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

Dialectical 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.

iTBS reveals the roles of domain-general cognitive control and language-specific brain regions during word formation rule learning.

Repeated exposure to word forms and meanings improves lexical knowledge acquisition. However, the roles of domain-general and language-specific brain regions during this process remain unclear. To investigate this, we applied intermittent theta burst stimulation over the domain-general (group left dorsolateral prefrontal cortex) and domain-specific (Group L IFG) brain regions, with a control group receiving sham intermittent theta burst stimulation. Intermittent theta burst stimulation effects were subsequently assessed in functional magnetic resonance imaging using an artificial word learning task which consisted of 3 learning phases. A generalized psychophysiological interaction analysis explored the whole brain functional connectivity, while dynamic causal modeling estimated causal interactions in specific brain regions modulated by intermittent theta burst stimulation during repeated exposure. Compared to sham stimulation, active intermittent theta burst stimulation improved word learning performance and reduced activation of the left insula in learning phase 2. Active intermittent theta burst stimulation over the domain-general region increased whole-brain functional connectivity and modulated effective connectivity between brain regions during repeated exposure. This effect was not observed when active intermittent theta burst stimulation was applied to the language-specific region. These findings suggest that the domain-general region plays a crucial role in word formation rule learning, with intermittent theta burst stimulation enhancing whole-brain connectivity and facilitating efficient information exchange between key brain regions during new word learning.

[The efficacy of magnetic transcranial stimulation in treating treatment-resistant or prolonged depression in a clinical sample].

INTRODUCTION: Depression is a common, serious and often chronic disorder and one of the leading causes of disability worldwide. The annual prevalence of depression is 5-10%, twice as high among women as men and the lifetime prevalence is at least 20%. Up to a third of depressed individuals meet criteria for treatment-resistant depression, where two antidepressants have been tried for at least 6 weeks each at therapeutic doses. As of January 2022 transcranial magnetic stimulation for adults with treatment-resistant depression that has not responded to other forms of treatment has been available by a service that is part of Primary Health Care of the Capital Area in Iceland. METHODS: This is a retrospective cohort study where participants completed a course of magnetic transcranial treatment for depression in the years 2022 and 2023. Two validated self-rating measures were used to assess depression. Information on previous treatment approaches for depression was collected from electronic health records. RESULTS: 104 individuals completed the treatment in these first two years, 60,6% women. Most had unipolar depression (86,5%), but a small subgroup had bipolar depression (13,5%). The proportion of responders varied according to the measures used, 36,1% and 45,7%, respectively, and the same was true for remission where the proportions were 12,4% and 31,5%, respectively, higher for the longer inventory. The drop-out rate was only 12,5% and no serious adverse events were reported during the treatment. CONCLUSION: The results support that magnetic transcranial stimulation, as provided by this service is effective in treating treatment-resistant or longstanding depression in a real life clinical setting and the low drop-out rate supports that the treatment is generally very well tolerated.

The influence of menstrual phase on synaptic plasticity induced via intermittent theta-burst stimulation.

BACKGROUND: Ovarian hormones influence the propensity for short-term plasticity induced by repetitive transcranial magnetic stimulation (rTMS). Estradiol appears to enhance the propensity for neural plasticity. It is currently unknown how progesterone influences short-term plasticity induced by rTMS. OBJECTIVE: The present research investigates whether the luteal versus follicular phase of the menstrual cycle influence short-term plasticity induced by intermittent theta-burst stimulation (iTBS). We tested the hypothesis that iTBS would increase motor evoked potentials (MEPs) during the follicular phase. Further, we explored the effects of the luteal phase on iTBS-induced neural plasticity. METHOD: Twenty-nine adult females participated in a placebo-controlled study that delivered real and sham iTBS to the left primary motor cortex in separate sessions corresponding to the follicular phase (real iTBS), luteal phase (real iTBS), and a randomly selected day (sham iTBS). Outcomes included corticospinal excitability as measured by the amplitude of MEPs and short-interval intracortical inhibition (SICI) recorded from the right first dorsal interosseous muscle before and following iTBS (612 pulses). RESULTS: MEP amplitude was increased following real iTBS during the follicular condition. No significant changes in MEP amplitude were observed during the luteal or sham visits. SICI was unchanged by iTBS irrespective of menstrual phase. CONCLUSION: These findings suggest women experience a variable propensity for iTBS-induced short-term plasticity across the menstrual cycle. This information is important for designing studies aiming to induce plasticity via rTMS in women.

