Efficacy of superolateral medial forebrain bundle deep brain stimulation in obsessive-compulsive disorder

Abstract

The superolateral medial forebrain bundle (slMFB) is a white-matter structure connecting established targets for deep brain stimulation (DBS) in obsessive-compulsive disorder (OCD) [[1]Coenen V.A. Schlaepfer T.E. Sajonz B. Döbrössy M. Kaller C.P. Urbach H. et al.Tractographic description of major subcortical projection pathways passing the anterior limb of the internal capsule. Corticopetal organization of networks relevant for psychiatric disorders.NeuroImage Clin. 2020; : 102165https://doi.org/10.1016/j.nicl.2020.102165Crossref PubMed Scopus (35) Google Scholar]. Recently, it has been proposed as a stimulation target itself [[2]Coenen V.A. Schlaepfer T.E. Goll P. Reinacher P.C. Voderholzer U. Tebartz van Elst L. et al.The medial forebrain bundle as a target for deep brain stimulation for obsessive-compulsive disorder.CNS Spectr. 2017; 22: 8https://doi.org/10.1017/S1092852916000286Crossref Scopus (60) Google Scholar] (see supplement S1 for presumed mode of action). The authors now present clinical outcome data of this treatment approach in form of an open label case series.Nine consecutive patients (4 female) suffering from severe treatment-resistant OCD (mean duration of disease = 23.4 years, range 11–39 years) with a mean age of 39.2 years (range 25–52 years) have been treated with DBS of the slMFB by our research group (see supplement S2 for sample selection). All patients received various disease-specific prior treatments, reported substantial impairment in their daily life due to OCD symptoms and were classified as treatment-resistant by our multi-professional and specialized team (psychiatrists and psychologists) based on comprehensive visits and provided medical documents. They underwent DBS surgery between December 2017 and January 2020 and were followed up. The neurosurgical procedure including imaging, fiber tracking, surgery and postoperative care has been described in detail in patients with treatment-resistant depression [[3]Coenen V.A. Sajonz B. Reisert M. Bostroem J. Bewernick B. Urbach H. et al.Tractography-assisted deep brain stimulation of the superolateral branch of the medial forebrain bundle (slMFB DBS) in major depression.NeuroImage Clin. 2018; 20: 580-593https://doi.org/10.1016/j.nicl.2018.08.020Crossref PubMed Scopus (46) Google Scholar]. The target region is located in the corridor between red nucleus, substantia nigra/subthalamic nucleus and the mammillothalamic tract [2Coenen V.A. Schlaepfer T.E. Goll P. Reinacher P.C. Voderholzer U. Tebartz van Elst L. et al.The medial forebrain bundle as a target for deep brain stimulation for obsessive-compulsive disorder.CNS Spectr. 2017; 22: 8https://doi.org/10.1017/S1092852916000286Crossref Scopus (60) Google Scholar, 3Coenen V.A. Sajonz B. Reisert M. Bostroem J. Bewernick B. Urbach H. et al.Tractography-assisted deep brain stimulation of the superolateral branch of the medial forebrain bundle (slMFB DBS) in major depression.NeuroImage Clin. 2018; 20: 580-593https://doi.org/10.1016/j.nicl.2018.08.020Crossref PubMed Scopus (46) Google Scholar, 4Coenen V.A. Bewernick B.H. Kayser S. Kilian H. Boström J. Greschus S. et al.Superolateral medial forebrain bundle deep brain stimulation in major depression: a gateway trial.Neuropsychopharmacology. 