on pain threshold due to cold-water immersion of the right hand in a single-blind design. They found that rTMS at both frequencies significantly lowered the temperature at which cold sensation was detected, but only high-frequency rTMS produced a significant change in cold pain threshold.

Kanda et al.15 studied rTMS in nine normal subjects and concluded that stimulation of the sensorimotor cortex facilitated, while rTMS over the medial frontal cortex suppressed central processing of pain perception. Topper et al.16 studied rTMS over various cortical areas in two patients with pain due to cervical root avulsions and four normal controls. Experimental induction of pain was achieved by cold water immersion of the right hand. Using 1 hertz, 10 hertz, and 15 hertz rTMS for 2 seconds, they found that stimulation of the contralateral parietal cortex led to a reproducible reduction in pain intensity as measured by the VAS with pain relief lasting up to 10 minutes. There was no effect with rTMS in the control group.

In summary, rTMS has been shown to be effective in relieving acute and chronic pain due to various neurological disorders. It also relieved pain due to both central and peripheral lesions. The relief, however, was variable and usually short-lived. Further studies are needed to clarify the optimal parameters and elucidate the prognostic indicators that may predict sustained pain relief with rTMS.

TMS For Parkinson's Disease

The results of rTMS treatment studies for Parkinson's disease (PD) are conflicting. This may be due in part to variations in the stimulation parameters, as well as differing methodologies across studies. The effect of comorbid depression in PD also may have influenced the outcomes.

Wassermann and Lisanby17 reviewed the effects of rTMS as a treatment for PD in six studies. Three reported positive effects; one was neutral; and two reported worsening of measured tasks. Tsuji and Akamatsu18 concluded that the results of these studies did not prove or disprove the efficacy of rTMS for PD and suggested further studies to clarify the optimal stimulation parameters.

Given these discrepant results, we evaluated the most current evidence using a MEDLINE search to examine the role of rTMS for PD in studies reported subsequent to the first review. We found seven case-controlled trials, six indicating positive effects with rTMS and one showing similar improvement with both real and sham rTMS. The results of reported controlled trials are summarized in Table 2 (see page 150).19–22 The last study included 85 subjects and used the passage of electric current with electrodes fixed to the head to mimic real stimulation.22 Thus, it is possible that the electric current might have had some therapeutic effects.

Controlled Trials of TMS for Parkinson's Disease

Table 2:

Controlled Trials of TMS for Parkinson's Disease

In summary, rTMS may produce therapeutic benefit for Parkinson's disease. The magnitude and duration of this effect, however, are unclear. Optimal stimulation characteristics and predictors of treatment response also need to be better defined.

TMS for Other Movement Disorders

While there are no controlled trials assessing the efficacy of rTMS for the treatment of various movement disorders, neurophysiologic studies and case reports suggest a potential therapeutic role23–25 (Table 3).

Case Reports of TMS for Other Movement Disorders

Table 3:

Case Reports of TMS for Other Movement Disorders

rTMS for Seizure Disorders

Low-frequency (less than 1 hertz) rTMS reduces motor cortex excitability, while high-frequency (1 hertz or higher) rTMS can lead to seizures.26 In this context, we found one controlled trial, one open study, and several case reports which explored the possible therapeutic role of rTMS for seizures.

In an open study, Tergau et al.27 reported on nine patients with epilepsy using low-frequency rTMS (0.33 hertz; 100% MT; two trains of 500 pulses; 5 consecutive days). Eight of the nine patients had an improvement in the number or severity of seizures, or both. Mean seizure reduction after rTMS was 38.6% (SD 36.6; P = .017) based on self-rated seizure frequency for 4 weeks before and after the start of treatment. Further, the mean value of seizure-free period was increased from 11.0 (±7.5) to 15.3 (±9.0) days (P = .054). After 6 to 8 weeks, seizure activity again reached baseline levels, suggesting a short-lived effect.

