Vagus Nerve Stimulation Modulates Inflammation in Treatment-Resistant Depression Patients: A Pilot Study.

Vagal neurostimulation (VNS) is used for the treatment of epilepsy and major medical-refractory depression. VNS has neuropsychiatric functions and systemic anti-inflammatory activity. The objective of this study is to measure the clinical efficacy and impact of VNS modulation in depressive patients. Six patients with refractory depression were enrolled. Depression symptoms were assessed with the Montgomery-Asberg Depression Rating, and anxiety symptoms with the Hamilton Anxiety Rating Scale. Plasmas were harvested prospectively before the implantation of VNS (baseline) and up to 4 years or more after continuous therapy. Forty soluble molecules were measured in the plasma by multiplex assays. Following VNS, the reduction in the mean depression severity score was 59.9% and the response rate was 87%. Anxiety levels were also greatly reduced. IL-7, CXCL8, CCL2, CCL13, CCL17, CCL22, Flt-1 and VEGFc levels were significantly lowered, whereas bFGF levels were increased (p values ranging from 0.004 to 0.02). This exploratory study is the first to focus on the long-term efficacy of VNS and its consequences on inflammatory biomarkers. VNS may modulate inflammation via an increase in blood-brain barrier integrity and a reduction in inflammatory cell recruitment. This opens the door to new pathways involved in the treatment of refractory depression.

Electrocardiogram Corrected Q-T Interval Predicts Response to Vagus Nerve Stimulation in Depression.

INTRODUCTION: Recent studies have revealed a possible link between heart rate variability (HRV) and major depressive disorder (MDD), with decreased HRV in MDD compared with healthy subjects. Corrected Q-T interval (QTc) has been suggested to represent an indirect estimate of HRV, as QTc length is inversely correlated to parasympathetic activity in healthy subjects. This retrospective study assessed the ability of QTc length in predicting response to vagus nerve stimulation (VNS) treatment in refractory depression. METHODS: We measured QTc length in 19 patients suffering from refractory depression, selected to be implanted with VNS. Correlations were calculated between baseline QTc (preimplantation) and long-term mood response. RESULTS: Nineteen patients selected for VNS surgery were included in the study. Baseline 28-item Hamilton Depression Rating Scale scores were 28.5 ± 6.8 and decreased to 15.1 ± 9.5 at 12 months and 12.4 ± 10.4 at 24 months post-VNS. Among the 19 patients, 53% (10) were responders and 26% (5) were in remission at 12 months. Pretreatment QTc averaged 425.5 ± 22.0. Patients with longer baseline QTc displayed larger improvement, with a significant correlation between mood and QTc values after 12 months (r(18) = -0.526, P = 0.02) and also after 24 months of VNS therapy (r(17) = -0.573, P = 0.016). CONCLUSIONS: The presented analysis showed that increased QTc in patients with MDD might be used as a baseline biomarker for depressive episodes that might respond preferentially to VNS. The link between cardiovagal activity in depression and response to VNS treatment requires further investigation in larger cohorts and randomized controlled trials.

Safety and Efficacy of Accelerated Repetitive Transcranial Magnetic Stimulation Protocol in Elderly Depressed Unipolar and Bipolar Patients.

OBJECTIVE: Major depressive disorder (MDD) is a prevalent condition in older adults. Although antidepressant drugs are commonly prescribed, efficacy is variable, and older patients are more prone to side effects. Repetitive transcranial magnetic stimulation (rTMS) is an alternative therapy used increasingly in the treatment of MDD. Even though recent studies have shown efficacy of rTMS in elderly depressed patients, the safety and efficacy of accelerated rTMS has not been studied in this population. METHODS: Data were retrospectively analyzed for adults with treatment-resistant depression (N = 73, n = 19 ≥60years, n = 54 <60 years) who underwent an accelerated protocol of 30 sessions (2 sessions per day) of left dorsolateral prefrontal cortex high-frequency (20 Hz) rTMS. RESULTS: There were statistically significant improvements in depression and anxiety symptoms from baseline to post-treatment in both age groups, but those 60years and older showed statistically greater improvement in depression and anxiety symptom scores (p = 0.01) than those less than 60. There were significantly more responders (p = 0.001) and remitters (p = 0.023) in the older group. The age groups did not differ significantly in clinical and demographic characteristics or severity of current depressive episode, although baseline anxiety was less severe in those 60years and older. Unipolar and bipolar patients had a similar clinical response, and treatment appeared to be well tolerated by all patients. CONCLUSION: Our results suggest that accelerated rTMS protocol is a safe and effective treatment for unipolar and bipolar depressed subjects, including older adults.

