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1Hz right orbitofrontal TMS benefits depressed patients unresponsive to dorsolateral prefrontal cortex TMS

2023; Elsevier BV; Volume: 16; Issue: 6 Linguagem: Inglês

10.1016/j.brs.2023.10.005

1935-861X

Amourie Prentice, Ylka Kolken, Christina Clark Tuttle, Joris van Neijenhof, Richard Pitch, Iris van Oostrom, Vera Kruiver, Jonathan Downar, Alexander T. Sack, Martijn Arns, Nikita van der Vinne,

Neurological disorders and treatments

Major depressive disorder (MDD) remains a significant global health challenge. Patients failing to achieve remission despite multiple conventional therapeutic interventions (i.e., difficult-to-treat or treatment-resistant depression, TRD) constitute nearly 30 % of MDD cases [[1]Rush A.J. Trivedi M.H. Wisniewski S.R. Nierenberg A.A. Stewart J.W. Warden D. et al.Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report.Am J Psychiatr. 2006; 163: 1905-1917https://doi.org/10.1176/ajp.2006.163.11.1905Crossref PubMed Scopus (3807) Google Scholar]. Repetitive transcranial magnetic stimulation (TMS) has gained traction as a promising non-invasive approach in TRD, conventionally targeting the dorsolateral prefrontal cortex (DLPFC) [[2]Janicak P.G. Dokucu M.E. Transcranial magnetic stimulation for the treatment of major depression.Neuropsychiatric Dis Treat. 2015; 11: 1549-1560https://doi.org/10.2147/ndt.s67477Crossref PubMed Scopus (0) Google Scholar]. While high-frequency TMS applied to the left DLPFC has demonstrated remission rates ranging from 19 % to 37 % [[3]Berlim M.T. Eynde F van den Tovar-Perdomo S. Daskalakis Z.J. Response, remission and drop-out rates following high-frequency repetitive transcranial magnetic stimulation (rTMS) for treating major depression: a systematic review and meta-analysis of randomized, double-blind and sham-controlled trials.Psychol Med. 2014; 44: 225-239https://doi.org/10.1017/s0033291713000512Crossref PubMed Scopus (0) Google Scholar,[4]Carpenter L.L. Janicak P.G. Aaronson S.T. Boyadjis T. Brock D.G. Cook I.A. et al.Transcranial magnetic stimulation (TMS) for depression: a multisite, naturalistic, observational study of acute treatment outcomes in clinical practice.Depress Anxiety. 2012; 29: 587-596https://doi.org/10.1002/da.21969Crossref PubMed Scopus (236) Google Scholar] but augmented 1Hz-R-DLPFC results in no extra beneficial effect [[5]Sackeim H.A. Aaronson S.T. Carpenter L.L. Hutton T.M. Mina M. Pages K. Verdoliva S. West W.S. Clinical outcomes in a large registry of patients with major depressive disorder treated with Transcranial Magnetic Stimulation.J Affect Disord. 2020; 277: 65-74https://doi.org/10.1016/j.jad.2020.08.005Crossref PubMed Scopus (50) Google Scholar], many patients remain non-responders, and alternative stimulation sites and protocols may be required. An emerging candidate target is the orbital-frontal cortex (OFC), a region pivotal in processing reward/'non-reward' and implicated in MDD pathophysiology [[6]Rolls E.T. Cheng W. Feng J. The orbitofrontal cortex: reward, emotion and depression.Brain Commun. 2020; 2: fcaa196https://doi.org/10.1093/braincomms/fcaa196Crossref PubMed Scopus (124) Google Scholar]. Neuroimaging and deep brain stimulation studies have suggested that the right-lateral-OFC (R–OFC) may be a fruitful target for neuromodulation [[7]Cheng W. Rolls E.T. Qiu J. Liu W. Tang Y. Huang C.-C. et al.Medial reward and lateral non-reward orbitofrontal cortex circuits change in opposite directions in depression.Brain. 2016; 139: 3296-3309https://doi.org/10.1093/brain/aww255Crossref PubMed Scopus (191) Google Scholar,[8]Rao V. Sellers K. Wallace D.L. L Morgan B. Maryam B. Sani O.G. et al.Direct electrical stimulation of lateral orbitofrontal cortex acutely improves mood in individuals with symptoms of depression.Curr Biol. 2018; 28: 3893-3902https://doi.org/10.1016/j.cub.2018.10.026Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar]. Encouragingly, a case study reported improved mood and anhedonia in an MDD patient through 1Hz-TMS over the R–OFC, following non-response to DLPFC and dorsomedial PFC (DMPFC)-TMS (DMPFC) [[9]Fettes P. Peters S. Giacobbe P. Blumberger D.M. Downar J. Neural correlates of successful orbitofrontal 1 Hz rTMS following unsuccessful dorsolateral and dorsomedial prefrontal rTMS in major depression: a case report.Brain Stimul. 