Menkes and Gruenthal28 reported a case of focal cortical dysplasia that was treated with rTMS (0.5 hertz; 95% MT; 100 stimulations per session; twice a week for 4 weeks). The authors found a 70% reduction in seizure frequency and fewer EEG spikes during treatment compared with the pretreatment period.

Theodore et al.29 conducted a randomized, placebo-controlled, single-blind study of 24 patients with epilepsy. Parameters for rTMS were 1 hertz for 15 minutes twice daily at 120% MT for 1 week. The sham procedure angled the coil away from the scalp at 90 degrees. Weekly seizure frequency was compared for 8 weeks before and after 1 week of rTMS. When the 8-week baseline and poststimulation periods were compared, patients with active stimulation had a mean seizure frequency reduction of 0.045 (±0.13), and sham stimulated controls had a reduction of 0.004 (±0.20). After 2 weeks, actively treated subjects had a mean reduction in weekly seizure frequency of 0.16 (±0.18) and sham stimulated controls 0.01 (±0.24). None of these differences, however, achieved significance. Patients with neocortical foci had greater improvement than those with mesial temporal foci.

Graff-Guerrero et al.30 reported two patients with a diagnosis of epilepsia partialis continua who received high-frequency rTMS (20 hertz; 2-second train; 15 trains; 58-second ITI). Both patients showed decreased perfusion in the stimulated site after rTMS, suggesting reduced focal epileptogenic activity. In one patient, epileptic seizures stopped in 24 hours, but the other showed only minimal improvement, reflected by a decreased frequency of epileptic spikes.

Other applications of TMS for seizure disorders include the investigation of underlying cortical excitability, the determination of antiepileptic drug effects, preoperative localization of epileptic foci, and functional mapping.31

In summary, the limited data indicates a possible therapeutic effect with rTMS for seizures, particularly when given at low frequencies. It is hoped that the larger, better-controlled studies that are under way will confirm these potential effects. It is also important to clarify optimal stimulation parameters, especially location, since deeper cortical epileptic foci may be less amenable to rTMS.

TMS for OCD

We found three reported, randomized, double-blind, controlled trials of rTMS for OCD. Greenberg et al.32 compared high-frequency (20 hertz) right dorsolateral prefrontal cortex (DLPC) stimulation with left-sided stimulation in 12 patients with OCD. Significant improvement in symptoms occurred with right-sided stimulation, while left-sided stimulation had no therapeutic effect. Alonso et al.33 used rTMS at 1 hertz applied to the right frontal cortex compared to sham stimulation for 18 OCD patients. No significant improvement was seen in symptoms for either group. Sachdev et al.34 compared high-frequency (10 hertz) right DLPC stimulation with left-sided stimulation in 12 OCD patients. Overall, improvement was seen in both groups, with no significant difference between groups.

In summary, while therapeutic benefit and optimal stimulation characteristics are not clearly characterized, there is a signal that high frequency stimulation applied to the right side may improve OCD symptoms (Table 4, see page 152).

Controlled Trials of TMS for OCD

Table 4:

Controlled Trials of TMS for OCD

TMS for Schizophrenia

We found 15 studies that assessed rTMS for the treatment of schizophrenia. Nine were controlled trials, four of which used double-blind, randomized designs. There were also seven open trials and two case reports. Five controlled studies supported the use of adjunctive rTMS for schizophrenia, while four found no advantage.

Klein et al.35 compared low-frequency rTMS (1 hertz) applied to the right PFC with sham stimulation in 35 patients who were admitted for acute exacerbation of schizophrenia. The study found no significant difference between real and sham stimulation as measured on the Positive and Negative Syndrome Scale (PANSS), Brief Psychiatric Rating Scale (BPRS), Hamilton Depression Rating Scale (HDRS), and Abnormal Involuntary Movement Scale (AIMS).

Hoffman et al.36 studied three patients with schizophrenia and persistent auditory hallucinations. The authors compared low frequency (1 hertz) stimulation to the left temporoparietal cortex (TPC) with sham stimulation in a double-blind, placebo-controlled, crossover design. They reported positive results with left-sided stimulation as measured on a subjective rating scale for auditory hallucinations in two of the three patients.

