**7. Detailed review of sham-controlled trials using TMS for treatment refractory OCD**

In the following paragraphs, the sham-controlled or multi-arm therapeutic studies of TMS for OCD are described in detail. For an overview, please see **Table 1**.

In 2001, Pino Alonso published a sham-controlled TMS study whereby 18 OCD patients were administered active (N = 10) or sham (N = 8) rTMS for 18 sessions (3 times a week for 6 weeks). Active and sham treatments were administered using low frequency rTMS (1 Hz, 1200 pulses) to the right prefrontal cortex (PFC) using a 70 mm circular coil. The active group was administered 110% of the left hand resting motor threshold (MT) and the sham group was administered 20%MT. Raters and patients were blinded, and operators were unaware of the expected effects of the prescribed intensity. Neither the sham nor active treatment groups had significant reduction in their OCD symptoms following 18 sessions of low frequency rTMS over the right PFC with a circular coil for 6 weeks [8].

Sachdev et al. randomly designated 12 treatment-resistant OCD subjects to right (n = 6) or left (n = 6) prefrontal rTMS treatment groups. Both groups were administered a figure-8 coil for 10 treatments over 2 weeks at 10 Hz for 1500 pulses at 110% MT. An independent rater evaluated progress once a weekly during treatment then at the 1 month follow up. In both groups, there was a significant improvement after 2 weeks and at the 1 month follow up in the obsessions, compulsions, and total scores on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). There was not a significant difference between left and right-sided high frequency rTMS [9].


**Study** Haghihagi

Magstim figure 8

Left DLPFC

Crossover study:

21

+

—

+

YBOCS improved after active rTMS

20 sham

Crossover study: sham

21

then 20

> Elbeh [18]

Magstim figure 8

Right

1

Hz, 2000P, 100%MT

15

+

—

+ sham

Significant improvement compared to

No significant improvement compared

to sham

DLPFC

10 Sham

> Hawken [19]

Seo [20]

Tamas/remed

Right

1

Hz, 1200P, 100%MT

14

+

—

+ to sham

Significant reduction in YBOCS compared

DLPFC

Sham

13

figure 8

Pallanti [21]

Magstim 70-mm

SMA

1

Hz, 1200P, 100%MT

TAU: Antipsychotics

25

25

—

—

—

Effective in 2/3 patients.

Effective in ¼ patients.

figure 8

Pelissolo

Magstim 70-mm

Pre-SMA

1

Hz, 1500P, 100%MT

Sham: coil with mu

19

shield

20

+

—

+

No significant difference.

[22]

Shayganfard

Magstim figure 8

Left DLPFC

Crossover study:

10

+

—

+

YBOCS improved after active rTMS

http://dx.doi.org/10.5772/intechopen.73594

TMS for OCD

95

20 then Sham

Crossover study: sham

10

then 20 100%MT

Hz, 750P,

Hz, 750P, 100%MT

[23]

figure 8

Medtronic figure 8

SMA

1

Hz, 1200P, 110%MT

Sham: (coil rotated

12

away from head)

10

+

—

+

Active TMS had significant reduction in

YBOCS compared to sham

15

Hz, 2000P, 100%MT

 15

Hz, 100%MT

Hz, 100%MT then

[17]

**Device**

**Location**

**Protocol**

**Sample** 

**Blinding**

**Outcome**

**size**

**Patient**

**Operator Rater**


**Study** Alonso [8] Sachdev [9] Prasko [10] Sachdev [11]

Ruffini [12] Mantovani

Magstim figure 8

Pre-SMA

1

Hz, 1200P, 100%MT

Sham: coil with a mu

9

shield

 9

+

—

+

The active TMS group had 25%

reduction in YBOCS compared to 12%

reduction in sham

[13]

Mansur [14]

Gomes [15]

Ma [16]

αEEG guided

Midfrontal

648–872P, 80%MT

25

+

+

+

Significant reduction of YBOCS

compared to sham

rTMS (Cadwell

region

Sham

21

9

cm circular coil)

Neuro-MS figure 8

Pre-SMA

1 Sham

10

Hz, 1200P, 100%MT

12

+

—

+

Significant reduction in YBOCS

compared to sham

Medtronic figure 8

Right

10

Hz, 2000P, 110%MT

 13

+

—

+

There was no difference in any of the

outcome measures between active and

sham

DLPFC

Sham

14

Magstim figure 8

Left OFC

1

Hz, 600P, 80%MT

Sham: (coil

7

perpendicular to scalp)