Long-term Sustained Cognitive Benefits of Vagus Nerve Stimulation in Refractory Depression.

BACKGROUND: Treatment-resistant depression (TRD) is a serious chronic condition disabling patients functionally and cognitively. Chronic vagus nerve stimulation (VNS) is recognized for the management of TRD, but few studies have examined its long-term effects on cognitive dysfunction in unipolar and bipolar resistant depression. OBJECTIVE: The purpose of this study was to assess the course of cognitive functions and clinical symptoms in a cohort of patients treated with VNS for TRD. METHODS: In 14 TRD patients with VNS, standardized clinical and neuropsychological measures covering memory, attention/executive functions, and psychomotor speed were analyzed prestimulation and up to 2 years poststimulation. RESULTS: Vagus nerve stimulation patients significantly improved on cognitive and clinical measures. Learning and memory improved rapidly after 1 month of stimulation, and other cognitive functions improved gradually over time. Cognitive improvements were sustained up to 2 years of treatment. At 1 month, improvement in Montgomery-Åsberg Depression Rating Scale scores was not correlated with changes in any of the cognitive scores, whereas at 12 months, the change in Montgomery-Åsberg Depression Rating Scale score was significantly correlated with several measures (Stroop interference, verbal fluency, and Rey-Osterrieth Complex Figure delayed recall). CONCLUSIONS: In recent years, a growing interest in cognitive dysfunction in depression has emerged. Our results suggest that chronic VNS produces sustained clinical and cognitive improvements in TRD patients, with some mental functions improving as soon as 1 month after the initiation of the VNS therapy. Vagus nerve stimulation seems a very promising adjunctive therapy for TRD patients with cognitive impairment.

A 6-Year Follow-up Study of Vagus Nerve Stimulation Effect on Quality of Life in Treatment-Resistant Depression: A Pilot Study.

OBJECTIVES: Treatment-resistant depression (TRD) carries a major burden on those affected by this disease and significantly impacts their quality of life (QOL). Vagus nerve stimulation (VNS) has showed promising results on symptoms, but its impact on QOL remains underresearched. This study aims to evaluate the long-term effects of VNS on both QOL and clinical symptoms for TRD patients, through a naturalistic 6-year follow-up. METHOD: Outpatients with confirmed TRD were enrolled to receive VNS. None of the patients enrolled left the study or was lost at follow-up. Patients were evaluated at 1, 3, 6, 12, 24, 36, 48, 60, and 72 months for a total of 10 assessments using the 36 item Short Form questionnaire, Hamilton Rating Scale for Depression and Hamilton Anxiety Rating Scale. RESULTS: Ten patients were enrolled with a mean age of 50 years. This study shows a clinically and statistically significant improvement of the mental QOL (P = 0.012), physical QOL (P < 0.002), depressive symptoms (P < 0.001), and anxiety symptoms (P < 0.001). CONCLUSIONS: This long-term naturalistic study is the first to demonstrate that the therapeutic effect of VNS on TRD goes beyond clinical symptoms to improve the daily QOL of those affected.

Neurostimulation for Refractory Cervicogenic Headache: A Three-Year Retrospective Study.

BACKGROUND: Occipital nerve stimulation (ONS) has been used for the treatment of neuropathic pain conditions and could be a therapeutic approach for refractory cervicogenic headache (CeH). AIM: The aim of this study is to assess the efficacy and safety of unilateral ONS in patients suffering from refractory CeH. METHODS: We conducted a retrospective chart review on patients implanted from 2011 to 2013 at CHUM. The primary outcome was a 50% reduction in headache days per month. Secondary outcomes included change in EuroQol Group Visual Analog Scale rating of health-related quality of life (EQ VAS), six item headache impact test (HIT-6) score, hospital anxiety and depression scale (HADS) score, work status, and medication overuse. RESULTS: Sixteen patients fulfilled the inclusion criteria; they had suffered from daily moderate to severe CeH for a median of 15 years. At one year follow-up, 11 patients were responders (69%). There was a statistically significant improvement in the EQ VAS score (median change: 40 point increase, p = 0.0013) and HIT-6 score (median change: 17.5 point decrease, p = 0.0005). Clinically significant anxiety and depression scores both resolved amongst 60% of patients. At three years, six patients were responders (37.5%). Out of the 11 responders at one-year post implantation, five had remained headache responders (R-R) and one additional patient became a responder (NR-R). There was a statistically significant improvement in the EQ VAS score (median change: 15 point increase, p = 0.019) and HIT-6 score (median change: 7.5 point decrease, p = 0.0017) compared with baseline. Clinically significant anxiety and depression scores both, respectively, resolved among 22.5% and 33.9% of patients. Five out of seven disabled patients were back to work. CONCLUSION: ONS may be a safe and effective treatment modality for patients suffering from a refractory CeH. Further study may be warranted.