2017; 10: 165-167https://doi.org/10.1016/j.brs.2016.11.008Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar]. A follow-up case series in patients unresponsive to DMPFC-TMS found 30 % response and 24 % remission after a course of 1Hz R–OFC–TMS [[10]Feffer K. Fettes P. Giacobbe P. Daskalakis Z.J. Blumberger D.M. Downar J. 1Hz rTMS of the right orbitofrontal cortex for major depression: safety, tolerability and clinical outcomes.Eur Neuropsychopharmacol. 2018; 28: 109-117https://doi.org/10.1016/j.euroneuro.2017.11.011Crossref PubMed Scopus (61) Google Scholar] and a recent study established mood improvement after OFC augmentation to combined DLPFC 10Hz and iTBS [[11]Tadayonnejad R. Citrenbaum C. Ngo T.D.P. Corlier J. Wilke S.A. Slan A. Distler M.G. Hoftman G. Adelekun A.E. Leuchter M.K. Koek R.J. Ginder N.D. Krantz D. Artin H. Strouse T. Bari A.A. Leuchter A.F. Right lateral orbitofrontal cortex inhibitory transcranial magnetic stimulation for treatment of refractory mood and depression.Brain Stimul. 2023; 16: 1374-1376https://doi.org/10.1016/j.brs.2023.09.011Abstract Full Text Full Text PDF Scopus (0) Google Scholar]. Here we report on the clinical effectiveness of 1Hz-R–OFC–TMS in individuals previously unresponsive to conventional DLPFC-TMS, both as a singular treatment and as an augmentation. Drawing from patient samples in both the Netherlands (NL) and the United States (US), we assessed mood, anxiety and, for the Dutch sample, sleep outcomes. Additionally, we explored whether particular baseline demographic characteristics or clinical symptoms predict remission/non-remission following 1Hz-R–OFC–TMS. Our retrospective, naturalistic study enrolled 41 patients with non-psychotic TRD (i.e., at least two failed evidence-based treatments; nNL = 25; nUS = 16; detailed demographic/clinical characteristics are presented in Table S1). Data were collected from neurocare Clinics/neurocare Centers (www.neurocaregroup.com; https://neurocarecoa.com). Inclusion criteria consisted of: confirmed non-psychotic MDD diagnosis, established through standardized interviews (M.I.N.I., SCID); baseline Beck Depression Inventory (BDI-II) scores≥14; non-response to prior DLPFC-TMS treatment (defined by BDI-II scores decreased by<50 %). Pregnant patients, those with epilepsy, current psychosis, cardiac pacemakers, or cranial metal implants were excluded. Patients were switched to 1Hz-R–OFC–TMS after non-response to 42.4 ± 21.6 (NL) or 20.4 ± 7.4 (US) sessions of DLPFC-TMS, according to clinical judgment. Informed consent was obtained from all patients. In the NL sample, patients underwent an average of 24.4 ± 16.4 1Hz-R–OFC–TMS only sessions (1Hz, 60s on, 30s off, 15 trains, 120 % lower limb RMT) at Fp2, using a figure-8 coil with 120°-angled windings (Deymed DuoMag XT-100 with 90BFVT-LQC coil or MagVenture R30 with D-B80 coil; Fig. 1A). In the US sample, patients received an average of 20.1 ± 6.7 1Hz-R–OFC–TMS augmented to DLPFC stimulation (1Hz, 1200 pulses continuously, 120 % finger twitch RMT) at AF8, using a NeuroStar iron-core coil, positioned at an angle of +35°. In Supplementary Fig. S1 we provide SimNIBS simulations of the electric fields induced by Fp2 and AF8 stimulation (OFC), to show their differential modulation compared to F4 stimulation (DLPFC; https://simnibs.github.io/simnibs/build/html/). Depression severity was assessed using BDI-II, with subscales representing symptom clusters (Table S2). Anxiety levels were measured using the Depression Anxiety and Stress Scale (DASS). For the NL-sample, sleep disturbances were evaluated using the Pittsburg Sleep Quality Index (PSQI), and objective measures of sleep-wake patterns and activity were captured using an Actigraphy watch. Statistical results revealed no significant differences between the two samples regarding age, sex, antidepressant use, baseline depression severity, or comorbidities (Table S1). Detailed clinical outcomes are presented in Table