rTMS Protocol Research Articles

Repetitive Transcranial Magnetic Stimulation for Auditory Verbal Hallucinations in Schizophrenia: A Randomized Clinical Trial.

Auditory verbal hallucinations (AVH) are a common symptom of schizophrenia, increasing the patient's risks of suicide and violence. Repetitive transcranial magnetic stimulation (rTMS) is a potential treatment for AVH. To investigate the effect of imaging-navigated rTMS on AVH in patients with schizophrenia. This 6-week, double-blind, sham-controlled, randomized clinical trial was performed at the Anhui Mental Health Center, Hefei, China, from September 1, 2016, to August 31, 2021. Participants included 66 patients with AVH and schizophrenia. Data were analyzed from May 1, 2022, to March 31, 2023. Participants were randomly assigned 1:1 to either imaging-navigated active or sham rTMS over the left temporoparietal junction for 2 weeks. The primary outcome measured improvements in AVH from baseline to week 2 and week 6 using the Auditory Hallucination Rating Scale (AHRS) scores. In addition, the TMS-induced electric field strength was used to estimate improvements in AVH as a secondary outcome. A total of 62 participants (33 women [53%]; mean [SD] age, 27.4 [9.2] years) completed the 2-week treatments. Of these, 32 were randomized to the active rTMS group (18 women [56%]; mean [SD] age, 26.9 [9.2] years) and 30 to the sham treatment group (15 women [50%]; mean [SD] age, 27.8 [9.4] years). In the intention-to-treat analyses, patients receiving active rTMS showed a significantly greater reduction in AHRS scores compared with those receiving sham treatment at week 2 (difference, 5.96 [95% CI, 3.42-8.50]; t = 4.61; P < .001; Cohen d, 1.17 [95% CI, 0.62-1.71]). These clinical effects were sustained at week 6. Additionally, a stronger TMS-induced electric field within a predefined AVH brain network was associated with greater reductions in AHRS scores (B = 3.12; t = 3.58; P = .002). No serious adverse event was observed. The findings of this randomized clinical trial suggest that imaging-navigated rTMS may effectively and safely alleviate AVH in patients with schizophrenia. Findings also suggest that the electric field strength in the individualized AVH network is a vital parameter for optimizing the efficacy of the rTMS protocol. ClinicalTrials.gov Identifier: NCT02863094.

A novel dual-site OFC-dlPFC accelerated repetitive transcranial magnetic stimulation for depression: a pilot randomized controlled study.

This study aimed to evaluate a novel rTMS protocol for treatment-resistant depression (TRD), using an EEG 10-20 system guided dual-target accelerated approach of right lateral orbitofrontal cortex (lOFC) inhibition followed by left dorsolateral prefrontal cortex (dlPFC) excitation, along with comparing 20 Hz dlPFC accelerated TMS v. sham. Seventy five patients participated in this trial consisting of 20 sessions over 5 consecutive days comparing dual-site (cTBS of right lOFC followed sequentially by 20 Hz rTMS of left dlPFC), active control (sham right lOFC followed by 20 Hz rTMS of left dlPFC) and sham control (sham for both targets). Resting-state fMRI was acquired prior to and following treatment. Hamilton Rating Scale for Depression (HRSD-24) scores were similarly significantly improved at 4 weeks in both the Dual and Single group relative to Sham. Planned comparisons immediately after treatment highlighted greater HRSD-24 clinical responders (Dual: 47.8% v. Single:18.2% v. Sham:4.3%, χ2 = 13.0, p = 0.002) and in PHQ-9 scores by day 5 in the Dual relative to Sham group. We further showed that accelerated 20 Hz stimulation targeting the left dlPFC (active control) is significantly better than sham at 4 weeks. Dual stimulation decreased lOFC-subcallosal cingulate functional connectivity. Greater baseline lOFC-thalamic connectivity predicted better therapeutic response, while decreased lOFC-thalamic connectivity correlated with better response. Our novel accelerated dual TMS protocol shows rapid clinically relevant antidepressant efficacy which may be related to state-modulation. This study has implications for community-based accessible TMS without neuronavigation and rapid onset targeting suicidal ideation and accelerated discharge from hospital.

A phase I trial of accelerated intermittent theta burst rTMS for amnestic MCI

BackgroundEmerging evidence suggests that repetitive transcranial magnetic stimulation (rTMS) enhances cognition in mild cognitive impairment (MCI). Accelerated intermittent theta burst stimulation (iTBS) rTMS protocols are promising as they substantially reduce...

Efficacy of transcranial magnetic stimulation treatment in reducing neuropsychiatric symptomatology after traumatic brain injury.