16

+

—

Magstim figure 8

Left DLPFC 10

Hz, 1500P, 110%MT

Sham

8

 10

+

—

+

No significant difference between active

and sham after 10 sessions. There was a

significant difference after 20 treatments

There was a significant difference

between active and sham, which lasted

10

weeks after TMS ended

Left DLPFC 1

Hz, 110%MT

Sham

15

15

Magstim figure 8

Right PFC

Left PFC

10

Hz, 1500P, 110%MT

 6

10

Hz, 1500P, 110%MT

 6


—

+

No significant difference between

right and left high frequency. Both left

94 Transcranial Magnetic Stimulation in Neuropsychiatry

and right groups had significant OCD

improvement

Active did not have any greater benefit

than sham

significance of

laterality)

Magstim circular

Right PFC

1

Hz, 1200P, 110%MT

Sham: 20%MT

8

10

+

**Device**

**Location**

**Protocol**

**Sample** 

**Blinding**

**Outcome**

**size**

**Patient**

**Operator Rater**

+

No significant reduction in OCD

95


**Table 1.** Individual characteristics of sham-controlled therapeutic TMS studies for OCD. In 2006, Prasko conducted a sham-controlled study of 30 OCD patients, half were assigned to sham and half to active low frequency rTMS. Ten treatments over 2 weeks were administered of low frequency rTMS to the left DLPFC (1 Hz, 110% MT, total pulses not available to this

TMS for OCD

97

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In 2007, Perminder Sachdev published the results of a 2-week sham-controlled study for OCD in which the patients and raters were blinded; but the operators were not. Ten subjects were randomized to active and eight to sham. High- frequency (10 Hz, 5 second train, 25 second inter-train interval, 30 trains, 1500 total pulses, at 110% of resting right hand MT) rTMS was administered to the left DLPFC in 10 sessions over 2 weeks with a figure-8 coil. Patients were offered to extend treatment up to 20 sessions. No significant difference was found between the treatment groups in YBOCS or Maudsley Obsessive-Compulsive Inventory scores after 10 sessions. There was a significant difference in YBOCS after 20 treatments; however, it was not

In 2009, Chiara Ruffini published the results of a single-blind left OFC rTMS study of 23 patients with medication resistant OCD. Using a figure-8 coil, he administered low frequency, subthreshold rTMS (1 Hz, 80% MT, 600 pulses) to the left OFC (fp1 on EEG system) with the coil parallel to the scalp for the 16 subjects randomized to active. The coil was positioned perpendicular to the scalp for the seven subjects randomized to sham. There was a significant difference between active and sham low frequency stimulation of the left OFC which lasted until 10 weeks after rTMS ended. Only one of the seven patients had a placebo response, and of the 16 active patients, four had a greater than 35% reduction in the YBOCS from baseline. It is not clear (to this writer) why no one replicated the results of this study on a larger scale,

In 2010, Antonio Mantovani published the results of a 4 week double blinded study of 1HZ rTMS to the bilateral pre supplementary motor area (SMA) at 100%MT of the thumb for 1200 pulses in 18 medication and cognitive behavioral therapy (CBT) resistant OCD patients with a figure-8 coil. The operators were not blinded, and they used a sham coil with a mu shield; but the patients and raters were blinded. On average at 4 weeks, the active TMS group had a 25% reduction in YBOCS compared to a 12% reduction in the sham group. Patients who subsequently continued an additional 4 weeks of open label treatment generally had an additional three-point decrease in their YBOCS. The results were promising but the active group

In 2011, Carlos Gustavo Mansur published the results of a sham-controlled study of high frequency, high intensity right DLPFC rTMS for OCD using a figure-8 coil. In this study, operators were not blinded but the patients and raters were blinded. Thirteen patients received active and 14 patients received sham. rTMS was administered at 110% of resting left hand MT, 10HZ, 5 second trains, 25 second intervals, 40 trains, 2000 total pulses for 30 treatments over 6 weeks. There was no difference in any of the outcome measures between the active and sham groups [14].

In 2012, Pablo Vinicius Oliveira Gomes randomized 22 patients with moderate OCD into active (n = 12) or sham (n = 10) groups. The study was blinded to the subjects and raters; however, the TMS operators were not blinded. Patients received 10 rTMS treatment sessions

author). The active group did not have any greater benefit than the sham group [10].

significant after controlling for depression [11].

longer treatment duration in double blinded format [12].

only had nine completers [13].