2019; 44: 1224-1232https://doi.org/10.1038/s41386-019-0369-9Crossref PubMed Scopus (69) Google Scholar]. In contrast to Ref. [[3]Coenen V.A. Sajonz B. Reisert M. Bostroem J. Bewernick B. Urbach H. et al.Tractography-assisted deep brain stimulation of the superolateral branch of the medial forebrain bundle (slMFB DBS) in major depression.NeuroImage Clin. 2018; 20: 580-593https://doi.org/10.1016/j.nicl.2018.08.020Crossref PubMed Scopus (46) Google Scholar] all patients received segmented DBS electrodes (Vercise Cartesia, Boston Scientific, Valencia, USA). Eight patients received a rechargeable pulse generator (Vercise Gevia, Boston Scientific); one patient received a non-rechargeable pulse generator (Vercise PC, Boston Scientific). Pulse generators were placed subclavicularly.Comprehensive symptom development (clinical outcome) was assessed regularly up to 36 months following stimulation onset, using clinician-based psychometric measurements (see supplement S3 and S4). We here focus on the Yale-Brown obsessive compulsive scale (Y-BOCS) [[5]Goodman W. Price L. Rasmussen S. Mazure C. Fleischmann R. Hill C. et al.The Yale-Brown obsessive compulsive scale. I. Development, use, and reliability.Arch Gen Psychiatr. 1989; 46: 1006-1011https://doi.org/10.1001/archpsyc.1989.01810110048007Crossref PubMed Scopus (6052) Google Scholar] as measurement of symptom severity.At baseline, mean Y-BOCS sum score of the sample was 31.0 (SD = 5.7). After three months of active stimulation three patients reached response criterion (>35% reduction of Y-BOCS sum score [[6]Farris S.G. McLean C.P. Van Meter P.E. Simpson H.B. Foa E.B. Treatment response, symptom remission, and wellness in obsessive-compulsive disorder.J Clin Psychiatr. 2013; 74: 21639Crossref Google Scholar]) and three other patients reached >20% reduction of Y-BOCS sum score at this time point.Mean duration until response criterion was reached for the first time was three months (ranging from stimulation onset to eight months). After one year of stimulation (range 10–13 months) seven patients were classified as responders and sustained response until last follow-up (FU, ranging from 11 to 36 months of stimulation, depending on date of surgery). Two patients responded occasionally only (Fig. 1F). As three-month data is available for six out of nine patients, this time point has been selected for short-term evaluation: By this time, mean Y-BOCS sum score had decreased by 43.1% (SD = 23.6, n = 6) compared to baseline. This score had decreased by 55.9% (SD = 20.0) after one year of stimulation and by 53.5% (SD = 23.7) at last FU. In absolute numbers this refers to a mean reduction of 12.2 points (SD = 6.7, n = 6) at three months, 16.9 (SD = 5.4) after one year and 16.2 (SD = 6.7) at last FU. For absolute scores see supplement Table S1, where improvement of depressive symptoms and global functioning is depicted, as well.Current applied therapeutically ranged between 1.4 and 5.5mA. For detailed information on stimulation settings see supplement S7. Stimulation related side effects resembled the ones described in previous publications on slMFB DBS in depression [[4]Coenen V.A. Bewernick B.H. Kayser S. Kilian H. Boström J. Greschus S. et al.Superolateral medial forebrain bundle deep brain stimulation in major depression: a gateway trial.Neuropsychopharmacology. 2019; 44: 1224-1232https://doi.org/10.1038/s41386-019-0369-9Crossref PubMed Scopus (69) Google Scholar] and could be resolved immediately by adjustments of the stimulation parameters. All further adverse events are listed in the supplement material (S8).Comparing our data to existing literature, after three months of stimulation our results resemble the Y-BOCS reduction rates 45.1% (95% CI = [29.4%; 60.8%]) reported in a meta-analysis on DBS in OCD [[8]Alonso P. Cuadras D. Gabriels L. Denys D. Goodman W. Greenberg B.D. et al.Deep brain stimulation for obsessive-compulsive disorder: a meta-analysis of treatment outcome and predictors of response.PLoS One. 2015; 10https://doi.org/10.1371/journal.pone.0133591Crossref Scopus (193) Google Scholar] but exceed this rate notably in the long run. Regarding size equivalent studies, some agreement with the clinical effects we report here, was achieved by DBS of the anteromedial subthalamic nucleus (amSTN) in a comparably affected sample with OCD (n = 8) [[7]Mallet L. Polosan M. Jaafari N. Baup N. Welter M.