Theta Burst Stimulation Protocols Research Articles

Pilot study with randomised control of dual site theta burst transcranial magnetic stimulation (TMS) for methamphetamine use disorder: a protocol for the TARTAN study

BackgroundTranscranial magnetic stimulation (TMS) (including the theta burst stimulation (TBS) form of TMS used in this study) is a non-invasive means to stimulate nerve cells in superficial areas of the brain. In recent years, there has been a growth in the application of TMS to investigate the modulation of neural networks involved in substance use disorders. This study examines the feasibility of novel TMS protocols for the treatment of methamphetamine (MA) use disorder in an ambulatory drug and alcohol treatment setting.MethodsThirty participants meeting the criteria for moderate to severe MA use disorder will be recruited in community drug and alcohol treatment settings and randomised to receive active TMS or sham (control) intervention. The treatment is intermittent TBS (iTBS) applied to the left dorsolateral prefrontal cortex (DLPFC), then continuous TBS (cTBS) to the left orbitofrontal cortex (OFC). Twelve sessions are administered over 4 weeks with opt-in weekly standardized cognitive behaviour therapy (CBT) counselling and a neuroimaging sub-study offered to participants. Primary outcomes are feasibility measures including recruitment, retention and acceptability of the intervention. Secondary outcomes include monitoring of safety and preliminary efficacy data including changes in substance use, cravings (cue reactivity) and cognition (response inhibition).DiscussionThis study examines shorter TBS protocols of TMS for MA use disorder in real-world drug and alcohol outpatient settings where withdrawal and abstinence from MA, or other substances, are not eligibility requirements. TMS is a relatively affordable treatment and staff of ambulatory health settings can be trained to administer TMS. It is a potentially scalable and translatable treatment for existing drug and alcohol clinical settings. TMS has the potential to provide a much-needed adjuvant treatment to existing psychosocial interventions for MA use disorder. A limitation of this protocol is that the feasibility of follow-up is only examined at the end of treatment (4 weeks).Trial registrationAustralia New Zealand Clinical Trial Registry ACTRN12622000762752. Registered on May 27, 2022, and retrospectively registered (first participant enrolled) on May 23, 2022, with protocol version 7 on February 24, 2023.

A 10-day theta burst stimulation intervention facilitates the clinical rehabilitation of patients following an isolated limb fracture: A longitudinal SHAM-controlled pilot study.

We investigated if theta burst stimulation (TBS) could enhance recovery by reducing key symptoms when implemented acutely post-fracture in participants with an isolated upper limb fracture (IULF). This was a pilot study with a randomized matched pair, sham-controlled, participant-blind design of a 10-day prolonged continuous TBS protocol. Two main groups were included: I) participants with IULF receiving active TBS; and II) patients with IULF receiving SHAM/placebo. Another group (III) of healthy individuals were the reference group. Disability and pain intensity were collected through questionnaires (DASH & NRA) at three timepoints (baseline; 72 h post-intervention & 3 months post-injury). Group III completed the baseline assessment. 79 participants were enrolled. Individuals in the ACTIVE and SHAM groups had similar baseline measures. For disability, the interaction between Intervention and Time approached significance (F = 2.33; p = 0.11), whereas it was significant for pain (F = 3.42; p = 0.04). At 3 months post-injury, the ACTIVE group reported reduced disability (F = 4.71; p = 0.04) and pain (F = 5.84; p = 0.02) at three months post-injury compared to the SHAM group, with clinical measures from ACTIVE group being like controls. In IULF patients, a 10-day TBS intervention implemented acutely post-trauma had beneficial effects on symptoms of functional recovery and pain at 3 months post-trauma.

Theta burst stimulation for enhancing upper extremity motor functions after stroke: a systematic review of clinical and mechanistic evidence.

