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Background: Intermittent Theta Burst Stimulation (iTBS), a non-invasive brain stimulation technique, is recognized for its ability to modulate cortical neuronal activity. However, its effects over time and the dynamics following stimulation are less well understood. Understanding the temporal dynamics of iTBS effects is essential for optimizing the timing and frequency of stimulation in therapeutic applications. Objective: This study investigated the temporal changes in protein expression induced by iTBS in Neuro-2a cells. Methods: We analyzed protein expression in retinoic acid-differentiated Neuro-2a cells at multiple time points — 0.5, 3, 6, 12, and 24 hours post-iTBS — using Western blot and immunocytochemistry techniques. Results: Our findings reveal a significant early increase in neurotransmitter receptor subunits, neurotrophic factors, and cytoskeletal proteins within the first 0.5 hour following iTBS. Notably, proteins such as mGLuR1, NMDAR1, GABBR2, and β-tubulin III showed substantial increase in expression. However, the effects of iTBS on protein expression was not sustained at later timepoints. Conclusion: Our results suggest that iTBS can transiently alter the expression of specific proteins in Neuro-2a cells. Future research should investigate the potential benefits of repeated stimulations within the early time window to refine iTBS interventions, potentially expanding their research and clinical applications. [ABSTRACT FROM AUTHOR]

Abnormalities in large-scale neuronal networks—the frontoparietal central executive network (CEN)—are consistent findings in bipolar disorder and potential therapeutic targets for transcranial magnetic stimulation (TMS). The present study aimed to assess the effects of CEN neurocircuit-based sequential TMS on the clinical symptoms and cognitive functions of adolescents with bipolar II disorder. The study was a single-blinded, randomized, placebo-control trial. Participants with DSM-5-defined bipolar disorder II were recruited and randomized to receive either a sham treatment (n = 20) or an active TMS treatment (n = 22). The active group patients were taking medication, with intermittent theta burst stimulation (iTBS) treatment provided as adjunctive treatment targeting the left DLPFC, the left ITG, and the left PPC nodes consecutively. Patients completed the measurements of HAMD and the Das-Naglieri Cognition Assessment System at baseline and 3 weeks after the intervention. A significant group-by-time interaction was observed in the HAMD, total cognition, and planning. Post-hoc analysis revealed that patients in the active group significantly improved HAMD scores following neurostimulation. Moreover, within-subject analysis indicated that the active group significantly improved in scores of total cognition and planning, while the sham group did not. No significant differences were seen in the other cognitive measures. The neurocircuit-based sequential TMS protocol targeting three CEN nodes, in conjunction with medication, safely and effectively improved depressive symptoms and cognitive function in adolescents with bipolar II disorder. • Abnormalities in the CEN are consistent findings in bipolar disorder and potential therapeutic targets for TMS. • Neurocircuit-based sequential iTBS might be a novel and safe alternative in the treatment of adolescents with PBD. • Three weeks of CEN-targeted iTBS over the left DLPFC, ITG, and PPC improved depression symptoms and executive performance. [ABSTRACT FROM AUTHOR]

To explore the influence of intermittent theta burst stimulation (iTBS) dual-target stimulation on lower limb function in patients with incomplete spinal cord injury (iSCI). A randomized, single -blind, sham-controlled trial was used in this study. Thirty iSCI patients with lower limb dysfunction meeting the inclusion criteria were randomly divided into a sham group and an iTBS group, with 15 cases in each group. The iTBS group received conventional rehabilitation therapy combined with iTBS dual-target stimulation on the central cerebral sulcus and the nerve root of the spinal cord injury segment. The sham group was treated with conventional rehabilitation therapy combined with iTBS dual-target sham stimulation therapy. Comprehensive functional assessment was performed on all patients before treatment, on the day 3 and day 21 of treatment. The main evaluation indicators were as follows: amplitude and latency of motor-evoked potential (MEP) in the anterior tibial muscles of both lower limbs, latency of sensory-evoked potential (SEP) of both lower limbs, knee flexor strength and knee extensor strength, lower extremity motor score (LEMS), lower extremity sensory score, spinal cord independence measure (SCIM) score, and gait parameters (stride speed, stride frequency, stride length, and ground reaction force). On day 21 of treatment, in the iTBS group, the MEP amplitude of the anterior tibial muscles increased, the latency of MEP shortened, knee flexor strength and knee extensor strength increased, and the LEMS and SCIM score of both lower limbs increased. In addition, there were statistically significant differences in the muscle strength of the knee flexion muscle, knee extensor muscle, MEP amplitude, LEMS, and SCIM between the 2 groups (P < 0.05). Among the 10 patients who could walk with an assisted walker, the step length and step frequency of the iTBS group were increased compared with the sham group after treatment (P < 0.01), and the ground reaction force was increased (P < 0.05). There was no significant difference in the lower extremity sensory score of the lower limbs between the 2 groups (P > 0.05). ITBS dual-target stimulation can significantly improve the motor function of both lower limbs in patients with iSCI but does not significantly improve the sensory function of both lower limbs. Therefore, this treatment mode may participate in the reconstruction and repair of some nerve circuits in patients with iSCI. In addition, iTBS dual-target stimulation can improve the ability of iSCI patients to perform daily living. [ABSTRACT FROM AUTHOR]

Objective：To explore the overall modulatory effect of the intermittent theta burst stimulation (iTBS), a novel non-invasive brain stimulation technique, on the topology of the brain functional network in stroke patients. Method：Sixteen patients with stroke were recruited. Based on their brain resting-state functional magnetic resonance images, the changes of the brain network topological properties, including the clustering coefficient, characteristic path length, local and global efficiency, "small-world", assortativity and hierarchy, were analyzed before and after one session of left M1 iTBS. Result：The clustering coefficient, local efficiency and normalized hierarchy coefficient decreased significantly after one session of the iTBS, the global efficiency decreased near significantly, and the σ value of "smallworld" increased close to significantly; while the other topological properties showed no significant change following the iTBS intervention. Conclusion：The findings of the present study indicated that the left M1 iTBS may modulate the global network topological characteristics of the brain functional network in patients with stroke. [ABSTRACT FROM AUTHOR]