Neuropsychiatric disorders are highly disabling in traumatic brain injury (TBI) patients, and psychopharmacological treatments often fail to adequately mitigate their detrimental effects. Repetitive transcranial magnetic stimulation (rTMS) is an emerging treatment in neurology and psychiatry, showing potential in treating psychiatric disorders. This study investigates the efficacy of a novel, dual-site sequential rTMS protocol designed to treat neuropsychiatric symptoms in a TBI patient who was refractory to conventional treatments. A 34-year-old woman with severe head trauma and complex psychopathology underwent 20 daily sessions of focal-coil rTMS, combining inhibitory stimulation (1 Hz) on the right dorsolateral prefrontal cortex (DLPFC) and excitatory (10 Hz) on the left DLPFC, guided by a neuronavigation system. Psychiatric and neurocognitive assessments were conducted at baseline and at 2, 4, and 8 weeks following the beginning of rTMS treatment. After 2 weeks of treatment, the patient showed decreased impulsivity and obsessive-compulsive symptoms, along with improvements in attention and processing speed. After 4 weeks, impulsivity further declined, though no other significant changes were noted. At 8 weeks, a persistent positive effect was observed, including enhanced positive emotions. These findings suggest that guided, alternating neurostimulation of the DLPFC may modulate activity within cortico-striato-thalamo-cortical circuits, providing a promising alternative for managing neuropsychiatric symptoms in TBI patients who are resistant to traditional treatments.

Multiband EEG signature decoded using machine learning for predicting rTMS treatment response in major depression.

Major depressive disorder (MDD) is a global health challenge with high prevalence. Further, many diagnosed with MDD are treatment resistant to traditional antidepressants. Repetitive transcranial magnetic stimulation (rTMS) offers promise as an alternative solution, but identifying objective biomarkers for predicting treatment response remains underexplored. Electroencephalographic (EEG) recordings are a cost-effective neuroimaging approach, but traditional EEG analysis methods often do not consider patient-specific variations and fail to capture complex neuronal dynamics. To address this, we propose a data-driven approach combining iterated masking empirical mode decomposition (itEMD) and sparse Bayesian learning (SBL). Our results demonstrated significant prediction of rTMS outcomes using this approach (Protocol 1: r=0.40, p<0.01; Protocol 2: r=0.26, p<0.05). From the decomposition, we obtained three key oscillations: IMF-Alpha, IMF-Beta, and the remaining residue. We also identified key spatial patterns associated with treatment outcomes for two rTMS protocols: for Protocol 1 (10Hz left DLPFC), important areas include the left frontal and parietal regions, while for Protocol 2 (1Hz right DLPFC), the left and frontal, left parietal regions are crucial. Additionally, our exploratory analysis found few significant correlations between oscillation specific predictive features and personality measures. This study highlights the potential of machine learning-driven EEG analysis for personalized MDD treatment prediction, offering a pathway for improved patient outcomes.

Perturbational complexity index in assessing responsiveness to rTMS treatment in patients with disorders of consciousness: a cross-over randomized controlled trial study

BackgroundDisorders of Consciousness (DoC) caused by severe brain injuries represent a challenging clinical entity, which is easy to misdiagnosis and lacks effective treatment options. Repetitive Transcranial Magnetic Stimulation (rTMS) is a non-invasive neuroelectric stimulation method that shows promise in improving consciousness for DoC, especially in minimally conscious state (MCS). However, there is little evidence of its effectiveness, especially in RCT studies.MethodsTwenty MCS patients participated in a double-blind, randomized, crossover, sham-controlled clinical study to evaluate the safety and efficacy of rTMS for MCS. Subjects were randomized into two groups: one group received rTMS-active for 10 consecutive days (n = 10), and the other group received rTMS-sham for 10 consecutive days (n = 10). After a 10-day washout period, the two groups were crossed over and received the opposite treatment. the rTMS protocol consisted of 2,000 pulses per day in the left dorsolateral prefrontal cortex (L-DLPFC), sent at 10 Hz. The stimulation intensity was 90% of the resting motor threshold. Coma Recovery Scale Revised (CRS-R), the main evaluation index, was evaluated before and after each phase in a double-blind manner. Meanwhile RS-EEG and TMS-EEG data were acquired and relative alpha power (RAP), and perturbational complexity index based on state transitions (PCIst) were caculated.ResultsOne-way ANOVA revealed significantly higher scores in rTMS-active treatment compared to rTMS-sham across various measures, including CRS-R total score, RAP, PCIst (all P < 0.05). Among the 20 MCS patients, 7 (35%) were identified as responders following rTMS treatment. Compared to rTMS-sham, responder scores for CRS-R, RAP, and PCIst (all P < 0.05) were significantly elevated after rTMS-active treatment. Conversely, there was no significant difference observed in non-responders. Furthermore, post-hoc analysis revealed that baseline PCIst was significantly higher in responders than non-responders. Upon a 6-month follow-up, CRS-R scores significantly increased in all 20 patients (P = 0.026). However, the responder group exhibited a more favorable prognosis compared to the non-responder group (P = 0.031).ConclusionsApplying 10 Hz rTMS to L-DLPFC significantly increased consciousness level in MCS patients. PCIst is a neurophysiological index that has the potential to evaluate and predict therapeutic efficacy.Trial registrationwww.ClinicalTrials.gov, identifier: NCT05187000.