Evaluating real-world effectiveness of accelerated transcranial magnetic stimulation for treatment-resistant depression in a tertiary referral center based in Quebec, Canada.

OBJECTIVE: To assess the effectiveness of accelerated transcranial magnetic stimulation (TMS) for treatment-resistant depression (TRD) in a tertiary referral center in Quebec, Canada, focusing on a real-world clinical setting. METHODS: We reviewed the data of 247 TRD patients treated between January 2012 and May 2022 who received accelerated TMS. Participants were adults diagnosed with unipolar or bipolar depression, resistant to at least two antidepressant trials, and assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS). RESULTS: Significant symptom reduction was found in the completer sample (N = 147), with 46.3 % of patients meeting post-treatment response criteria and 36.1 % achieving remission. Baseline severity of depression, age, and the number of antidepressant trials were key predictors of treatment outcomes. Patients who did not complete treatment had generally more severe depressive and anxious symptoms and greater treatment resistance. No significant differences in response rates were observed across different TMS coils. CONCLUSION: The study demonstrated the effectiveness and tolerability of accelerated TMS for TRD in a real-world clinical setting.

Elevated allostatic load is associated with poorer response to repetitive transcranial magnetic stimulation in treatment-resistant depression.

This cohort study investigated whether allostatic load (AL) is associated with treatment response to repetitive transcranial magnetic stimulation (rTMS) in treatment-resistant depression (TRD). Pre-treatment blood samples measured AL across multiple systems. Pre- and post-treatment mood changes were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS). Associations between AL and treatment outcomes were explored. Higher pre-treatment AL was significantly associated with poorer post-treatment response status but was not significantly associated with smaller reduction in MADRS score after 4 weeks of treatment. Identifying biomarker profiles informed by the AL model could enhance treatment decisions in TRD, reducing risks associated with prolonged, ineffective rTMS trials and emphasizing the need for reliable predictive biomarkers.

Intravenous ketamine for treatment-resistant depression patients who have failed to respond to transcranial magnetic stimulation: A case series.

BACKGROUND: For individuals with treatment-resistant depression (TRD), transcranial magnetic stimulation (TMS) has become a well-established approach. In the past decade, intravenous (IV) racemic ketamine has also emerged as a potential treatment for TRD. Currently, little data is available on the clinical effects of IV racemic ketamine in TRD patients who experienced TMS-failure. METHODS: Twenty-one (21) TRD patients who had failed to respond to a standard course of high-frequency left-dorsolateral prefrontal cortex TMS were subsequently scheduled to received IV racemic ketamine infusions. The IV racemic ketamine protocol consisted of 0,5 mg/kg infusions over 60 min, 3 times a week over 2 weeks. RESULTS: Treatment was safe with minimal side-effects. Mean baseline MADRS score was 27.6 ± 6.4 (moderate depression), decreasing down to 18.6 ± 8.9 (mild depression) post-treatment. Mean percent improvement was 34.5 % ± 21.1 from baseline to post-treatment. Paired sample t-test showed significant MADRS score decrease pre- to post-treatment [t(20) = 7.212, p < .001]. Overall, four (4) patients (19.0 %) responded and two (2) of those achieved remission (9.5 %). LIMITATIONS: Limitations of this case series include its retrospective and uncontrolled open-label nature, the lack of self-rating and standardized adverse events questionnaires, as well as follow-ups beyond the immediate treatment period. CONCLUSIONS: Novel ways to increase the clinical effects of ketamine are being explored. We discuss potential combination approaches of ketamine with other modalities to augment its effects. Given the global burden of TRD, novel approaches are needed to curb the current mental health epidemic around the world.

Transcranial magnetic stimulation and intravenous ketamine combination therapy for treatment-resistant bipolar depression: A case report.

