Researchers have found that focusing powerful non-invasive magnet stimulation on a specific brain area can improve the symptoms of Obsessive-Compulsive Disorder (OCD).
This opens the way to treat the large minority of sufferers who do not respond to conventional treatment.
The work is presented at the ECNP Conference in Copenhagen.
OCD is broadly defined as recurrent thoughts or urges, or excessive repetitive behaviours which an individual feels driven to perform.
Around 12 adults in every thousand suffer from OCD in any given year, although 2.3% of adults will suffer at some point in their life.
It is generally treated through exposure and response prevention (ERP) therapy (which exposes the patient to the content of his obsessions\urges without performing the compulsions) and medication, such as SSRIs (Selective Serotonin Reuptake Inhibitors e.g. fluoxetine (Prozac/Sarafem) or Sertraline (Paxil) or Serotonin Reuptake Inhibitors e.g. clomipramine (Anafranil), however between a third and a half of patients don’t respond well to treatment
Deep Transcranial Magnetic Stimulation (dTMS) is a type of brain stimulation technique where pulsed magnetic fields are generated by a coil placed on the scalp.
This field activates the neuronal circuits at the target brain area, resulting in symptom improvement. It is clinically used for treatment of some difficult cases of depression.
Dr Lior Carmi (along with Prof. Joseph Zohar and Prof. Abraham Zangen), from the Chaim Sheba Medical Center in Israel, led an international group of scientists in a multi-centre randomised controlled trial (RCT) spread over 11 centres. 99 patients with Obsessive Compulsive Disorder were assigned to either be treated with dTMS, or to receive pretend treatment (sham treatment).
All the patients in the trial had previously failed to respond to antidepressant treatment.
Dr Carmi said “An interesting point about this trial is that we deliberately provoked the patients for about 5 minutes before each dTMS session.
We did this by tailoring a provocation for each patient according to their own specific OCD obsessions.
For example, if someone had obsessions about getting contaminated, we exposed him to a situation in which these obsessions where aroused, for instance, touching a bathroom’s door handle or the trash can.
Another example would be if someone had obsessions regarding not closing the water tap at home, we deliberately aroused the doubt about that.
All these exposures were designed for each individual patient.
During the first meeting with the patient we learned his symptoms and created a list of which exposures to use during the study.
The idea is to deliver the treatment when the brain circuitry is aroused and not while the patient is thinking about the shopping he needs to do after the session will be over.”
The sessions consisted of 6 weeks of daily dTMS (20Hz) treatment focused on specific areas of the brain related to OCD**.
This is the first time these areas have been targeted for this disorder.
The degree of response was measured using the generally-accepted Yale-Brown Obsessive Compulsive Scale (YBOCS) questionnaire.
After 6 weeks, 38% of those being treated responded to the treatment.
They showed an average reduction of more than 30% in symptom severity, as opposed to 11% of patients receiving the sham treatment.
A month after treatment finished the response rate was 45.2% in the active group versus 17.8% in the sham group.
Around a third of both the treated group and the untreated group complained of headaches, but only 2 dropped out over the trial due to pain.
Lior Carmi said, “Researchers have tested TMS for OCD in the past, but this is the first time we have stimulated this region of the brain and done so while we tailored exposures to each patient.
In addition, we have done so using a standardised protocol in a multi-centre randomised trial (at 11 cites in U.S, Canada and Israel).
This means that we have achieved these positive results although the variety of patients and variety of clinicians who rated the response.
Where the existing treatment works for OCD, it can work well; our method is primarily aimed at those who do not respond to conventional treatment.”
A month after treatment finished the response rate was 45.2% in the active group versus 17.8% in the sham group. Around a third of both the treated group and the untreated group complained of headaches, but only 2 dropped out over the trial due to pain. The image is in the public domain.
Commenting, Professor Jose M Menchon (Bellvitge University Hospital, University of Barcelona, Barcelona, Spain) said:
“This is a very exciting study because it shows positive results in OCD using deep transcranial magnetic stimulation.
Until now, the clinical trials with TMS in OCD had been carried out with non-deep TMS, which may have limitations in its effect because the magnetic field can only reach the cortical surface.
However, deep TMS allows reaching and modulating deeper brain regions that can be more critically involved in OCD.
Deep TMS may become a useful therapeutic strategy if these positive results are confirmed in further studies.”
All exposures were designed and approved by an expert clinician. The study was approved by ethics committees and Institutional Review Boards.