Effects of intermittent theta burst stimulation add-on to dialectical behavioral therapy in borderline personality disorder: results of a randomized, sham-controlled pilot trial

AbstractDialectical behavioral therapy (DBT) and repetitive transcranial magnetic stimulation (rTMS) are both effective in borderline personality disorder (BPD). We hypothesized that intermittent theta burst stimulation (iTBS), a modified rTMS protocol that provides unilateral stimulation to the left dorsolateral prefrontal cortex, would enhance the effects of DBT and reduce BPD-specific symptoms more than sham stimulation. We performed a single-blind, randomized, sham-controlled pilot study to evaluate iTBS as an add-on to 8-week DBT for BPD in routine inpatient treatment. A total of 53 BPD patients were randomly assigned to either iTBS (n = 25) or sham stimulation (n = 28) in weeks 4–8 of DBT; 40 patients were eligible for inclusion in the analyses according to pre-specified criteria (≥ 16 of 20 iTBS sessions). The primary endpoint was change on the 23-item Borderline Symptom List; secondary endpoints were changes in depressive symptoms and general level of functioning. A mixed model repeated measures analysis with a 2 × 2 factorial between-subjects design showed no significant effect of add-on iTBS treatment, but a distinct trend was observed in favor of iTBS (Cohen’s d = 0.23 for group difference). We found a main effect of DBT with and without iTBS over time, indicating efficacy of 8 weeks’ DBT (d = 0.89–1.12). iTBS may be beneficial as an add-on to DBT in the long term and warrants further evaluation in larger studies. Trial registration Registered at drks.de (no. DRKS00020413) on January 13, 2020.

Predictors of response to accelerated rTMS in the treatment of treatment-resistant depression.

Accelerated repetitive transcranial magnetic stimulation (rTMS) is a promising treatment for treatment-resistant depression (TRD). We aimed to investigate the existence of clinical predictive factors in response to accelerated rTMS in the treatment of TRD. In total, 119 TRD patients who received accelerated rTMS were included in this study. The stimulation protocol was 15Hz stimulation over the the left dorsolateral prefrontal cortex. The protocol consisted of 25 sessions, each session lasting 30min for a total of 3000 pulses. Five sessions were applied per day for 5 consecutive days. At baseline (T0), day 5 (immediately after treatment) (T1), 4 weeks after treatment (T2), depression severity was evaluated using the 17-item Hamilton Depression Rating Scale (HAMD-17), cognitive function was evaluated using Wisconsin Card Sorting Test (WCST), the intensity of suicidal ideation was evaluated using the Columbia-Suicide Severity Rating Scale (C-SSRS). Systemic immune-inflammation index (SII) was calculated at T0 and T2. The HAMD-17 scores, WCST performance, the C-SSRS scores at T1 and T2 were improved from T0 (P < 0.01). The SII at T2 was lower than at T0 (P < 0.01). The response rates at T1 and T2 were 57.98% (69/119) and 48.74% (58/119), respectively. The results of binary logistic analysis showed that shorter course of depression, two failed antidepressant trials, no history of ECT treatment, and lower levels of SII were predictive factors for accelerated rTMS treatment response at T1 and T2 (P < 0.05), while not having a history of hospitalization was a predictive factor for response at T2 (P < 0.05) but not at T1 (P > 0.05). Based on ROC curve analysis, the optimal cut-off values of SII for discriminating responders from non-responders at T1 and T2 were < 478.56 and < 485.03, respectively. The AUC of SII at T0 predicting response for T1 and T2 were 0.729 and 0.797. We found several clinical predictors of better responses to the accelerated rTMS. Identifying clinical predictors of response is relevant to personalize and adapt rTMS protocols in TRD patients.