Objective: Treatment and management for difficult-to-treat depression are challenging, especially in a subset of patients who are at high risk for relapse and recurrence. The conditions that represent this subset are recurrent depressive disorder (RDD) and bipolar disorder (BD). In this context, we aimed to examine the effectiveness of maintenance transcranial magnetic stimulation (TMS) on a real-world clinical basis by retrospectively extracting data from the TMS registry data in Tokyo, Japan. Methods: Data on patients diagnosed with treatment-resistant RDD and BD who received maintenance intermittent theta burst stimulation (iTBS) weekly after successful treatment with acute iTBS between March 2020 and October 2023 were extracted from the registry. Results: All patients (21 cases: 10 cases with RDD and 11 cases with BD) could sustain response, and 19 of them further maintained remission. In this study, maintenance iTBS did not exacerbate depressive symptoms in any of the cases, but may rather have the effect of stabilizing the mental condition and preventing recurrence. Conclusions: This case series is of great clinical significance because it is the first study to report on the effectiveness of maintenance iTBS for RDD and BD, with a follow-up of more than 2 years. Further validation with a randomized controlled trial design with a larger sample size is warranted. [ABSTRACT FROM AUTHOR]

Aims/Background High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) and intermittent theta burst stimulation (iTBS) are emerging neuromodulation techniques for major depressive disorder (MDD). However, clinical trials directly comparing their efficacy are limited. This meta-analysis aimed to evaluate the antidepressant effects and safety profiles of iTBS versus HF-rTMS for MDD. Methods A systematic literature search was conducted in major databases to identify randomized controlled trials (RCTs) comparing iTBS and HF-rTMS for MDD. The primary outcome measures were response rate, remission rate, and common side effects. Meta-analysis was performed using fixed-effects and random-effects models. Publication bias was assessed. Results Seven RCTs were included in the meta-analysis. No significant differences were found in response rate (odds ratio (OR) 0.97, 95% confidence interval (95% CI) 0.81 to 1.16, p = 0.75) or remission rate (OR 1.06, 95% CI 0.85 to 1.31, p = 0.62) between iTBS and HF-rTMS. Both active stimulations showed significantly higher response rates than sham treatment. The odds of response were 4–5 times greater for iTBS versus sham (OR 4.84, 95% CI 2.66 to 8.80, p < 0.001) and 3–4 times greater for HF-rTMS versus sham (OR 3.85, 95% CI 2.08 to 7.13, p < 0.001). No differences in common side effects such as headache were observed between iTBS and HF-rTMS. Conclusion iTBS and HF-rTMS have comparable efficacy and safety profiles in treating MDD based on current evidence. Both neuromodulation techniques are superior to sham stimulation. iTBS could be considered an alternative to HF-rTMS, with the advantage of shorter daily treatment duration. Further large RCTs with long-term follow-up are warranted to confirm these findings. [ABSTRACT FROM AUTHOR]

Growing evidence suggests that cognitive dysfunction significantly impacts patients' quality of life. Intermittent theta burst stimulation (iTBS) has emerged as a potential intervention for cognitive dysfunction. However, consensus on the iTBS protocol for cognitive impairment is lacking. We conducted searches in the Cochrane Central Register of Controlled Trials, EMBASE, PubMed, Chinese National Knowledge Infrastructure, Wanfang Database and the Chongqing VIP Chinese Science and Technology Periodical Database from their inception to January 2024. Random-effects meta-analyzes were used to calculate standardized mean differences and 95% confidence intervals. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation approach. Twelve studies involving 506 participants were included in the meta-analysis. The analysis showed a trend toward improvement of total cognitive function, activities of daily living and P300 latency compared to sham stimulation in patients with cognitive dysfunction. Subgroup analysis demonstrated that these effects were restricted to patients with post-stroke cognitive impairment but not Alzheimer's disease or Parkinson's disease. Furthermore, subthreshold stimulation also exhibited a significant improvement. The results suggest that iTBS may improve cognitive function in patients with cognitive dysfunction, although the quality of evidence remains low. Further studies with better methodological quality should explore the effects of iTBS on cognitive function. [ABSTRACT FROM AUTHOR]

BackgroundIntermittent Theta Burst Stimulation (iTBS), a non-invasive brain stimulation technique, is recognized for its ability to modulate cortical neuronal activity. However, its effects over time and the dynamics following stimulation are less well understood. Understanding the temporal dynamics of iTBS effects is essential for optimizing the timing and frequency of stimulation in therapeutic applications.ObjectiveThis study investigated the temporal changes in protein expression induced by iTBS in Neuro-2a cells.MethodsWe analyzed protein expression in retinoic acid-differentiated Neuro-2a cells at multiple time points — 0.5, 3, 6, 12, and 24 hours post-iTBS — using Western blot and immunocytochemistry techniques.ResultsOur findings reveal a significant early increase in neurotransmitter receptor subunits, neurotrophic factors, and cytoskeletal proteins within the first 0.5 hour following iTBS. Notably, proteins such as mGLuR1, NMDAR1, GABBR2, and β-tubulin III showed substantial increase in expression. However, the effects of iTBS on protein expression was not sustained at later timepoints.ConclusionOur results suggest that iTBS can transiently alter the expression of specific proteins in Neuro-2a cells. Future research should investigate the potential benefits of repeated stimulations within the early time window to refine iTBS interventions, potentially expanding their research and clinical applications.