Subsequently, Hoffman et al.37 reported on 12 patients with schizophrenia and refractory auditory hallucinations. Low-frequency rTMS (1 hertz over the left TPC) was applied in a double-blind, crossover design. Active stimulation significantly reduced hallucinations in comparison with sham stimulation.

Rollnik et al.38 studied rTMS for 12 patients with schizophrenia (four women and eight men, ages 25 to 63) in a randomized, double-blind, crossover design. These subjects received 2 weeks of daily, left prefrontal high-frequency rTMS (20 hertz; 2-second trains; 20 trains; 80% MT). BPRS scores significantly decreased with active versus sham procedure (P = .05). Of note, depressive and anxiety symptoms did not change. The authors concluded that rTMS may be effective in the treatment of refractory psychotic patients. d'Alfonso et al.39 studied nine patients with schizophrenia and medication-resistant auditory hallucinations. They used low-frequency stimulation over the auditory cortex and found significant improvements from baseline as measured on the Topography of Voices Rating Scale.

Hoffman et al.40 studied 24 patients with a diagnosis of schizophrenia or schizoaffective disorder who had medication-resistant auditory hallucinations. They compared low frequency (1 hertz) stimulation of the left TPC with sham stimulation and found a positive effect with real rTMS as measured by a VAS.

By contrast, Holi et al.41 examined the effects of rTMS in a double-blind study of 22 chronic, hospitalized patients with schizophrenia. They compared high-frequency real rTMS (10 hertz; 20 5-second trains; 100% MT; 30-second ITI) over the left prefrontal cortex to sham stimulation for 2 weeks. Although there was a significant improvement from baseline in both groups for most symptoms, no significant differences were found between groups. Further, a decrease of more than 20% on the total baseline PANSS score was found in seven control patients but in only one patient in the real rTMS group. Thus, there appeared to be no therapeutic effect with real rTMS in these chronic, severely ill patients.

Schonfeldt-Lecuona et al.42 studied 12 patients with schizophrenia, paranoid type, who had resistant auditory hallucinations for more than 6 months. They compared low-frequency, left superior temporal gyrus stimulation with sham stimulation and found no effects for rTMS.

McIntosh et al.43 applied low-frequency rTMS over the left temporal-parietal cortex in 16 patients with treatment-resistant hallucinations for at least 2 months. This was a randomized, double-blind, sham-controlled, crossover design. The stimulation parameters (1 hertz; 80% MT) were given for 4 days, with daily duration escalating from 4 to 8 to 12 to 16 minutes on subsequent days. Each minute of stimulation was followed by 15 seconds of rest to check coil position and allow the subject to move. There was comparable improvement in baseline hallucination scores with both real and sham TMS.

Franck et al.44 reported a patient with schizophrenia whose hallucinations improved after 10 sessions with 1 hertz TMS treatment near Wernicke's area. The patient previously had failed to respond to combined antipsychotic treatment.

In summary, there is conflicting data to support rTMS for treatment of hallucinations in schizophrenia. Further studies are needed to confirm or refute the potential therapeutic role of rTMS for auditory hallucinations, as well as other symptoms in schizophrenia. Optimal stimulation characteristics (eg, high-frequency versus low-frequeny stimulation also need clarification (Table 5, see page 154). Further, evidence of reduced brain response to rTMS and deficits in cortial inhibition must be accounted for in this population.45

Controlled Trials of rTMS for Schizophrenia

Table 5:

Controlled Trials of rTMS for Schizophrenia

TMS for Catatonia

Because ECT is an effective treatment for catatonia and there are some similar biological actions between ECT and TMS, it was hypothesized that TMS might be effective for catatonia. Grisaru et al.46 published the first case of catatonia that improved with TMS. This was a 24-year-old woman with a previous history of psychosis who presented with catatonia unresponsive to 15 days of haloperidol. Adjunctive high-frequency rTMS over the right prefrontal cortex (20 hertz; 80% MT; 20 2-second trains; 58-second ITI) was given daily for 10 working days. Catatonic symptoms improved within 24 hours of the first treatment session and persisted throughout her course of treatment.

