Comparing Two Transcranial Temporal Interference Stimulation Protocols for Depressive Disorder: a Secondary Data Analysis

Comparing Two Transcranial Temporal Interference Stimulation Protocols for Depressive Disorder: a Secondary Data Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Comparing Two Transcranial Temporal Interference Stimulation Protocols for Depressive Disorder: a Secondary Data Analysis Huijie Lei, Simeng Zhang, mulan Huang, liwen Feng, hengfen Gong, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8637906/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 11 You are reading this latest preprint version Abstract Background: Transcranial temporal interference stimulation (tTIS) is a novel noninvasive approach for depression, but the optimal protocol remains unclear. We conducted a secondary data analysis of two studies to compare two tTIS protocols. Methods : We reanalyzed the raw data from two studies: one group of patients (N = 30; mean age = 34.7 ± 10.8 years)received an intensive protocol (five tTIS sessions within one week), and another group (N = 20; mean age = 36.0 ± 12.2 years) participated in a less intensive protocol (five sessions over three weeks). Changes from baseline (T0) in the 17-item Hamilton Depression Rating Scale (HAMD-17) and the Hamilton Anxiety Rating Scale (HAMA) were analyzed at three time points: shortly after five tTIS sessions (T1), at one-week (T2) and four-week follow-ups (T3). Response and remission rates were also evaluated. Results : Both protocols showed significant reductions in the HAMD and HAMA scores at T1, T2 and T3 compared to T0. However, reductions in HAMD scores were significantly large in the intensive protocol at T1 and T2. Additionally, the intensive protocolshowed markedly higher response rates for depression at T1 (60% vs. 20%). No significant protocol differences were observed in HAMA scores, although the intensive protocol displayed a higher response rate at T1 (55% vs. 15%) and T2 (70% vs. 40%) , and a higher remission rate at T3 (40% vs. 5%). Conclusions: A relatively intensive tTIS protocol appears to yield a faster, greater, and more sustained therapeutic effect. Health sciences/Diseases Health sciences/Medical research Biological sciences/Neuroscience Depression Anxiety Transcranial temporal interference stimulation Amygdala Stimulation protocol Figures Figure 1 Introduction Depressive disorder ranks among the leading causes of global disability, significantly impairing patients’ quality of life and imposing a substantial economic burden on society. 1 While pharmacotherapy and psychotherapy represent first-line treatment, both interventions are time-consuming and hampered by relatively high dropout rates and low response rates. 2 , 3 Consequently, exploring new possibilities for the treatment of depression has gained increasing attention. Current noninvasive brain stimulation techniques, such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), offer promising options due to their relatively low cost, painless application, and good tolerability. 4 – 6 The brain stimulation delivered by these techniques typically involves the placement of electromagnetic coils or surface electrodes on the scalp. However, a major limitation is their inability to selectively stimulate deep brain regions crucially implicated in emotion processing, specifically structures of the limbic system, 7 without activating overlying cortical areas. Grossman and colleagues proposed a novel noninvasive deep brain stimulation technique called transcranial temporal interference stimulation (tTIS), which enables higher spatial resolution for stimulation of deep structures. 8 With tTIS, two kilohertz-frequency electric fields (e.g., 2 kHz and 2.1 kHz) are applied via scalp electrodes to an individual. The temporal interference between the two-superimposing high-frequency electric currents generates a low-frequency electrical envelope (e.g., 100 Hz) at the targeted brain region. 9 Given that altered limbic system function is believed to contribute to the pathophysiology of depression, 10 tTIS could offer a viable focal deep-brain stimulation intervention for alleviating depressive symptoms. While prior studies have confirmed the safety of tTIS, 11 its therapeutic effects on depressive disorders remain largely unexplored. The amygdala is a key component of the limbic system and plays a significant role in processing emotional, stressful, and painful stimulus events. 12 The amygdala is a bilateral structure, but evidence from animal and human research indicates that the amygdala in the right hemisphere preferentially processes negative emotions, such as fear. 13 , 14 Clinical neuroimaging studies have indicated that aberrant functional connectivity of the right amygdala is linked to depression. 15 , 16 Recently, two studies (Wu et al. 17 and Li et al. 18 , both submitted) that we were involved in examined for the first time the clinical effectiveness of tTIS of the right amygdala for depressive disorder. Although both studies provided preliminary evidence for the effectiveness of right amygdala-targeted tTIS, we observed substantial differences between the two studies in the extent of patients’ clinical improvement following tTIS intervention. Initially, it seemed to us reasonable to attribute the larger clinical effects found in one study (Wu et al. 17 ) to the use of a relatively intensive stimulation protocol (five sessions administered within one week), which contrasted with the smaller clinical effects found in the other study (Li et al. 18 ) using a less intensive protocol (five sessions delivered over three weeks). However, this inference may or may not be correct because the studies differed from each other not only in the stimulation protocol used but also in the nature of the patient sample examined, and in the instruments and time points used to assess the clinical outcomes following the right amygdala-targeted tTIS intervention. Therefore, we performed a secondary data analysis of the raw data from each study, with the objective first to make the two studies comparable in terms of patient characteristics, instruments, and follow-up periods, and then to reanalyze the clinical outcomes. The results of this analysis should contribute to determining the optimal tTIS protocol for depressive disorder. Methods Participants In the present study, we selected a subset of participants with comparable baseline clinical characteristics from the two studies of interest (Wu et al. 17 and Li et al. 18 ). Both studies recruited participants aged 18–65 years who were in a current depressive episode (including both first and recurrent episodes) as diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). 19 The details of the two studies of interest are presented in Table S1 . Ethics approval and study protocols were granted by the Institutional Review Board of Ruijin Hospital and Shanghai Pudong New Area Mental Health Center. All methods were carried out in accordance with relevant guidelines, regulations and approved procedures, including the principles of the Declaration of Helsinki. All participants provided informed consent, and the studies were registered at ClinicalTrials.gov (NCT0646126017, 17 NCT0647727618 18 ). One study 17 used a randomized sham-controlled parallel group design, whereas the other study 18 used a single-group pre-/post-intervention design. In the present study, we selected participants from the former study who received active tTIS treatment. Demographic information, medical history, psychiatric history, baseline depression and anxiety scores for the patients included in the current study are shown in Table 1 . Table 1 Demographic and clinical characteristics Less intensive protocol (N = 20) Intensive protocol (N = 30) t test /Chi Square test Age 36.0 (12.2) 34.7 (10.8) t = .40, p = .694 Sex M: 7 (35%) F: 13 (65%) M: 13 (43%) F: 17 (57%) ᵡ 2 = .35, p = .556 Education (year) 14.5 (3.1) 14.4 (2.5) t = .02, p = .983 Antidepressant drugs Yes: 10 (50%) No: 10 (50%) Yes: 19 (63%) No: 11 (37%) ᵡ 2 = .88 , p = .349 History of depression Yes: 13 (65%) No: 7 (35%) Yes: 21 (70%) No: 9 (30%) ᵡ 2 = .14, p = .710 HAMD T0 23.2 (3.5) 23.2 (6.0) t = − .03, p = .980 HAMA T0 26.0 (6.3) 24.3 (8.4) t = .78, p = .438 HAMD=Hamilton Depression Rating Scale. HAMA=Hamilton Anxiety Rating Scale. Procedures In both studies of interest, 17, 18 the baseline measurements involved the review of eligibility criteria, and collection of demographic information, medical history, psychiatric history, treatment history, confirmation of depression diagnosis, and a review of safety considerations to receive tTIS or undergo an MRI. For the treatment part, both studies used individualized tTIS target parameters based on the structural MRI of participants. Two paired electric fields were delivered at frequencies of 2000 Hz and 2100 Hz, creating a 100 Hz envelope at the right amygdala. Each session lasted approximately 20 minutes. More details can be found in the studies. 