-L. Fontaine D. et al.Subthalamic nucleus stimulation in severe obsessive–compulsive disorder.N Engl J Med. 2008; 359: 2121-2134Crossref PubMed Scopus (663) Google Scholar]. Three months of amSTN stimulation resulted in 13 points reduction of Y-BOCS score whereas we achieved 12.2 points reduction (n = 6) in the same time frame. The long-term outcome with 51.2% (SD = 21.2) reduction rate after 46 months (n = 12) and 9/11 responders [[9]Mallet L. Du Montcel S.T. Clair A.-H. Arbus C. Bardinet E. Baup N. et al.Long-Term effects of subthalamic stimulation in obsessive-compulsive disorder: follow-up of a randomized controlled trial. Brain Stimulation.Basic, Translational, and Clinical Research in Neuromodulation. 2019; 12: 1080-1082Google Scholar] is similar to our last follow-up results, as well. The amSTN is an anatomically distinct target from ours. However, especially with respect to other publications [[1]Coenen V.A. Schlaepfer T.E. Sajonz B. Döbrössy M. Kaller C.P. Urbach H. et al.Tractographic description of major subcortical projection pathways passing the anterior limb of the internal capsule. Corticopetal organization of networks relevant for psychiatric disorders.NeuroImage Clin. 2020; : 102165https://doi.org/10.1016/j.nicl.2020.102165Crossref PubMed Scopus (35) Google Scholar], principal overlap of the stimulated area is conceivable. Surprisingly, diplopia is not reported as side effect in Ref. [[7]Mallet L. Polosan M. Jaafari N. Baup N. Welter M.-L. Fontaine D. et al.Subthalamic nucleus stimulation in severe obsessive–compulsive disorder.N Engl J Med. 2008; 359: 2121-2134Crossref PubMed Scopus (663) Google Scholar], although we consider it a characteristic side effect in slMFB stimulation [[4]Coenen V.A. Bewernick B.H. Kayser S. Kilian H. Boström J. Greschus S. et al.Superolateral medial forebrain bundle deep brain stimulation in major depression: a gateway trial.Neuropsychopharmacology. 2019; 44: 1224-1232https://doi.org/10.1038/s41386-019-0369-9Crossref PubMed Scopus (69) Google Scholar]. The comparison with existing literature demonstrates that DBS of the slMFB might reduce OCD symptoms just as much or even more than DBS of other targets and supports further research on efficacy and safety of this target.Beyond OCD symptoms, eventually depressive symptoms decreased quickly after stimulation onset in seven patients (supplement Table S1). This antidepressant effect is not surprising but expectable as previous studies on DBS of the slMFB in treatment-resistant depression have demonstrated rapid response onsets [[4]Coenen V.A. Bewernick B.H. Kayser S. Kilian H. Boström J. Greschus S. et al.Superolateral medial forebrain bundle deep brain stimulation in major depression: a gateway trial.Neuropsychopharmacology. 2019; 44: 1224-1232https://doi.org/10.1038/s41386-019-0369-9Crossref PubMed Scopus (69) Google Scholar]. This result supports the idea of a shared disease-network and is in line with the underlying hypothesis of a normalization of the reward network induced by the modulation of the slMFB-activity [[1]Coenen V.A. Schlaepfer T.E. Sajonz B. Döbrössy M. Kaller C.P. Urbach H. et al.Tractographic description of major subcortical projection pathways passing the anterior limb of the internal capsule. Corticopetal organization of networks relevant for psychiatric disorders.NeuroImage Clin. 2020; : 102165https://doi.org/10.1016/j.nicl.2020.102165Crossref PubMed Scopus (35) Google Scholar,[2]Coenen V.A. Schlaepfer T.E. Goll P. Reinacher P.C. Voderholzer U. Tebartz van Elst L. et al.The medial forebrain bundle as a target for deep brain stimulation for obsessive-compulsive disorder.CNS Spectr. 