S3. To summarize, 1Hz-R–OFC–TMS achieved response in 6/25 (24 %; NL), 8/16 (50 %; US), and remission in 6/25 (24 %; NL), 5/16 (31 %; US). Repeated measures ANOVA revealed significant reductions in depression severity (BDI-II scores) for both samples following 1Hz-R–OFC–TMS (F(1,39) = 64.921, p < .001). Notably, the mood improvement associated with 1Hz-R–OFC–TMS was especially pronounced in the US sample (Fig. 1B), also evidenced by the significant interactions between TMS protocol and country sample (F(1,39) = 9.540, p = .004) and between TMS protocol and time (F(1,39) = 17.337, p < .001; detailed statistical results in Table S4). Furthermore, repeated measures ANOVAs revealed significant improvements (p ≤ .001) following 1Hz-R–OFC–TMS in anxiety, anhedonia, non-anhedonia, cognitive-affective, somatic and performance, cognitive, and non-cognitive symptom clusters, as well as sleep on PSQI global score (p = .008; Table S5 and Fig. S2). None of the available demographic/clinical characteristics (age, sex, antidepressant usage, baseline BDI-II, symptom clusters, anxiety, sleep) showed any significant predictive association with 1Hz-R–OFC–TMS remission/non-remission status following Bonferroni correction, although patients with higher anhedonia showed a trend towards higher probability of remission (Table S6). The remission rates, ranging from 24 % (NL) to 31 % (US), collectively propose that a strategic shift in stimulation site, thereby impacting another independent neural circuit, holds promise for patients unresponsive to DLPFC-TMS. These findings align with prior studies [9Fettes P. Peters S. Giacobbe P. Blumberger D.M. Downar J. Neural correlates of successful orbitofrontal 1 Hz rTMS following unsuccessful dorsolateral and dorsomedial prefrontal rTMS in major depression: a case report.Brain Stimul. 2017; 10: 165-167https://doi.org/10.1016/j.brs.2016.11.008Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar, 10Feffer K. Fettes P. Giacobbe P. Daskalakis Z.J. Blumberger D.M. Downar J. 1Hz rTMS of the right orbitofrontal cortex for major depression: safety, tolerability and clinical outcomes.Eur Neuropsychopharmacol. 2018; 28: 109-117https://doi.org/10.1016/j.euroneuro.2017.11.011Crossref PubMed Scopus (61) Google Scholar, 11Tadayonnejad R. Citrenbaum C. Ngo T.D.P. Corlier J. Wilke S.A. Slan A. Distler M.G. Hoftman G. Adelekun A.E. Leuchter M.K. Koek R.J. Ginder N.D. Krantz D. Artin H. Strouse T. Bari A.A. Leuchter A.F. Right lateral orbitofrontal cortex inhibitory transcranial magnetic stimulation for treatment of refractory mood and depression.Brain Stimul. 2023; 16: 1374-1376https://doi.org/10.1016/j.brs.2023.09.011Abstract Full Text Full Text PDF Scopus (0) Google Scholar], and underscore the clinical significance of 1Hz-R–OFC–TMS given that remission rates reported for DLPFC-TMS span between 19 % to 37 % [[3]Berlim M.T. Eynde F van den Tovar-Perdomo S. Daskalakis Z.J. Response, remission and drop-out rates following high-frequency repetitive transcranial magnetic stimulation (rTMS) for treating major depression: a systematic review and meta-analysis of randomized, double-blind and sham-controlled trials.Psychol Med. 2014; 44: 225-239https://doi.org/10.1017/s0033291713000512Crossref PubMed Scopus (0) Google Scholar,[4]Carpenter L.L. Janicak P.G. Aaronson S.T. Boyadjis T. Brock D.G. Cook I.A. et al.Transcranial magnetic stimulation (TMS) for depression: a multisite, naturalistic, observational study of acute treatment outcomes in clinical practice.Depress Anxiety. 2012; 29: 587-596https://doi.org/10.1002/da.21969Crossref PubMed Scopus (236) Google Scholar]. Moreover, the more pronounced mood improvement associated with 1Hz-R–OFC–TMS in the US sample could be linked to distinctions between the two samples: different sites for OFC stimulation (NL:Fp2; US:AF8), and US patients transitioned from DLPFC-TMS to 1Hz-R–OFC–TMS much sooner on average than their NL counterparts (NL:42.4, US:20.4 DLPFC sessions). Therefore, we cannot discount the potential impact of a higher number of DLPFC-TMS sessions. While our study found no significant predictive associations between clinical characteristics and 