Saba et al.47 reported on an 18-year-old woman with catatonia who had failed 3 days of treatment with lorazepam. She was then treated with rTMS monotherapy over the left DLPC for 2 weeks (10 hertz; 80% MT; 10 sessions; 1,600 stimuli per day). Catatonic symptoms were assessed at baseline and then every 3 days. Her ratings dropped from a 19 on the Catatonic Rating Scale at baseline to 3 by day 12. She subsequently was diagnosed with paranoid schizophrenia, started on antipsychotic medications, and discharged to home in 4 weeks.

While there is a paucity of data, these positive case reports suggest that rTMS may have promise in the treatment of catatonia. Unfortunately, controlled trials in this patient population are unlikely.

TMS for Bipolar Mania

Our literature review yielded three trials using rTMS for mania (two controlled and one open), as well as one case report. Grisaru et al.48 conducted the first controlled trial for mania, employing adjunctive high-frequency rTMS over the right or left DLPC in 16 patients. Parameters included a frequency of 20 hertz, 66% to 76% MT, train duration of 2 seconds, ITI of 1 minute; and total treatment with 20 trains per day for 10 days. The authors reported significant improvement from baseline in manic symptoms with rTMS over the right DLPC. Of note, some subjects showed worsening of symptoms with left-sided stimulation, which might have affected the results.

Using the same stimulation parameters, Erfurth et al.49 concluded that rTMS monotherapy over the right prefrontal region was effective in treating mania in a 59-year-old woman refractory to sulthiame (an anticonvulsant used in Europe). She was treated daily during the first 2 weeks and then three times during weeks 3 and 4. Based on the Bech-Rafaelson Mania Scale, her symptoms steadily decreased (ie, 28 on day 0, 24 on day 7, 15 on day 14, 10 on day 21, and 8 on day 28), and she was discharged after 4 weeks of rTMS treatments.

Again, using similar stimulation parameters, Kaptsan et al.50 compared the effect of right prefrontal rTMS to sham stimulation over the same region in 25 inpatients with mania, 19 of whom completed the study. They did not find a difference between active and sham stimulation; however, their patients were more ill, with psychotic symptoms in 16 of 19 patients.

Michael et al.51 replicated the therapeutic effect reported by Grisaru et al.48 for rTMS over the right prefrontal region in an open trial of 16 patients with mania, using similar stimulation parameters.

In summary, there is some support for right-sided rTMS in mania, but larger trials will be necessary to confirm any potential benefit (Table 6, see page 155).

Controlled Trials of TMS for Mania

Table 6:

Controlled Trials of TMS for Mania

TMS for Posttraumatic Stress Disorder

Three studies assessed the therapeutic effect of rTMS for posttraumatic stress disorder (PTSD). One was double-blind, placebo-controlled, and two were open-label designs. Grisaru et al.52 noted improvement in core PTSD symptoms with bilateral rTMS over the motor cortex in 10 patients. Improvement was assessed by the Impact of Events Scale, Symptom Check-List-90, and Clinical Global Impression (CGI) scale.

Rosenberg et al.53 reported significant improvement in depressive symptoms — 50% or greater improvement in baseline HDRS and Profile of Moods States (POMS) scores — but only minimal improvement in PTSD symptoms in 12 patients with comorbid depression.

Cohen et al.54 compared right DLPC rTMS (10 hertz, 1 hertz, or sham stimulation) given daily for 10 days in 24 patients with PTSD. Improvements were seen both in core symptoms of PTSD and anxiety symptoms, based on the PTSD Checklist, the Treatment Outcome PTSD Scale, the Hamilton Anxiety Scale, and the Hebrew Version of the Clinically Administered PTSD Scale.