Classical, spaced, or accelerated transcranial magnetic stimulation of motor cortex for treating neuropathic pain: A 3-arm parallel non-inferiority study

BackgroundRepetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex (M1) at high frequency (HF) is an effective treatment of neuropathic pain. The classical HF-rTMS protocol (CHF-rTMS) includes a daily session for one week as an induction phase of treatment followed by more spaced sessions. Another type of protocol without an induction phase and based solely on spaced sessions of HF-rTMS (SHF-rTMS) has also been shown to produce neuropathic pain relief. However, CHF-rTMS and SHF-rTMS of M1 have never been compared regarding their analgesic potential. Another type of rTMS paradigm, called accelerated intermittent theta burst stimulation (ACC-iTBS), has recently been proposed for the treatment of depression, the other clinical condition for which HF-rTMS is proposed as an effective therapeutic strategy. ACC-iTBS combines a high number of pulses delivered in short sessions grouped into a few days of stimulation. This type of protocol has never been applied to M1 for the treatment of pain. Methods/DesignThe objective of this single-centre randomized study is to compare the efficacy of three different rTMS protocols for the treatment of chronic neuropathic pain: CHF-rTMS, SHF-rTMS, and ACC-iTBS. The CHF-rTMS will consists of 10 stimulation sessions, including 5 daily sessions of 10Hz-rTMS (3,000 pulses per session) over one week, then one session per week for 5 weeks, for a total of 30,000 pulses delivered in 10 stimulation days. The SHF-rTMS protocol will only include 4 sessions of 20Hz-rTMS (1,600 pulses per session), one every 15 days, for a total of 6,400 pulses delivered in 4 stimulation days. The ACC-iTBS protocol will comprise 5 sessions of iTBS (600 pulses per session) completed in half a day for 2 consecutive days, repeated 5 weeks later, for a total of 30,000 pulses delivered in 4 stimulation days. Thus, CHF-rTMS and ACC-iTBS protocols will share a higher total number of TMS pulses (30,000 pulses) compared to SHF-rTMS protocol (6,400 pulses), while CHF-rTMS protocol will include a higher number of stimulation days (10 days) compared to ACC-iTBS and SHF-rTMS protocols (4 days). In all protocols, the M1 target will be defined in the same way and stimulated at the same intensity using a navigated rTMS (nTMS) procedure. The evaluation will be based on clinical outcomes with various scales and questionnaires assessed every week, from two weeks before the 7-week period of therapeutic stimulation until 4 weeks after. Additionally, three sets of neurophysiological outcomes (resting-state electroencephalography (EEG), nTMS-EEG recordings, and short intracortical inhibition measurement with threshold tracking method) will be assessed the week before and after the 7-week period of therapeutic stimulation. DiscussionThis study will make it possible to compare the analgesic efficacy of the CHF-rTMS and SHF-rTMS protocols and to appraise that of the ACC-iTBS protocol for the first time. This study will also make it possible to determine the respective influence of the total number of pulses and days of stimulation delivered to M1 on the extent of pain relief. Thus, if their analgesic efficacy is not inferior to that of CHF-rTMS, SHF-rTMS and especially the new ACC-iTBS protocol could be an optimal compromise of a more easy-to-perform rTMS protocol for the treatment of patients with chronic neuropathic pain.

Metaanalysis of Repetitive Transcranial Magnetic Stimulation (rTMS) Efficacy for OCD Treatment: The Impact of Stimulation Parameters, Symptom Subtype and rTMS-Induced Electrical Field.

Background: Repetitive transcranial magnetic stimulation (rTMS) has recently demonstrated significant potential in treating obsessive-compulsive disorder (OCD). However, its effectiveness depends on various parameters, including stimulation parameters, OCD subtypes and electrical fields (EFs) induced by rTMS in targeted brain regions that are less studied. Methods: Using the PRISMA approach, we examined 27 randomized control trials (RCTs) conducted from 1985 to 2024 using rTMS for the treatment of OCD and conducted several meta-analyses to investigate the role of rTMS parameters, including the EFs induced by each rTMS protocol, and OCD subtypes on treatment efficacy. Results: A significant, medium effect size was found, favoring active rTMS (gPPC = 0.59, p < 0.0001), which was larger for the obsession subscale. Both supplementary motor area (SMA) rTMS (gPPC = 0.82, p = 0.048) and bilateral dorsolateral prefrontal cortex (DLPFC) rTMS (gPPC = 1.14, p = 0.04) demonstrated large effect sizes, while the right DLPFC showed a significant moderate effect size for reducing OCD severity (gPPC = 0.63, p = 0.012). These protocols induced the largest EFs in dorsal cognitive, ventral cognitive and sensorimotor circuits. rTMS protocols targeting DLPFC produced the strongest electrical fields in cognitive circuits, while pre-supplementary motor area (pre-SMA) and orbitofrontal cortex (OFC) rTMS protocols induced larger fields in regions linked to emotional and affective processing in addition to cognitive circuits. The pre-SMA rTMS modulated more circuits involved in OCD pathophysiology-sensorimotor, cognitive, affective, and frontolimbic-with larger electrical fields than the other protocols. Conclusions: While rTMS shows moderate overall clinical efficacy, protocols targeting ventral and dorsal cognitive and sensorimotor circuits demonstrate the highest potential. The pre-SMA rTMS appears to induce electrical fields in more circuits relevant to OCD pathophysiology.

