Right lateral orbitofrontal cortex inhibitory transcranial magnetic stimulation for treatment of refractory mood and depression

Abstract

High-frequency repetitive Transcranial Magnetic Stimulation (rTMS) of the left dorsolateral prefrontal cortex (DLPFC) is an effective treatment for Major Depressive Disorder (MDD), but up to half of patients can have significant residual depressive symptoms using this treatment approach [[1]Somani A. Kar S.K. Efficacy of repetitive transcranial magnetic stimulation in treatment-resistant depression: the evidence thus far.Gen Psychiatr. 2019; 32e100074PubMed Google Scholar]. Developing new approaches to enhance rTMS treatment efficacy is critically important considering that the majority of patients pursue rTMS only after failing to respond to available pharmacological and psychotherapeutic treatment options. Right lateral orbitofrontal cortex (rlOFC) has been shown to play a prominent role in the circuit mechanisms of depression [[2]Rolls E.T. Cheng W. Feng J. The orbitofrontal cortex: reward, emotion and depression.Brain Commun. 2020; 2: fcaa196Crossref PubMed Scopus (140) Google Scholar], but has not been extensively studied as a treatment target. In this open-label case series study, we examined the safety, feasibility, and efficacy of sequential bilateral rlOFC inhibitory augmentation stimulation for patients showing limited response to 20 sessions of conventional high-frequency left DLPFC stimulation. 33 patients (average age = 42.9 ± 16.8, 20 female) with moderately-severe MDD (average Inventory of Depressive Symptomatology-Self-Report [IDS-SR] [[3]Rush A.J. Giles D.E. Schlesser M.A. Fulton C.L. Weissenburger J. Burns C. The inventory for depressive Symptomatology (IDS): preliminary findings.Psychiatr Res. 1986; 18: 65-87Crossref PubMed Scopus (760) Google Scholar] = 44 ± 10.8, Patient Health Questionnaire [PHQ-9] = 19 ± 4.1) with a high degree of negative ruminative thinking (Ruminative Response Scale [[4]Nolen-Hoeksema S. Morrow J. A prospective study of depression and posttraumatic stress symptoms after a natural disaster: the 1989 Loma Prieta Earthquake.J Pers Soc Psychol. 1991; 61: 115-121Crossref PubMed Scopus (2326) Google Scholar] [RRS] = 64 ± 14.4) were enrolled in this study and underwent a course of treatment at the UCLA TMS Clinical and Research Service. They were highly treatment-resistant as evidenced by having tried on average 7.7 ± 4 different antidepressant medications (antidepressants and antipsychotics) and 1.5 ± 2 courses of psychotherapy with suboptimal improvement. The UCLA Institutional Review Board approved this retrospective analysis of de-identified data. Clinical measures were collected prior to, after every five sessions, and at the end of treatment. Because of its high negative predictive value, the IDS-SR was used to assess symptom improvement during treatment. The PHQ-9 was used to assess the overall treatment outcome. Patients initially received treatment with 10 Hz rTMS (3000 pulses) administered to left DLPFC with the stimulating coil placed using the Beam F3 method and stimulation intensity titrated as tolerated to 120% of motor threshold (MT), which was determined at the first treatment session. We utilized a measurement-based care paradigm previously described [5Lee J.C. Wilson A.C. Corlier J. Tadayonnejad R. Marder K.G. Pleman C.M. et al.Strategies for augmentation of high-frequency left-sided repetitive transcranial magnetic stimulation treatment of major depressive disorder.J Affect Disord. 2020; 277: 964-969Crossref PubMed Scopus (13) Google Scholar, 6Tadayonnejad R. Wilson A.C. Chu S.A. Corlier J. Citrenbaum C. Ngo T.D.P. et al.Use of right orbitofrontal repetitive transcranial magnetic stimulation (rTMS) augmentation for treatment-refractory obsessive-compulsive disorder with comorbid major depressive disorder.Psychiatr Res. 2022; 317114856Crossref PubMed Scopus (5) Google Scholar, 7Tadayonnejad R. Wilson A.C. Corlier J. Lee J.C. Ginder N.D. Levitt J.G. et al.Sequential multi-locus transcranial magnetic stimulation for treatment of obsessive-compulsive disorder with comorbid major depression: a case series.Brain Stimul. 2020; 13: 1600-1602Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar] to augment treatment in these patients, all of whom had limited benefit from up to 20 treatment sessions (e.g., ≤20% improvement on the IDS). Starting after treatment session 10, 10 Hz stimulation was augmented with theta burst priming (600 pulses of intermittent Theta Burst Stimulation [iTBS] at 80% of MT preceding 10 Hz stimulation) for at least 10 sessions, which previously has been shown to augment response to 10 Hz stimulation [[5]Lee J.C. Wilson A.C. Corlier J. Tadayonnejad R. Marder K.G. Pleman C.M. et al.Strategies for augmentation of high-frequency left-sided repetitive transcranial magnetic stimulation treatment of major depressive disorder.J Affect Disord. 