17 , 18 In the study 17 that used the relatively intensive protocol, participants received tTIS treatment consisting of five sessions administered daily (though not necessarily on consecutive days). In the study 18 that employed the less intensive protocol, five sessions were administered over a three-week period (e.g., Mondays and Thursdays during the first two weeks, and one session in the third week). Outcomes The primary outcomes we analyzed and compared were the changes in the outcome from baseline (T0) to three time points: after the completion of five tTIS sessions (T1), at one-week follow-up (T2), and at four-week follow-up (T3) (see Table S1 ). The instrument used to measure severity of depression involved the Hamilton Depression Rating Scale (HAMD-17). 20 Anxiety severity was measured using the Hamilton Anxiety Rating Scale (HAMA). 21 Secondary outcomes we analyzed and compared included clinical response and remission rates for depression and anxiety at three time points (T1, T2, and T3). Clinical remission was defined 22 , 23 as a change from T0 to T1, T2, or T3 in the HAMD score of ≤ 7, or HAMA score of ≤ 7; clinical response was defined as a reduction in the HAMD or HAMA score of at least 50% at T1, T2, or T3 relative to T0. Statistical analysis We conducted three separate two-way ANOVAs on the outcome data, including protocol as a between-subjects factor (2 levels: relatively intensive protocol and less intensive protocol) and time as a within-subjects factor (two levels: T0 and T1, T0 and T2, and T0 and T3) at each follow-up time point to test whether a difference between the protocols existed in the effect of time (i.e., in the change from baseline in the outcome variable at each time point). If these analyses yielded a significant two-way interaction, we conducted one-way ANOVAs (using Bonferroni-corrected levels of significance) to test both the simple main effect of time for each protocol and the simple main effect of protocol at T1, T2, and T3. These analyses allowed us to determine whether changes from baseline in the outcome measures occurring within each protocol at each time point were significant (i.e., whether the difference between pre- and post-stimulation was in fact significant in the protocol at the follow-up time point under consideration), as well as determining whether a significant difference between the protocols existed in the changes from baseline at each time point. We conducted Pearson's chi-square tests to assess differences of response and remission rates between the two protocols at each time point. All tests were two-tailed with statistical significance set at p < 0.05. All statistical analyses were performed using IBM SPSS Statistics (Version 26.0). Results No significant differences were observed between the patients who participated in the study using the intensive protocol and the patients who participated in the study employing the less intensive protocol in terms of age, years of education, sex distribution, antidepressant use, or history of depression. The severity of depression and anxiety at baseline (T0) also showed no significant differences between the two groups (Table 1 ). Primary outcomes At T1, the two-way ANOVA on the HAMD score yielded a significant main effect of time [(F(1, 48) = 139.73, p < .001, partial η 2 = .744)] and a significant protocol-by-time interaction [(F(1, 48) = 9.20, p = .004, partial η 2 = .161)], indicating that the reduction in the HAMD score from T0 to T1 varied significantly by protocol. Tests of simple main effects showed that the effect of time was significant for both the less intensive protocol [(F(1, 48) = 32.18, p < .001, partial η 2 = .401)] and the intensive protocol [(F(1, 48) = 137.89, p < .001, partial η 2 = .742)]. In addition, tests of simple main effects of protocol revealed a significant difference between the protocols in the HAMD score at T1 [(F(1, 48) = 8.29, p = .006, partial η 2 = .147)], with the relatively intensive protocol showing a lower score than the less intensive protocol, whereas no significant difference between the two protocols was detected in the score at T0 [(F(1, 48) = .001, p = .982)] (Fig. 1 A). Thus, these results reflect that although the HAMD score was significantly lower at T1 than T0 for both protocols, the reduction was significantly larger in the study using the intensive protocol than in the study employing the less intensive protocol. Similarly, the two-way ANOVA of the HAMD score revealed a significant main effect of time [(F(1, 45) = 101.54, p < .001, partial η2 = .693)], and a significant protocol-by-time interaction [(F(1, 45) = 7.03, p = .011, partial η2 = .135)] at T2. The effect of time was significant for both the less intensive protocol [(F(1, 45) = 24.00, p < .001, partial η 2 = .348)] and the intensive protocol [(F(1, 45) = 95.17, p < .001, partial η 2 = .679)]. In addition, a significant difference between the protocols was observed in the HAMD score at T2 [(F(1, 45) = 5.82, p = .020, partial η 2 = .114)], whereas no significant difference between the two protocols existed in the score at T0 [(F(1, 45) = .01, p = .915)] (Fig. 1 A). Similar to the data at T1, these results indicate that although the HAMD score was significantly lower at T2 than at T0 for both protocols, the reduction at T2 was significantly larger following the intensive protocol than after the less intensive protocol. At T3, however, the two-way ANOVA of the HAMD score showed a significant main effect of time [(F(1, 48) = 109.49, p < .001, partial η2 = .695)], with a nonsignificant protocol-by-time interaction [(F(1, 48) = 2.33, p = .134)]. These results indicate that the HAMD score, averaged across the two protocols, exhibited a significant reduction from T0 to T3, but that the reduction over time did not vary significantly by protocol (Fig. 1 A). For HAMA, the two-way ANOVA showed a significant main effect of time at T1 [(F(1, 47) = 86.43, p < .001, partial η2 = .648)], T2 [(F(1, 45) = 100.92, p < .001, partial η2 = .692)], and T3 [(F(1, 48) = 109.18, p < .001, partial η2 = .695)], along with nonsignificant protocol-by-time interactions at the three time points [T1: F(1, 47) = 1.93, p = .171; T2: F(1, 45) = 2.28, p = .138; T3: F(1, 48) = .55, p = .462]. These results show that the HAMA score was significantly lower at T1, T2, and T3 compared to T0, yet no between-protocol difference existed in the score reduction at each time point (Fig. 1 B). Secondary outcomes Response and remission rates for depression and anxiety at each time point for the two tTIS protocols are presented in Table 2 . For the HAMD, the intensive protocol exhibited a significantly higher response rate (60% vs 20%, p = .005) and remission rate (10% vs 5%, p = .043) than the less intensive protocol at T1, but these between-protocol differences were not significant at T2 and T3. On the HAMA, the intensive protocol was associated with a significantly higher response rate than the less intensive protocol at T1 (55% vs 15%, p = .005) and T2 (70% vs 40%, p = .037). Additionally, the remission rate was significantly higher for the intensive protocol than for the less intensive protocol at T3 (40% vs 5%, p = .006). Table 2 Response and remission rates by protocol from baseline over time Less intensive protocol (n = 20) Intensive protocol (n = 30) t /Chi Square test HAMD Response rate T1-T0 n = 4 (20%) n = 18 (60%) ᵡ 2 = 7.79, p = .005 Response rate T2-T0 n = 7 (35%) n = 17 (63%) ᵡ 2 = 3.60, p = .058 Response rate T3-T0 n = 8 (40%) n = 15 (50%) ᵡ 2 = .48, p = .487 Remission rate T1-T0 n = 1 (5%) n = 10 (33%) ᵡ 2 = 4.08, p = .043 Remission rate T2-T0 n = 2 (10%) n = 9 (33%) ᵡ 2 = 2.31, p = .129 Remission rate T3-T0 n = 4 (20%) n = 8 (27%) ᵡ 2 = .04, p = .839 HAMA Response rate T1-T0 n = 3 (15%) n = 16 (55%) ᵡ 2 = 8.05, p = .005 Response rate T2-T0 n = 8 (40%) n = 19 (70%) ᵡ 2 = 4.34, p = .037 Response rate T3-T0 n = 8 (40%) n = 17 (57%) ᵡ 2 = 1.33, p = .248 Remission rate T1-T0 n = 1 (5%) n = 8 (28%) ᵡ 2 = 2.66, p = .103 Remission rate T2-T0 n = 4 (20%) n = 11 (41%) ᵡ 2 = 2.28, p = .132 Remission rate T3-T0 n = 1 (5%) n = 12 (40%) ᵡ 2 = 7.64, p = .006 Response was defined as a reduction ≥ 50% in score from T0 (baseline); remission was defined as HAMD score ≤ 7 or HAMA score ≤ 7. HAMD=Hamilton Depression Rating Scale. HAMA=Hamilton Anxiety Rating Scale. Discussion In this study, we carried out a secondary data analysis to compare the clinical effectiveness of a relatively intensive right amygdala-targeted tTIS protocol (5 sessions within one week) used in one study 17 of patients with depressive disorder with that of a less intensive protocol (5 sessions over three weeks) used in another study 18 of patients with depressive disorder. Our comparison was restricted to patients with similar demographic and clinical characteristics who were assessed with the same clinical instruments at the same points in time. The results indicated that both tTIS protocols yielded significant reductions in depressive symptoms after the completion of five tTIS sessions, as well as at one-week follow-up and at four-week follow-up, when compared with symptom severity at baseline. For example, response rates at four-week follow-up reached 50% and 40% following the intensive and less intensive protocol, respectively. The respective depression remission rates were 27% and 20%. However, although both protocols produced clinical improvement, the degree of improvement in symptom severity was significantly larger for the intensive protocol than the less intensive protocol after the end of tTIS intervention and at one-week follow-up. For example, the response rate was 60% after the completion of the intensive protocol, which contrasted with the response rate of 20% for the less intensive protocol. Yet, the between-protocol difference in response and remission rates became smaller over time, being not significant at one- and four-week follow-up. Thus, the intensive tTIS protocol seemed to have a comparative advantage in providing significant rapid relief of depression. Yet, its advantage over the less intensive protocol was not maintained over a longer follow-up period. Moreover, both tTIS protocols were associated with significant reductions in the level of anxiety at each follow-up assessment. However, although both protocols improved anxiety symptoms, the intensive protocol was associated with a significantly higher response rate than the less intensive protocol after the end of tTIS intervention (55% vs 15%) and at one-week follow-up (70% vs 40%). Additionally, the remission rate was significantly higher for the intensive protocol than for the less intensive protocol at four-week follow-up (40% vs 5%). Thus, in contrast to depression severity (as measured with the HAMD-17), the relatively intensive tTIS protocol appeared to produce both a rapid and sustained relief of anxiety (measured with the HAMA). Moreover, the response and remission rates in patients who received the relatively intensive tTIS protocol were higher for the HAMA than HAMD-17, indicating that this protocol improved the severity of anxiety more than the severity of depressive symptoms. The relatively intensive tTIS protocol appeared to yield faster and more enduring clinical effects than the less intensive protocol. We hypothesize that the shorter tTIS repetition interval incorporated in the intensive protocol rapidly promoted a sustained shift in amygdala activity. Furthermore, the intensive protocol could have mitigated the decay of tTIS effects between sessions, resulting in a powerful cumulative effect that led to relatively robust and sustained changes in neuroplasticity within the amygdala. 24 Unexpectedly, the intensive protocol tended to yield larger effects on anxiety than on depression, which may be attributed to the choice of the amygdala as the target for stimulation. It may be hypothesized that the changes in amygdala function induced by especially the intensive tTIS protocol primarily impacted anxious mood, fears, tension, and somatic anxiety, as indexed by the HAMA, while having a smaller effect on depressed mood, retardation, and loss of pleasure, as captured by the HAMD-17. In line with this interpretation, the amygdala and other connected brain regions, specifically the nucleus accumbens, are believed to have related, but distinct, roles in affective behavior. 25 On this view, the amygdala serves primarily avoidance behavior, whereas the nucleus accumbens mediates reward-related behavior. Hence, it may be worthwhile to consider the use of tTIS targeting the nucleus accumbens, in addition to or as an alternative to the amygdala, for treating depressive disorder. Indeed, a recent tTIS study targeting the nucleus accumbens reported significant clinical improvements in patients with depressive disorder, with larger reductions in HAMD-17 than HAMA scores. 26 The present study has several limitations. Most importantly, we conducted a secondary data analysis, which by its nature is observational and retrospective. This means that we were dependent on the methods used and data collected in the two studies of interest. Although we were able to make the two studies comparable in terms of patient populations, outcome measures, and follow-up, we had no control over the design used in these studies, which was not the same. One study 17 evaluated the clinical effects of tTIS using a randomized sham-controlled parallel group design, whereas the other study 18 used a single-group pre-/post-intervention design. The latter design is highly suspectable to confounding, including history, maturation, and placebo effects. Consequently, the results of the present study should be interpreted with caution because the comparison of the two tTIS protocols is complicated by a difference in design between the studies. In conclusion, this study suggests that use of a relatively intensive amygdala-targeted tTIS protocol yields a faster and more enduring relief of clinical symptoms in patients with depressive disorder than use of a less intensive protocol. The relatively intensive protocol seems to be able to alleviate both depression and anxiety symptoms, although the protocol may have a greater impact on the latter type of symptoms than on the former one, which may stem from using the amygdala rather than a key region within the brain’s reward system as the stimulation target. The present results should be considered as preliminary and tentative, representing an initial step to identifying the most optimal tTIS protocol for symptom relief in patients with depressive disorder. To achieve this goal, further work is required to evaluate the various tTIS protocol parameters, including the frequency of and interval between individual sessions, and the stimulation target, 27–29 which all could affect the clinical effectiveness of tTIS intervention. Furthermore, it would be useful to explore if greater clinical benefits to patients can be obtained by combining tTIS with other interventions, including pharmacotherapy and psychotherapy. Declarations Acknowledgments The tTIS device mentioned in this study was provided by Suzhou Neurodome Medical Technology (Shanghai, China) under a research-use agreement. Company personnel provided routine device training only and did not access identifiable data or influence analyses. Funding This study is funded by the National Natural and Science Foundation of China (grant reference number 82471495) to Chencheng Zhang. Disclosure Statement The authors declare no conflict of interest. Author Contributions Huijie Lei: Writing - original draft, Software, Methodology, Formal analysis. Simeng Zhang: Data curation. Mulan Huang: Data curation. Liwen Feng: Data curation. Hengfen Gong: Data curation, Conceptualization. Qingyuan Xue: Data curation. Sijia Tang: Data curation. Haiyan Jin: Data curation, Conceptualization. Jingjing Zhang: Data curation, Conceptualization. Odin van der Stelt: Conceptualization, Writing - review & editing. Yong Lu: Writing - review & editing, Conceptualization, Supervision. Chencheng Zhang: Conceptualization, Supervision. Yiru Fang: Writing - review & editing, Conceptualization, Supervision. Data Availability Statement The data that support the findings of this study are available from the corresponding author upon reasonable request. References Vos, T. et al. Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. 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Center, Shanghai Tongji University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Simeng","middleName":"","lastName":"Zhang","suffix":""},{"id":587908941,"identity":"f5cca4e8-5785-4b17-9685-ca1c7fe8c233","order_by":2,"name":"mulan Huang","email":"","orcid":"","institution":"Shanghai Pudong New Area Mental Health Center, Shanghai Tongji University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"mulan","middleName":"","lastName":"Huang","suffix":""},{"id":587908942,"identity":"5bc61c2b-29eb-4101-8a0c-c6df64059afb","order_by":3,"name":"liwen Feng","email":"","orcid":"","institution":"Shanghai Pudong New Area Mental Health Center, Shanghai Tongji University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"liwen","middleName":"","lastName":"Feng","suffix":""},{"id":587908943,"identity":"8da7cbe3-b70f-4af0-9444-8dafb7ed41c5","order_by":4,"name":"hengfen Gong","email":"","orcid":"","institution":"Shanghai Pudong New Area Mental Health Center, Shanghai Tongji University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"hengfen","middleName":"","lastName":"Gong","suffix":""},{"id":587908945,"identity":"489f2c42-02a6-4dde-9907-32ee62b9b132","order_by":5,"name":"qingyuan Xue","email":"","orcid":"","institution":"Ruijin Hospital, Shanghai Jiao Tong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"qingyuan","middleName":"","lastName":"Xue","suffix":""},{"id":587908948,"identity":"d6c6dac5-107f-48a6-959d-0a809ebf58c6","order_by":6,"name":"sijia Tang","email":"","orcid":"","institution":"Shanghai Jiao Tong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"sijia","middleName":"","lastName":"Tang","suffix":""},{"id":587908950,"identity":"aa772c35-045b-42e5-aaf9-2cf84164460a","order_by":7,"name":"haiyan Jin","email":"","orcid":"","institution":"Ruijin Hospital, Shanghai Jiao Tong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"haiyan","middleName":"","lastName":"Jin","suffix":""},{"id":587908951,"identity":"401f3018-3554-4591-a40e-abd16a6876bf","order_by":8,"name":"jingjing Zhang","email":"","orcid":"","institution":"Ruijin Hospital, Shanghai Jiao Tong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"jingjing","middleName":"","lastName":"Zhang","suffix":""},{"id":587908952,"identity":"a4dd5c07-3ad8-4453-982f-65a2044caec5","order_by":9,"name":"Odin van der Stelt","email":"","orcid":"","institution":"Ruijin Hospital, Shanghai Jiao Tong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Odin","middleName":"van der","lastName":"Stelt","suffix":""},{"id":587908955,"identity":"34a1d34f-8be5-4744-82fc-2bff17df61f1","order_by":10,"name":"yong Lu","email":"","orcid":"","institution":"Ruijin Hospital, Shanghai Jiao Tong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"yong","middleName":"","lastName":"Lu","suffix":""},{"id":587908959,"identity":"88b41b37-f76e-4295-995f-a046c25e418f","order_by":11,"name":"chencheng Zhang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAq0lEQVRIiWNgGAWjYBACNvYGBgbGBpK08BwgVQuDRAKpWvgkHz/8+HOHXZ68A/Oxj1+Icph0mrGE5JnkYsMDbMmzZYjTksPGYNjGnLixgceYWYIoLZJn2BgS2+pJ0SLBw8ZwsO1w4nwGHmPGD0Rp4UkzlmxsO564gZktmZkYHQzy7YeBIdZWnTi/vfkw4w+i9MCAwWEGBmYekrTINwCjlDRbRsEoGAWjYKQAAHy7K8yWoUiuAAAAAElFTkSuQmCC","orcid":"","institution":"Ruijin Hospital, Shanghai Jiao Tong University School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"chencheng","middleName":"","lastName":"Zhang","suffix":""},{"id":587908960,"identity":"835d0ae6-d607-4ff4-8f08-5fc02a4715c6","order_by":12,"name":"yiru Fang","email":"","orcid":"","institution":"Ruijin Hospital, Shanghai Jiao Tong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"yiru","middleName":"","lastName":"Fang","suffix":""}],"badges":[],"createdAt":"2026-01-19 09:53:56","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8637906/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8637906/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":102327940,"identity":"05a808a1-93e0-4963-a2dd-de67a93a1886","added_by":"auto","created_at":"2026-02-10 14:44:25","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":792495,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eChanges in depression and anxiety from baseline over time across different stimulation protocols.\u003c/strong\u003e The white points represent the mean values for each group. Depression score decreased significantly more in the intensive protocol at T1 (after 5 sessions of tTIS) and T2 (one-week follow-up) compared to the less intensive protocol. A. Total score of HAMD. B. Total score of HAMA. HAMD=Hamilton Depression Rating Scale. HAMA=Hamilton Anxiety Rating Scale. n.s.= not significant. **p \u0026lt; .01, *p \u0026lt; .05\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8637906/v1/0fdafda40a953f2f4389ebe0.png"},{"id":102328020,"identity":"918a983f-56a4-4e88-ad4e-274ddf5a532f","added_by":"auto","created_at":"2026-02-10 14:44:42","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1536127,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8637906/v1/ada6aa81-d5ea-45dc-b0ec-b1a6a38257b9.pdf"},{"id":102327939,"identity":"c53e51c4-9fba-4af7-8a98-edbcffcc905a","added_by":"auto","created_at":"2026-02-10 14:44:25","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":16215,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementary.docx","url":"https://assets-eu.researchsquare.com/files/rs-8637906/v1/88664d47b89556c5b149c25b.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Comparing Two Transcranial Temporal Interference Stimulation Protocols for Depressive Disorder: a Secondary Data Analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eDepressive disorder ranks among the leading causes of global disability, significantly impairing patients\u0026rsquo; quality of life and imposing a substantial economic burden on society.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e While pharmacotherapy and psychotherapy represent first-line treatment, both interventions are time-consuming and hampered by relatively high dropout rates and low response rates.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e Consequently, exploring new possibilities for the treatment of depression has gained increasing attention. Current noninvasive brain stimulation techniques, such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), offer promising options due to their relatively low cost, painless application, and good tolerability.\u003csup\u003e\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e The brain stimulation delivered by these techniques typically involves the placement of electromagnetic coils or surface electrodes on the scalp. However, a major limitation is their inability to selectively stimulate deep brain regions crucially implicated in emotion processing, specifically structures of the limbic system,\u003csup\u003e7\u003c/sup\u003e without activating overlying cortical areas.\u003c/p\u003e \u003cp\u003eGrossman and colleagues proposed a novel noninvasive deep brain stimulation technique called transcranial temporal interference stimulation (tTIS), which enables higher spatial resolution for stimulation of deep structures.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e With tTIS, two kilohertz-frequency electric fields (e.g., 2 kHz and 2.1 kHz) are applied via scalp electrodes to an individual. The temporal interference between the two-superimposing high-frequency electric currents generates a low-frequency electrical envelope (e.g., 100 Hz) at the targeted brain region.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e Given that altered limbic system function is believed to contribute to the pathophysiology of depression,\u003csup\u003e10\u003c/sup\u003e tTIS could offer a viable focal deep-brain stimulation intervention for alleviating depressive symptoms. While prior studies have confirmed the safety of tTIS,\u003csup\u003e11\u003c/sup\u003e its therapeutic effects on depressive disorders remain largely unexplored.\u003c/p\u003e \u003cp\u003eThe amygdala is a key component of the limbic system and plays a significant role in processing emotional, stressful, and painful stimulus events.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e The amygdala is a bilateral structure, but evidence from animal and human research indicates that the amygdala in the right hemisphere preferentially processes negative emotions, such as fear.