About a third of patients suffering from major depression develop treatment-resistant depression (TRD). Although repetitive transcranial magnetic stimulation (rTMS) and intravenous ketamine have proven effective for the management of TRD, many patients remain refractory to treatment. We present the case of a patient suffering from bipolar TRD. The patient was referred to us after failure to respond to first-and second-line pharmacotherapy and psychotherapy. After minimal response to both rTMS and ketamine alone, we attempted a combination rTMS and ketamine protocol, which led to complete and sustained remission. Various comparable and complimentary mechanisms of antidepressant action of ketamine and rTMS are discussed, which support further study of this combination therapy. Future research should focus on the feasibility, tolerability, and efficacy of this novel approach.

Efficacy of ketamine intervention to decrease alcohol use, cravings, and withdrawal symptoms in adults with problematic alcohol use or alcohol use disorder: A systematic review and comprehensive analysis of mechanism of actions.

BACKGROUND: Alcohol use disorder is highly prevalent and has important economical, societal, psychiatric, and medical consequences. All currently approved therapeutic approaches targeting alcohol dependence have relatively modest effects and high relapse rates. Recent evidence suggests that ketamine may be an effective intervention to treat alcohol use disorder and alcoholic withdrawal. This systematic review aimed to assess the current level of evidence for this intervention. METHODS: This systematic review was carried out following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was registered on the international database of systematic reviews PROSPERO. Medline(Ovid), CINAHL Complete(EBSCOhost), PsycINFO(Ovid), EBM Reviews(Ovid), EMBASE(Ovid), and Google Scholar were searched for studies using ketamine to treat harmful alcohol use, craving, or withdrawal states in humans. Studies of any methodology that evaluated ketamine in isolation or combination with other interventions were included. The risk of bias was assessed using specific Cochrane critical appraisal tools. RESULTS: Of 1922 abstracts identified, 8 full-text articles were eligible for inclusion, yielding a total sample size of 634 participants. Five studies investigated the impact of ketamine on alcohol use and/or cravings and/or withdrawal in outpatient settings. Three studies looked at the effect of adding ketamine to conventional treatment of withdrawal symptoms in participants admitted to intensive care unit for severe alcohol withdrawal. Results on primary outcomes were mixed within and across trials. CONCLUSIONS: Despite promising results, the current evidence does not permit definitive conclusions about the efficacy of ketamine in alcohol use disorders or withdrawal. Future studies are warranted.

Allostatic load as a predictor of response to repetitive transcranial magnetic stimulation in treatment resistant depression: Research protocol and hypotheses.

Treatment resistant depression is challenging because patients who fail their initial treatments often do not respond to subsequent trials and their course of illness is frequently marked by chronic depression. Repetitive transcranial magnetic stimulation (rTMS) is a well-established treatment alternative, but there are several limitations that decreases accessibility. Identifying biomarkers that can help clinicians to reliably predict response to rTMS is therefore necessary. Allostatic load (AL), which represents the 'wear and tear' on the body and brain which accumulates as an individual is exposed to chronic stress could be an interesting staging model for TRD and help predict rTMS treatment response. We propose an open study which aims to test whether patients with a lower pre-treatment AL will have a stronger antidepressant response to 4 week-rTMS treatment. We will also assess the relation between healthy lifestyle behaviors, AL, and rTMS treatment response. Blood samples for AL parameters will be collected before the treatment. The AL indices will summarize neuroendocrine (cortisol, Dehydroepiandrosterone), immune (CRP, fibrinogen, ferritin), metabolic (glycosylated hemoglobin, total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, uric acid, body mass index, waist circumference), and cardiovascular (heart rate, systolic and diastolic blood pressure) functioning. Mood assessment (Montgomery-Åsberg Depression Rating Scale and Inventory of Depressive symptomatology) will be measured before the treatment and at two-week intervals up to 4 weeks. With the help of different lifestyle questionnaires, a healthy lifestyle index (i.e., a single score based on lifestyle factors) will be created. We will use linear and logistic regressions to assess AL in relation to changes in mood score. Hierarchical regression will be done in order to assess the association between AL, healthy lifestyle index and mood score. Long-lasting and unsuccessful antidepressant trials may increase the chance of not responding to future trials of antidepressants and it can therefore increase treatment resistance. It is essential to identify reliable biomarkers that can predict treatment responses.