2017; 22: 8https://doi.org/10.1017/S1092852916000286Crossref Scopus (60) Google Scholar,[10]Schlaepfer T.E. Bewernick B.H. Kayser S. Hurlemann R. Coenen V.A. Deep brain stimulation of the human reward system for major depression—rationale, outcomes and outlook.Neuropsychopharmacology. 2014; 39: 1303-1314https://doi.org/10.1038/npp.2014.28Crossref PubMed Scopus (108) Google Scholar]. Further imaging studies proving this hypothesis on a functional level are pending.Generally, results of this report have to be interpreted cautiously as this is an open-label case series. Although visits at our unit are standardized, we did not follow a formalized research protocol. This results in continuous open stimulation without controlled sham-phases and might result in an overestimation of improvement as well as the unstable concomitant medication and psychotherapy. Therefore, future studies should be designed as RCTs to generate deeper insight into the efficacy and safety-profile of the treatment. Nevertheless, considering the enormous burden of illness of OCD in its severest form as reported here, the large effect, the long-term efficacy data and the safety-profile reported, we believe that this report clearly makes the point of adding the slMFB to brain stimulation target studies for this disease.Previous presentationThis manuscript has not been previously published other than in form of abstracts and is not currently under consideration by any other journal. Part of the data have been presented in abstracts/poster sessions at the ACNP annual meetings 2018 (Hollywood, FL) and 2019 (Orlando, FL) and at the DGPPN Congress 2018 (Berlin, Germany). We have since then acquired additional data that make our results more reliable.FundingThis research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors. The superolateral medial forebrain bundle (slMFB) is a white-matter structure connecting established targets for deep brain stimulation (DBS) in obsessive-compulsive disorder (OCD) [[1]Coenen V.A. Schlaepfer T.E. Sajonz B. Döbrössy M. Kaller C.P. Urbach H. et al.Tractographic description of major subcortical projection pathways passing the anterior limb of the internal capsule. Corticopetal organization of networks relevant for psychiatric disorders.NeuroImage Clin. 2020; : 102165https://doi.org/10.1016/j.nicl.2020.102165Crossref PubMed Scopus (35) Google Scholar]. Recently, it has been proposed as a stimulation target itself [[2]Coenen V.A. Schlaepfer T.E. Goll P. Reinacher P.C. Voderholzer U. Tebartz van Elst L. et al.The medial forebrain bundle as a target for deep brain stimulation for obsessive-compulsive disorder.CNS Spectr. 2017; 22: 8https://doi.org/10.1017/S1092852916000286Crossref Scopus (60) Google Scholar] (see supplement S1 for presumed mode of action). The authors now present clinical outcome data of this treatment approach in form of an open label case series. Nine consecutive patients (4 female) suffering from severe treatment-resistant OCD (mean duration of disease = 23.4 years, range 11–39 years) with a mean age of 39.2 years (range 25–52 years) have been treated with DBS of the slMFB by our research group (see supplement S2 for sample selection). All patients received various disease-specific prior treatments, reported substantial impairment in their daily life due to OCD symptoms and were classified as treatment-resistant by our multi-professional and specialized team (psychiatrists and psychologists) based on comprehensive visits and provided medical documents. They underwent DBS surgery between December 2017 and January 2020 and were followed up. The neurosurgical procedure including imaging, fiber tracking, surgery and postoperative care has been described in detail in patients with treatment-resistant depression [[3]Coenen V.A. Sajonz B. Reisert M. Bostroem J. Bewernick B. Urbach H. et al.Tractography-assisted