Seizure Risk Associated With the Use of Transcranial Magnetic Stimulation for Coma Recovery in Individuals With Disordered Consciousness After Severe Traumatic Brain Injury.

Repetitive Transcranial Magnetic Stimulation (rTMS) is emerging as a promising treatment for persons with disorder of consciousness (DoC) following traumatic brain injury (TBI). Clinically, however, there are concerns about rTMS exacerbating baseline seizure risk. To advance understanding of risks, this article reports evidence of DoC-TBI rTMS-related seizure risk. Acute and sub-acute hospitals. Persons in states of DoC 6.5months to 15years after TBI (n=20) who received active rTMS (n=17) or placebo rTMS (n=3). After completing placebo procedures, placebo participants completed active rTMS procedures. These 3 participants are included in the active group. Meta-analysis of data from 3 clinical trials; 2 within-subject, 1 double blind randomized placebo-controlled. Each trial used the same rTMS protocol, provided at least 30 rTMS sessions, and delivered rTMS to the dorsolateral prefrontal cortex. During each study's rTMS treatment phase, seizure occurrences were compared between active and placebo groups using logistic regression. After stratifying active group by presence/absence of seizure occurrences, sub-groups were compared using contingency chi-square tests of independence and relative risk (RR) ratios. Two unique participants experienced seizures (1 active, 1 placebo). Post seizure, both participants returned to baseline neurobehavioral function. Both participants received antiepileptics during remaining rTMS sessions, which were completed without further seizures. rTMS-related seizure incidence rate is 59 per 1000 persons. Logistic regression revealed no difference in seizure occurrence by treatment condition (active vs placebo) or when examined with seizure risk factors (P >.1). Presence of ventriculoperitoneal shunt elevated seizure risk (RR=2.0). Collectively, findings indicate a low-likelihood that the specified rTMS protocol exacerbates baseline seizure rates in persons with DoC after TBI. In presence of VP shunts, however, rTMS likely elevates baseline seizure risk and mitigation of this increased risk with pharmacological seizure prophylaxis should be considered.

TMS-induced plasticity improving cognitive control in OCD II: Task-based neural predictors of treatment response

ObjectiveRepetitive transcranial magnetic stimulation (rTMS) has the potential to increase the clinical effect of exposure with response prevention (ERP) psychotherapy for obsessive-compulsive disorder (OCD). We investigated the use of task-based functional MRI (tb-fMRI) for predicting clinical outcomes to different rTMS protocols combined with ERP in OCD. Method61 adults with OCD underwent rTMS and ERP and were randomized to different high frequency rTMS conditions: left dorsolateral prefrontal cortex (DLPFC; n=19), left pre-supplementary motor area (preSMA; n=23), and control stimulation at the vertex at low intensity (n=19). The Tower of London task and Stop-Signal Task were used to assess pretreatment activation during planning and inhibitory control, respectively. We adopted a Bayesian region-based approach to test whether clinical improvement can be predicted by tb-fMRI-derived measures of task-related brain activation or functional connectivity between task-relevant regions and the bilateral amygdala. ResultsFor the vertex group, but not the DLPFC/preSMA rTMS conditions, higher activation in several task-relevant regions during planning and response inhibition, and lower error-related activation, corresponded with better short-term clinical improvement. Lower precuneus activation with increased planning taskload correlated with symptom reduction in the DLPFC group. In the preSMA group, higher error-related activation and lower inhibition-related insular-amygdalar connectivity was associated with symptom reduction. ConclusionsPretreatment tb-fMRI-derived measures of activation and connectivity during planning and inhibition-related processes are associated with clinical response for specific rTMS conditions in OCD. Future placebo-controlled trials with larger sample sizes should combine clinical information and neural correlates to improve prediction of clinical outcome.

Differential analgesic effects of high-frequency or accelerated intermittent theta burst stimulation of M1 on experimental tonic pain: Correlations with cortical activity changes assessed by TMS-EEG