Prolonged intermittent theta burst stimulation in the treatment of major depressive disorder: a case series.

Intermittent theta burst stimulation (iTBS) using 600 pulses is an effective and FDA-cleared transcranial magnetic stimulation (TMS) protocol for major depressive disorder (MDD). Prolonged iTBS (piTBS) using 1,800 pulses could increase the effectiveness of TMS for MDD, but its real-world effectiveness is still debated. We assessed the safety, tolerability, and preliminary effectiveness of a 3x daily piTBS 1,800 pulses protocol delivered over 2 weeks in 27 participants. Only four participants (18.2%) achieved response, two of them achieving remission (9.1%). Five participants (18.5%) experienced tolerability issues. Future studies should focus on the neurophysiological effects of TBS protocols to determine optimal parameters.

Differential Effects of Speech and Language Therapy and rTMS in Chronic Versus Subacute Post-stroke Aphasia: Results of the NORTHSTAR-CA Trial.

BACKGROUND & OBJECTIVE: Contralesional 1-Hz repetitive transcranial magnetic stimulation (rTMS) over the right pars triangularis combined with speech-language therapy (SLT) has shown positive results on the recovery of naming in subacute (5-45 days) post-stroke aphasia. NORTHSTAR-CA is an extension of the previously reported NORTHSTAR trial to chronic aphasia (>6 months post-stroke) designed to compare the effectiveness of the same rTMS protocol in both phases. METHODS: Sixty-seven patients with left middle cerebral artery infarcts (28 chronic, 39 subacute) were recruited (01-2014 to 07-2019) and randomized to receive rTMS (N = 34) or sham stimulation (N = 33) with SLT for 10 days. Primary outcome variables were Z-score changes in naming, semantic fluency and comprehension tests and adverse event frequency. Intention-to-treat analyses tested between-group effects at days 1 and 30 post-treatment. Chronic and subacute results were compared. RESULTS: Adverse events were rare, mild, and did not differ between groups. Language outcomes improved significantly in all groups irrespective of treatment and recovery phase. At 30-day follow-up, there was a significant interaction of stimulation and recovery phase on naming recovery (P <.001). Naming recovery with rTMS was larger in subacute (Mdn = 1.91/IQR = .77) than chronic patients (Mdn = .15/IQR = 1.68/P = .015). There was no significant rTMS effect in the chronic aphasia group. CONCLUSIONS: The addition of rTMS to SLT led to significant supplemental gains in naming recovery in the subacute phase only. While this needs confirmation in larger studies, our results clarify neuromodulatory vs training-induced effects and indicate a possible window of opportunity for contralesional inhibitory stimulation interventions in post-stroke aphasia. NORTHSTAR TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT02020421.

Effects of exogenous melatonin on sleep and circadian rhythms in women with premenstrual dysphoric disorder.

We previously found normal polysomnographic (PSG) sleep efficiency, increased slow-wave sleep (SWS), and a blunted melatonin secretion in women with premenstrual dysphoric disorder (PMDD) compared to controls. Here, we investigated the effects of exogenous melatonin in five patients previously studied. They took 2 mg of slow-release melatonin 1 h before bedtime during their luteal phase (LP) for three menstrual cycles. At baseline, patients spent every third night throughout one menstrual cycle sleeping in the laboratory. Measures included morning urinary 6-sulfatoxymelatonin (aMt6), PSG sleep, nocturnal core body temperature (CBT), visual analog scale for mood (VAS-Mood), Prospective Record of the Impact and Severity of Menstrual Symptoms (PRISM), and ovarian plasma hormones. Participants also underwent two 24-hour intensive physiological monitoring (during the follicular phase and LP) in time-isolation/constant conditions to determine 24-hour plasma melatonin and CBT rhythms. The same measures were repeated during their third menstrual cycle of melatonin administration. In the intervention condition compared to baseline, we found increased urinary aMt6 (p < 0.001), reduced objective sleep onset latency (p = 0.01), reduced SWS (p < 0.001), and increased Stage 2 sleep (p < 0.001). Increased urinary aMt6 was correlated with reduced SWS (r = -0.51, p < 0.001). Circadian parameters derived from 24-hour plasma melatonin and CBT did not differ between conditions, except for an increased melatonin mesor in the intervention condition (p = 0.01). Ovarian hormones were comparable between the conditions (p ≥ 0.28). Symptoms improved in the intervention condition, as measured by the VAS-Mood (p = 0.02) and the PRISM (p < 0.001). These findings support a role for disturbed melatonergic system in PMDD that can be partially corrected by exogenous melatonin.