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

BACKGROUND: Although 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. METHODS: Participants 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. RESULTS: We 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. LIMITATIONS: Our study has a limited sample size and larger samples are needed to confirm safety and efficacy. CONCLUSIONS: SAINT 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.

Cortical plasticity in AQP4-positive NMOSD: a transcranial magnetic stimulation study.

Aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD) is an autoimmune disease characterized by suboptimal recovery from attacks and long-term disability. Experimental data suggest that AQP4 antibodies can disrupt neuroplasticity, a fundamental driver of brain recovery. A well-established method to assess brain LTP is through intermittent theta-burst stimulation (iTBS). This study aimed to explore neuroplasticity in AQP4-NMOSD patients by examining long-term potentiation (LTP) through iTBS. We conducted a proof-of-principle study including 8 patients with AQP4-NMOSD, 8 patients with multiple sclerosis (MS), and 8 healthy controls (HC) in which iTBS was administered to induce LTP-like effects. iTBS-induced LTP exhibited significant differences among the 3 groups (p: 0.006). Notably, AQP4-NMOSD patients demonstrated impaired plasticity compared to both HC (p = 0.01) and pwMS (p = 0.02). This pilot study provides the first in vivo evidence supporting impaired neuroplasticity in AQP4-NMOSD patients. Impaired cortical plasticity may hinder recovery following attacks suggesting a need for targeted rehabilitation strategies.

Dose-dependent target engagement of a clinical iTBS protocol: An interleaved TMS-fMRI study in healthy subjects.

BACKGROUND: Intermittent theta burst stimulation (iTBS) of the dorsolateral prefrontal cortex (DLPFC) is widely applied as therapeutic intervention in mental health, however understanding of its mechanisms is still incomplete. Prior MRI studies have mainly used offline iTBS or short sequences in concurrent TMS-fMRI. This study investigated a full 600 stimuli iTBS protocol using interleaved TMS-fMRI in comparison with two control conditions in healthy subjects. METHODS: In a crossover design, 18 participants underwent three sessions of interleaved iTBS-fMRI: 1) left DLPFC at 40% resting motor threshold (rMT) intensity, 2) left DLPFC at 80% rMT intensity, and 3) left primary motor cortex (M1) at 80% rMT intensity. We compared immediate blood-oxygen-level-dependent (BOLD) responses during interleaved iTBS-fMRI across these conditions including correlations between individual fMRI BOLD activation and iTBS induced electric field (E-field) strength at the target sites. RESULTS: Whole-brain analysis showed increased activation in several regions following iTBS. Specifically, left DLPFC, as well as bilateral M1, anterior cingulate cortex, and insula showed increased activation during 80% rMT left DLPFC stimulation. Increased BOLD activity in the left DLPFC was not observed with 40% rMT left DLPFC stimulation nor left M1 80% rMT iTBS, whereas activation in other regions was found to overlap between conditions. Of note, BOLD activation and E-field intensities were only correlated for M1 stimulation, but not for the DLPFC conditions. CONCLUSIONS: The study showed dosage and target specific BOLD activation during interleaved TMS-fMRI with 600 stimuli iTBS in healthy subjects. Future studies may use our approach for demonstrating target engagement.

Dual stimulation with iTBS-cTBS treatment in postpartum obsessive-compulsive disorder: a case report.

AIM OF THE STUDY: This study aimed to present a case of intermittent theta-burst stimulation (iTBS) and continuous theta-burst stimulation (cTBS) dual stimulation for the treatment of postpartum obsessive-compulsive disorder (OCD). The objective was to provide a referenceable therapy in cases where medication and psychotherapy treatment are not preferred or contraindicated. This case further emphasized the importance of non-invasive neuromodulation techniques in improving the condition of postpartum OCD patients. MATERIALS AND METHODS: A 32-year-old female was diagnosed with OCD 2 months after delivery. The patient refused to take medication and psychotherapy due to concerns that it would interfere with the infant's breastfeeding. Subsequently, a 2-week combined iTBS and cTBS treatment was carried out. The patient's obsessive-compulsive symptoms, anxiety, and depression improved. There were no significant adverse effects during the treatment, and the treatment effect remained 2 weeks after the end of the treatment. CONCLUSION: This clinical case provides evidence that the combined iTBS and cTBS treatment can potentially effectively alleviate obsessive-compulsive symptoms in the short term. Notably, this therapeutic approach may offer a promising solution for postpartum OCD patients, as it addresses practical concerns such as medication safety for breastfeeding mothers and the specific needs of this population. To further establish the efficacy of this combined therapy, future randomized controlled trials with large samples and long-term follow-up are warranted to validate its therapeutic potential.