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e Clinical neuroimaging studies have indicated that aberrant functional connectivity of the right amygdala is linked to depression.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e Recently, two studies (Wu et al. \u003csup\u003e17\u003c/sup\u003e and Li et al.\u003csup\u003e18\u003c/sup\u003e, both submitted) that we were involved in examined for the first time the clinical effectiveness of tTIS of the right amygdala for depressive disorder. Although both studies provided preliminary evidence for the effectiveness of right amygdala-targeted tTIS, we observed substantial differences between the two studies in the extent of patients\u0026rsquo; clinical improvement following tTIS intervention. Initially, it seemed to us reasonable to attribute the larger clinical effects found in one study (Wu et al. \u003csup\u003e17\u003c/sup\u003e) to the use of a relatively intensive stimulation protocol (five sessions administered within one week), which contrasted with the smaller clinical effects found in the other study (Li et al.\u003csup\u003e18\u003c/sup\u003e) using a less intensive protocol (five sessions delivered over three weeks). However, this inference may or may not be correct because the studies differed from each other not only in the stimulation protocol used but also in the nature of the patient sample examined, and in the instruments and time points used to assess the clinical outcomes following the right amygdala-targeted tTIS intervention. Therefore, we performed a secondary data analysis of the raw data from each study, with the objective first to make the two studies comparable in terms of patient characteristics, instruments, and follow-up periods, and then to reanalyze the clinical outcomes. The results of this analysis should contribute to determining the optimal tTIS protocol for depressive disorder.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eParticipants\u003c/h2\u003e \u003cp\u003eIn the present study, we selected a subset of participants with comparable baseline clinical characteristics from the two studies of interest (Wu et al. \u003csup\u003e17\u003c/sup\u003e and Li et al.\u003csup\u003e18\u003c/sup\u003e). Both studies recruited participants aged 18\u0026ndash;65 years who were in a current depressive episode (including both first and recurrent episodes) as diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).\u003csup\u003e19\u003c/sup\u003e The details of the two studies of interest are presented in Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e. Ethics approval and study protocols were granted by the Institutional Review Board of Ruijin Hospital and Shanghai Pudong New Area Mental Health Center. All methods were carried out in accordance with relevant guidelines, regulations and approved procedures, including the principles of the Declaration of Helsinki. All participants provided informed consent, and the studies were registered at ClinicalTrials.gov (NCT0646126017,\u003csup\u003e17\u003c/sup\u003e NCT0647727618\u003csup\u003e18\u003c/sup\u003e). One study\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e used a randomized sham-controlled parallel group design, whereas the other study\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e used a single-group pre-/post-intervention design. In the present study, we selected participants from the former study who received active tTIS treatment. Demographic information, medical history, psychiatric history, baseline depression and anxiety scores for the patients included in the current study are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographic and clinical characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLess intensive protocol\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;20)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIntensive protocol\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;30)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003et test /Chi Square test\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36.0 (12.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34.7 (10.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003et = .40, p = .694\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM: 7 (35%)\u003c/p\u003e \u003cp\u003eF: 13 (65%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM: 13 (43%)\u003c/p\u003e \u003cp\u003eF: 17 (57%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eᵡ\u003csup\u003e2\u003c/sup\u003e = .35, p = .556\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEducation (year)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14.5 (3.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14.4 (2.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003et = .02, p = .983\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntidepressant drugs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes: 10 (50%)\u003c/p\u003e \u003cp\u003eNo: 10 (50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes: 19 (63%)\u003c/p\u003e \u003cp\u003eNo: 11 (37%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eᵡ\u003csup\u003e2\u003c/sup\u003e \u003cem\u003e= .88\u003c/em\u003e, p = .349\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistory of depression\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes: 13 (65%)\u003c/p\u003e \u003cp\u003eNo: 7 (35%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes: 21 (70%)\u003c/p\u003e \u003cp\u003eNo: 9 (30%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eᵡ\u003csup\u003e2\u003c/sup\u003e = .14, p = .710\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHAMD T0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23.2 (3.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23.2 (6.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003et\u0026thinsp;=\u0026thinsp;\u0026minus;\u0026thinsp;.03, p = .980\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHAMA T0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26.0 (6.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24.3 (8.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003et = .78, p = .438\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eHAMD=Hamilton Depression Rating Scale. HAMA=Hamilton Anxiety Rating Scale.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eProcedures\u003c/h3\u003e\n\u003cp\u003eIn both studies of interest,\u003csup\u003e17, 18\u003c/sup\u003e the baseline measurements involved the review of eligibility criteria, and collection of demographic information, medical history, psychiatric history, treatment history, confirmation of depression diagnosis, and a review of safety considerations to receive tTIS or undergo an MRI. For the treatment part, both studies used individualized tTIS target parameters based on the structural MRI of participants. Two paired electric fields were delivered at frequencies of 2000 Hz and 2100 Hz, creating a 100 Hz envelope at the right amygdala. Each session lasted approximately 20 minutes. More details can be found in the studies.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn the study\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e that used the relatively intensive protocol, participants received tTIS treatment consisting of five sessions administered daily (though not necessarily on consecutive days). In the study\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e that employed the less intensive protocol, five sessions were administered over a three-week period (e.g., Mondays and Thursdays during the first two weeks, and one session in the third week).\u003c/p\u003e\n\u003ch3\u003eOutcomes\u003c/h3\u003e\n\u003cp\u003eThe primary outcomes we analyzed and compared were the changes in the outcome from baseline (T0) to three time points: after the completion of five tTIS sessions (T1), at one-week follow-up (T2), and at four-week follow-up (T3) (see Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e). The instrument used to measure severity of depression involved the Hamilton Depression Rating Scale (HAMD-17).\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e Anxiety severity was measured using the Hamilton Anxiety Rating Scale (HAMA).