In addition, McCann55 reported two cases of PTSD that improved with rTMS applied to the right frontal region.

In summary, these studies indicate that TMS may be efficacious for PTSD, particularly right frontal stimulation (Table 7).

Controlled and Open Trials of TMS for PTSD

Table 7:

Controlled and Open Trials of TMS for PTSD

rTMS for Nicotine Dependence

We found two controlled trials of TMS for nicotine dependence that reported promising results. Johann et al.56 studied 11 tobacco-dependent smokers, using a randomized, placebo-controlled design. They compared high-frequency rTMS over the left DLPC with sham stimulation and found a significant decrease in cravings with real rTMS as measured on a VAS.

Eichhammer et al.57 studied 14 treatment-seeking smokers using high-frequency stimulation (20 hertz) over the left DLPC, comparing active and sham stimulation in a double-blind, crossover design. They found a significant decrease in the number of cigarettes smoked with active versus sham stimulation.

The sample sizes in these studies were small, however, and these findings need replication in larger trials (Table 8).

Controlled Trials of TMS for Nicotine Dependence

Table 8:

Controlled Trials of TMS for Nicotine Dependence

Summary

While the therapeutic use of rTMS has focused primarily on depression, several other neuropsychiatric disorders have also been considered. The database thus far is modest but promising for some of these conditions (eg, pain disorders, schizophrenia).58 Paralleling the experience with depression, the optimal application of stimulation parameters, difficulty in developing an adequate sham condition, and reliance on small samples from single sites render interpretation of positive results preliminary.

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Controlled Trials of rTMS for Pain Management

Study Subjects/Assessments Study Design Results Comments
Lefaucheur et al.8 n = 18 Chronic, medication-resistant neurogenic pain Assessment: 0–10 VAS DB, PC Motor cortex 10 Hz, 0.5 Hz, or sham 20-minute sessions Significant decrease in the mean pain level only with 10 Hz rTMS. Only high-frequency rTMS effective in reducing pain.
Rollnik et al.9 n = 12 Chronic, resistant pain Assessment: 0–10 VAS PC Motor cortex 20 Hz, 80% MT 20 2-second trains 20-minute sessions 800 pulses per second All patients experienced analgesic effects. One patient with cervical myelopathy reported persistent relief. for several days No significant difference between active and sham stimulation. The small sample size may have failed to detect beneficial effect with rTMS. Unclear if pain medication was continued.
Canavero et al.10 n = 9 Central pain Assessments: VAS/NRS at the end of first train and every 10 minutes thereafter for next hour; self-report over next 24 hours PC (TMS, subhypnotic propofol test, and sham) Motor cortex contralateral to pain 0.2 Hz 2 trains of 10 stimuli at maximal power (100% of machine capacity) 10-second ITI Sham stimulation ineffective. TMS and propofol relieved central pain partially for up to 16 hours. Positive correlation between TMS and propofol test (r = 0.89, P = .002). TMS may be useful in patients selected for ECS, as its effects correlated with propofol test. However, it was unclear if pain medication was continued.
Lefaucheur et al.11 n = 60 Intractable pain secondary to thalamic stroke, brainstem stroke, spinal cord lesions, brachial plexus lesions, or trigeminal nerve lesions Assessments: VAS before and after stimulation PC Motor cortex contralateral to pain 10 Hz 20 minutes Percent pain reduction significantly greater with real versus sham stimulation. rTMS was effective in reducing chronic pain.
Tamura et al.12 SPECT in 7 normal subjects rCBF changes in 10 normal subjects Capsaicin injections Assessment: 0–10 VAS SB Motor cortex 1 Hz, sham, control condition Acute pain induced by capsaicin injections rTMS induced early recovery. rTMS over motor cortex beneficial for acute pain. rTMS induced functional changes in mPFC and ACC.
Pleger et al.13 n = 10 Unilateral CPRS I Assessments: Subjective VAS PC Motor cortex contralateral to CRPS-affected side 10 Hz 7 of 10 patients improved significantly. rTMS may be useful for CPRS I.
Summers et al.14 n = 40 Healthy volunteers Assessments: 0–10 VAS, 0–100% depression PC, SB Contralateral parietal cortex 1 Hz, 20 Hz, or sham Comparison of pain threshold after cold-water immersion of right hand Both 1 Hz and 20 Hz rTMS significantly reduced temperature at which cold sensation was detected. rTMS can alter sensory thresholds and influence the sensation of pain in healthy adults.

