Adjuvant intermittent theta burst stimulation over dorsomedial prefrontal cortex in treatment-resistant obsessive-compulsive disorder type: Letter to the editor

Repetitive transcranial magnetic stimulation (rTMS) holds promise in the treatment of resistant obsessive-compulsive disorder (OCD). Advances in technology have enabled the stimulation of deeper brain structures such as dorsomedial prefrontal cortex (dmPFC) and anterior cingulate cortex(ACC), which are components of cortico–striato–thalamo–cortical pathway (CSTC), implicated in OCD [[1]Dunlop K. Woodside B. Olmsted M. Colton P. Giacobbe P. Downar J. Reductions in cortico-striatal hyperconnectivity accompany successful treatment of obsessive-compulsive disorder with dorsomedial prefrontal rTMS.Neuropsychopharmacology. 2016; 41: 1395-1403https://doi.org/10.1038/npp.2015.292Crossref PubMed Scopus (73) Google Scholar]. A multisite RCT using the H7 coil demonstrated the efficacy and tolerability of high frequency rTMS over ACC/dmPFC [[2]Carmi L. Tendler A. Bystritsky A. Hollander E. Blumberger D.M. Daskalakis J. et al.Efficacy and safety of deep transcranial magnetic stimulation for obsessive-compulsive disorder: a prospective multicenter randomized double-blind placebo-controlled trial.Am J Psychiatr. 2019; 176: 931-938https://doi.org/10.1176/appi.ajp.2019.18101180Crossref PubMed Scopus (107) Google Scholar]. This led to the United States Food and Drug Administration (FDA) approval and the Conformité Européene (CE) certification for the device. The double cone coil is a less expensive alternative, which is capable of stimulating the dmPFC and has shown encouraging results in open-labeled trials [[1]Dunlop K. Woodside B. Olmsted M. Colton P. Giacobbe P. Downar J. Reductions in cortico-striatal hyperconnectivity accompany successful treatment of obsessive-compulsive disorder with dorsomedial prefrontal rTMS.Neuropsychopharmacology. 2016; 41: 1395-1403https://doi.org/10.1038/npp.2015.292Crossref PubMed Scopus (73) Google Scholar,[3]Modirrousta M. Shams E. Katz C. Mansouri B. Moussavi Z. Sareen J. et al.The efficacy of deep repetitive transcranial magnetic stimulation over the medial prefrontal cortex in obsessive compulsive disorder: results from an open-label study.Depress Anxiety. 2015; 32: 445-450https://doi.org/10.1002/da.22363Crossref PubMed Scopus (32) Google Scholar]. Further, the Magventure™ DB-80 double-cone coil has received FDA clearance for OCD due to its substantial equivalence to the H7 coil [[4]510(k) Premarket Notification n.dhttps://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm?ID=K193006Date accessed: September 29, 2020Google Scholar]. However, there is no published evidence on the use of the novel theta burst stimulation (TBS) protocols using deep coils in OCD. Intermittent TBS (iTBS) is purported to have similar but possibly more robust neurophysiological effect over the targeted cortical region as compared to high frequency rTMS (HF-rTMS) [[5]Huang Y.-Z. Edwards M.J. Rounis E. Bhatia K.P. Rothwell J.C. Theta burst stimulation of the human motor cortex.Neuron. 2005; 45: 201-206https://doi.org/10.1016/j.neuron.2004.12.033Abstract Full Text Full Text PDF PubMed Scopus (2437) Google Scholar]. TBS has the advantage of shorter duration of intervention and lower intensity of stimulation, which may improve the acceptability and tolerability. In this background, we report our experience of treating 12 patients with treatment-resistant OCD with intermittent TBS (iTBS) using D-B80 double cone coil over bilateral dmPFC-ACC. Twelve patients receiving treatment for OCD from a tertiary care center in India were administered deep rTMS as an add-on treatment (Table- 1). Symptom severity was assessed using Yale-Brown Obsessive compulsive scale (YBOCS) [[6]Goodman W.K. Price L.H. Rasmussen S.A. Mazure C. Fleischmann R.L. Hill C.L. et al.The Yale-Brown obsessive compulsive scale. I. Development, use, and reliability.Arch Gen Psychiatr. 1989; 46: 1006-1011Crossref PubMed Scopus (5978) Google Scholar] before and after the iTBS treatment course. Based on the evidence suggesting dmPFC/ACC dysfunction in OCD and demonstrated efficacy of high frequency rTMS (HF-rTMS) over this target [[1]Dunlop K. Woodside B. Olmsted M. Colton P. Giacobbe P. Downar J. Reductions in cortico-striatal hyperconnectivity accompany successful treatment of obsessive-compulsive disorder with dorsomedial prefrontal rTMS.Neuropsychopharmacology. 