deep brain stimulation of the superolateral branch of the medial forebrain bundle (slMFB DBS) in major depression.NeuroImage Clin. 2018; 20: 580-593https://doi.org/10.1016/j.nicl.2018.08.020Crossref PubMed Scopus (46) Google Scholar]. The target region is located in the corridor between red nucleus, substantia nigra/subthalamic nucleus and the mammillothalamic tract [2Coenen V.A. Schlaepfer T.E. Goll P. Reinacher P.C. Voderholzer U. Tebartz van Elst L. et al.The medial forebrain bundle as a target for deep brain stimulation for obsessive-compulsive disorder.CNS Spectr. 2017; 22: 8https://doi.org/10.1017/S1092852916000286Crossref Scopus (60) Google Scholar, 3Coenen V.A. Sajonz B. Reisert M. Bostroem J. Bewernick B. Urbach H. et al.Tractography-assisted deep brain stimulation of the superolateral branch of the medial forebrain bundle (slMFB DBS) in major depression.NeuroImage Clin. 2018; 20: 580-593https://doi.org/10.1016/j.nicl.2018.08.020Crossref PubMed Scopus (46) Google Scholar, 4Coenen V.A. Bewernick B.H. Kayser S. Kilian H. Boström J. Greschus S. et al.Superolateral medial forebrain bundle deep brain stimulation in major depression: a gateway trial.Neuropsychopharmacology. 2019; 44: 1224-1232https://doi.org/10.1038/s41386-019-0369-9Crossref PubMed Scopus (69) Google Scholar]. In contrast to Ref. [[3]Coenen V.A. Sajonz B. Reisert M. Bostroem J. Bewernick B. Urbach H. et al.Tractography-assisted deep brain stimulation of the superolateral branch of the medial forebrain bundle (slMFB DBS) in major depression.NeuroImage Clin. 2018; 20: 580-593https://doi.org/10.1016/j.nicl.2018.08.020Crossref PubMed Scopus (46) Google Scholar] all patients received segmented DBS electrodes (Vercise Cartesia, Boston Scientific, Valencia, USA). Eight patients received a rechargeable pulse generator (Vercise Gevia, Boston Scientific); one patient received a non-rechargeable pulse generator (Vercise PC, Boston Scientific). Pulse generators were placed subclavicularly. Comprehensive symptom development (clinical outcome) was assessed regularly up to 36 months following stimulation onset, using clinician-based psychometric measurements (see supplement S3 and S4). We here focus on the Yale-Brown obsessive compulsive scale (Y-BOCS) [[5]Goodman W. Price L. Rasmussen S. Mazure C. Fleischmann R. Hill C. et al.The Yale-Brown obsessive compulsive scale. I. Development, use, and reliability.Arch Gen Psychiatr. 1989; 46: 1006-1011https://doi.org/10.1001/archpsyc.1989.01810110048007Crossref PubMed Scopus (6052) Google Scholar] as measurement of symptom severity. At baseline, mean Y-BOCS sum score of the sample was 31.0 (SD = 5.7). After three months of active stimulation three patients reached response criterion (>35% reduction of Y-BOCS sum score [[6]Farris S.G. McLean C.P. Van Meter P.E. Simpson H.B. Foa E.B. Treatment response, symptom remission, and wellness in obsessive-compulsive disorder.J Clin Psychiatr. 2013; 74: 21639Crossref Google Scholar]) and three other patients reached >20% reduction of Y-BOCS sum score at this time point. Mean duration until response criterion was reached for the first time was three months (ranging from stimulation onset to eight months). After one year of stimulation (range 10–13 months) seven patients were classified as responders and sustained response until last follow-up (FU, ranging from 11 to 36 months of stimulation, depending on date of surgery). Two patients responded occasionally only (Fig. 1F). As three-month data is available for six out of nine patients, this time point has been selected for short-term evaluation: By this time, mean Y-BOCS sum score had decreased by 43.1% (SD = 23.6, n = 6) compared to baseline. This score had decreased by 55.9% (SD = 20.0) after one year of stimulation and by 53.5% (SD = 23.7) at last FU. In absolute numbers this