Controlled Trials of TMS for Parkinson's Disease

Study Subjects/Assessment Study Design Results Comments
Shimamoto et al.19 n = 18 Assessments: Modified Hand Y, UPRDS, Schwab and England ADL DB, PC Real: n = 9; sham: n = 9 Frontal area Pulse intensity of 700 v 0.2 Hz 60 times per sessions (ie, 30 times per side) Once a week for 2 months rTMS significantly decreased modified Hand Y and UPRDS scores after 2 months. Schwab and England ADL scores were increased significantly. No change in controls. rTMS beneficial for PD symptoms.
Sommer et al.20 n = 20; 11 PD patients, nine healthy controls Assessments: finger tapping frequency PC Contralateral motor cortex of the more affected hand 1 Hz 900 stimuli Real rTMS increased finger tapping frequency. No change with sham stimuli or or in controls. Improvement with real rTMS.
Khedor et al.21 n = 36 No medications Assessments: UPRDS, walking speed (self-assessment scales on days 1, 5, 10 and after 1 month) DB, PC, randomized 5 Hz 2,000 pulses per day for 10 days Real rTMS resulted in significant, long-term improvement of motor function. A 10-day course of rTMS produced significant improvement in motor symptoms up to 1 month.
Okabe et al.22 n = 85 Assessments: UPRDS, HDRS, subjective VAS DB, PC, randomized Three stimulation groups: Motor cortex, occipital, sham (vertex, 0.2 Hz) 100 stimuli, 1.1 times MT Once weekly for 8 weeks UPRDS and HDRS scores improved equally in all groups. No significant changes in subjective scores across groups. Possible placebo effect of 0.2 Hz rTMS. Sham produced effects similar to real stimulation.

Case Reports of TMS for Other Movement Disorders

Study Subjects Study Design Results Comments
Karp et al.24 Case report Tic disorder Motor cortex 1 Hz rTMS decreased the frequency of tics. Possible therapeutic effect of TMS in tic disorder.
Siebner et al.25 Case report Writer's cramp Motor cortex 1 Hz Prolonged cortical silent period and and decreased writing pressure. Transient improvement. Possible therapeutic effects.

Controlled Trials of TMS for OCD

Study Subjects/Assessment Study Design Results Comments
Greenberg et al.32 n = 12 M/F: 6/6 Mean age: 36.9 Assessments: YBOCS, HDRS, NIMH Self-Rating Scale DB, randomized, crossover Lateral DLPC 20 Hz, 80% MT 2 seconds per minute for 20 minutes Right DLPC stimulation significantly decreased compulsive urges for up to 8 hours and improved mood. Left DLPC stimulation showed no effect on symptoms. Only right DLPC stimulation improved OCD and mood symptoms.
Alonso et al.33 n = 18 M/F: 6/12 Mean age: 35.27 Assessments: YBOCS, HDRS DB, PC Real: n = 10; sham: n = 8 Right PFC 1 Hz 110% MT for real rTMS, 20% MT for sham rTMS 18 sessions Low-frequency rTMS over right PFC equal to sham procedure. Low-frequency, right PFC rTMS did not improve OCD symptoms.
Sachdev et al.34 n = 12 resistant patients with OCD M/F: 9/3 Mean age: 40.5 Assessments: YBOCS, MADRS, BDI, Spielberger State-Trait Anxiety Inventory DB, randomized, parallel design Lateral DLPC 10 Hz Daily for 2 weeks Assessed at weeks 1, 2, and 4 Overall improvement in OCD symptoms in 25% of patients. No difference between right and left rTMS. Improvement with rTMS on either side. Placebo effect could not be ruled out.