This systematic review aimed to evaluate the effects of different theta burst stimulation (TBS) protocols on improving upper extremity motor functions in patients with stroke, their associated modulators of efficacy, and the underlying neural mechanisms. We conducted a meta-analytic review of 29 controlled trials published from January 1, 2000, to August 29, 2023, which investigated the effects of TBS on upper extremity motor, neurophysiological, and neuroimaging outcomes in poststroke patients. TBS significantly improved upper extremity motor impairment (Hedge's g=0.646, p=0.003) and functional activity (Hedge's g=0.500, p<0.001) compared to controls. Meta-regression revealed a significant relationship between the percentage of patients with subcortical stroke and the effect sizes of motor impairment (p=0.015) and functional activity (p=0.018). Subgroup analysis revealed a significant difference in the improvement of upper extremity motor impairment between studies using 600-pulse and 1200-pulse TBS (p=0.002). Neurophysiological studies have consistently found that intermittent TBS increases ipsilesional corticomotor excitability. However, evidence to support the regional effects of continuous TBS, as well as the remote and network effects of TBS, is still mixed and relatively insufficient. In conclusion, TBS is effective in enhancing poststroke upper extremity motor function. Patients with preserved cortices may respond better to TBS. Novel TBS protocols with a higher dose may lead to superior efficacy compared with the conventional 600-pulse protocol. The mechanisms of poststroke recovery facilitated by TBS can be primarily attributed to the modulation of corticomotor excitability and is possibly caused by the recruitment of corticomotor networks connected to the ipsilesional motor cortex.

Female Cerebellum Seems Sociable; An iTBS Investigation.

The cerebellum has been shown to be engaged in tasks other than motor control, including cognitive and affective functions. Prior neuroimaging studies have documented the role of this area in social cognition and despite these findings, no studies have yet examined the causal relationship between the cerebellum and social cognition. This study aimed to investigate the role of the cerebellum in empathy and theory of mind (ToM) in a randomized, placebo-controlled, double-blind, parallel study. 32 healthy participants were assigned to either a sham or active group. For the active group, an intermittent theta-burst stimulation (iTBS) protocol at 100% of the motor threshold was applied to the cerebellum, while the control group received sham stimulation. An eyes-closed EEG session, the Empathy Quotient (EQ) test, and the Reading the Mind in the Eyes Test (RMET) were administered before and after the iTBS session. The results demonstrated differences in cognitive empathy, ToM, and a decrease in the activity of the default mode network (DMN) between the active and sham groups in females. Females also showed a decrease in the activity of the affective empathy network and connectivity in the DMN. We conclude that cognitive empathy and ToM are associated with cerebellar activity, and due to sex-related differences in the cortical organization of this area which is modulated by sex hormones, the stimulation of the cerebellum in males and females yields different results.

A Controlled Clinical Study of Accelerated High-Dose Theta Burst Stimulation in Patients with Obsessive–Compulsive Disorder

Background. Obsessive–compulsive disorder (OCD) is frequently treated using a combination of counseling, drugs, and, more recently various transcranial stimulation protocols, but all require several weeks to months for clinically significant improvement, so there is a need for treatments with faster onset. This study investigated whether an accelerated high-dose theta burst stimulation (ahTBS) protocol significantly improves the efficacy of OCD compared to traditional 1-Hz repetitive transcranial magnetic stimulation (rTMS) in the routine clinical setting. Method. Forty-five patients with OCD were randomized into two groups and treated with ahTBS or 1-Hz rTMS for 5 days. Patients were assessed at baseline at the end of treatment using the Yale–Brown Obsessive–Compulsive Scale (Y-BOCS). Results. After 5 days of treatment, there was a significant decrease in Y-BOCS scores in both groups ( p &lt; 0.001 ), and the difference between the two groups was not statistically significant (group × time interaction, F = 1.90, p = 0.18 ). There was also no statistically significant difference in other secondary outcome indicators, including depression, anxiety symptoms, and response rate. However, the ahTBS group had a greater trend in response rate. Neuropsychological testing showed no negative cognitive side effects of either treatment. Conclusion. Accelerated high-dose TBS is as safe and has comparable short-term efficacy to traditional 1-Hz rTMS for the clinical treatment of OCD. Further research is needed to explore optimal ahTBS parameters, validate the utility of this treatment modality, and identify factors predictive of rapid clinical response to guide clinical decision-making. This trial is registered with NCT05221632.