In 2006, Prasko conducted a sham-controlled study of 30 OCD patients, half were assigned to sham and half to active low frequency rTMS. Ten treatments over 2 weeks were administered of low frequency rTMS to the left DLPFC (1 Hz, 110% MT, total pulses not available to this author). The active group did not have any greater benefit than the sham group [10].

In 2007, Perminder Sachdev published the results of a 2-week sham-controlled study for OCD in which the patients and raters were blinded; but the operators were not. Ten subjects were randomized to active and eight to sham. High- frequency (10 Hz, 5 second train, 25 second inter-train interval, 30 trains, 1500 total pulses, at 110% of resting right hand MT) rTMS was administered to the left DLPFC in 10 sessions over 2 weeks with a figure-8 coil. Patients were offered to extend treatment up to 20 sessions. No significant difference was found between the treatment groups in YBOCS or Maudsley Obsessive-Compulsive Inventory scores after 10 sessions. There was a significant difference in YBOCS after 20 treatments; however, it was not significant after controlling for depression [11].

In 2009, Chiara Ruffini published the results of a single-blind left OFC rTMS study of 23 patients with medication resistant OCD. Using a figure-8 coil, he administered low frequency, subthreshold rTMS (1 Hz, 80% MT, 600 pulses) to the left OFC (fp1 on EEG system) with the coil parallel to the scalp for the 16 subjects randomized to active. The coil was positioned perpendicular to the scalp for the seven subjects randomized to sham. There was a significant difference between active and sham low frequency stimulation of the left OFC which lasted until 10 weeks after rTMS ended. Only one of the seven patients had a placebo response, and of the 16 active patients, four had a greater than 35% reduction in the YBOCS from baseline. It is not clear (to this writer) why no one replicated the results of this study on a larger scale, longer treatment duration in double blinded format [12].

In 2010, Antonio Mantovani published the results of a 4 week double blinded study of 1HZ rTMS to the bilateral pre supplementary motor area (SMA) at 100%MT of the thumb for 1200 pulses in 18 medication and cognitive behavioral therapy (CBT) resistant OCD patients with a figure-8 coil. The operators were not blinded, and they used a sham coil with a mu shield; but the patients and raters were blinded. On average at 4 weeks, the active TMS group had a 25% reduction in YBOCS compared to a 12% reduction in the sham group. Patients who subsequently continued an additional 4 weeks of open label treatment generally had an additional three-point decrease in their YBOCS. The results were promising but the active group only had nine completers [13].

In 2011, Carlos Gustavo Mansur published the results of a sham-controlled study of high frequency, high intensity right DLPFC rTMS for OCD using a figure-8 coil. In this study, operators were not blinded but the patients and raters were blinded. Thirteen patients received active and 14 patients received sham. rTMS was administered at 110% of resting left hand MT, 10HZ, 5 second trains, 25 second intervals, 40 trains, 2000 total pulses for 30 treatments over 6 weeks. There was no difference in any of the outcome measures between the active and sham groups [14].

In 2012, Pablo Vinicius Oliveira Gomes randomized 22 patients with moderate OCD into active (n = 12) or sham (n = 10) groups. The study was blinded to the subjects and raters; however, the TMS operators were not blinded. Patients received 10 rTMS treatment sessions

**Study** Carmi [25]

Brainsway dTMS

dmPFC/

20 Hz

16

+

+

+

Improvement compared to sham

No difference between 1

 Hz & 1

Hz sham

96 Transcranial Magnetic Stimulation in Neuropsychiatry

ACC

Sham: 20 Hz

1 Hz Sham: 1 Hz

Brainsway

Brainsway dTMS

dmPFC/

20

Hz, 2000P, 100%MT

 47 47

+

+

+

Improvement compared to sham

ACC

Sham

Ltd. [26]

**Table 1.**

Individual characteristics of sham-controlled therapeutic TMS studies for OCD.

H7

7

7

8

H7

**Device**

**Location**

**Protocol**

**Sample** 

**Blinding**

**Outcome**

**size**

**Patient**

**Operator Rater**

over 2 weeks utilizing a figure-8 coil with low frequency (1 Hz), 1200 pulses at 100% MT over the bilateral pre SMA. They were assessed 3 months after completing TMS. At the 2 week and 14 week assessments, the active group had a significant reduction of 35% in YBOCS scores compared to the sham group who had a 6.2% reduction [15].

group, patients were administered 15 sessions of rTMS over 3 weeks with a 70 mm Figure 8 coil at 1 Hz, 1200 pulses, 100%MT over the SMA. One quarter of the refractory OCD patients who were treated with antipsychotics responded compared to the subjects treated with rTMS

TMS for OCD

99

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In 2016, Antoine Pelissolo published the results of a randomized double-blind study of 40 SSRI treatment-resistant OCD patients. Subjects were randomized into active (n = 16) or sham (n = 15) groups. The patients and raters were blinded; however, the operators were not. Both groups were administered rTMS with the 70 mm figure-8 coil at 1 Hz for 1500 pulses, 100%MT to the pre-SMA for 4 weeks. The sham coil utilized a mu-metal shield over the figure-8 coil. The active group did not have a significant reduction in YBOCS compared to sham [22].