Background: Stroke is a significant global cause of mortality and morbidity, and post-stroke cognitive impairment (PSCI) affects up to half of stroke patients. Despite the availability of pharmacological and non-pharmacological interventions, there is a lack of definitive effective treatments for PSCI. Non-invasive brain stimulation, particularly intermittent theta burst stimulation (iTBS), has emerged as a promising therapy for the treatment of PSCI. Objective: This systematic review and meta-analysis aimed to evaluate the efficacy and safety of iTBS in enhancing cognitive function among patients with PSCI. Methods: A comprehensive search was conducted across multiple databases, including PubMed, Web of Science, Scopus, Cochrane Library, and CNKI, to identify relevant randomized controlled trials published before April 2023. The primary outcome measured changes in global cognitive scales, while the secondary outcomes focused on improvements in attention, orientation, visual-spatial perception, and activities of daily living. Results: The meta-analysis encompassed six studies involving 325 patients. The results demonstrated that iTBS led to a significant improvement in global cognitive scales (SMD = 1.12, 95% CI = [0.59 to 1.65], P < 0.0001), attention (SMD = 0.48, 95% CI [0.13 to 0.82], P = 0.007), visual perception (SMD = 0.99, 95% CI [0.13 to 1.86], P = 0.02), and activities of daily living (SMD = 0.82, 95% CI [0.55 to 1.08], P < 0.00001). However, there was no significant effect on orientation (SMD = 0.36, 95% CI [− 0.04 to 0.76], P = 0.07). Subgroup analysis based on the number of sessions was conducted, revealing a significant improvement in global cognition among patients with PSCI across the three categories (10 sessions, 20 sessions, and 30 sessions) with no between-group difference (P = 0.28). None of the included studies reported any serious adverse effects. Conclusion: In conclusion, iTBS appears to be a safe and effective non-invasive treatment that can enhance the cognitive abilities and daily living skills of patients with post-stroke cognitive impairment. However, our conclusion is constrained by the limited number of studies. Further high-quality, large-sample RCTs with extended follow-up periods are necessary to validate these findings. Integrating iTBS with brain imaging techniques, such as functional near-infrared spectroscopy and functional magnetic resonance, could aid in understanding the mechanism of iTBS action. [ABSTRACT FROM AUTHOR]

Objective: We present the protocol of a feasibility randomised controlled trial (RCT) of intermittent theta burst stimulation (iTBS) for young people with anorexia nervosa (AN). Effective first‐line psychological therapies exist for young people with AN, but little is known about how to treat those who do not respond. Non‐invasive neuromodulation, such as iTBS, could address unmet treatment needs by targeting neurocircuitry associated with the development and/or maintenance of AN. Design: Sixty‐six young people (aged 13–30 years) with persistent AN will be randomly allocated to receive 20 sessions of real or sham iTBS over the left dorsolateral prefrontal cortex in addition to their usual treatment. Outcomes will be measured at baseline, post‐treatment (1‐month post‐randomisation) and 4‐months post‐randomisation (when unblinding will occur). Additional open follow‐ups will be conducted at 12‐ and 24‐months post‐randomisation. The primary feasibility outcome is the proportion of participants retained in the study at 4‐months. Secondary outcomes include AN symptomatology, other psychopathology, quality of life, service utilisation, neurocognitive processes, and neuroimaging measures. Discussion: Findings will inform the development of a future large‐scale RCT. They will also provide exploratory data on treatment efficacy, and neural and neurocognitive predictors and correlates of treatment response to iTBS in AN. HIGHLIGHTS: This paper presents a study protocol of a triple‐blind feasibility randomised controlled trial (RCT) with an open longer‐term follow‐up, using intermittent theta burst stimulation (iTBS) for young people with AN.It provides a clinical and scientific rationale for conducting a neuromodulation RCT in eating disorders.It is hoped that the findings will inform the development of a future large‐scale RCT investigating the clinical efficacy of iTBS for AN. [ABSTRACT FROM AUTHOR]

Objective: Poststroke cognitive impairment substantially affects patients' quality of life. This study explored the therapeutic efficacy of intermittent theta burst stimulation combined with cognitive training for poststroke cognitive impairment. Design: The experimental group received intermittent theta burst stimulation and cognitive training, whereas the control group only received cognitive training, both for 6 wks. The outcome measures were the Loewenstein Occupational Therapy Cognitive Assessment, modified Barthel Index, transcranial Doppler ultrasonography, and functional near-infrared spectroscopy. Results: After therapy, between-group comparisons revealed a substantial difference in the Loewenstein Occupational Therapy Cognitive Assessment scores (P = 0.024). Improvements in visuomotor organization and thinking operationswere more noticeable in the experimental group than in the other groups (P = 0.017 and P = 0.044, respectively). After treatment, the resistance index of the experimental group differed from that of the control group; channels 29, 37, and 41 were activated (P < 0.05). The active locations were the left dorsolateral prefrontal cortex, prefrontal polar cortex, and left Broca's region. Conclusions: Intermittent theta burst stimulation combinedwith cognitive training had a superior effect on improving cognitive function and everyday activities comparedwith cognitive training alone, notably in visuomotor organization and thinking operations. Intermittent theta burst stimulation may enhance cognitive performance by improving network connectivity. [ABSTRACT FROM AUTHOR]

Magnetic stimulation can noninvasively modulate the neuronal excitability through different stimulatory patterns. The present study hypothesized that trans-spinal magnetic stimulation with intermittent theta burst stimulatory pattern can modulate respiratory motor outputs in a pre-clinical rat model of cervical spinal cord injury. In vivo animal study. The effect of trans-spinal magnetic intermittent theta burst stimulation on diaphragmatic activity was assessed in adult rats with unilateral cervical spinal cord contusion at 2 weeks postinjury. The results demonstrated that unilateral cervical spinal cord contusion significantly attenuated the inspiratory activity and motor evoked potential of the diaphragm. Trans-spinal magnetic intermittent theta burst stimulation significantly increased the inspiratory activity of the diaphragm in cervical spinal cord contused rats. Inspiratory bursting was also recruited by trans-spinal magnetic intermittent theta burst stimulation in the rats without diaphragmatic activity after cervical spinal cord injury. In addition, trans-spinal magnetic intermittent theta burst stimulation is associated with increases in oxygen consumption and carbon dioxide production. These results suggest that trans-spinal magnetic intermittent theta burst stimulation can induce respiratory neuroplasticity. We propose that trans-spinal theta burst magnetic stimulation may be considered a potential rehabilitative strategy for improving the respiratory activity after cervical spinal cord injury. This will require future clinical study. [ABSTRACT FROM AUTHOR]