P29: Prolonged Intermittent Theta-Burst Stimulation of the Left Dorsolateral Prefrontal Cortex for Older Adults with Treatment-Resistant Depression: Effectiveness and Safety

Objective:Treatment-resistant depression (TRD) is not uncommon in older people. Brain stimulation, such as 4-6 weeks of repetitive transcranial magnetic stimulation (rTMS) or theta burst stimulation (TBS) targeting the left dorsolateral prefrontal cortex, has been evidenced as an essential intervention for adult TRD and also documented in the current international treatment guideline. In 2018, Taiwan Food and Drug Administration cleared the rTMS as a treatment option for TRD and now rTMS is still a treatment at their own expense in Taiwan. Additionally, prolonged intermittent TBS (piTBS) protocol has been proven its similar antidepressant efficacy as standard 4-6 weeks rTMS/iTBS in adult TRD, but in a shorter treatment course of 2 weeks. For older adults with depression, 4-6 weeks of treatment course may burden their caregiver due to their limited ambulation and transportation ability. However, hitherto there was no study to investigate the antidepressant efficacy of left-sided prefrontal piTBS in treating older TRD.Methods:A chart review was performed at a single Taiwan hospital from 2018 to 2020. 17-items Hamilton Depression Rating Scale (HDRS-17) was measured before and after the piTBS intervention. Maudsley Staging Method was used for the depression treatment refractoriness.Results:We identified 23 old adults with TRD (mean [SD] age, 66.0[5.2]; 78% female) who underwent 10-20 sessions of daily piTBS (1800 pulses/session; 10sessions, n=18, 15sessions,n=4, 20session,n=1). On continuous outcomes, mean(SD) HDRS-17 total scores improved from 20.5(6.62) to 11.8(7.7) after receiving piTBS intervention. The mean percent improvement of HDRS-17 was 46.0%±29.4%. Dichotomous outcomes showed response rate of 43.5% and remission rate of 34.8%. No seizures or other serious adverse events were noted, and no premature discontinuation was noted.Conclusion:This study is the largest study demonstrating the piTBS protocol provides a comparable reduction in depression symptoms in older adults with TRD, similar to the effectiveness in adult TRD and the efficacy of standard sequential bilateral rTMS/iTBS in older TRD in the FOUR-D trial. Regarding desirable efficiency and effectiveness, piTBS may be an optimal form of rTMS in treating older adults with TRD. Further large comparative effectiveness trials with standard iTBS or high-frequency rTMS in this population are warranted.

An Avenue for Optimization of Theta Burst Stimulation Protocols? Comments on the FOUR-D Randomized Noninferiority Clinical Trial.

An Avenue for Optimization of Theta Burst Stimulation Protocols? Comments on the FOUR-D Randomized Noninferiority Clinical Trial.

The use of theta burst stimulation in patients with schizophrenia - A systematic review.

Transcranial magnetic stimulation (TMS) can offer therapeutic benefits and provide value in neurophysiological research. One of the newer TMS paradigms is theta burst stimulation (TBS) which can be delivered in two patterns: continuous (cTBS - inducing LTD-like effects) and intermittent (iTBS - inducing LTP-like effects). This review paper aims to explore studies that have utilized TBS protocols over different areas of the cortex to study the neurophysiological functions and treatment of patients with schizophrenia. PubMed was searched using the following keywords "schizophrenia", "schizoaffective", or "psychosis", and "theta burst stimulation". Out of the 90 articles which were found, thirty met review inclusion criteria. The inclusion criteria included studying the reported effect (clinical, physiological, or both) of at least one session of TBS on human subjects, and abstracts (at minimum) must have been in English. The main target areas included prefrontal cortex (12 studies - 10 dorsolateral prefrontal cortex (DLPFC), 2 dorsomedial prefrontal cortex (DMPFC)) vermal cerebellum (5), and temporo-parietal cortex (8). Other target areas included inferior parietal lobe (2), and motor cortex (3). TBS neurophysiological effect was explored in 5 studies using functional magnetic resonance image (fMRI), magnetic resonance spectroscopy (MRS), electroencephalography (EEG), electromyography (EMG) and positron emission topography (PET) scan. Overall, TBS can offer great therapeutic potential as it is well-tolerated, feasible, and has few, if any, adverse effects. TBS may be targeted to treat specific symptomatology, as an augmenting intervention to pharmacotherapy, or even improving patient's insight into their diagnosis.