refers to a mean reduction of 12.2 points (SD = 6.7, n = 6) at three months, 16.9 (SD = 5.4) after one year and 16.2 (SD = 6.7) at last FU. For absolute scores see supplement Table S1, where improvement of depressive symptoms and global functioning is depicted, as well. Current applied therapeutically ranged between 1.4 and 5.5mA. For detailed information on stimulation settings see supplement S7. Stimulation related side effects resembled the ones described in previous publications on slMFB DBS in depression [[4]Coenen V.A. Bewernick B.H. Kayser S. Kilian H. Boström J. Greschus S. et al.Superolateral medial forebrain bundle deep brain stimulation in major depression: a gateway trial.Neuropsychopharmacology. 2019; 44: 1224-1232https://doi.org/10.1038/s41386-019-0369-9Crossref PubMed Scopus (69) Google Scholar] and could be resolved immediately by adjustments of the stimulation parameters. All further adverse events are listed in the supplement material (S8). Comparing our data to existing literature, after three months of stimulation our results resemble the Y-BOCS reduction rates 45.1% (95% CI = [29.4%; 60.8%]) reported in a meta-analysis on DBS in OCD [[8]Alonso P. Cuadras D. Gabriels L. Denys D. Goodman W. Greenberg B.D. et al.Deep brain stimulation for obsessive-compulsive disorder: a meta-analysis of treatment outcome and predictors of response.PLoS One. 2015; 10https://doi.org/10.1371/journal.pone.0133591Crossref Scopus (193) Google Scholar] but exceed this rate notably in the long run. Regarding size equivalent studies, some agreement with the clinical effects we report here, was achieved by DBS of the anteromedial subthalamic nucleus (amSTN) in a comparably affected sample with OCD (n = 8) [[7]Mallet L. Polosan M. Jaafari N. Baup N. Welter M.-L. Fontaine D. et al.Subthalamic nucleus stimulation in severe obsessive–compulsive disorder.N Engl J Med. 2008; 359: 2121-2134Crossref PubMed Scopus (663) Google Scholar]. Three months of amSTN stimulation resulted in 13 points reduction of Y-BOCS score whereas we achieved 12.2 points reduction (n = 6) in the same time frame. The long-term outcome with 51.2% (SD = 21.2) reduction rate after 46 months (n = 12) and 9/11 responders [[9]Mallet L. Du Montcel S.T. Clair A.-H. Arbus C. Bardinet E. Baup N. et al.Long-Term effects of subthalamic stimulation in obsessive-compulsive disorder: follow-up of a randomized controlled trial. Brain Stimulation.Basic, Translational, and Clinical Research in Neuromodulation. 2019; 12: 1080-1082Google Scholar] is similar to our last follow-up results, as well. The amSTN is an anatomically distinct target from ours. However, especially with respect to other publications [[1]Coenen V.A. Schlaepfer T.E. Sajonz B. Döbrössy M. Kaller C.P. Urbach H. et al.Tractographic description of major subcortical projection pathways passing the anterior limb of the internal capsule. Corticopetal organization of networks relevant for psychiatric disorders.NeuroImage Clin. 2020; : 102165https://doi.org/10.1016/j.nicl.2020.102165Crossref PubMed Scopus (35) Google Scholar], principal overlap of the stimulated area is conceivable. Surprisingly, diplopia is not reported as side effect in Ref. [[7]Mallet L. Polosan M. Jaafari N. Baup N. Welter M.-L. Fontaine D. et al.Subthalamic nucleus stimulation in severe obsessive–compulsive disorder.N Engl J Med. 2008; 359: 2121-2134Crossref PubMed Scopus (663) Google Scholar], although we consider it a characteristic side effect in slMFB stimulation [[4]Coenen V.A. Bewernick B.H. Kayser S. Kilian H. Boström J. Greschus S. et al.Superolateral medial forebrain bundle deep brain stimulation in major depression: a gateway trial.Neuropsychopharmacology. 