Accelerated intermittent theta burst stimulation (AiTBS) has attracted much attention in the past few years as a new form of brain stimulation paradigm. However, it is unclear the relative efficacy of AiTBS on cortical excitability compared to conventional high-frequency rTMS. Using concurrent TMS and electroencephalogram (TMS-EEG), this study systematically compared the efficacy on cortical excitability and a typical clinical application (i.e. pain), between AiTBS with different intersession interval (ISIs) and 10-Hz rTMS. Participants received 10-Hz rTMS, AiTBS-15 (3 iTBS sessions with a 15-min ISI), AiTBS-50 (3 iTBS sessions with a 50-min ISI), or Sham stimulation over the primary motor cortex on four separate days. All four protocols included a total of 1800 pulses but with different session durations (10-Hz rTMS ​= ​18, AiTBS-15 ​= ​40, and AiTBS-50 ​= ​110 ​min). AiTBS-50 and 10-Hz rTMS were more effective in pain reduction compared to AiTBS-15. Using single-pulse TMS-induced oscillation, our data revealed low gamma oscillation as a shared cortical excitability change across all three active rTMS protocols but demonstrated completely opposite directions. Changes in low gamma oscillation were further associated with changes in pain perception across the three active conditions. In contrast, a distinct pattern of TMS-evoked potentials (TEPs) was revealed, with 10-Hz rTMS decreasing inhibitory N100 amplitude and AiTBS-15 reducing excitatory P60 amplitude. These changes in TEPs were also covarying with low gamma power changes. Sham stimulation indicated no significant effect on either cortical excitability or pain perception. These results are relevant only for provoked experimental pain, without being predictive for chronic pain, and revealed a change in low gamma oscillation, particularly around the very particular frequency of 40 ​Hz, shared between AiTBS and high-frequency rTMS. Conversely, cortical excitability (balance between excitation and inhibition) assessed by TEP recording was modulated differently by AiTBS and high-frequency rTMS paradigms.

Brain state-dependent repetitive transcranial magnetic stimulation for motor stroke rehabilitation: a proof of concept randomized controlled trial.

In healthy subjects, repetitive transcranial magnetic stimulation (rTMS) targeting the primary motor cortex (M1) demonstrated plasticity effects contingent on electroencephalography (EEG)-derived excitability states, defined by the phase of the ongoing sensorimotor μ-oscillation. The therapeutic potential of brain state-dependent rTMS in the rehabilitation of upper limb motor impairment post-stroke remains unexplored. Proof-of-concept trial to assess the efficacy of rTMS, synchronized to the sensorimotor μ-oscillation, in improving motor impairment and reducing upper-limb spasticity in stroke patients. We conducted a parallel group, randomized double-blind controlled trial in 30 chronic stroke patients (clinical trial registration number: NCT05005780). The experimental intervention group received EEG-triggered rTMS of the ipsilesional M1 [1,200 pulses; 0.33 Hz; 100% of the resting motor threshold (RMT)], while the control group received low-frequency rTMS of the contralesional motor cortex (1,200 pulses; 1 Hz, 115% RMT), i.e., an established treatment protocol. Both groups received 12 rTMS sessions (20 min, 3× per week, 4 weeks) followed by 50 min of physiotherapy. The primary outcome measure was the change in upper-extremity Fugl-Meyer assessment (FMA-UE) scores between baseline, immediately post-treatment and 3 months' follow-up. Both groups showed significant improvement in the primary outcome measure (FMA-UE) and the secondary outcome measures. This included the reduction in spasticity, measured objectively using the hand-held dynamometer, and enhanced motor function as measured by the Wolf Motor Function Test (WMFT). There were no significant differences between the groups in any of the outcome measures. The application of brain state-dependent rTMS for rehabilitation in chronic stroke patients is feasible. This pilot study demonstrated that the brain oscillation-synchronized rTMS protocol produced beneficial effects on motor impairment, motor function and spasticity that were comparable to those observed with an established therapeutic rTMS protocol. ClinicalTrials.gov, identifier [NCT05005780].

Maintenance Repetitive Transcranial Magnetic Stimulation for Major Depressive Disorder: A Meta-analysis.

Repetitive transcranial magnetic stimulation (rTMS) is an effective therapy for acute treatment of major depressive disorder (MDD). However, the efficacy and optimal strategy of delivering maintenance rTMS beyond acute treatment remains unclear. This meta-analysis aims to quantify the treatment effect of maintenance rTMS therapy in MDD and compares the difference in treatment effect between the fixed and rescue maintenance rTMS protocols. We conducted a meta-analysis of 14 studies (N = 705) comparing depression rating scores before and after maintenance rTMS. Standardized mean scores adjusted for sample size (Hedges g) were used as the effect size. Subgroup analysis was performed to compare the fixed and rescue maintenance rTMS treatment. Maintenance rTMS was associated with a statistically significant improvement in depression scores (standardized mean difference [SMD] = 0.75; confidence interval [CI] = -1.25 to -0.25). The random effects model had the Q value = 142.67 (P < 0.0001) and I2 = 90%, supporting significant heterogeneity among studies. The prediction interval yielded a possible effect size from -2.54 to 1.05. The subgroup analysis showed a stronger treatment effect for rescue maintenance protocol (SMD = -1.17; CI = -2.13 to -0.21) compared to fixed maintenance protocol (SMD = -0.45; CI = -1.00.16). Although not statistically significant (Q-between = 2.56, df-between = 1, P = 0.1096), a large difference in effect size was observed between subgroups. Maintenance rTMS appears to be an effective strategy for maintaining remission and preventing relapse in MDD. Significant heterogeneity among the studies warrants caution in interpreting the results. These findings suggest the need for standard protocols and consensus guidelines for the optimal delivery of maintenance rTMS treatment.