Theta-burst stimulation as a therapeutic tool in neurological pathology: a systematic review.

TBS (theta-burst stimulation) is a novel therapeutic approach in a wide range of neurological diseases. The present systematic review aims to identify the various protocols used in the last years, to assess study quality and to offer a general overview of the current state of the literature. The systematic review was conducted according to the Preferred Reporting Item for Systematic Review and Meta-Analyses (PRISMA) guidelines. We applied the following inclusion criteria: (1) population over 18 years old with diagnosed neurological disorders, (2) patients treated with sessions of theta-burst stimulation, (3) randomized-controlled clinical trials, (4) articles in the English language, and (5) studies that report response and score reduction on a validated scale of the investigated disorder or remission rates. We included in the final analysis 56 randomized controlled trials focusing on different neurological pathologies (stroke, Parkinson`s disease, multiple sclerosis, tinnitus, dystonia, chronic pain, essential tremor and tic disorder), and we extracted data regarding study design, groups and comparators, sample sizes, type of coil, stimulation parameters (frequency, number of pulses, intensity, stimulation site etc.), number of sessions, follow-up, assessment through functional connectivity and neurological scales used. We observed a great interstudy heterogenicity that leads to a difficulty in drawing plain conclusions. TBS protocols have shown promising results in improving various symptoms in patients with neurological disorders, but larger and more coherent studies, using similar stimulation protocols and evaluation scales, are needed to establish guideline recommendations.

TMS must not harm participants: guidelines for evaluating TMS protocol safety

ABSTRACT Transcranial magnetic stimulation (TMS) can modulate a targeted brain region to assess whether that region is involved in a cognitive process. When TMS is employed in cognitive neuroscience, participants are typically healthy volunteers, and the technique is described as noninvasive. However, TMS parameters can be set such that stimulation produces long-lasting effects. Critically, TMS effects that have any possibility of lasting beyond a participant’s time in the lab are potentially harmful. In this editorial, evidence is considered that indicates a 20-Hz multi-day TMS protocol has long-lasting effects, and a continuous theta-burst stimulation protocol needs further testing before it is deemed noninvasive. The following guidelines are provided for TMS protocol evaluation: 1) Effects must be shown to completely dissipate before participants leave the lab by testing well beyond the expected duration. 2) Participants should complete a cognitive test battery before TMS and after the effects are expected to dissipate. 3) Protocols should not be employed that produce effects lasting longer than the time in the lab. 4) The number of participants should ensure error bars are small, and results generalize to the population. 5) Results should be assessed at the group and individual-participant level, and effects should dissipate for every participant. 6) Bayesian analysis should be conducted to evaluate evidence in favor of the null hypothesis. 7) Effects should be assessed in multiple cortical regions. It is hoped that these guidelines will be employed to ensure the continued use of TMS as a valuable tool in the field of cognitive neuroscience.