1Hz-R–OFC–TMS remission/non-remission, electroencephalogram-derived biomarkers (e.g., Brainmarker-I, OFC-theta band activity) may offer promise due to their demonstrated associations in prior research [8,12. Additionally, with the non-significant trend found towards anhedonia, future research focused specifically on anhedonia could be of interest in determining whether it truly can predict remission/non-remission following 1Hz-R–OFC–TMS. Limitations (more extensively discussed in the supplement) include a relatively small sample size (which may be underpowered to detect subtle predictors), the absence of a control group, the differential administration of OFC-TMS as either a full switch or augmentation, and heterogeneity of baseline characteristics and intervention parameters between the two samples. However, given the heterogeneity in terms of length of treatment but similar remission rates in the samples, the established treatment effects are possibly not just a consequence of more sessions. This is supported by the recent finding of Tadayonnejad et al. [[11]Tadayonnejad R. Citrenbaum C. Ngo T.D.P. Corlier J. Wilke S.A. Slan A. Distler M.G. Hoftman G. Adelekun A.E. Leuchter M.K. Koek R.J. Ginder N.D. Krantz D. Artin H. Strouse T. Bari A.A. Leuchter A.F. Right lateral orbitofrontal cortex inhibitory transcranial magnetic stimulation for treatment of refractory mood and depression.Brain Stimul. 2023; 16: 1374-1376https://doi.org/10.1016/j.brs.2023.09.011Abstract Full Text Full Text PDF Scopus (0) Google Scholar], where a greater rate of symptom improvement was established after the addition of right OFC augmentation. The robustness and scope of the observed improvements despite this heterogeneity is promising for generalizability of the findings. Future studies on 1Hz-R–OFC–TMS incorporating control groups (sham, continued DLPFC-TMS) and larger sample sizes would address limitations of the currently available literature on 1Hz-R–OFC–TMS. In conclusion, our study supports the clinical utility of 1Hz-R–OFC–TMS for TRD in patients unresponsive to conventional DLPFC-TMS. The robust effects seen in these two open-label samples encourage future large-scale randomized trials of 1Hz-R–OFC–TMS. Further work to compare a continued DLPFC stimulation treatment arm (10Hz or 1Hz) with a switch to 1Hz-OFC, and to elucidate specific clinical and/or biological markers (e.g., EEG) of 1Hz-R–OFC–TMS responders might play a crucial role in patient selection, ultimately enhancing treatment outcomes. [[12]Voetterl H. Wingen G van Michelini G. Griffiths K.R. Gordon E. DeBeus R. et al.Brainmarker-I differentially predicts remission to various attention-deficit/hyperactivity disorder treatments: a blinded discovery, transfer and validation study.Biological Psychiatry Cognitive Neurosci Neuroimaging. 2022; https://doi.org/10.1016/j.bpsc.2022.02.007Abstract Full Text Full Text PDF Scopus (10) Google Scholar]. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JD has received research support from NIH, CIHR, Brain Canada, Ontario Brain Institute, the Klarman Family Foundation, the Arrell Family Foundation, and the Buchan Family Foundation, in-kind equipment support for investigator-initiated trials from MagVenture, is an advisor for BrainCheck, Arc Health Partners and Salience Neuro Health, and is a co-founder of Ampa Health. ATS is Chief Scientific Advisor of PlatoScience, Scientific Advisor of Alpha Brain Technologies, CEO of Neurowear Medical B.V., Director of the International Clinical TMS Certification Course (www.tmscourse.eu) and got equipment support from MagVenture, Deymed Medical and MagStim Company. MA holds equity/stock in neurocare and Sama Therapeutics, serves as consultant to Synaeda, Sama Therapeutics and Roche and is named inventor on patents and intellectual property but receives no royalties. Brainclinics Foundation received equipment support from MagVenture and Deymed. The following authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper: AP, YK, CT, JN, RP, IO, VK and NV. The following are the Supplementary data to this article. Download .docx (2.68 MB) Help with docx files Multimedia component 1