Enhancing neuroplasticity in major depression: A novel 10 Hz-rTMS protocol is more effective than iTBS

BackgroundRepetitive transcranial magnetic stimulation (rTMS) is an effective treatment in major depressive disorder (MDD). However, intermittent theta-burst stimulation (iTBS) and rTMS protocols using 10 Hz stimulation frequency might differ in their effect on neuroplasticity and on clinical symptoms. This study compares the effect of iTBS and a novel 10 Hz-rTMS with shortened single session duration, on motor excitability and neuroplasticity and on clinical symptoms in MDD. Methods30 patients with MDD received either iTBS or the novel 10 Hz-rTMS daily over three weeks to the left dorsolateral prefrontal cortex. Before and after the interventions, motor excitability, short-latency intracortical inhibition and long-term-potentiation-like plasticity in the motor cortex and clinical symptoms were measured by use of transcranial magnetic stimulation. ResultsAfter the intervention, the level of neuroplasticity increased and clinical symptoms of depression were reduced in both groups, though both effects were significantly stronger after the novel 10 Hz-rTMS. Importantly, the changes in neuroplasticity and clinical symptoms were correlated: the stronger neuroplasticity increased, the stronger was the improvement of clinical symptoms. LimitationsShort intervention period of 3 weeks. Clinical symptoms were measured by self-assessment only and are therefore preliminary. ConclusionsThe novel 10 Hz-rTMS is more effective in increasing neuroplasticity in MDD and potentially also in reducing clinical symptoms than iTBS. This might be due to a differential mode of action on neuroplasticity and to the stimulation frequency of 10 Hz (within the alpha range) being more suitable to reset the brain's activity and to support neuroplastic changes.

The role of sex and age in the differential efficacy of 10 Hz and intermittent theta-burst (iTBS) repetitive transcranial magnetic stimulation (rTMS) treatment of major depressive disorder (MDD)

BackgroundSex- and age-dependent outcome differences have been observed in treatment of Major Depressive Disorder (MDD), including 10 Hz repetitive Transcranial Magnetic Stimulation (rTMS). We examined whether there are sex- and age-dependent differences in outcome with intermittent Theta Burst Stimulation (iTBS), another rTMS protocol. MethodsThe relationship between biological sex, age, and treatment outcome was retrospectively examined among 414 patients with MDD treated with 10 Hz or iTBS rTMS. Linear mixed-effects modeling was used to examine the association between treatment and change in the 30-item Inventory of Depressive Symptomatology Self-Report (IDS-SR30) score from baseline to treatments 10 and 30, with biological sex (M/F), protocol (iTBS/10 Hz), age (≥/<50 years old), and time (treatment 1/10/30) included as fixed effects. The three-way sex-protocol-time and age-protocol-time interactions were used to determine any differential relationships between protocol and outcome dependent on sex and age. Post-hoc t-tests were conducted to examine differences in improvement. ResultsThere was a significant three-way sex-protocol-time interaction at treatments 10 (p = 0.016) and 30 (p = 0.031). Males showed significantly greater improvement with iTBS than females at treatments 10 (p = 0.041) and 30 (p = 0.035), while females showed numerically greater improvement with 10 Hz treatment. While there was not a significant three-way age-protocol-time interaction, there was a significant interaction between age (≥50 years old) and time at treatments 10 (p = 0.007) and 30 (p = 0.042), and among age, sex, and time at treatment 30 (p = 0.028). LimitationsRetrospective naturalistic treatment protocol. ConclusionsiTBS appeared less efficacious in females than in males, and rTMS overall was more efficacious in patients over fifty, particularly females.

Fast depressive symptoms improvement in bipolar I disorder after Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT): A two-site feasibility and safety open-label trial