Controlled Trials of rTMS for Schizophrenia

Study Subjects/Assessment Study Design Results Comments
Klein et al.35 n = 35; hospitalized for acute exacerbation Assessments: PANSS, BPRS, HDRS, AIMS PC, randomized Right PFC, 1 Hz, 1 minute 2 stimulations 3-minute ITI Daily for 10 days Real rTMS was equal to sham procedure. Slight improvement in all scores over time. No significant differences between active and sham stimulation.
Hoffman et al.36 n = 3; persistent AHs Assessment: Rating Scale for AH individualized for each patient (10 = narrative description of AHs by patient; 0 = no AHs) DB, PC, crossover Left TPC, 1 Hz Two patients showed near total resolution of AH with real rTMS. Positive results with low-frequency stimulation over the left side.
Hoffman et al.37 n = 12 8 with schizophrenia, paranoid type; 4 with schizoaffective disorder; all with chronic daily AHs Assessment: PANSS DB, PC, crossover Left TPC, 1 HZ, 80% MT Localization with functional neuroimaging Significant improvement in AHs was seen with active stimulation based on improvements in severity of hallucinations on PANSS scores. Low-frequency stimulation over the left side improved AHs.
Rollnik et al.38 n =12 Assessment: BPRS DB, PC, randomized, crossover Left PFC, 20 Hz, 80% MT 20-minute sessions, daily for 2 weeks Significant improvement in BPRS with real rTMS. High-frequency real rTMS superior to sham procedures.
d'Alfonso et al.39 n = 9 Medication-resistant with AHs Assements: Topography of Voices Rating Scale, Auditory Imaging Test, other neuropsychological measures Auditory cortex 1 Hz, 80% MT, 20-minute sessions daily for 2 weeks (10 days total) AH assessed at baseline, 1 week, and end of study by investigator blind to data collection Significant improvement observed between baseline and 2 weeks. Improvement also was seen on Auditory Imaging Test. Positive effects on AHs with low-frequency TMS.
Hoffman et al.40 n = 24 Schizophrenia, schizoaffective disorder Medication-resistant AHs Assessment: VAS PC Left TPC 1 Hz, 90% MT 9 days AHs significantly improved with real rTMS. Duration of protective improvement varied; 52% maintained improvement for at least 15 weeks. Well tolerated. Positive effect on AHs with low-frequency stimulation.
Holi et al.41 n = 22 Chronic, hospitalized patients Assessments: PANSS, self-reported symptoms, MMSE, hormone levels at baseline and after 2 weeks DB, PC, randomized Left PFC 10 Hz, 100% MT 20 5-second trains 30-second ITI No therapeutic effect. Significant reduction in total PANSS scores in seven patients with sham stimulation and only one patient with active stimulation. A significant nonspecific effect of treatment was seen. No therapeutic effect with real stimulation.
Schonfeldt-Lecuona et al.42 n = 12 Paranoid type; resistant AHs for more than 6 months Assessment: AHs scored on items from Haddock Self-Rating Scale PC, crossover 1 Hz, 90% MT 16 minutes No difference seen in AH scores between active and sham stimulation. No effect with rTMS in patients with paranoid schizophrenia and chronic AHs.
McIntosh et al.43 n = 16 Treatment-resistant AHs for at least 2 months Assessments: Baseline and daily PANSS, intensity of AHs measured on 10-point Likert Scale, AVLT DB, PC, crossover Left TPC, 1 Hz, 80% MT 4 days Started at 4 minutes and increased to 16 minutes on day 4 No significant difference between low-frequency real rTMS and sham stimulation. No significant effects of rTMS on symptoms or memory measures.