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

BACKGROUND: Repetitive 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. METHODS: 30 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. RESULTS: After 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. LIMITATIONS: Short intervention period of 3 weeks. Clinical symptoms were measured by self-assessment only and are therefore preliminary. CONCLUSIONS: The 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.

Case report: Tremor in the placebo condition of a blinded clinical trial of intermittent theta-burst stimulation for cocaine use disorder.

We report a case of a new-onset, persistent tremor that developed during a clinical trial (NCT02927236) of intermittent theta burst stimulation [iTBS, a form of repetitive magnetic transcranial magnetic stimulation (rTMS)] for cocaine use disorder. Although the participant exhibited an exceptionally strong clinical response, subsequent unblinding revealed that they received sham iTBS. This case highlights the potential for strong functional neurological placebo responses in rTMS trials, and functional disorders might be a marker of a placebo response. Additionally, we note the possibility that the weak e-fields produced by some sham rTMS systems may induce clinically relevant effects.

Evidence for Intermittent Theta Burst Transcranial Magnetic Stimulation for Dysphagia after Stroke: A Systematic Review and Meta-analysis.

Dysphagia is the most common serious complication after stroke, with an incidence of about 37-78%, which seriously affects the independence of patients in daily life and clinical recovery. Repetitive transcranial magnetic stimulation (rTMS), as a non-invasive neuromodulation technique, is an emerging option for post-stroke dysphagia. Theta burst stimulation (TBS) is a new mode of transcranial magnetic stimulation that simulates the frequency of pulses released in the hippocampus.Intermittent theta burst stimulation (iTBS) has been shown to increase cortical excitability and improve swallowing function in patients. Our study sought to summarize existing clinical randomized controlled trials to provide evidence-based medical evidence for the clinical use of iTBS. A computer search was conducted on 4 Chinese (Chinese Biomedical Literature Database, VIP Information Resource System, CNKI, and Wanfang Medical Science) and 4 English (including Cochrane Library, Embase, PubMed, Web of Science) databases to retrieve all randomized controlled trials in Chinese and English that explored the effects of Intermittent Theta Burst Stimulation for post-stroke dysphagia. The retrieval years are from database construction to 23 November 2023. The primary outcome measure was a change in Penetration/Aspiration Scale (PAS), Standardized Swallowing Assessment (SSA) and Functional Oral Intake Scale (FOIS), Secondary outcomes included Fiberoptic Endoscopic Dysphagia Severity Scale (FEDSS), water-swallowing test (WST) etc. A meta-analysis by Standardized Mean Difference (SMD) and 95% confidence interval (CI) was performed with RevMan 5.3. we appraise risk of bias(RoB) of each study with the Cochrane RoB tool. Detailed instructions for using the Cochrane RoB tool are provided in the Cochrane Handbook for Systematic Reviews of Interventions (The Cochrane Handbook). Nine studies were obtained from eight databases after screening by inclusion and exclusion criteria, 567 patients from 9 studies were included in the meta-analysis, and one study was included in the qualitative analysis due to different control groups. Two of the nine studies had an unclear risk of bias, and four studies were at low risk. The results showed that iTBS significantly improved SSA, PAS, FOIS, and PAS scores in stroke patients compared to the control group(P < 0.05), and promoted swallowing function recovery. Our systematic review provides the first evidence of the efficacy of iTBS in improving dysphagia in stroke patients. However, the number of available studies limits the persuasiveness of the evidence and further validation by additional randomized controlled trials is needed.

Effects of one-week bilateral cerebellar iTBS on resting-state functional brain network and multi-task attentional performance in healthy individuals: A randomized, sham-controlled trial.