Intermittent theta burst stimulation (iTBS), a time-saving and cost-effective repetitive transcranial magnetic stimulation regime, has been shown to improve cognition in patients with Alzheimer's disease (AD). However, the specific mechanism underlying iTBS-induced cognitive enhancement remains unknown. Previous studies suggested that mitochondrial functions are modulated by magnetic stimulation. Here, we showed that iTBS upregulates the expression of iron-sulfur cluster assembly 1 (ISCA1, an essential regulatory factor for mitochondrial respiration) in the brain of APP/PS1 mice. In vivo and in vitro studies revealed that iTBS modulates mitochondrial iron-sulfur cluster assembly to facilitate mitochondrial respiration and function, which is required for ISCA1. Moreover, iTBS rescues cognitive decline and attenuates AD-type pathologies in APP/PS1 mice. The present study uncovers a novel mechanism by which iTBS modulates mitochondrial respiration and function via ISCA1-mediated iron-sulfur cluster assembly to alleviate cognitive impairments and pathologies in AD. We provide the mechanistic target of iTBS that warrants its therapeutic potential for AD patients. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is manifested by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and caudoputamen (Cp), leading to the development of motor and non-motor symptoms. The contribution of oxidative stress to the development and progression of PD is increasingly recognized. Experimental models show that strengthening antioxidant defenses and reducing pro-oxidant status may have beneficial effects on disease progression. In this study, the neuroprotective potential of intermittent theta burst stimulation (iTBS) is investigated in a 6-hydroxydopamine (6-OHDA)-induced PD model in rats seven days after intoxication which corresponds to the occurrence of first motor symptoms. Two-month-old male Wistar rats were unilaterally injected with 6-OHDA to mimic PD pathology and were subsequently divided into two groups to receive either iTBS or sham stimulation for 21 days. The main oxidative parameters were analyzed in the caudoputamen, substantia nigra pars compacta, and serum. iTBS treatment notably mitigated oxidative stress indicators, simultaneously increasing antioxidative parameters in the caudoputamen and substantia nigra pars compacta well after 6-OHDA-induced neurodegeneration process was over. Serum analysis confirmed the systemic effect of iTBS with a decrease in oxidative markers and an increase in antioxidants. Prolonged iTBS exerts a modulatory effect on oxidative/antioxidant parameters in the 6-OHDA-induced PD model, suggesting a potential neuroprotective benefit, even though at this specific time point 6-OHDA-induced oxidative status was unaltered. These results emphasize the need to further explore the mechanisms of iTBS and argue in favor of considering it as a therapeutic intervention in PD and related neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Abstract Background Intermittent theta burst stimulation (iTBS) when applied over the left dorsolateral prefrontal cortex (DLPFC) has been shown to be equally effective and safe to treat depression compared to traditional repetitive transcranial magnetic stimulation (rTMS) paradigms. This protocol describes a funded single-centre, double-blind, randomized placebo-controlled, clinical trial to investigate the antidepressive effects of iTBS and factors associated with an antidepressive response. Methods In this trial, outpatients (N = 96, aged 22–65 years) meeting the diagnostic criteria for at least moderate depression (Montgomery and Aasberg Depression Rating Scale score ≥ 20) will be enrolled prospectively and receive ten, once-a-day sessions of either active iTBS or sham iTBS to the left DLPFC, localized via a neuronavigation system. Participants may have any degree of treatment resistance. Prior to stimulation, participants will undergo a thorough safety screening and a brief diagnostic assessment, genetic analysis of brain-derived neurotropic factor, 5-HTTLPR and 5-HT1A, and cerebral MRI assessments. A selection of neuropsychological tests and questionnaires will be administered prior to stimulation and after ten stimulations. An additional follow-up will be conducted 4 weeks after the last stimulation. The first participant was enrolled on June 4, 2022. Study completion will be in December 2027. The project is approved by the Regional Ethical Committee of Medicine and Health Sciences, Northern Norway, project number 228765. The trial will be conducted according to Good Clinical Practice and published safety guidelines on rTMS treatment. Discussion The aims of the present trial are to investigate the antidepressive effect of a 10-session iTBS protocol on moderately depressed outpatients and to explore the factors that can explain the reduction in depressive symptoms after iTBS but also a poorer response to the treatment. In separate, but related work packages, the trial will assess how clinical, cognitive, brain imaging and genetic measures at baseline relate to the variability in the antidepressive effects of iTBS. Trial registration ClinicalTrials.gov NCT05516095. Retrospectively registered on August 25, 2022.

Abstract Background Recently, there has been an ongoing interest in the mechanism of intermittent theta burst stimulation (iTBS) in major depressive disorder. Studying the metabolite changes induced by iTBS may help to understand the mechanism. Methods Eleven participants with major depressive disorder received 10 days iTBS treatment. Magnetic resonance imaging (MRI) was used to target the region of the left dorsolateral prefrontal cortex (DLPFC) in each participant. We analyzed the effects of iTBS on metabolites using high-throughput profiling and assessed its impact on depressive symptoms. These analyses were considered exploratory, and no correction for multiple comparisons was applied. Results Among the 318 measured metabolites, a significant increase in cystine, asymmetric dimethylarginine (ADMA), 1-methylhistidine, indoleacetic acid (IAA), diethanolamine (DEA), dopa, riboflavin-5′-monophosphate (FMN), and a significant decrease in alphalinolenic acid (ALA), gamma-linolenic acid (GLA), serotonin, linoleic acid (LA) (p