Controlled Trials of TMS for Mania

Study Subjects Study Design Results Comments
Grisaru et al.48 n = 16 Patients with bipolar mania Assessments: BPRS Mania Scale, CGI DB, controlled High-frequency stimulation Right versus left PFC 20 Hz, 2-second trains 20 trains per day 10 treatment days Improvement in mania with right-sided stimulation. No improvement or worsening with left-sided stimulation. Right PFC rTMS demonstrated antimanic effects.
Kapstain et al.50 n = 25 Inpatients with bipolar mania Assessments: BPRS, Mania Scale, CGI DB, PC Right PFC 20 Hz 19 completed study; 16 had psychotic symptoms. No improvement. No difference between right PFC real rTMS versus sham stimulation in more severely ill manic patients.

Controlled and Open Trials of TMS for PTSD

Study Subjects/Assessment Study Design Results Comments
Grisaru et al.52 n = 10 Assessments: Impact of Events Scale, Symptom Check-List-90, CGI Open design Alternating right and left motor cortex 0.3 Hz 30 pulses, 15 on each side 1 minute ITI, one session Significant improvement seen on various measures used. rTMS lowered core symptoms of PTSD.
Rosenberg et al.53 n = 12 Comorbid depression Assessments: MISS, HDRS, SCID-C, Profile of Mood States Open-label Left PFC 1 Hz or 5 Hz, 90% MT 6,000 stimulations over 10 days Antidepressant medications also given Significant improvement in depressive symptoms. Minimal improvement in PTSD symptoms. Left PFC rTMS improved depression but not PTSD.
Cohen et al.54 n = 24 Assessments: PTSD Checklist, Treatment Outcome PTSD Scale, Hamilton Anxiety Scale, HDRS, Hebrew version of clinically administered PTSD scale DB, PC Right DLPC 10 Hz, 1 Hz, or sham 80% MT 10 days Improvements in core symptoms of PTSD as well as anxiety symptoms during active high-frequency stimulation. Mean PTSD Checklist scores decreased by 29.3% from baseline to end of treatment. rTMS over right DLPCimproved PTSD symptoms.

Controlled Trials of TMS for Nicotine Dependence

Study Subjects/Assessment Study Design Results Comments
Johann et al.55 n = 11 Tobacco-dependent smokers Assessment: Cravings measured on VAS PC, randomized Left DLPC, 20 Hz Real rTMS versus sham stimulation on successive days Craving decreased with active stimulation. rTMS may be helpful in achieving abstinence.
Eichhammer et al.56 n = 14 Treatment-seeking smokers Assessments: Evaluated on number of cigarettes smoked in an ad libitum period; effects on cravings measured on VAS DB, crossover Left DLPC 20 Hz Compared single days of active versus sham stimulation rTMS decreased the number of cigarettes smoked during an ad libitum period, compared with sham stimulation. High-frequency rTMS may be useful for smoking cessation.

Educational Objectives

  1. Explain the putative mechanism of action for repetitive transcranial magnetic stimulation (rTMS).

  2. Discuss data from controlled treatment trials with rTMS for various neurological and psychiatric disorders.

  3. Describe the current status of rTMS for the treatment of disorders other than depression.

Authors

Dr. Khurshid is a psychiatric resident, Southern Illinois University School of Medicine, Department of Internal Medicine, Division of Internal Medicine and Psychiatry, Springfield, IL. Dr. Janicak is professor of psychiatry, Rush University Medical Center, and medical director, Rush Psychiatric Clinical Research Center, Chicago, IL.

Address reprint requests to: Khurshid A. Khurshid, MD, Southern Illinois University School of Medicine, Department of Internal Medicine, Division of Internal Medicine and Psychiatry, PO Box 19636, Springfield, IL 62794-9396; or e-mail kkhurshid@siumed.edu.

Dr. Khurshid has no industry relationships to disclose. Dr. Janicak receives grant or research support from Neuronetics Inc.

10.3928/00485713-20050201-07

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