BACKGROUND: Cerebellar intermittent theta burst stimulation (iTBS) modulates the excitability of the cerebral cortex and may enhance attentional performance. To date, few studies have conducted iTBS on healthy subjects for one week and used electroencephalography (EEG) to investigate the effect of multiple stimulation sessions on resting-state functional brain networks and the daily stimulation effect on attentional performance. METHODS: 16 healthy subjects participated in a one-week experiment, receiving bilateral cerebellar iTBS or sham stimulation and engaging in multi-task attentional training. The primary measures were the one-week attentional performance and pre- and post-experiment resting-state EEG activities. Amplitude Envelope Correlation (AEC) was used to construct the functional connectivity in the eye-open (EO) and eye-closed (EC) phases. RESULTS: At least three sessions of iTBS were required to enhance multi-task performance significantly, whereas only one or two sessions failed to elicit the improvement. Compared with the control group, iTBS induced significant changes in PSD, AEC functional connectivity, and AEC network properties during the EO phase, while it had little effect during the EC phase. During the EO phase, the network property changes of the iTBS subject were correlated with improved attentional performance. CONCLUSION: The multi-task performance requires multiple stimulations to enhance. iTBS affects the resting-state alpha band brain activities during the EO rather than the EC phase. The AEC network properties may serve as a biomarker to assess the attentional potential of healthy subjects.

Prolonged intermittent theta burst stimulation targeting the left prefrontal cortex and cerebellum does not affect executive functions in healthy individuals.

Repetitive transcranial magnetic stimulation (rTMS) for alleviating negative symptoms and cognitive dysfunction in schizophrenia commonly targets the left dorsolateral prefrontal cortex (LDLPFC). However, the therapeutic effectiveness of rTMS at this site remains inconclusive and increasingly, studies are focusing on cerebellar rTMS. Recently, prolonged intermittent theta-burst stimulation (iTBS) has emerged as a rapid-acting form of rTMS with promising clinical benefits. This study explored the cognitive and neurophysiological effects of prolonged iTBS administered to the LDLPFC and cerebellum in a healthy cohort. 50 healthy participants took part in a cross-over study and received prolonged (1800 pulses) iTBS targeting the LDLPFC, cerebellar vermis, and sham iTBS. Mixed effects repeated measures models examined cognitive and event-related potentials (ERPs) from 2-back (P300, N200) and Stroop (N200, N450) tasks after stimulation. Exploratory non-parametric cluster-based permutation tests compared ERPs between conditions. There were no significant differences between conditions for behavioural and ERP outcomes on the 2-back and Stroop tasks. Exploratory cluster-based permutation tests of ERPs did not identify any significant differences between conditions. We did not find evidence that a single session of prolonged iTBS administered to either the LDLPFC or cerebellum could cause any cognitive or ERP changes compared to sham in a healthy sample.

Hypothalamic-pituitary-adrenal axis hyperactivity is normalized after successful intermittent theta-burst stimulation in resistant depressed patients.

The present pilot study assessed the effects of multi-session intermittent theta-burst stimulation (iTBS) applied to the left dorsolateral prefrontal cortex in 17 treatment resistant depressed inpatients (TRDs) showing cortisol non-suppression to the overnight dexamethasone suppression test (DST) at baseline (i.e., maximum post-DST cortisol [CORmax] level > 130 nmol/L). After 20 iTBS sessions, the DST was repeated in all TRDs. At baseline, post-DST CORmax levels were higher in TRDs compared to healthy control subjects (HCs; n = 17) (p < 0.0001). After 20 iTBS sessions, post-DST CORmax levels decreased from baseline (p < 0.03) and were comparable to HCs. Decreases in post-DST CORmax levels were related to decreases in 17-item Hamilton Depression Rating Scale (HAMD-17) scores (ρ = 0.53; p < 0.03). At endpoint, 10 TRDs showed DST normalization (among them 7 were responders [i.e., HAMD-17 total score > 50% decrease from baseline]), and 7 did not normalize their DST (among them 6 were non-responders) (p < 0.05). Our results suggest that successful iTBS treatment may restore normal glucocorticoid receptor feedback inhibition at the pituitary level.