Repetitive transcranial magnetic stimulation (rTMS) targeting the visual cortex (VC) has shown antidepressant effects for major depressive disorder (MDD) in sham-controlled trials, but comparisons with rTMS targeting the left dorsolateral prefrontal cortex (DLPFC) are lacking. We aimed to determine the non-inferiority of intermittent theta-burst stimulation (iTBS) over VC vs DLPFC for MDD. Participants randomly received navigated iTBS over the left V 1 or the left DLPFC twice daily for 14 days with a 3-month follow-up. The primary outcome was change in Hamilton Depression Rating Scale (HAMD-17) score from baseline to treatment end, with 2.5 points as the non-inferiority margin. Secondary outcomes included: improvement in Montgomery-Asberg Depression Rating Scale (MADRS), Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA); response and remission rates; suicidal ideation and adverse events. Of 75 randomized patients, 67 completed full treatment, including 52 first-episode patients and 15 relapsers. The primary outcome indicated the non-inferiority of VC (adjusted difference 1.14, lower 97.5 % CI −1.24; p =.002), confirmed by improvements in objective cognitive task and protein levels, as did most secondary outcomes. Reduced suicidal ideation after treatment, incidence of eye discomfort and pain score were lower in the VC group. Left VC iTBS has the potential to be non-inferior to DLPFC iTBS in most first-episode MDD in improving depressive symptoms and cognitive function, with less suicidal ideation and adverse events. Given the limited sample size, the lack of a sham control and the use of antidepressants, the findings should be interpreted with caution. • This is a randomized, double-blind, non-inferiority trial. • A newer stimulation model (iTBS) is performed twice a day for 14 consecutive days. • A precise positioning by neuro-navigation is performed. • The VC iTBS may be an effective treatment for MDD, with fewer adverse events. • Multifaceted objective measurements ensure the reliability of outcomes. [ABSTRACT FROM AUTHOR]

Background: Intermittent theta burst stimulation (iTBS) is a promising noninvasive therapy to restore the excitability of the cortex, and subsequently improve the function of the upper extremities. Several studies have demonstrated the effectiveness of iTBS in restoring upper limb function and modulating cortical excitability. We aimed to evaluate the effects of iTBS on upper limb motor recovery after stroke. Objective: The purpose of this article is to evaluate the influence of intermittent theta-burst stimulation on upper limb motor recovery and improve the quality of life. Method: A literature search was conducted using PubMed, EMBASE, MEDLINE, The Cochrane Library, Web of Science, and CBM, including only English studies, to identify studies that investigated the effects of iTBS on upper limb recovery, compared with sham iTBS used in control groups. Effect size was reported as standardized mean difference (SMD) or weighted mean difference (WMD). Results: Ten studies were included in the meta-analysis. The results of the metaanalysis indicated that when compared to the control group, the iTBS group had a significant difference in the Fugl-Meyer Assessment (FMA) and Action Research Arm Test (ARAT) (WMD: 3.20, 95% CI: 1.42 to 4.97; WMD: 3.72, 95% CI: 2.13 to 5.30, respectively). In addition, there was also a significant improvement in the modified Ashworth scale (MAS) compared to the sham group (WMD: -0.56; 95% CI: -0.85 to -0.28). More evidence is still needed to confirm the effect of Barthel Index (BI) scores after interventions. However, no significant effect was found for the assessment of Motor Evoked Potential (MEP) amplitude and MEP latency (SMD: 0.35; 95% CI: -0.21 to 0.90; SMD: 0.35, 95% CI: -0.18 to 0.87; SMD: 0.03, 95% CI: -0.49 to 0.55; respectively). Conclusion: Our results showed that iTBS significantly improved motor impairment, functional activities, and reduced muscle tone of upper limbs, thereby increasing the ability to perform Activities of Daily Living (ADL) in stroke patients, while there were no significant differences in MEPs. In conclusion, iTBS is a promising non-invasive brain stimulation as an adjunct to therapy and enhances the therapeutic effect of conventional physical therapy. In the future, more randomized controlled trials with large sample sizes, high quality, and follow-up are necessary to explore the neurophysiological effects. [ABSTRACT FROM AUTHOR]

Background: Upper limb motor recovery is one of the important goals of stroke rehabilitation. Intermittent theta burst stimulation (iTBS), a new type of repetitive transcranial magnetic stimulation (rTMS), is considered a potential therapy. However, there is still no consensus on the efficacy of iTBS for upper limb motor dysfunction after stroke. Stimulus dose may be an important factor affecting the efficacy of iTBS. Therefore, we aim to investigate and compare the effects and neural mechanisms of three doses of iTBS on upper limb motor recovery in stroke patients, and our hypothesis is that the higher the dose of iTBS, the greater the improvement in upper limb motor function. Methods: This prospective, randomized, controlled trial will recruit 56 stroke patients with upper limb motor dysfunction. All participants will be randomized in a 1:1:1:1 ratio to receive 21 sessions of 600 pulses active iTBS, 1,200 pulses active iTBS, 1,800 pulses active iTBS, or 1,800 pulses sham iTBS in addition to conventional rehabilitation training. The primary outcome is the Fugl-Meyer Assessment of the Upper Extremity (FMA-UE) score from baseline to end of intervention, and the secondary outcomes are the Wolf Motor Function Test (WMFT), Grip Strength (GS), Modified Barthel Index (MBI), and Stroke Impact Scale (SIS). The FMA-UE, MBI, and SIS are assessed pre-treatment, post-treatment, and at the 3-weeks follow-up. The WMFT, GS, and resting-state functional magnetic resonance imaging (rs-fMRI) data will be obtained pre- and post-treatment. Discussion: The iTBS intervention in this study protocol is expected to be a potential method to promote upper limb motor recovery after stroke, and the results may provide supportive evidence for the optimal dose of iTBS intervention. [ABSTRACT FROM AUTHOR]

Background: Intermittent theta burst stimulation (iTBS) when applied over the left dorsolateral prefrontal cortex (DLPFC) has been shown to be equally effective and safe to treat depression compared to traditional repetitive transcranial magnetic stimulation (rTMS) paradigms. This protocol describes a funded single-centre, double-blind, randomized placebo-controlled, clinical trial to investigate the antidepressive effects of iTBS and factors associated with an antidepressive response. Methods: In this trial, outpatients (N = 96, aged 22–65 years) meeting the diagnostic criteria for at least moderate depression (Montgomery and Aasberg Depression Rating Scale score ≥ 20) will be enrolled prospectively and receive ten, once-a-day sessions of either active iTBS or sham iTBS to the left DLPFC, localized via a neuronavigation system. Participants may have any degree of treatment resistance. Prior to stimulation, participants will undergo a thorough safety screening and a brief diagnostic assessment, genetic analysis of brain-derived neurotropic factor, 5-HTTLPR and 5-HT1A, and cerebral MRI assessments. A selection of neuropsychological tests and questionnaires will be administered prior to stimulation and after ten stimulations. An additional follow-up will be conducted 4 weeks after the last stimulation. The first participant was enrolled on June 4, 2022. Study completion will be in December 2027. The project is approved by the Regional Ethical Committee of Medicine and Health Sciences, Northern Norway, project number 228765. The trial will be conducted according to Good Clinical Practice and published safety guidelines on rTMS treatment. Discussion: The aims of the present trial are to investigate the antidepressive effect of a 10-session iTBS protocol on moderately depressed outpatients and to explore the factors that can explain the reduction in depressive symptoms after iTBS but also a poorer response to the treatment. In separate, but related work packages, the trial will assess how clinical, cognitive, brain imaging and genetic measures at baseline relate to the variability in the antidepressive effects of iTBS. Trial registration: ClinicalTrials.gov NCT05516095. Retrospectively registered on August 25, 2022. [ABSTRACT FROM AUTHOR]