2019; 44: 1224-1232https://doi.org/10.1038/s41386-019-0369-9Crossref PubMed Scopus (69) Google Scholar]. The comparison with existing literature demonstrates that DBS of the slMFB might reduce OCD symptoms just as much or even more than DBS of other targets and supports further research on efficacy and safety of this target. Beyond OCD symptoms, eventually depressive symptoms decreased quickly after stimulation onset in seven patients (supplement Table S1). This antidepressant effect is not surprising but expectable as previous studies on DBS of the slMFB in treatment-resistant depression have demonstrated rapid response onsets [[4]Coenen V.A. Bewernick B.H. Kayser S. Kilian H. Boström J. Greschus S. et al.Superolateral medial forebrain bundle deep brain stimulation in major depression: a gateway trial.Neuropsychopharmacology. 2019; 44: 1224-1232https://doi.org/10.1038/s41386-019-0369-9Crossref PubMed Scopus (69) Google Scholar]. This result supports the idea of a shared disease-network and is in line with the underlying hypothesis of a normalization of the reward network induced by the modulation of the slMFB-activity [[1]Coenen V.A. Schlaepfer T.E. Sajonz B. Döbrössy M. Kaller C.P. Urbach H. et al.Tractographic description of major subcortical projection pathways passing the anterior limb of the internal capsule. Corticopetal organization of networks relevant for psychiatric disorders.NeuroImage Clin. 2020; : 102165https://doi.org/10.1016/j.nicl.2020.102165Crossref PubMed Scopus (35) Google Scholar,[2]Coenen V.A. Schlaepfer T.E. Goll P. Reinacher P.C. Voderholzer U. Tebartz van Elst L. et al.The medial forebrain bundle as a target for deep brain stimulation for obsessive-compulsive disorder.CNS Spectr. 2017; 22: 8https://doi.org/10.1017/S1092852916000286Crossref Scopus (60) Google Scholar,[10]Schlaepfer T.E. Bewernick B.H. Kayser S. Hurlemann R. Coenen V.A. Deep brain stimulation of the human reward system for major depression—rationale, outcomes and outlook.Neuropsychopharmacology. 2014; 39: 1303-1314https://doi.org/10.1038/npp.2014.28Crossref PubMed Scopus (108) Google Scholar]. Further imaging studies proving this hypothesis on a functional level are pending. Generally, results of this report have to be interpreted cautiously as this is an open-label case series. Although visits at our unit are standardized, we did not follow a formalized research protocol. This results in continuous open stimulation without controlled sham-phases and might result in an overestimation of improvement as well as the unstable concomitant medication and psychotherapy. Therefore, future studies should be designed as RCTs to generate deeper insight into the efficacy and safety-profile of the treatment. Nevertheless, considering the enormous burden of illness of OCD in its severest form as reported here, the large effect, the long-term efficacy data and the safety-profile reported, we believe that this report clearly makes the point of adding the slMFB to brain stimulation target studies for this disease. Previous presentationThis manuscript has not been previously published other than in form of abstracts and is not currently under consideration by any other journal. Part of the data have been presented in abstracts/poster sessions at the ACNP annual meetings 2018 (Hollywood, FL) and 2019 (Orlando, FL) and at the DGPPN Congress 2018 (Berlin, Germany). We have since then acquired additional data that make our results more reliable. This manuscript has not been previously published other than in form of abstracts and is not currently under consideration by any other journal. Part of the data have been presented in abstracts/poster sessions at the ACNP annual meetings 2018 (Hollywood, FL) and 2019 (Orlando, FL) and at the DGPPN Congress 2018 (Berlin, Germany). We have since then acquired additional data that make our results more reliable. FundingThis research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.