In 2017, Mehran Shayganfard published the results of a single-blind crossover study of high frequency rTMS to the left DLPFC of 10 OCD patients using a figure-8 coil. Stimulation was administered at 20 Hz, 100% resting right hand MT, 1.5 second train, 25 trains, totaling 750 pulses, 5 days a week for 2 weeks. Sham stimulation was done with the coil angled away from the skull. After 2 weeks, patients switched conditions for an additional 2 weeks. In both groups, the patient's YBOCS improved after the active rTMS condition and not after the sham condition [23, 24]. This was the second single blinded study this group did with the same crossover after 2 weeks [17, 23]. Methodologically, they should do a double-blind non-cross-

over study, and at a significantly later date offer the sham patients active treatment.

improvements were still present a month after treatments ended [25, 26].

Between 2012 and 2014, a feasibility study used an H-coil designed to target the medial prefrontal cortices and anterior cingulate cortices (ACC) bilaterally (HAC or H7 coil) in 41 treatment-resistant obsessive-compulsive-disorder (OCD) patients with moderate to severe symptoms. Treatments were administered after the patient's individual symptoms were provoked, and improvements were measured using the YBOCS. Initially the study had four arms, a high frequency arm of 20 Hz, a sham 20 Hz arm, a low frequency arm of 1 Hz and a sham 1 Hz arm. Because the interim analysis showed no difference between the sham and 1 Hz arms, the study was continued with just high frequency and sham. At the end of the study, the response rate in the 20 Hz arm was much greater than in the sham group and the

Subsequently, from 2014 to 2017 94 patients with moderate to severe treatment-resistant OCD were randomized in a multicenter double-blind study to either 20 Hz active or sham dTMS, at 100% resting MT of the foot, 2 second trains, 20 second inter train intervals, 2000 total pulses per day. Treatments were administered daily for 29 days over 6 weeks after the patient's individual symptoms were provoked, with a follow up at week 10. Although the study has been completed with a public announcement of positive results, the details have not been published yet.

OCD is uniquely suited for intervention with TMS. However, rTMS interventions in OCD that focus on the lateral prefrontal cortices in both high and low frequency are not consistently efficacious. Most of the small sham-controlled studies treating the SMA, left DLPFC, and right DLPFC with low frequency as well as high frequency showed benefit. This is consistent with

where two thirds were responders [21].

**8. Conclusion-key results**

In 2014, Xiaoyan Ma published a randomized single-blind sham-controlled study that enrolled 46 subjects with moderate to severe OCD. The study's goal was to determine the treatment effect of using the patient's individualized alpha electroencephalogram (αEEG)-guided rTMS (αTMS) in OCD patients. Treatment was administered with a 9 cm circular coil placed over the midfrontal region. Twenty-five OCD patients received αTMS at 80% resting MT of the hand, 4 seconds stimulation, 56 seconds interval, 20 minutes stimulation daily, total pulses varied by patient's alpha between 648 and 872 pulses per day for 10 treatment sessions over 2 weeks. Twenty-one patients received sham stimulation using an unplugged coil with acoustic effects from another coil at a distance. At the end of treatment and the 1 week follow up, the obsession component of the YBOCS was significantly reduced in the active treatment group compared to the sham group [16].

In 2015, Mohammad Haghihagi published the results of a single blinded crossover trial of 21 OCD patients. Stimulation was administered at 20 Hz, 100% resting right hand MT, 1.5 second train, 25 trains, totaling 750 pulses, 5 days a week for 2 weeks. Sham stimulation was done with the coil angled away from the skull. After 2 weeks, patients switched conditions for an additional 2 weeks. In both groups, the patient's YBOCS improved after the active rTMS condition and not during the sham condition [17].