Intermittent theta burst stimulation (iTBS), an emerging and highly efficient paradigm of repetitive transcranial magnetic stimulation (rTMS), has been demonstrated to mitigate cognitive impairment in Alzheimer's disease. Previous clinical studies have shown that the cognitive improvement of iTBS could last several weeks after treatment. Nonetheless, it is largely uncertain how the long-term effects of iTBS treatment are sustained. To investigate whether iTBS has a long-term effect on AD-type pathologies, 6-month-old APP/PS1 mice are administrated with 30 consecutive days of iTBS treatment. After a 2-month interval, morphological alterations in the brain are examined by immunohistochemistry and immunofluorescence staining, while levels of associated proteins are assessed by Western blot at the age of 9 months. We find that iTBS treatment significantly diminishes Aβ burden in the cerebral cortex and hippocampus of APP/PS1 mice. Moreover, we observe that iTBS treatment inhibits the expression of BACE1 and elevates the level of IDE, suggesting that the reduction of Aβ load could be attributed to the inhibition of Aβ production and facilitation of Aβ degradation. Furthermore, iTBS treatment attenuates neuroinflammation, neuronal apoptosis, and synaptic loss in APP/PS1 mice. Collectively, these data indicate that 1 month of iTBS treatment ameliorates pathologies in the brain of AD mice for at least 2 months. We provide the novel evidence that iTBS may exert after-effects on AD-type pathologies via inhibition of Aβ production and facilitation of Aβ degradation.

Objective: Intermittent theta-burst stimulation (iTBS), which is a form of repetitive transcranial magnetic stimulation (rTMS), can produce 600 pulses to the left dorsolateral prefrontal cortex (DLPFC) in a stimulation time of just over 3 min. The objective of this systematic review was to compare the safety and efficacy of iTBS and high-frequency (= 5 Hz) rTMS (HF-rTMS) for patients with treatment-resistant depression (TRD). Methods: Randomized controlled trials (RCTs) comparing the efficacy and safety of iTBS and HF-rTMS were identified by searching English and Chinese databases. The primary outcomes were study-defined response and remission. Results: Two RCTs (n = 474) investigating the efficacy and safety of adjunctive iTBS (n = 239) versus HF-rTMS (n = 235) for adult patients with TRD met the inclusion criteria. Among the two included studies (Jadad score = 5), all were classified as high quality. No group differences were found regarding the overall rates of response (iTBS group: 48.0% versus HF-rTMS group: 45.5%) and remission (iTBS group: 30.0% versus HF-rTMS group: 25.2%; all Ps > 0.05). The rates of discontinuation and adverse events such as headache were similar between the two groups (all Ps > 0.05). Conclusion: The antidepressant effects and safety of iTBS and HF-rTMS appeared to be similar for patients with TRD, although additional RCTs with rigorous methodology are needed. [ABSTRACT FROM AUTHOR]

• TMS measures of cortical excitability modulation are variable and unstable across time. • Significant facilitation was found only on the brain hemisphere where iTBS was applied. • Cortical-excitability modulation was stable and no associations were found between psychological factors and modulation. Transcranial Magnetic Stimulation (TMS) allows for cortical-excitability (CE) assessment and its modulation has been associated with neuroplasticity-like phenomena, thought to be impaired in neuropsychiatric disorders. However, the stability of these measures has been challenged, defying their potential as biomarkers. This study aimed to test the temporal stability of cortical-excitability modulation and study the impact of individual and methodological factors in determining within- and between-subject variability. We recruited healthy-subjects to assess motor cortex (MC) excitability modulation, collecting motor evoked potentials (MEP) from both hemispheres, before and after left-sided intermittent theta burst stimulation (iTBS), to obtain a measure of MEPs change (delta-MEPs). To assess stability across-time, the protocol was repeated after 6 weeks. Socio-demographic and psychological variables were collected to test association with delta-MEPs. We found modulatory effects on left MC and not on right hemisphere following iTBS of left MC. Left delta-MEP was stable across-time when performed immediately after iTBS (ICC = 0.69), only when obtained first in left hemisphere. We discovered similar results in a replication cohort testing only left MC (ICC = 0.68). No meaningful associations were found between demographic and psychological factors and delta-MEPs. Delta-MEP is stable immediately after modulation and not impacted by different individual factors, including expectation about TMS-effect. Motor cortex excitability modulation immediately after iTBS should be further explored as a potential biomarker for neuropsychiatric diseases. [ABSTRACT FROM AUTHOR]

Background: Recently, there has been an ongoing interest in the mechanism of intermittent theta burst stimulation (iTBS) in major depressive disorder. Studying the metabolite changes induced by iTBS may help to understand the mechanism. Methods: Eleven participants with major depressive disorder received 10 days iTBS treatment. Magnetic resonance imaging (MRI) was used to target the region of the left dorsolateral prefrontal cortex (DLPFC) in each participant. We analyzed the effects of iTBS on metabolites using high-throughput profiling and assessed its impact on depressive symptoms. These analyses were considered exploratory, and no correction for multiple comparisons was applied. Results: Among the 318 measured metabolites, a significant increase in cystine, asymmetric dimethylarginine (ADMA), 1-methylhistidine, indoleacetic acid (IAA), diethanolamine (DEA), dopa, riboflavin-5′-monophosphate (FMN), and a significant decrease in alphalinolenic acid (ALA), gamma-linolenic acid (GLA), serotonin, linoleic acid (LA) (p < 0.05) were detected in the patients after iTBS treatment. In Pearson correlation analysis, the plasma levels of LA, FMN and ADMA at baseline were significantly related to the reduction rate of the 17‐item Hamilton Depression Rating Scale and the Patient Health Questionnaire-9 scores (p < 0.05). Conclusions: Our study highlights that LA, FMN, ADMA and their relationship with oxidative stress, may be key factors in the antidepressant efficacy of iTBS. [ABSTRACT FROM AUTHOR]