Mechanisms of intermittent theta-burst stimulation attenuating nerve injury after ischemic reperfusion in rats through endoplasmic reticulum stress and ferroptosis.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) exerts neuroprotective effects early in cerebral ischemia/reperfusion (I/R) injury. Intermittent theta-brust stimulation (iTBS), a more time-efficient modality of rTMS, improves the efficiency without at least decreasing the efficacy of the therapy. iTBS elevates cortical excitability, and in recent years it has become increasingly common to apply iTBS to patients in the early post-IS period. However, little is known about the neuroprotective mechanisms of iTBS. Endoplasmic reticulum stress (ERS), and ferroptosis have been shown to be involved in the development of I/R injury. We aimed to investigate the potential regulatory mechanisms by which iTBS attenuates neurological injury after I/R in rats. METHODS: Rats were randomly divided into three groups: sham-operated group, MCAO/R group, and MCAO/R + iTBS group, and were stimulated with iTBS 36 h after undergoing middle cerebral artery occlusion (MCAO) or sham-operated. The expression of ERS, ferroptosis, and apoptosis-related markers was subsequently detected by western blot assays. We also investigated the mechanism by which iTBS attenuates nerve injury after ischemic reperfusion in rats by using the modified Neurological Severity Score (mNSS) and the balance beam test to measure nerve function. RESULTS: iTBS performed early in I/R injury attenuated the levels of ERS, ferroptosis, and apoptosis, and improved neurological function, including mNSS and balance beam experiments. It is suggested that this mode of stimulation reduces the cost per treatment by several times without compromising the efficacy of the treatment and could be a practical and less costly intervention.

Real-world retrospective study of repetitive transcranial magnetic stimulation (TMS) treatment for bipolar and unipolar depression using TMS registry data in Tokyo.

Despite the prevalence of empirical practice, evidence supporting the use of repetitive transcranial magnetic stimulation (rTMS) in treating bipolar depression (BD) is sparse compared to that for unipolar depression. Therefore, this study aimed to conduct a retrospective observational analysis using TMS registry data to compare the efficacy of rTMS treatment for BD and unipolar depression. Data from 20 patients diagnosed with unipolar and BD were retrospectively extracted from the TMS registry to ensure age and sex matching. The primary outcomes of this registry study were measured using the 21-item Hamilton Depression Rating Scale (HAM-D21) and Montgomery-Åsberg Depression Rating Scale (MADRS). Analysis did not reveal significant differences between the two groups in terms of depression severity, motor threshold, or stimulus intensity at baseline. Similarly, no significant differences were observed in absolute or relative changes in the total HAM-D21 and MADRS scores. Furthermore, the response and remission rates following rTMS treatment did not differ significantly between groups. The only adverse event reported in this study was scalp pain at the stimulation site; however, the incidence and severity were not significantly different between the groups. In conclusion, this retrospective study, using real-world TMS registry data, suggests that rTMS treatment for BD could be as effective as that for unipolar depression. These findings underscore the need for further validation in prospective randomized controlled trials with larger sample sizes.

Effects of accelerated intermittent theta-burst stimulation in modulating brain of Alzheimer's disease.

Intermittent theta-burst stimulation (iTBS) is emerging as a noninvasive therapeutic strategy for Alzheimer's disease (AD). Recent advances highlighted a new accelerated iTBS (aiTBS) protocol, consisting of multiple sessions per day and higher overall pulse doses, in brain modulation. To examine the possibility of applying the aiTBS in treating AD patients, we enrolled 45 patients in AD at early clinical stages, and they were randomly assigned to either receive real or sham aiTBS. Neuropsychological scores were evaluated before and after treatment. Moreover, we detected cortical excitability and oscillatory activity changes in AD, by the single-pulse TMS in combination with EEG (TMS-EEG). Real stimulation showed markedly better performances in the group average of Auditory Verbal Learning Test scores compared to baseline. TMS-EEG revealed that aiTBS has reinforced this memory-related cortical mechanism by increasing cortical excitability and beta oscillatory activity underlying TMS target. We also found an enhancement of local natural frequency after aiTBS treatment. The novel findings implicated that high-dose aiTBS targeting left DLPFC is rapid-acting, safe, and tolerable in AD patients. Furthermore, TMS-related increase of specific neural oscillation elucidates the mechanisms of the AD cognitive impairment ameliorated by aiTBS.

Combining transcranial magnetic stimulation with training to improve social cognition impairment in schizophrenia: a pilot randomized controlled trial.