\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eSecondary outcomes we analyzed and compared included clinical response and remission rates for depression and anxiety at three time points (T1, T2, and T3). Clinical remission was defined\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e as a change from T0 to T1, T2, or T3 in the HAMD score of \u0026le;\u0026thinsp;7, or HAMA score of \u0026le;\u0026thinsp;7; clinical response was defined as a reduction in the HAMD or HAMA score of at least 50% at T1, T2, or T3 relative to T0.\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eWe conducted three separate two-way ANOVAs on the outcome data, including protocol as a between-subjects factor (2 levels: relatively intensive protocol and less intensive protocol) and time as a within-subjects factor (two levels: T0 and T1, T0 and T2, and T0 and T3) at each follow-up time point to test whether a difference between the protocols existed in the effect of time (i.e., in the change from baseline in the outcome variable at each time point). If these analyses yielded a significant two-way interaction, we conducted one-way ANOVAs (using Bonferroni-corrected levels of significance) to test both the simple main effect of time for each protocol and the simple main effect of protocol at T1, T2, and T3. These analyses allowed us to determine whether changes from baseline in the outcome measures occurring within each protocol at each time point were significant (i.e., whether the difference between pre- and post-stimulation was in fact significant in the protocol at the follow-up time point under consideration), as well as determining whether a significant difference between the protocols existed in the changes from baseline at each time point. We conducted Pearson's chi-square tests to assess differences of response and remission rates between the two protocols at each time point. All tests were two-tailed with statistical significance set at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05. All statistical analyses were performed using IBM SPSS Statistics (Version 26.0).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eNo significant differences were observed between the patients who participated in the study using the intensive protocol and the patients who participated in the study employing the less intensive protocol in terms of age, years of education, sex distribution, antidepressant use, or history of depression. The severity of depression and anxiety at baseline (T0) also showed no significant differences between the two groups (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePrimary outcomes\u003c/h2\u003e \u003cp\u003eAt T1, the two-way ANOVA on the HAMD score yielded a significant main effect of time [(F(1, 48)\u0026thinsp;=\u0026thinsp;139.73, p \u0026lt; .001, partial η\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.744)] and a significant protocol-by-time interaction [(F(1, 48)\u0026thinsp;=\u0026thinsp;9.20, p = .004, partial η\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.161)], indicating that the reduction in the HAMD score from T0 to T1 varied significantly by protocol. Tests of simple main effects showed that the effect of time was significant for both the less intensive protocol [(F(1, 48)\u0026thinsp;=\u0026thinsp;32.18, p \u0026lt; .001, partial η\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.401)] and the intensive protocol [(F(1, 48)\u0026thinsp;=\u0026thinsp;137.89, p \u0026lt; .001, partial η\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.742)]. In addition, tests of simple main effects of protocol revealed a significant difference between the protocols in the HAMD score at T1 [(F(1, 48)\u0026thinsp;=\u0026thinsp;8.29, p = .006, partial η\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.147)], with the relatively intensive protocol showing a lower score than the less intensive protocol, whereas no significant difference between the two protocols was detected in the score at T0 [(F(1, 48) = .001, p = .982)] (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). Thus, these results reflect that although the HAMD score was significantly lower at T1 than T0 for both protocols, the reduction was significantly larger in the study using the intensive protocol than in the study employing the less intensive protocol.\u003c/p\u003e \u003cp\u003eSimilarly, the two-way ANOVA of the HAMD score revealed a significant main effect of time [(F(1, 45)\u0026thinsp;=\u0026thinsp;101.54, p \u0026lt; .001, partial η2 = .693)], and a significant protocol-by-time interaction [(F(1, 45)\u0026thinsp;=\u0026thinsp;7.03, p = .011, partial η2 = .135)] at T2. The effect of time was significant for both the less intensive protocol [(F(1, 45)\u0026thinsp;=\u0026thinsp;24.00, p \u0026lt; .001, partial η\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.348)] and the intensive protocol [(F(1, 45)\u0026thinsp;=\u0026thinsp;95.17, p \u0026lt; .001, partial η\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.679)]. In addition, a significant difference between the protocols was observed in the HAMD score at T2 [(F(1, 45)\u0026thinsp;=\u0026thinsp;5.82, p = .020, partial η\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.114)], whereas no significant difference between the two protocols existed in the score at T0 [(F(1, 45) = .01, p = .915)] (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). Similar to the data at T1, these results indicate that although the HAMD score was significantly lower at T2 than at T0 for both protocols, the reduction at T2 was significantly larger following the intensive protocol than after the less intensive protocol.\u003c/p\u003e \u003cp\u003eAt T3, however, the two-way ANOVA of the HAMD score showed a significant main effect of time [(F(1, 48)\u0026thinsp;=\u0026thinsp;109.49, p \u0026lt; .001, partial η2 = .695)], with a nonsignificant protocol-by-time interaction [(F(1, 48)\u0026thinsp;=\u0026thinsp;2.33, p = .134)]. These results indicate that the HAMD score, averaged across the two protocols, exhibited a significant reduction from T0 to T3, but that the reduction over time did not vary significantly by protocol (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA).\u003c/p\u003e \u003cp\u003eFor HAMA, the two-way ANOVA showed a significant main effect of time at T1 [(F(1, 47)\u0026thinsp;=\u0026thinsp;86.43, p \u0026lt; .001, partial η2 = .648)], T2 [(F(1, 45)\u0026thinsp;=\u0026thinsp;100.92, p \u0026lt; .001, partial η2 = .692)], and T3 [(F(1, 48)\u0026thinsp;=\u0026thinsp;109.18, p \u0026lt; .001, partial η2 = .695)], along with nonsignificant protocol-by-time interactions at the three time points [T1: F(1, 47)\u0026thinsp;=\u0026thinsp;1.93, p = .171; T2: F(1, 45)\u0026thinsp;=\u0026thinsp;2.28, p = .138; T3: F(1, 48) = .55, p = .462]. These results show that the HAMA score was significantly lower at T1, T2, and T3 compared to T0, yet no between-protocol difference existed in the score reduction at each time point (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSecondary outcomes\u003c/h3\u003e\n\u003cp\u003eResponse and remission rates for depression and anxiety at each time point for the two tTIS protocols are presented in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. For the HAMD, the intensive protocol exhibited a significantly higher response rate (60% vs 20%, p = .005) and remission rate (10% vs 5%, p = .043) than the less intensive protocol at T1, but these between-protocol differences were not significant at T2 and T3. On the HAMA, the intensive protocol was associated with a significantly higher response rate than the less intensive protocol at T1 (55% vs 15%, p = .005) and T2 (70% vs 40%, p = .037). Additionally, the remission rate was significantly higher for the intensive protocol than for the less intensive protocol at T3 (40% vs 5%, p = .006).