2016; 41: 1395-1403https://doi.org/10.1038/npp.2015.292Crossref PubMed Scopus (73) Google Scholar], all the patients were treated with iTBS. Each patient received 600 magnetic pulses per hemisphere per session delivered in 20 trains with 8 second inter-train interval. Each train consisted of 10 bursts of three biphasic pulses delivered at 50 Hz, bursts repeated at 5Hz. The intervention was administered using MagPro X100 (MagVenture, Farum, Denmark) device with cool MagVenture D-B80 coil. In two patients, dmPFC was localized via structural MRI-guided neuronavigation using BrainSight frameless stereotaxic system (Rogue Research, Montreal, Canada) based on the MNI coordinates of x0, y+30, z+30 [[1]Dunlop K. Woodside B. Olmsted M. Colton P. Giacobbe P. Downar J. Reductions in cortico-striatal hyperconnectivity accompany successful treatment of obsessive-compulsive disorder with dorsomedial prefrontal rTMS.Neuropsychopharmacology. 2016; 41: 1395-1403https://doi.org/10.1038/npp.2015.292Crossref PubMed Scopus (73) Google Scholar]. In the remaining patients, dmPFC was localized based on scalp heuristics i.e. 25% of nasion-inion distance from nasion [[7]Mir-Moghtadaei A. Giacobbe P. Daskalakis Z.J. Blumberger D.M. Downar J. Validation of a 25% nasion–inion heuristic for locating the dorsomedial prefrontal cortex for repetitive transcranial magnetic stimulation.Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation. 2016; 9: 793-795https://doi.org/10.1016/j.brs.2016.05.010Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar]. The left and right dmPFC were stimulated independently using standardized techniques i.e., the coil was placed over the midline, with the handle oriented laterally to direct the stimulation at the opposite hemisphere [[8]Dunlop K. Gaprielian P. Blumberger D. Daskalakis Z.J. Kennedy S.H. Giacobbe P. et al.MRI-guided dmPFC-rTMS as a treatment for treatment-resistant major depressive disorder.JoVE. 2015; e53129https://doi.org/10.3791/53129Crossref Scopus (22) Google Scholar]. The stimulation was attempted to be delivered at 90–100% of leg resting motor threshold (RMT). As leg RMT was not measurable in 3 patients, stimulation was attempted at the highest tolerable amplitude as a proportion of hand motor threshold (table- 1). RMT was determined based on visual inspection of toe or thumb movements on stimulation of the respective contralateral motor cortex. Two of the 12 patients dropped out after 6 & 9 sessions due to scalp discomfort and headache respectively; another patient dropped after 10 sessions due to logistic reasons. All the other patients received a minimum of 14 sessions. Three patients underwent iTBS immediately after symptom provocation using images, videos or in-vivo exposure evoking moderate severity of distress to activate the pathological circuitry [[2]Carmi L. Tendler A. Bystritsky A. Hollander E. Blumberger D.M. Daskalakis J. et al.Efficacy and safety of deep transcranial magnetic stimulation for obsessive-compulsive disorder: a prospective multicenter randomized double-blind placebo-controlled trial.Am J Psychiatr. 2019; 176: 931-938https://doi.org/10.1176/appi.ajp.2019.18101180Crossref PubMed Scopus (107) Google Scholar]. All the patients continued treatment with SRI along with/without an augmenting agent during the course of iTBS and no medication changes were made during the course of treatment. They had not responded to a mean of 5.5(2.1) trials with serotonin reuptake inhibitors (SRI) and 2(1.4) trials with augmenting agents. Four of them had failed behavior therapy in the past. None of the patients were receiving concurrent behavior therapy. Twelve patients (8 males), with a mean age and duration of illness of 34.5(10.8) years and 13(6.8) years respectively, were treated with iTBS. Six of them had comorbid psychiatric conditions (Table 1). They received a mean of 16.5(5.8) sessions of iTBS. There was a statistically significant decrease in the YBOCS scores [31.4(6.6) vs 23.3 (9.9), t(11) = 3.53 p < 0.005)] with a mean decrease of 25.44%. Five of the 12 patients (41.67%) satisfied the international consensus criteria for treatment response i.e. >35% reduction in Y-BOCS scores [[9]Mataix-Cols D. Fernández de la Cruz L. Nordsletten A.E. Lenhard F. Isomura K. Simpson H.B. Towards an international expert consensus for defining treatment response, remission, recovery and relapse in obsessive-compulsive disorder.World Psychiatr. 2016; 15: 80-81https://doi.org/10.1002/wps.20299Crossref PubMed Scopus (172) Google Scholar].Table. 