The study was funded by Brainsway Ltd..
Obsessive–compulsive disorder (OCD) is characterized by repetitive, irrational, and intrusive thoughts and compulsions, resulting in significant socio-occupational dysfunction. While there are several treatment options available, the mainstay treatment has been psychopharmacological approach in the form of serotonin-reuptake inhibitors or psychotherapy in the form of cognitive behavior therapy or both.
Despite adequate treatment, nearly 40% of patients do not respond to either treatment, warranting need for developing newer treatment strategies.
Furthermore, invasive treatment strategies such as deep brain stimulation or surgical procedures have shown partial success.
In this scenario, noninvasive brain stimulation approaches such as transcranial magnetic stimulation (TMS) and transcranial electric current stimulation (tECS) hold promise in alleviating symptoms in OCD and other neuropsychiatric disorders.[3,4]
These noninvasive techniques involve application of either magnetic field or electric current transcranially over the scalp to modulate specific brain regions to alleviate the symptoms. The noninvasive neuromodulation in OCD focuses on specific brain regions considered to be functioning abnormally.
The rationale for choosing the target region is based on their involvement in the neurobiological basis of OCD. Converging evidence indicates the involvement of cortico-striato-thalamo-cortical (CSTC) circuits in the pathophysiology of OCD.
Neuroimaging studies have shown the involvement of prefrontal-cortical regions in the neurobiological basis of OCD. Indeed, structural and functional changes corresponding to the regions subserving the CSTC circuits explain the neurobiological alterations seen in OCD.
In this review, we describe and discuss various studies that have examined the effects of repetitive TMS (rTMS) and transcranial direct current stimulation (tDCS) in alleviating the symptoms in OCD patients.
REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION IN OBSESSIVE–COMPULSIVE DISORDER
rTMS is a noninvasive brain stimulation technique used in various neuropsychiatric conditions. rTMS uses low-intensity magnetic field to stimulate specific brain areas by inducing neurophysiologic changes. Low-frequency stimulation, i.e., <5 Hz, leads to decreased neuronal activity while high-frequency stimulation, i.e., >10 Hz, increases neuronal activity.
A recent modification to this technique in the form of deep TMS seems to allow stimulation of deeper and larger brain structures as compared to conventional rTMS. In this section, we review the evidence of rTMS utilization in OCD around specific areas of stimulation.
SUPPLEMENTARY MOTOR AREA
There is evidence that suggests reduced cortico-subcortical inhibition and cortical hyperexcitability result in the repetitive behavior associated with OCD.
An open-label study by Mantovani et al., 2006 had shown initially that low-frequency rTMS over supplementary motor area (SMA) had led to significant improvement of OC symptoms in 10 patients with comorbid Tourette syndrome.
This improvement in clinical symptoms had correlated with improved resting-state cortical motor threshold and also sustained up to 3 months follow-up.
Later, a double-blind, randomized controlled trial (RCT) from the same study group in 18 patients with resistant OCD showed greater reduction of symptoms in active stimulation compared to sham stimulation.
However, this was not statistically significant (P = 0.154).
In another RCT with 22 patients with resistant OCD, low-frequency active rTMS treatment significantly reduced the symptoms score and this improvement remained stable at 12 weeks of follow-up compared to sham rTMS.
However, an RCT from France, in 40 patients with resistant OCD, failed to demonstrate significant difference between active and sham low-frequency stimulation of SMA.
An open-label case series observation, from India, in 17 patients with resistant OCD, had shown that low-frequency rTMS is less likely to produce improvement in severely ill patients.
Another open-label study from India had shown significant improvement in 12 patients with treatment-refractory OCD over 15 sessions of low-frequency rTMS.
However, an RCT from our center involving 36 patients with refractory OCD failed to demonstrate any significant difference between active and sham low-frequency rTMS over bilateral pre-SMA.
A pilot open-label trial had shown significant reduction of OCD in two-third of patients treated with rTMS for 3 weeks who had not previously responded to antidepressant trial.
In a recent open-label study from Korea, 4 weeks of low-frequency TMS over SMA did not produce any significant change in OCD symptoms.
A 6-week, multisite RCT had shown clinically significant reduction in symptoms in patients with refractory OCD.
The symptom reduction achieved at the end of 6 weeks remained stable for further 6 weeks. The studies conducted using rTMS over pre-SMA/SMA is shown in Table 1.