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eResponse and remission rates by protocol from baseline over time\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLess intensive protocol\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;20)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIntensive protocol\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;30)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003et /Chi Square test\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHAMD\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eResponse rate T1-T0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;4 (20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;18 (60%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eᵡ\u003c/b\u003e\u003csup\u003e\u003cb\u003e2\u003c/b\u003e\u003c/sup\u003e \u003cb\u003e= 7.79, p = .005\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eResponse rate T2-T0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;7 (35%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;17 (63%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eᵡ\u003csup\u003e2\u003c/sup\u003e = 3.60, p = .058\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eResponse rate T3-T0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;8 (40%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;15 (50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eᵡ\u003csup\u003e2\u003c/sup\u003e \u003cem\u003e=\u003c/em\u003e .48, p = .487\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRemission rate T1-T0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;1 (5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;10 (33%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eᵡ\u003c/b\u003e\u003csup\u003e\u003cb\u003e2\u003c/b\u003e\u003c/sup\u003e \u003cb\u003e= 4.08, p = .043\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRemission rate T2-T0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;2 (10%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;9 (33%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eᵡ\u003csup\u003e2\u003c/sup\u003e \u003cem\u003e=\u003c/em\u003e 2.31, p = .129\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRemission rate T3-T0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;4 (20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;8 (27%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eᵡ\u003csup\u003e2\u003c/sup\u003e \u003cem\u003e=\u003c/em\u003e .04, p = .839\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHAMA\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eResponse rate T1-T0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;3 (15%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;16 (55%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eᵡ\u003c/b\u003e\u003csup\u003e\u003cb\u003e2\u003c/b\u003e\u003c/sup\u003e \u003cb\u003e= 8.05, p = .005\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eResponse rate T2-T0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;8 (40%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;19 (70%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eᵡ\u003c/b\u003e\u003csup\u003e\u003cb\u003e2\u003c/b\u003e\u003c/sup\u003e \u003cb\u003e= 4.34, p = .037\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eResponse rate T3-T0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;8 (40%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;17 (57%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eᵡ\u003csup\u003e2\u003c/sup\u003e \u003cem\u003e=\u003c/em\u003e 1.33, p = .248\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRemission rate T1-T0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;1 (5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;8 (28%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eᵡ\u003csup\u003e2\u003c/sup\u003e = 2.66, p = .103\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRemission rate T2-T0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;4 (20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;11 (41%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eᵡ\u003csup\u003e2\u003c/sup\u003e \u003cem\u003e=\u003c/em\u003e 2.28, p = .132\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRemission rate T3-T0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;1 (5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;12 (40%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eᵡ\u003c/b\u003e\u003csup\u003e\u003cb\u003e2\u003c/b\u003e\u003c/sup\u003e \u003cb\u003e= 7.64, p = .006\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eResponse was defined as a reduction\u0026thinsp;\u0026ge;\u0026thinsp;50% in score from T0 (baseline); remission was defined as HAMD score\u0026thinsp;\u0026le;\u0026thinsp;7 or HAMA score\u0026thinsp;\u0026le;\u0026thinsp;7. HAMD=Hamilton Depression Rating Scale. HAMA=Hamilton Anxiety Rating Scale.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, we carried out a secondary data analysis to compare the clinical effectiveness of a relatively intensive right amygdala-targeted tTIS protocol (5 sessions within one week) used in one study\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e of patients with depressive disorder with that of a less intensive protocol (5 sessions over three weeks) used in another study\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e of patients with depressive disorder. Our comparison was restricted to patients with similar demographic and clinical characteristics who were assessed with the same clinical instruments at the same points in time. The results indicated that both tTIS protocols yielded significant reductions in depressive symptoms after the completion of five tTIS sessions, as well as at one-week follow-up and at four-week follow-up, when compared with symptom severity at baseline. For example, response rates at four-week follow-up reached 50% and 40% following the intensive and less intensive protocol, respectively. The respective depression remission rates were 27% and 20%. However, although both protocols produced clinical improvement, the degree of improvement in symptom severity was significantly larger for the intensive protocol than the less intensive protocol after the end of tTIS intervention and at one-week follow-up. For example, the response rate was 60% after the completion of the intensive protocol, which contrasted with the response rate of 20% for the less intensive protocol. Yet, the between-protocol difference in response and remission rates became smaller over time, being not significant at one- and four-week follow-up. Thus, the intensive tTIS protocol seemed to have a comparative advantage in providing significant rapid relief of depression. Yet, its advantage over the less intensive protocol was not maintained over a longer follow-up period.\u003c/p\u003e \u003cp\u003eMoreover, both tTIS protocols were associated with significant reductions in the level of anxiety at each follow-up assessment. However, although both protocols improved anxiety symptoms, the intensive protocol was associated with a significantly higher response rate than the less intensive protocol after the end of tTIS intervention (55% vs 15%) and at one-week follow-up (70% vs 40%). Additionally, the remission rate was significantly higher for the intensive protocol than for the less intensive protocol at four-week follow-up (40% vs 5%). Thus, in contrast to depression severity (as measured with the HAMD-17), the relatively intensive tTIS protocol appeared to produce both a rapid and sustained relief of anxiety (measured with the HAMA). Moreover, the response and remission rates in patients who received the relatively intensive tTIS protocol were higher for the HAMA than HAMD-17, indicating that this protocol improved the severity of anxiety more than the severity of depressive symptoms.\u003c/p\u003e \u003cp\u003eThe relatively intensive tTIS protocol appeared to yield faster and more enduring clinical effects than the less intensive protocol. We hypothesize that the shorter tTIS repetition interval incorporated in the intensive protocol rapidly promoted a sustained shift in amygdala activity. Furthermore, the intensive protocol could have mitigated the decay of tTIS effects between sessions, resulting in a powerful cumulative effect that led to relatively robust and sustained changes in neuroplasticity within the amygdala.\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e Unexpectedly, the intensive protocol tended to yield larger effects on anxiety than on depression, which may be attributed to the choice of the amygdala as the target for stimulation. It may be hypothesized that the changes in amygdala function induced by especially the intensive tTIS protocol primarily impacted anxious mood, fears, tension, and somatic anxiety, as indexed by the HAMA, while having a smaller effect on depressed mood, retardation, and loss of pleasure, as captured by the HAMD-17. In line with this interpretation, the amygdala and other connected brain regions, specifically the nucleus accumbens, are believed to have related, but distinct, roles in affective behavior.