Parkinson’s disease (PD) is manifested by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and caudoputamen (Cp), leading to the development of motor and non-motor symptoms. The contribution of oxidative stress to the development and progression of PD is increasingly recognized. Experimental models show that strengthening antioxidant defenses and reducing pro-oxidant status may have beneficial effects on disease progression. In this study, the neuroprotective potential of intermittent theta burst stimulation (iTBS) is investigated in a 6-hydroxydopamine (6-OHDA)-induced PD model in rats seven days after intoxication which corresponds to the occurrence of first motor symptoms. Two-month-old male Wistar rats were unilaterally injected with 6-OHDA to mimic PD pathology and were subsequently divided into two groups to receive either iTBS or sham stimulation for 21 days. The main oxidative parameters were analyzed in the caudoputamen, substantia nigra pars compacta, and serum. iTBS treatment notably mitigated oxidative stress indicators, simultaneously increasing antioxidative parameters in the caudoputamen and substantia nigra pars compacta well after 6-OHDA-induced neurodegeneration process was over. Serum analysis confirmed the systemic effect of iTBS with a decrease in oxidative markers and an increase in antioxidants. Prolonged iTBS exerts a modulatory effect on oxidative/antioxidant parameters in the 6-OHDA-induced PD model, suggesting a potential neuroprotective benefit, even though at this specific time point 6-OHDA-induced oxidative status was unaltered. These results emphasize the need to further explore the mechanisms of iTBS and argue in favor of considering it as a therapeutic intervention in PD and related neurodegenerative diseases.

Suicidal ideation is a serious symptom of major depressive disorder (MDD). Intermittent theta burst stimulation (iTBS) is a safe, effective brain stimulation treatment for alleviating suicidal ideation in adults with MDD. This study aimed to examine the clinical efficacy of iTBS on reducing suicidal ideation in adolescent MDD with suicide attempt. In a randomized, sham-controlled protocol, a total of 10 sessions of iTBS was administrated to the left dorsolateral prefrontal cortex (DLPFC) in patients once a day for two weeks. The suicidal ideation and depressive symptoms were assessed using Beck Scale for Suicide Ideation-Chinese Version (BSI-CV), Hamilton Rating Scale for Depression (HAMD-24), and Self-rating Depression Scale (SDS) at baseline and after 10 treatment sessions. Forty-five patients were randomized assigned to either active iTBS (n = 23) or sham group (n = 22). The suicidal ideation and depressive symptoms of the active iTBS group were significantly ameliorated over 2 weeks of treatment. Further, higher baseline SDS, HAMD-24 and BSI-CV scores in the active iTBS group were associated with greater reductions. A larger sample size and double-blinded clinical trial should be conducted to verify the reliability and reproducibility. The current study suggested that daily iTBS of the left DLPFC for 2 weeks could effectively and safely alleviate suicidal ideation and mitigate depression in adolescent MDD, especially for individuals with relatively more severe symptoms. Although caution is warranted, the findings could provide further evidence for the effectiveness and safety of iTBS in clinical practice. • After daily iTBS of the left DLPFC for 2 weeks treatment, the suicidal ideation and depressive symptoms were significantly ameliorated in the active iTBS group compared with the sham group. • The improvement in the SDS, HAMD-24 and BSI-CV scores (pre-iTBS minus post-iTBS) were markedly greater in the active iTBS group. • The alleviating efficacy was more effective among adolescent patients with more severe symptoms. [ABSTRACT FROM AUTHOR]

Objective: Neurocognitive dysfunction is thought to be one of the core clinical features of schizophrenia, and older adults with schizophrenia exhibited greater overall cognitive deficits than younger adults. The aim of this systematic review was to examine the neurocognitive effects of intermittent theta burst stimulation (iTBS) as an adjunctive treatment for older adults suffering from schizophrenia. Methods: Randomized double-blinded controlled trials (RCTs) investigating the neurocognitive effects of adjunctive active iTBS versus sham iTBS in older adults with schizophrenia were systematically identified by independent investigators searching Chinese and English databases. Results: Two double-blinded RCTs (n = 132) compared the neurocognitive effects of adjunctive active iTBS (n = 66) versus sham iTBS (n = 66) in patients that fulfilled the inclusion criteria of this systematic review and were analyzed. One RCT found significant superiority of active iTBS over sham iTBS in improving neurocognitive performance in older adults with schizophrenia. In the other RCT, the findings on the neurocognitive effects of iTBS as measured by three different measurement tools were inconsistent. The dropout rate was reported in the two RCTs, ranging from 3.8% (3/80) to 7.7% (4/52). Conclusion: There is preliminary evidence that adjunctive iTBS may have some beneficial effects in the treatment of neurocognitive function in older patients with schizophrenia. Future RCTs with larger sample sizes focusing on the neurocognitive effects of adjunctive iTBS in older adults with schizophrenia are warranted to verify these findings. [ABSTRACT FROM AUTHOR]