2020; 277: 964-969Crossref PubMed Scopus (13) Google Scholar]. Because these subjects continued to show limited benefit after the priming intervention (after treatment session 20 [T20]), they subsequently received sequential bilateral augmentation with 1200 pulses of 1 Hz inhibitory rTMS administered to the rlOFC (defined as the FP2 electrode location from the International 10–20 EEG System, Fig. 1A) delivered at 120–140% MT. There were no significant adverse events and no subjects discontinued treatment before completing the full course of treatment. There was no significant change in depressive symptoms from baseline to T20 (average total IDS-SR: baseline = 44 ± 10.8 vs T20 = 43 ± 10.5, P = 0.28) or in the IDS-SR mood subcomponent (measured by summing mood-related items of IDS-SR [[8]Wardenaar K.J. Vreeburg S.A. van Veen T. Giltay E.J. Veen G. Penninx B.W. et al.Dimensions of depression and anxiety and the hypothalamo-pituitary-adrenal axis.Biol Psychiatr. 2011; 69: 366-373Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar], average IDS-SRMood: baseline = 21 ± 4.5 vs T20 = 21 ± 5.0, P = 0.74). Following the addition of rlOFC augmentation (average number of sessions including rlOFC = 15 ± 5.4), patients showed significant improvement in total symptom severity (total IDS-SR posttreatment = 36 ± 14.4, P = 0.0004), mood (IDS-SRMood posttreatment = 17 ± 6.9, P = 0.0001), and negative rumination (total RRS: T20 = 61 ± 14.9, posttreatment = 54 ± 16.1, P = 0.001). Linear mixed effects modeling with the raw score as the dependent variable and time and presence of rlOFC augmentation as independent variables showed significant interactions between the addition of rlOFC and time on total IDS-SR (P = 0.0004, Fig. 1. B), IDS-SRMood (P = 0.0002, Fig. 1. C), and RRS scores (P = 0.0006, Fig. 1. D), indicating that the rate of symptom improvement was greater after the addition of rlOFC augmentation. 24% of patients had a full response (≥50% reduction in PHQ-9) and an additional 24% a partial response (20–50% reduction in PHQ-9) to a full course of treatment including rlOFC augmentation. These findings extend prior work on the role of inhibitory stimulation of the rlOFC. Stimulation of this region as a sole target was reported to be an effective treatment in patients with MDD who did not respond to a prior course of dorsomedial prefrontal cortex rTMS [[9]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: 109-117Crossref PubMed Scopus (65) Google Scholar]. Our group also recently showed that utilizing the rlOFC inhibitory rTMS as an adjunctive target in patients with primary obsessive-compulsive disorder (OCD) and comorbid refractory depression resulted in significant improvement not only in OCD but also depressive symptom severity [[6]Tadayonnejad R. Wilson A.C. Chu S.A. Corlier J. Citrenbaum C. Ngo T.D.P. et al.Use of right orbitofrontal repetitive transcranial magnetic stimulation (rTMS) augmentation for treatment-refractory obsessive-compulsive disorder with comorbid major depressive disorder.Psychiatr Res. 2022; 317114856Crossref PubMed Scopus (5) Google Scholar]. While it is possible that these patients were late responders to DLPFC stimulation or benefited from augmentation with extra pulses in general, there are several reasons why we believe it is more likely than not that the encouraging results reported here result specifically from rlOFC stimulation. First, our group and others have reported that ≤20% symptom improvement at treatment 10 has at least 77.1–89.3% negative predictive value (NPV) for treatment response [[10]Mirman A.M. Corlier J. Wilson A.C. Tadayonnejad R. Marder K.G. Pleman C.M. et al.Absence of early mood improvement as a robust predictor of rTMS nonresponse in major depressive disorder.Depress Anxiety. 2022; 39: 123-133Crossref PubMed Scopus (7) Google Scholar]. It is reasonable to surmise that ≤20% improvement at session 20 (which all of these patients had) would have even higher NPV, making it quite unlikely that continued stimulation with the same protocol would have been beneficial. Second, results of our electric field modeling (Fig. 1A.) showed that the FP2 coil placement primarily and relatively selectively engaged rlOFC, further suggesting that rlOFC stimulation is a distinct augmentation intervention. In conclusion, this novel sequential bilateral augmentation strategy using rlOFC inhibitory stimulation in MDD patients not responding to conventional left DLPFC stimulation was safe, effective, and associated with significant improvement in mood, negative rumination, and overall depression symptom severity. Prospective controlled and neuroimaging studies should be performed to systematically examine the benefits and circuit mechanisms of inhibitory rlOFC stimulation in treatment-resistant MDD. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Leuchter discloses that within the past 36 months he has received research support from the National Institute of Health, Department of Defense, and eFovea, Inc. He has served as a consultant to iFovea, Options MD, and ElMindA. He was Chief Scientific Officer of Brain Biomarker Analytics LLC (BBA) and had equity interest in BBA. Other authors declare no conflict of interest. Reza Tadayonnejad's research is supported by the National Institute of Mental Health (K23MH116117, R01MH121089) and the Brain & Behavior Research Foundation (NARSAD-27111). We thank the Ryan Family for their generous support of innovative approaches to depression treatment and groundbreaking TMS technology.

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