Schizophrenia is a severe, chronic mental disorder that profoundly impacts patients' everyday lives. The illness's core features include positive and negative symptoms and cognitive impairments. In particular, deficits in the social cognition domain showed a tighter connection to patients' everyday functioning than the other symptoms. Social remediation interventions have been developed, providing heterogeneous results considering the possibility of generalizing the acquired improvements in patients' daily activities. In this pilot randomized controlled trial, we investigated the feasibility of combining fifteen daily cognitive and social training sessions with non-invasive brain stimulation to boost the effectiveness of the two interventions. We delivered intermittent theta burst stimulation (iTBS) over the left dorsolateral prefrontal cortex (DLPFC). Twenty-one patients were randomized into four groups, varying for the assigned stimulation condition (real vs. sham iTBS) and the type of cognitive intervention (training vs. no training). Clinical symptoms and social cognition tests were administered at five time points, i.e., before and after the treatment, and at three follow-ups at one, three, and six months after the treatments' end. Preliminary data show a trend in improving the competence in managing emotion in participants performing the training. Conversely, no differences were found in pre and post-treatment scores for emotion recognition, theory of mind, and attribution of intentions scores. The iTBS intervention did not induce additional effects on individuals' performance. The methodological approach's novelty and limitations of the present study are discussed.

Left prefrontal intermittent theta burst stimulation ameliorates tinnitus distress and symptoms of depression - A feasibility study.

Tinnitus remains a notoriously difficult to treat clinical entity. 1-2% of the entire population report relevant emotional distress due to tinnitus, and causal treatments are lacking. Repetitive transcranial magnetic stimulation (rTMS), most commonly of auditory cortical areas, has shown mixed results in the past. Prefrontal rTMS, including intermittent theta burst stimulation (iTBS) has shown more promising results in the treatment of depression, and clinical data suggests a meaningful overlap between tinnitus and depression. Therefore, we performed a feasibility study of 28 consecutive patients with tinnitus treated with an iTBS protocol over the left dorsolateral prefrontal cortex for three weeks. After treatment, we observed significant ameliorations of tinnitus distress as measured by the Tinnitus Handicap Inventory Questionnaire (THI), the Tinnitus Functional Index (TFI), the Mini-Tinnitus Questionnaire (Mini-TQ) and also of depression as measured by the Major Depression Inventory (MDI). Effect sizes were small to moderate and short-lived. Treatment response rates, defined as improvement of the THI of at least 7 points, were 35.7%. At follow-up twelve weeks after end of treatment, severity of tinnitus and depression returned to approximately baseline level on a descriptive level. Amelioration of depressive symptoms correlated only with TFI change, but not that of other measures of tinnitus distress. The data suggest that a prefrontal iTBS protocol might be applied in the treatment of tinnitus and open avenues for future neurostimulatory treatments other than those of auditory regions.

Neural response during prefrontal theta burst stimulation: Interleaved TMS-fMRI of full iTBS protocols.

BACKGROUND: Left prefrontal intermittent theta-burst stimulation (iTBS) has emerged as a safe and effective transcranial magnetic stimulation (TMS) treatment protocol in depression. Though network effects after iTBS have been widely studied, the deeper mechanistic understanding of target engagement is still at its beginning. Here, we investigate the feasibility of a novel integrated TMS-fMRI setup and accelerated echo planar imaging protocol to directly observe the immediate effects of full iTBS treatment sessions. OBJECTIVE/HYPOTHESIS: In our effort to explore interleaved iTBS-fMRI feasibility, we hypothesize that TMS will induce acute BOLD signal changes in both the stimulated area and interconnected neural regions. METHODS: Concurrent TMS-fMRI with full sessions of neuronavigated iTBS (i.e. 600 pulses) of the left dorsolateral prefrontal cortex (DLPFC) was investigated in 18 healthy participants. In addition, we conducted four TMS-fMRI sessions in a single patient on long-term maintenance iTBS for bipolar depression to test the transfer to clinical cases. RESULTS: Concurrent TMS-fMRI was feasible for iTBS sequences with 600 pulses. During interleaved iTBS-fMRI, an increase of the BOLD signal was observed in a network including bilateral DLPFC regions. In the clinical case, a reduced BOLD response was found in the left DLPFC and the subgenual anterior cingulate cortex, with high variability across individual sessions. CONCLUSIONS: Full iTBS sessions as applied for the treatment of depressive disorders can be established in the interleaved iTBS-fMRI paradigm. In the future, this experimental approach could be valuable in clinical samples, for demonstrating target engagement by iTBS protocols and investigating their mechanisms of therapeutic action.