\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e On this view, the amygdala serves primarily avoidance behavior, whereas the nucleus accumbens mediates reward-related behavior. Hence, it may be worthwhile to consider the use of tTIS targeting the nucleus accumbens, in addition to or as an alternative to the amygdala, for treating depressive disorder. Indeed, a recent tTIS study targeting the nucleus accumbens reported significant clinical improvements in patients with depressive disorder, with larger reductions in HAMD-17 than HAMA scores.\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe present study has several limitations. Most importantly, we conducted a secondary data analysis, which by its nature is observational and retrospective. This means that we were dependent on the methods used and data collected in the two studies of interest. Although we were able to make the two studies comparable in terms of patient populations, outcome measures, and follow-up, we had no control over the design used in these studies, which was not the same. One study\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e evaluated the clinical effects of tTIS using a randomized sham-controlled parallel group design, whereas the other study\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e used a single-group pre-/post-intervention design. The latter design is highly suspectable to confounding, including history, maturation, and placebo effects. Consequently, the results of the present study should be interpreted with caution because the comparison of the two tTIS protocols is complicated by a difference in design between the studies.\u003c/p\u003e \u003cp\u003eIn conclusion, this study suggests that use of a relatively intensive amygdala-targeted tTIS protocol yields a faster and more enduring relief of clinical symptoms in patients with depressive disorder than use of a less intensive protocol. The relatively intensive protocol seems to be able to alleviate both depression and anxiety symptoms, although the protocol may have a greater impact on the latter type of symptoms than on the former one, which may stem from using the amygdala rather than a key region within the brain\u0026rsquo;s reward system as the stimulation target. The present results should be considered as preliminary and tentative, representing an initial step to identifying the most optimal tTIS protocol for symptom relief in patients with depressive disorder. To achieve this goal, further work is required to evaluate the various tTIS protocol parameters, including the frequency of and interval between individual sessions, and the stimulation target,\u003csup\u003e27\u0026ndash;29\u003c/sup\u003e which all could affect the clinical effectiveness of tTIS intervention. Furthermore, it would be useful to explore if greater clinical benefits to patients can be obtained by combining tTIS with other interventions, including pharmacotherapy and psychotherapy.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe tTIS device mentioned in this study was provided by Suzhou Neurodome Medical Technology (Shanghai, China) under a research-use agreement. Company personnel provided routine device training only and did not access identifiable data or influence analyses.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is funded by the National Natural and Science Foundation of China (grant reference number 82471495) to Chencheng Zhang.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosure Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflict of interest.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHuijie Lei: Writing - original draft, Software, Methodology, Formal analysis. Simeng Zhang: Data curation. Mulan Huang: Data curation. Liwen Feng: Data curation. Hengfen Gong: Data curation, Conceptualization. Qingyuan Xue: Data curation. Sijia Tang: Data curation. Haiyan Jin: Data curation, Conceptualization. Jingjing Zhang: Data curation, Conceptualization. Odin van der Stelt: Conceptualization, Writing - review \u0026amp; editing. Yong Lu: Writing - review \u0026amp; editing, Conceptualization, Supervision. Chencheng Zhang: Conceptualization, Supervision. Yiru Fang: Writing - review \u0026amp; editing, Conceptualization, Supervision.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eVos, T. et al. 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Physiol.\u003c/em\u003e \u003cb\u003e598\u003c/b\u003e (4), 805\u0026ndash;816 (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVan Rooij, S. J., Arulpragasam, A. R., McDonald, W. M. \u0026amp; Philip, N. S. Accelerated TMS-moving quickly into the future of depression treatment. \u003cem\u003eNeuropsychopharmacology\u003c/em\u003e \u003cb\u003e49\u003c/b\u003e (1), 128\u0026ndash;137 (2024).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Depression, Anxiety, Transcranial temporal interference stimulation, Amygdala, Stimulation protocol","lastPublishedDoi":"10.21203/rs.3.rs-8637906/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8637906/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eTranscranial temporal interference stimulation (tTIS) is a novel noninvasive approach for depression, but the optimal protocol remains unclear. We conducted a secondary data analysis of two studies to compare two tTIS protocols.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: We reanalyzed the raw data from two studies: one group of patients (N = 30; mean age = 34.7 ± 10.8 years)received an intensive protocol (five tTIS sessions within one week), and another group (N = 20; mean age = 36.0 ± 12.2 years) participated in a less intensive protocol (five sessions over three weeks). Changes from baseline (T0) in the 17-item Hamilton Depression Rating Scale (HAMD-17) and the Hamilton Anxiety Rating Scale (HAMA) were analyzed at three time points: shortly after five tTIS sessions (T1), at one-week (T2) and four-week follow-ups (T3). Response and remission rates were also evaluated.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: Both protocols showed significant reductions in the HAMD and HAMA scores at T1, T2 and T3 compared to T0. However, reductions in HAMD scores were significantly large in the intensive protocol at T1 and T2. Additionally, the intensive protocolshowed markedly higher response rates for depression at T1 (60% vs. 20%). No significant protocol differences were observed in HAMA scores, although the intensive protocol displayed a higher response rate at T1 (55% vs. 15%) and T2 (70% vs. 40%) , and a higher remission rate at T3 (40% vs. 5%).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eA relatively intensive tTIS protocol appears to yield a faster, greater, and more sustained therapeutic effect.\u003c/p\u003e","manuscriptTitle":"Comparing Two Transcranial Temporal Interference Stimulation Protocols for Depressive Disorder: a Secondary Data Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-10 14:44:20","doi":"10.21203/rs.3.rs-8637906/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-02T17:27:36+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-23T10:34:19+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-12T07:16:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"255943048126875458713706304822663090209","date":"2026-03-01T20:37:11+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"308068199849742724246419490021199215813","date":"2026-02-25T08:37:42+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"47189337863402881345912596494071827313","date":"2026-02-24T18:59:03+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-06T08:04:28+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-06T08:00:59+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-02-02T06:03:08+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-26T09:36:21+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2026-01-26T08:54:58+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7264a098-859a-4bd9-aed2-642cba3b989b","owner":[],"postedDate":"February 10th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[{"id":62543130,"name":"Health sciences/Diseases"},{"id":62543131,"name":"Health sciences/Medical research"},{"id":62543132,"name":"Biological sciences/Neuroscience"}],"tags":[],"updatedAt":"2026-04-02T17:39:29+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-10 14:44:20","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8637906","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8637906","identity":"rs-8637906","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}