Network effects of Stanford Neuromodulation Therapy (SNT) in treatment-resistant major depressive disorder: a randomized, controlled trial

Here, we investigated the brain functional connectivity (FC) changes following a novel accelerated theta burst stimulation protocol known as Stanford Neuromodulation Therapy (SNT) which demonstrated significant antidepressant efficacy in treatment-resistant depression (TRD). In a sample of 24 patients (12 active and 12 sham), active stimulation was associated with significant pre- and post-treatment modulation of three FC pairs, involving the default mode network (DMN), amygdala, salience network (SN) and striatum. The most robust finding was the SNT effect on amygdala-DMN FC (group*time interaction F(1,22) = 14.89, p < 0.001). This FC change correlated with improvement in depressive symptoms (rho (Spearman) = −0.45, df = 22, p = 0.026). The post-treatment FC pattern showed a change in the direction of the healthy control group and was sustained at the one-month follow-up. These results are consistent with amygdala-DMN connectivity dysfunction as an underlying mechanism of TRD and bring us closer to the goal of developing imaging biomarkers for TMS treatment optimization.Trial registration: ClinicalTrials.gov NCT03068715

Эффект основанных на метапластичности протоколов транскраниальной стимуляции тета-вспышками на показатели рабочей памяти

The study of the metaplasticity-based transcranial magnetic stimulation (TMS) protocols is an extensively studied approach to increase the effectiveness of stimulation. However, the effects of protocols with different intervals between the TMS blocks on cognitive functions are poorly understood. The study was aimed to assess the effects of two theta-burst transcranial stimulation (iTBS) protocols with short and long intervals between blocks on the working memory (WM) performance in healthy volunteers. A total of 16 participants were underwent a single TMS session of each protocol, which were applied in random order (iTBS 0–15 — two iTBS blocks over the left dorsolateral prefrontal cortex (DLPFC) iTBS with an interval of 15 min between blocks followed by stimulation of the vertex area in 60 min after the first block; iTBS 0–60 — iTBS block over the left DLPFC iTBS, block of the vertex stimulation after 15 min, and the second block of iTBS over the left DLPFC iTBS 60 min after the first one; iTBS 0 — one block of iTBS over the left DLPFC iTBS and two blocks of the vertex stimulation; control protocol — three blocks of the vertex stimulation with similar intervals). WM was assessed using the n-back test before the first block and after the second and the third stimulation blocks. No significant effects of protocols on WM or differences between protocols in alterations of test results and the responder rates to TMS between protocols were observed. The trend toward statistical signficance was reported for the protocol with short interval (iTBS 0–15). Furthermore, low reproducibility of individual iTBS effect was reported. The study of protocols with short intervals between blocks involving larger cohort of volunteers and taking into account the other factors potentially influencing the effect of the protocol (number of blocks and duration of a single block) seems to be promising.

Long-term potentiation and spatial memory training stimulate the hippocampal expression of RyR2 calcium release channels.

Introduction: Neuronal Ca2+ signals generated through the activation of Ca2+-induced Ca2+ release in response to activity-generated Ca2+ influx play a significant role in hippocampal synaptic plasticity, spatial learning, and memory. We and others have previously reported that diverse stimulation protocols, or different memory-inducing procedures, enhance the expression of endoplasmic reticulum-resident Ca2+ release channels in rat primary hippocampal neuronal cells or hippocampal tissue. Methods and Results: Here, we report that induction of long-term potentiation (LTP) by Theta burst stimulation protocols of the CA3-CA1 hippocampal synapse increased the mRNA and protein levels of type-2 Ryanodine Receptor (RyR2) Ca2+ release channels in rat hippocampal slices. Suppression of RyR channel activity (1 h preincubation with 20 μM ryanodine) abolished both LTP induction and the enhanced expression of these channels; it also promoted an increase in the surface expression of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits GluR1 and GluR2 and caused a moderate but significant reduction of dendritic spine density. In addition, training rats in the Morris water maze induced memory consolidation, which lasted for several days after the end of the training period, accompanied by an increase in the mRNA levels and the protein content of the RyR2 channel isoform. Discussion: We confirm in this work that LTP induction by TBS protocols requires functional RyR channels. We propose that the increments in the protein content of RyR2 Ca2+ release channels, induced by LTP or spatial memory training, play a significant role in hippocampal synaptic plasticity and spatial memory consolidation.