DORSOLATERAL PREFRONTAL CORTEX
Dorsolateral prefrontal cortex (DLPFC) exerts control over multiple subcortical structures that are clinically relevant for attention, concentration, and executive functions. Dysfunction in DLPFC and related circuits had been implicated in various symptom dimensions of OCD.
Right dorsolateral prefrontal cortex
High-frequency 20 Hz single-session stimulation in 12 patients, with each patient randomized to receive over right/left DLPFC or mid-occipital regions, had shown that only after right DLPFC stimulation, compulsive urges reduced significantly and the effect lasted about 8 h after stimulation.
One of the earliest sham-controlled RCT reported that low-frequency 1 Hz stimulation over right DLPFC, three sessions per week for 6 weeks, was ineffective in producing any significant change in patients with OCD.
In an open-label study, adjunctive high-frequency rTMS to the right DLPFC did not show any significant change of obstetric cholestasis (OC) symptoms in 42 patients. However, both depression and anxiety scores reduced significantly.
In 30 treatment-resistant OCD patients, high-frequency 10 Hz stimulation over right DLPFC consisting of 30 sessions failed to show any significant difference between active and sham condition.
Forty-five patients randomized to three arms to receive low-frequency 1 Hz versus high-frequency 10 Hz versus sham stimulation over right DLPFC had concluded that only 1 Hz stimulation had significantly reduced symptoms. A 3-week RCT, comparing active versus sham stimulations of low-frequency 1 Hz stimulation over right DLPFC reported superiority of active simulation over sham in relieving OCD symptoms.
Left dorsolateral prefrontal cortex
A sham-controlled double-blind study suggested that 2 weeks of high-frequency rTMS over left DLPFC was ineffective in bringing any change in Yale-Brown OC scale (YBOCS) scores. However, when extended for 4 weeks, active stimulation reduced OC symptoms significantly but not after controlling for change in depression scores.
A novel study from Egypt had attempted application of high-frequency 20 Hz over left DLPFC with 15 sessions as monotherapy in 20 drug-free patients with OCD.
However, there was no significant change between active and sham stimulation.
In the same study, when high-frequency stimulation was applied as an add-on to antidepressant medication over left DLPFC, it led to significant reduction in symptoms.
Low-frequency 1 Hz rTMS applied over left DLPFC as an add-on to medications in 30 patients did not show any significant change between active and sham stimulation.
Bilateral dorsolateral prefrontal cortex
Electroencephalography-guided, frequency-balanced, bilateral DLPFC stimulation over 10 sessions using a sham-controlled design in 46 OCD patients had shown significant reduction of obsessions and anxiety symptoms in active stimulation compared to sham stimulation.
A single-blind RCT with intra-individual cross-over design using bilateral high-frequency 20 Hz DLPFC stimulation reported significant reduction of symptoms with active stimulation.
Both responders and partial responders were observed only in true condition in this study. Another intra-individual sham-controlled study, involving high frequency over bilateral DLPFC had reported significant reduction in symptoms as well as cognitive performance after true stimulation condition.
This same study group also replicated the finding on efficacy of bilateral DLPFC high-frequency 20 Hz stimulation in improving symptoms but not cognitive function. Further, sequential administration of low-frequency 1 Hz stimulation over DLPFC and SMA did not produce any significant change in symptoms. The key rTMS studies with DLPFC as the target region are summarized in Table 2.
Neuroimaging studies suggest hyper-excitability of orbitofrontal cortex (OFC) along with other cortical/subcortical structures in the pathophysiology of OCD. A retrospective study from India had suggested that there is a role of applying low-frequency 1 Hz to inhibit this hyper-excitable state of left OFC and ameliorating symptoms.
A double-blind RCT study that involved the administration of low-frequency rTMS over right OFC demonstrated significant reduction of symptoms in addition to reduction of metabolism in bilateral OFC in positron emission tomography. Another study conducted on 23 medication-resistant OCD patients that applied low-frequency rTMS over left OFC for 15 days reported significant reduction in symptoms in true condition that lasted till 10 weeks but not 12 weeks. The key rTMS studies with OFC as the target region are summarized in Table 3.
European College of Neuropsychopharmacology
Press Office – European College of Neuropsychopharmacology
The image is in the public domain.
Original Research: The findings will be presented at the a href=”https://www.ecnp.eu/Congress2019/ECNPcongress” rel=”noopener” target=”_blank”>ECNP Conference in Copenhagen.