1Clinical profile and outcome.Case NoAge/GenderDuration of illness (years)Co-morbidityFailed trials of SRIs/augmenting agentsTotal number of iTBS sessionsiTBS dose parametersY-BOCS (Baseline)Y-BOCS (Follow-up)% change in Y-BOCS137/M15GAD8/4∗26600-1200 pulses with 90–100% leg RMT301453.3237/F11Nil4/3∗20aiTBS given after symptom provocation, ∞ iTBS given using neuro-navigation, ∗ failed trial of behavior therapy. ∞600 pulses with 120% hand RMT37355.4348/M20Nil5/317600 pulses with 120% hand RMT31310438/M22Nil4/123aiTBS given after symptom provocation, ∞ iTBS given using neuro-navigation, ∗ failed trial of behavior therapy. ∞600-1200 pulses with 90–100% leg RMT281353.5519/M4Nil3/09aiTBS given after symptom provocation, ∞ iTBS given using neuro-navigation, ∗ failed trial of behavior therapy.600 pulses with 90% leg RMT382144.7626/M8Psychosis6/2∗6600 pulses with 90% leg RMT37370726/M13Schizophrenia3/110600 pulses with 90% leg RMT14140836/F10Schizophrenia4/014600 pulses with 90% leg RMT362336.1928/M6Schizophrenia8/320600 pulses with 90–100% leg RMT282414.21024/F6Somatoform disorder5/118600 pulses with 90% hand RMT286751137/M17Nil9/4∗19600 pulses with 90% leg RMT353014.21258/F25Nil8/320600 pulses with 90% leg RMT35328.5SRI – serotonin reuptake inhibitors, iTBS – intermittent theta burst stimulation, Y-BOCS – Yale-Brown Obsessive Compulsive Scale, GAD – Generalized anxiety disorder, RMT – resting motor threshold.a iTBS given after symptom provocation, ∞ iTBS given using neuro-navigation, ∗ failed trial of behavior therapy. Open table in a new tab SRI – serotonin reuptake inhibitors, iTBS – intermittent theta burst stimulation, Y-BOCS – Yale-Brown Obsessive Compulsive Scale, GAD – Generalized anxiety disorder, RMT – resting motor threshold. To the best of our knowledge, this is the first report demonstrating preliminary evidence for the use of iTBS using deep TMS in resistant OCD. Considering the briefer stimulation duration and lower intensity of intervention, iTBS may be a promising protocol for deep rTMS in resistant OCD. Although D-B80 coil has been shown to be capable of stimulating deeper cortical structures like ACC and dmPFC [[1]Dunlop K. Woodside B. Olmsted M. Colton P. Giacobbe P. Downar J. Reductions in cortico-striatal hyperconnectivity accompany successful treatment of obsessive-compulsive disorder with dorsomedial prefrontal rTMS.Neuropsychopharmacology. 2016; 41: 1395-1403https://doi.org/10.1038/npp.2015.292Crossref PubMed Scopus (73) Google Scholar], it may require higher stimulation intensities due to dispersion of magnetic flux as the depth of target region increases [[10]Deng Z.-D. Lisanby S.H. Peterchev A.V. Electric field depth–focality tradeoff in transcranial magnetic stimulation: simulation comparison of 50 coil designs.Brain Stimul. 2013; 6: 1-13https://doi.org/10.1016/j.brs.2012.02.005Abstract Full Text Full Text PDF PubMed Scopus (501) Google Scholar], lowering its tolerability. In line with this, 2 subjects dropped out of the intervention citing poor tolerability i.e. headache and scalp discomfort. There were no other serious adverse events including seizures. It is interesting to note that 2 out of 3 subjects in whom symptom provocation was attempted had shown substantial decline in the YBOCS score (53.5% and 44.7%). Although symptom provocation has been employed during rTMS to activate the pathological circuitry [[2]Carmi L. Tendler A. Bystritsky A. Hollander E. Blumberger D.M. Daskalakis J. et al.Efficacy and safety of deep transcranial magnetic stimulation for obsessive-compulsive disorder: a prospective multicenter randomized double-blind placebo-controlled trial.Am J Psychiatr. 2019; 176: 931-938https://doi.org/10.1176/appi.ajp.2019.18101180Crossref PubMed Scopus (107) Google Scholar], there is a need to study systematically the differential effect of rTMS with and without symptom provocation. A few limitations have to be kept in mind while interpreting the findings. This is an open-labeled case-series and the assessments were un-blinded. We were not able to elicit leg motor threshold (which lies deeper in the medial aspect of motor cortex) in 3 subjects. Nevertheless, one of the 3 patients responded to stimulation based on hand motor cortex stimulation. Four patients had a comorbid psychotic illness, one of them improved; it is possible that comorbid psychosis may have some effect on treatment response. In conclusion, our report provides preliminary evidence in support of efficacy of iTBS in treatment-resistant OCD. The protocol has to be evaluated in sham-controlled trials to establish its efficacy and tolerability. We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.

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