In 2016, Khaled Elbeh randomized 45 patients into a trial to evaluate the effects of different rTMS frequencies over the right DLPFC at 100% resting left hand MT using a figure-8 coil. Fifteen patients received low frequency (1 Hz), 15 high frequency (10 Hz), and 15 received sham. The operators were not blinded. All groups were administered 10 sessions over 2 weeks of 2000 pulses each at 100% MT; then, patients were followed for 3 months post rTMS. The low frequency group but not the high frequency group's YBOCS was significantly different than sham. The effects did not last 3 months [18].

In 2016, Emily Hawken published a two-site randomized, placebo-controlled clinical trial for patients with refractory OCD using low frequency rTMS to the bilateral SMA. Ten patients received active and 12 patients were in the placebo group, where the operators rotated the coil away from the skull. rTMS was administered at 1HZ, 110% of resting hand MT, 1200 pulses for 25 sessions over 6 weeks with a figure-8 coil. Active TMS recipients obtained significant reductions in their YBOCS compared to sham. Benefits were maintained for 6 weeks after treatment [19]. This is the third small sham-controlled study showing the benefits low frequency figure-8 rTMS over the SMA.

In 2016, Ho Jun Seo published a 3-week single-blind study of low frequency rTMS to the right DLPFC with a figure-8 coil (Tamas, Remed). Fourteen patients received active and 13 patients received sham rTMS, 1 Hz, 1200 pulses, 100%MT of the left hand 5 days a week for 3 weeks. The active group had a significant YBOCS reduction compared to sham [20].

In 2016, Stefano Pallanti published the results of an open-label trial with 50 patients with SSRI refractory OCD. Patients were randomized into either the TAU (treatment as usual) (n = 25) or rTMS (n = 25) groups. The TAU group was treated with antipsychotic drugs. In the rTMS group, patients were administered 15 sessions of rTMS over 3 weeks with a 70 mm Figure 8 coil at 1 Hz, 1200 pulses, 100%MT over the SMA. One quarter of the refractory OCD patients who were treated with antipsychotics responded compared to the subjects treated with rTMS where two thirds were responders [21].

In 2016, Antoine Pelissolo published the results of a randomized double-blind study of 40 SSRI treatment-resistant OCD patients. Subjects were randomized into active (n = 16) or sham (n = 15) groups. The patients and raters were blinded; however, the operators were not. Both groups were administered rTMS with the 70 mm figure-8 coil at 1 Hz for 1500 pulses, 100%MT to the pre-SMA for 4 weeks. The sham coil utilized a mu-metal shield over the figure-8 coil. The active group did not have a significant reduction in YBOCS compared to sham [22].

In 2017, Mehran Shayganfard published the results of a single-blind crossover study of high frequency rTMS to the left DLPFC of 10 OCD patients using a figure-8 coil. Stimulation was administered at 20 Hz, 100% resting right hand MT, 1.5 second train, 25 trains, totaling 750 pulses, 5 days a week for 2 weeks. Sham stimulation was done with the coil angled away from the skull. After 2 weeks, patients switched conditions for an additional 2 weeks. In both groups, the patient's YBOCS improved after the active rTMS condition and not after the sham condition [23, 24]. This was the second single blinded study this group did with the same crossover after 2 weeks [17, 23]. Methodologically, they should do a double-blind non-crossover study, and at a significantly later date offer the sham patients active treatment.

Between 2012 and 2014, a feasibility study used an H-coil designed to target the medial prefrontal cortices and anterior cingulate cortices (ACC) bilaterally (HAC or H7 coil) in 41 treatment-resistant obsessive-compulsive-disorder (OCD) patients with moderate to severe symptoms. Treatments were administered after the patient's individual symptoms were provoked, and improvements were measured using the YBOCS. Initially the study had four arms, a high frequency arm of 20 Hz, a sham 20 Hz arm, a low frequency arm of 1 Hz and a sham 1 Hz arm. Because the interim analysis showed no difference between the sham and 1 Hz arms, the study was continued with just high frequency and sham. At the end of the study, the response rate in the 20 Hz arm was much greater than in the sham group and the improvements were still present a month after treatments ended [25, 26].

Subsequently, from 2014 to 2017 94 patients with moderate to severe treatment-resistant OCD were randomized in a multicenter double-blind study to either 20 Hz active or sham dTMS, at 100% resting MT of the foot, 2 second trains, 20 second inter train intervals, 2000 total pulses per day. Treatments were administered daily for 29 days over 6 weeks after the patient's individual symptoms were provoked, with a follow up at week 10. Although the study has been completed with a public announcement of positive results, the details have not been published yet.