BackgroundAlthough there are a few first-line treatment options for bipolar depression, none are rapid-acting. A new rTMS protocol, Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT®), has been shown to have a rapid antidepressant effect in major depressive disorder (MDD). We examined the preliminary safety, tolerability, and efficacy of SAINT for the treatment of depression in a small sample of persons with treatment-resistant bipolar I disorder. MethodsParticipants with treatment-resistant bipolar I disorder currently experiencing moderate to severe depression were treated with open-label SAINT. Resting-state functional MRI (fMRI) was used to generate individualized treatment targets for each participant based on the region of the left dorsolateral prefrontal cortex most anticorrelated with the subgenual anterior cingulate cortex. Participants were treated with 10 iTBS sessions daily, with 50-min intersession intervals, for up to 5 consecutive days. The primary outcome was change in Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to immediate follow-up after treatment. ResultsWe treated 10 participants and found a mean reduction of 16.9 in MADRS scores, with a 50 % response rate and 40 % remission rate immediately following treatment. 60 % of participants met remission criteria within the 1-month period following treatment. No serious adverse events, manic episodes, or cognitive side effects were observed. LimitationsOur study has a limited sample size and larger samples are needed to confirm safety and efficacy. ConclusionsSAINT has shown preliminary feasibility, safety, tolerability, and efficacy in treating treatment-resistant bipolar I depression. Double-blinded sham-controlled trials with larger samples are needed to confirm safety and efficacy.

Efficacy of personalized repetitive transcranial magnetic stimulation based on functional reserve to enhance ambulatory function in patients with Parkinson’s disease: study protocol for a randomized controlled trial

BackgroundRepetitive transcranial magnetic stimulation (rTMS) is one of the non-invasive brain stimulations that modulate cortical excitability through magnetic pulses. However, the effects of rTMS on Parkinson’s disease (PD) have yielded mixed results, influenced by factors including various rTMS stimulation parameters as well as the clinical characteristics of patients with PD. There is no clear evidence regarding which patients should be applied with which parameters of rTMS. The study aims to investigate the efficacy and safety of personalized rTMS in patients with PD, focusing on individual functional reserves to improve ambulatory function.MethodsThis is a prospective, exploratory, multi-center, single-blind, parallel-group, randomized controlled trial. Sixty patients with PD will be recruited for this study. This study comprises two sub-studies, each structured as a two-arm trial. Participants are classified into sub-studies based on their functional reserves for ambulatory function, into either the motor or cognitive priority group. The Timed-Up and Go (TUG) test is employed under both single and cognitive dual-task conditions (serial 3 subtraction). The motor dual-task effect, using stride length, and the cognitive dual-task effect, using the correct response rate of subtraction, are calculated. In the motor priority group, high-frequency rTMS targets the primary motor cortex of the lower limb, whereas the cognitive priority group receives rTMS over the left dorsolateral prefrontal cortex. The active comparator for each sub-study is bilateral rTMS of the primary motor cortex of the upper limb. Over 4 weeks, the participants will undergo 10 rTMS sessions, with evaluations conducted pre-intervention, mid-intervention, immediately post-intervention, and at 2-month follow-up. The primary outcome is a change in TUG time between the pre- and immediate post-intervention evaluations. The secondary outcome variables are the TUG under cognitive dual-task conditions, Movement Disorder Society-Unified Parkinson’s Disease Rating Scale Part III, New Freezing of Gait Questionnaire, Digit Span, trail-making test, transcranial magnetic stimulation-induced motor-evoked potentials, diffusion tensor imaging, and resting state functional magnetic resonance imaging.DiscussionThe study will reveal the effect of personalized rTMS based on functional reserve compared to the conventional rTMS approach in PD. Furthermore, the findings of this study may provide empirical evidence for an rTMS protocol tailored to individual functional reserves to enhance ambulatory function in patients with PD.Trial registrationClinicalTrials.gov NCT06350617. Registered on 5 April 2024.

Pilot Study of Personalized Transcranial Magnetic Stimulation with Spectral Electroencephalogram Analyses for Assessing and Treating Persons with Autism.

Autism spectrum condition (ASC) is a neurodevelopmental condition that is only partly responsive to prevailing interventions. ASC manifests core challenges in social skills, communication, and sensory function and by repetitive stereotyped behaviors, along with imbalances in the brain's excitatory (E) and inhibitory (I) signaling. Repetitive transcranial magnetic stimulation (rTMS) has shown promise in ASC and may be a useful addition to applied behavioral analysis (ABA), a gold-standard psychotherapeutic intervention. We report an open-label clinical pilot (initial) study in which ABA-treated ASC persons (n = 123) received our personalized rTMS protocol (PrTMS). PrTMS uses low TMS pulse intensities and continuously updates multiple cortical stimulation locales and stimulation frequencies based on the spectral EEG and psychometrics. No adverse effects developed, and 44% of subjects had ASC scale scores reduced to below diagnostic cutoffs. Importantly, in PrTMS responders, the spectral EEG regression flattened, implying a more balanced E/I ratio. Moreover, with older participants, alpha peak frequency increased, a positive correlate of non-verbal cognition. PrTMS may be an effective ASC intervention, offering improved cognitive function and overall symptomatology. This warrants further research into PrTMS mechanisms and specific types of subjects who may benefit, along with validation of the present results and exploration of broader clinical applicability.