Continuous Theta Burst Stimulation to the left anterior medial prefrontal cortex influences metacognitive efficiency

The contribution of the prefrontal areas to visual awareness is critical for the Global Neuronal Workspace Theory and higher-order theories of consciousness. The goal of the present study was to test the potential engagement of the anterior medial prefrontal cortex (aMPFC) in visual awareness judgements. We aimed to temporarily influence the neuronal dynamics of the left aMPFC via neuroplasticity-like mechanisms. We used different Theta Burst Stimulation (TBS) protocols in combination with a visual identification task and visual awareness ratings. Either continuous TBS (cTBS), intermittent TBS (iTBS), or sham TBS was applied prior to the experimental paradigm in a within-participant design. Compared with sham TBS, we observed an increase in participants’ ability to judge their perception adequately (metacognitive efficiency) following cTBS but not iTBS. The effect was accompanied by lower visual awareness ratings in incorrect responses. No significant differences in the identification task performance were observed. We interpret these results as evidence of the involvement of PFC in the brain network that underlies metacognition. Further, we discuss whether the results of TMS studies on perceptual metacognition can be taken as evidence for PFC involvement in awareness itself.

Effects of bilateral sequential theta-burst stimulation on 5-HT1A receptors in the dorsolateral prefrontal cortex in treatment-resistant depression: a proof-of-concept trial

Theta-burst stimulation (TBS) represents a brain stimulation technique effective for treatment-resistant depression (TRD) as underlined by meta-analyses. While the methodology undergoes constant refinement, bilateral stimulation of the dorsolateral prefrontal cortex (DLPFC) appears promising to restore left DLPFC hypoactivity and right hyperactivity found in depression. The post-synaptic inhibitory serotonin-1A (5-HT1A) receptor, also occurring in the DLPFC, might be involved in this mechanism of action. To test this hypothesis, we performed PET-imaging using the tracer [carbonyl-11C]WAY-100635 including arterial blood sampling before and after a three-week treatment with TBS in 11 TRD patients compared to sham stimulation (n = 8 and n = 3, respectively). Treatment groups were randomly assigned, and TBS protocol consisted of excitatory intermittent TBS to the left and inhibitory continuous TBS to the right DLPFC. A linear mixed model including group, hemisphere, time, and Hamilton Rating Scale for Depression (HAMD) score revealed a 3-way interaction effect of group, time, and HAMD on specific distribution volume (VS) of 5-HT1A receptor. While post-hoc comparisons showed no significant changes of 5-HT1A receptor VS in either group, higher 5-HT1A receptor VS after treatment correlated with greater difference in HAMD (r = −0.62). The results of this proof-of-concept trial hint towards potential effects of TBS on the distribution of the 5-HT1A receptor. Due to the small sample size, all results must, however, be regarded with caution.

The effects of left frontal intermittent theta burst stimulation on the efficacy of exposure-based therapy in acrophobia

Abstract Evidence-based treatments for anxiety disorders, as cognitive behavioral and pharmacological therapy achieves good therapeutic results. However, studies have shown that the therapy can be further optimized. Transcranial magnetic stimulation (TMS) may be useful as an adjunct to exposure-based therapy for anxiety disorders, as laboratory studies in healthy subjects have shown (Raij et al., 2018) that extinction learning, as an underlying mechanism in exposure therapy, can be improved using rTMS. The aim of this double-blind, randomized, placebo-controlled clinical trial with 76 patients with acrophobia is to verify whether the stimulation localization (left frontal cortex), shown to be benefical in healthy subjects, can be effectively used to enhance exposure therapy. For this purpose, patients underwent neuronavigational stimulation over the individually defined stimulation localization using the activating intermittent theta burst stimulation (iTBS) protocol before exposure therapy in virtual reality. Clinical symptoms were evaluated via questionnaires and two behavioral approach tests before, after, and for follow-up after 6 months. Furthermore, process variables during the exposure sessions, such as duration of exposure, and maximal anxiety depending on the stimulation groups were investigated. Research Category and Technology and Methods Clinical Research: 10. Transcranial Magnetic Stimulation (TMS) Keywords: rTMS, Anxiety disorders, Psychotherapy