Repetitive transcranial magnetic stimulation for major depressive disorder: basic principles and future directions.

Repetitive transcranial magnetic stimulation (rTMS) is a safe and well-tolerated intervention for major depressive disorder (MDD). Over 150 randomized controlled trials (RCTs) have been carried out, and its efficacy has been confirmed in dozens of meta-analyses. Real world data has also confirmed the effectiveness of rTMS for MDD in clinical practice, with the most recent literature indicating response rates of 40-50% and remission rates of 25-30%. In this review, we first offer an historical perspective, followed by a review of basic principles, such as putative mechanisms, procedures and protocols, stimulation targets, efficacy and durability of response, side effects, and the placebo controversy. In the second part of this review, we first discuss solutions to increase accessibility to rTMS, such as modifications to treatment equipment, protocols and setting. We continue with possible means to further increase effectiveness, such as treatment personalization and extension. We conclude by addressing the scheduling issue, with accelerated rTMS (arTMS) as a possible solution.

Vagus Nerve Stimulation for Treatment-Resistant Depression: a Case Series of Clinical Symptoms Associated with the End of Service Period.

BACKGROUND: This work describes the clinical symptoms associated with end of service (EOS) of the batteries of vagus nerve stimulation (VNS) generators in treatment-resistant depression (TRD). Because neurostimulator software may not provide reliable information on battery depletion, careful monitoring of clinical symptoms during the EOS period is an important concern in the follow-up of TRD patients treated with VNS therapy. METHODS: Twenty-six (26) patients were implanted and followed at the Centre Hospitalier de l'Université de Montréal. Fourteen (14) patients required battery replacement and we retrieved chart data up to 3 months before generator battery replacement. RESULTS: Our study demonstrated there might be a decrease or increase in VNS associated physical side effects, and possibly an increase in depressive symptoms during EOS. LIMITATIONS: Our observations are limited by the retrospective nature of this small case series, and larger prospective studies evaluating both VNS side effects and depressive symptoms are therefore needed to further validate those findings. CONCLUSION: Our study is the first to examine clinical symptoms associated with EOS of the batteries of VNS in TRD.

Non-invasive brain stimulation as add-on therapy for subacute post-stroke aphasia: a randomized trial (NORTHSTAR).

INTRODUCTION: Non-invasive brain stimulation (NIBS) with speech therapy might improve recovery from post-stroke aphasia. This three-armed sham-controlled blinded prospective proof-of-concept study tested 1 Hz subthreshold repetitive transcranial magnetic stimulation (rTMS) and 2-mA cathodal transcranial direct current stimulation (ctDCS) on the right pars triangularis in subacute post-stroke aphasia. PATIENTS AND METHODS: Sixty-three patients with left middle cerebral artery infarcts were recruited in five hospitals (Canada/United States/Germany, 01-2014/03-2018) and randomized to receive rTMS (N = 20), ctDCS (N = 24) or sham stimulation (N = 19) with ST for 10 days. Primary outcome variables were Z-score changes in naming, semantic fluency and comprehension tests and adverse event frequency. Secondary outcome variable was the percent change in the Unified Aphasia Score. Intention-to-treat analyses tested between-group effects at days 1 and 30 post-treatment with a pre-planned subgroup analysis for lesion location (affecting Broca's area or not). RESULTS: Naming was significantly improved by rTMS (median = 1.91/interquartile range = 0.77/p = .01) at 30 days versus ctDCS (median = 1.11/interquartile range = 1.51) and sham stimulation (median = 1.02/interquartile range = 1.71). All other primary results were non-significant. The rTMS effect was driven by the patient subgroup with intact Broca's area where NIBS tended to improve UnAS (median = 33.2%/interquartile range = 46.7%/p = .062) versus sham stimulation (median = 12.5%/interquartile range = 7.9%) at day 30. Conversely, in patients with infarcted Broca's area, UnAS tended to improve more with sham stimulation (median = 75.0%/interquartile range = 86.9%/p = .053) versus NIBS (median = 12.7%/interquartile range = 31.7).Conclusion: We found a delayed positive effect of low-frequency rTMS targeting the right pars triangularis on the recovery of naming performance in subacute post-stroke aphasia. This intervention may be beneficial only in patients with morphologically intact Broca's area.