Efficacy of Adjunctive D-Cycloserine to Intermittent Theta-Burst Stimulation for Major Depressive Disorder

The antidepressant effects of transcranial magnetic stimulation protocols for major depressive disorder (MDD) are thought to depend on synaptic plasticity. The theta-burst stimulation (TBS) protocol synaptic plasticity is known to be N-methyl-D-aspartate (NMDA)-receptor dependent, yet it is unknown whether enhancing NMDA-receptor signaling improves treatment outcomes in MDD. To test whether low doses of the NMDA-receptor partial-agonist, D-cycloserine, would enhance intermittent TBS (iTBS) treatment outcomes in MDD. This was a single-site 4-week, double-blind, placebo-controlled, randomized clinical trial conducted from November 6, 2019, to December 24, 2020, including 50 participants with MDD. Participants were recruited via advertisements and referral. Inclusion criteria were as follows: age 18 to 65 years with a primary diagnosis of MDD, a major depressive episode with score of 18 or more on the 17-item Hamilton Depression Rating Scale, a Young Mania Rating Scale score of 8 or less, and normal blood work (including complete blood cell count, electrolytes, liver function tests, and creatinine level). Participants were randomly assigned 1:1 to either iTBS plus placebo or iTBS plus D-cycloserine (100 mg) for the first 2 weeks followed by iTBS without an adjunct for weeks 3 and 4. The primary outcome was change in depressive symptoms as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) at the conclusion of treatment. Secondary outcomes included clinical response, clinical remission, and Clinical Global Impression (CGI) scores. A total of 50 participants (mean [SD] age, 40.8 [13.4] years; 31 female [62%]) were randomly assigned to treatment groups: iTBS plus placebo (mean [SD] baseline score, 30.3 [4.2]) and iTBS plus D-cycloserine (mean [SD] baseline score, 30.4 [4.5]). The iTBS plus D-cycloserine group had greater improvements in MADRS scores compared with the iTBS plus placebo group (mean difference, -6.15; 95% CI, -2.43 to -9.88; Hedges g = 0.99; 95% CI, 0.34-1.62). Rates of clinical response were higher in the iTBS plus D-cycloserine group than in the iTBS plus placebo group (73.9% vs 29.3%), as were rates of clinical remission (39.1% vs 4.2%). This was reflected in lower CGI-severity ratings and greater CGI-improvement ratings. No serious adverse events occurred. Findings from this clinical trial indicate that adjunctive D-cycloserine may be a promising strategy for enhancing transcranial magnetic stimulation treatment outcomes in MDD using iTBS requiring further investigation. ClinicalTrials.gov Identifier: NCT03937596.

Continuous theta burst stimulation for drug-resistant epilepsy.

IntroductionRepetitive transcranial magnetic stimulation (rTMS) may have anti-epileptic effects, especially in patients with neocortical lesions. Initial clinical trials demonstrated that the duration of the seizure reducing effect is relatively short-lived. In the context of a chronic condition like epilepsy, theta burst stimulation (TBS) may represent a potential solution in optimizing treatment practicality and durability as it was demonstrated to be associated with longer-lasting after-effects. TBS has been studied extensively in diverse neuropsychiatric conditions, but a therapeutic TBS protocol has not previously been applied in epilepsy patients.Materials and methodsWe performed a prospective open-label pilot study of 4-day accelerated continuous TBS (cTBS) treatment in patients with neocortical drug-resistant epilepsy (DRE). A treatment session consisted of 5 cTBS trains, each comprising 600 pulses presented in 50 Hz triplet bursts every 200 ms, delivered at 10-min intertrain-intervals, targeted over the epileptic focus (EF) using a neuronavigation-guided figure-of-8 coil. Safety and feasibility, and seizure frequency were assessed as primary and secondary endpoints, respectively, over a 4-week baseline period, a 1-week treatment period and a 7-week follow-up period, using adverse event logging, electro-encephalography, cognitive, and psychological questionnaires and a seizure diary kept by the patients and/or caregivers.ResultsSeven subjects (4M:3F; median age 48, interquartile ranges 25) underwent the treatment protocol. Adverse events were reported in all subjects but were mild and transient. No clinical or electrographic seizures were evoked during or immediately following stimulation. No deterioration was found in cognition nor in psycho-emotional well-being following treatment. Treatment burden was acceptable, but seems to depend on clinical effect, duration of ongoing effect and stimulation site. Median weekly seizure frequency and ratio of seizure-free weeks did not change significantly in this small patient cohort.ConclusionWe report the results of the first ever trial of cTBS as a treatment for neocortical DRE. A 4-day accelerated cTBS protocol over the EF appears safe and feasible. Although the design and sample size of this open-label pilot study is unfit to reliably identify a therapeutic effect, results encourage further exploration of cTBS as an anti-epileptic treatment and potential optimization compared to conventional rTMS in a dedicated randomized controlled trial. (clinicaltrials.gov: NCT02635633).

Adding a Second iTBS Block in 15 or 60 Min Time Interval Does Not Increase iTBS Effects on Motor Cortex Excitability and the Responder Rates.

The use of metaplasticity-based intermittent theta-burst stimulation (iTBS) protocols including several stimulation blocks could be a possible approach to increasing stimulation effectiveness. Our aim was to investigate the neurophysiological effects of two protocols with a short and a long interval between blocks. Seventeen healthy volunteers received four protocols in a pseudorandomized order: iTBS 0-15 (two blocks of active iTBS of primary motor cortex (M1) separated by 15 min and a control stimulation block of the vertex in 60 min from the first block); iTBS 0-60 (active iTBS, a control block in 15 min, and an active block in 60 min); iTBS 0 (active iTBS and two control blocks with the same intervals); and Control (three control blocks). The motor evoked potentials (MEPs) were measured before the first and after the second and third blocks. We have shown no significant differences between the effects of the protocols on both the motor cortex excitability and the responder rates. No significant changes of MEPs were observed after all the protocols. The reliability for the responsiveness to a single block between two sessions was insignificant. Our data confirm low reproducibility of the response to iTBS and suggest that the use of repeated protocols does not increase the responder rates or neurophysiological effects of iTBS.

Efficacy and safety of intermittent theta burst stimulation (iTBS) in treatment resistant depression

IntroductionRepetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulatory treatment option, which is used in a variety of neurological and psychiatric diseases. It is approved for depression treatment and recommended in international guidelines. A significant reduction in treatment duration was achieved by using theta burst stimulation (TBS) protocols, which are practicable and non-inferior to conventional TMS.ObjectivesTo analyse the efficacy and safety of intermittent theta burst stimulation (iTBS) of left DLPFC in inpatients with treatment-resistant depression.MethodsWe evaluated n=44 inpatients with treatment resistant major depressive disorder (n=37) and bipolar depression (n=7), who were treated with the 5 Hz intermittent TBS once daily for 3-6 weeks according to clinical decision. A total of 600 pulses and 200 bursts were applied in each treatment session. Clinical and response data were obtained by chart review.ResultsMean age at time of first stimulation was 54 years. 61,3 % of patients were female. On average, the current episode started 21 months before the first stimulation. In total, 924 treatment sessions were performed. On average, patients received 21 sessions. The mean MADRS Score pre-treatment was 27.2. Post-treatment, there was a clear reduction in depression severity (MADRS 18.3). No severe adverse events and no seizures occurred in this clinical observational analysis.ConclusionsIntermittent TBS is efficacious and safe in patients with chronic and refractory depression.DisclosureNo significant relationships.