Introduction: Executive function deficits (EFD) in late life depression (LLD) are associated with poor outcomes. Dysfunction of the cognitive control network (CCN) has been posited in the pathophysiology of LLD with EFD. Methods: Seventeen older adults with depression and EFD were randomized to iTBS or sham for 6 weeks. Intervention was delivered bilaterally using a recognized connectivity target. Results: A total of 89% (17/19) participants completed all study procedures. No serious adverse events occurred. Pre to post-intervention change in mean Montgomery-Asberg-depression scores was not different between iTBS or sham, p = 0.33. No significant group-by-time interaction for Montgomery-Asberg Depression rating scale scores (F3, 44 = 0.51; p = 0.67) was found. No significant differences were seen in the effects of time between the two groups on executive measures: Flanker scores (F1, 14 = 0.02, p = 0.88), Dimensional-change-card-sort scores F1, 14 = 0.25, p = 0.63, and working memory scores (F1, 14 = 0.98, p = 0.34). The Group-by-time interaction effect for functional connectivity (FC) within the Fronto-parietal-network was not significant (F1, 14 = 0.36, p = 0.56). No significant difference in the effect-of-time between the two groups was found on FC within the Cingulo-opercular-network (F1, 14 = 0, p = 0.98). Conclusion: Bilateral iTBS is feasible in LLD. Preliminary results are unsupportive of efficacy on depression, executive function or target engagement of the CCN. A future Randomized clinical trial requires a larger sample size with stratification of cognitive and executive variables and refinement in the target engagement. [ABSTRACT FROM AUTHOR]

Mind wandering (MW) is the intentional or unintentional experience of attending to internal task-unrelated thoughts while being occupied with an external task. Even though maintaining task focus is assumed to require executive functions (EF), it is not clear how and to what extent MW and EF interact. Research has found that activity in the dorsolateral prefrontal cortex (DLPFC) is associated with EF and MW. To understand the causal role of the DLPFC in relation to MW and EF, researchers have turned to non-invasive brain stimulation. Thus far, most studies have used transcranial direct current stimulation, but the results have been inconclusive. To further elucidate the relationship between the DLPFC, EF and MW, we conducted a pre-registered, sham-controlled, triple-blinded within-subject experiment by combining intermittent theta burst stimulation (iTBS) interleaved with a recently developed MW-EF task. In contrast to our expectations, participants reported significantly more MW following real iTBS as compared to sham stimulation. However, at the same time, psychomotor precision and EF improved, indicating that participants were able to engage in resource-intensive MW while simultaneously performing well on the task. We argue that iTBS enhanced the underlying executive resources that could be used to increase both MW and task performance in line with the resource-control view of MW. This finding opens exciting avenues for studying the complex interplay between MW and EF and provides empirical support for the utility of iTBS in improving executive performance during a demanding cognitive task. • Magnetic stimulation applied over the left prefrontal cortex, increased mind wandering. • Stimulation also improved executive performance and psychomotor precision. • The study was pre-registered, triple-blind and sham-controlled. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is associated with cognitive impairments that persist despite successful treatment. Transcranial magnetic stimulation is a noninvasive treatment for MDD that is associated with small procognitive effects on working memory and executive function. We hypothesized that pairing stimulation with N-methyl-D-aspartate (NMDA) receptor agonism would enhance the effects of stimulation and its procognitive effects.The effect of NMDA receptor agonism (D-cycloserine, 100 mg) on cognitive performance was tested in two randomized double-blind placebo-controlled trials: (1) acute effects of in the absence of stimulation (n = 20 healthy participants) and (2) a treatment study of individuals with MDD (n = 50) randomized to daily intermittent theta-burst stimulation (iTBS) with placebo or D-cycloserine for 2 weeks. Cognitive function was measured using the THINC-it battery, comprised of the Perceived Deficits Questionnaire, the Choice Reaction Time, the Trail Making Test, the Digit Symbol Substitution Test, and the 1-Back tests.D-cycloserine had no acute effect on cognition compared to placebo. iTBS + D-cycloserine was associated with significant improvements in subjective cognitive function and correct responses on the 1-Back when compared to iTBS + placebo. Improvements in subjective cognition paralleled depressive symptoms improvement, however 1-Back improvements were not attributable to improvement in depression.An intersectional strategy pairing iTBS with NMDA receptor agonism may restore cognitive function in MDD. [ABSTRACT FROM AUTHOR]

Introduction: Intermittent theta-burst stimulation (iTBS) is a non-invasive brain stimulation paradigm that has demonstrated promising therapeutic benefits for a variety of neuropsychiatric disorders. It has recently garnered widespread favor among researchers and clinicians, owing to its comparable potentiation effects as conventional high-frequency repetitive transcranial magnetic stimulation (rTMS), but administered in a much shorter time frame. However, there is still a lack of agreement over the optimal stimulation intensity, particularly when targeting the prefrontal regions. The objective of this study was to systematically investigate the influence of different stimulation intensities of iTBS, applied over the left dorsolateral prefrontal cortex (DLPFC), on brain activity and executive function in healthy adults. Methods: Twenty young healthy adults were enrolled in this randomized cross-over experiment. All participants received a single session iTBS over the left DLPFC at intensities of 50, 70, or 100% of their individual resting motor threshold (RMT), each on separate visits. Functional nearinfrared spectroscopy (fNIRS) was used to measure changes of hemoglobin concentrations in prefrontal areas during the verbal fluency task (VFT) before and after stimulation. Results: After stimulation, iTBS to the left DLPFC with 70% RMT maintained the concentration change of oxyhemoglobin (HbO) in the target area during the VFT. In contrast, 50% [t.17/= 2.203, P = 0.042, d = 0.523] and 100% iTBS [t.17/ = 2.947, P = 0.009, d = 0.547] significantly decreased change of HbO concentration, indicating an inverse U-shape relationship between stimulation intensity and prefrontal hemodynamic response in healthy young adults. Notably, improved VFT performance was only observed after 70% RMT stimulation [t.17/ = 2.511, P = 0.022, d = 0.592]. Moreover, a significant positive correlation was observed between task performance and the difference in HbO concentration change in the targeted area after 70% RMT stimulation (r = 0.496, P = 0.036) but not after 50 or 100% RMT stimulation. Conclusion: The linear relationship between stimulation intensity and behavioral outcomes reported in previous conventional rTMS studies may not be translated to iTBS. Instead, iTBS at 70% RMT may be more efficacious than 100% RMT. [ABSTRACT FROM AUTHOR]

Objective: To explore the effects of intermittent theta pulse stimulation (i TBS) combined with aerobic exercise training on glucose and lipid metabolism, cognitive function and auditory evoked potential P300 in elderly patients with type 2 diabetes mellitus (T2DM) and mild cognitive impairment (MCI) . Methods: A total of 117 elderly patients with T2DM and MCI who came to our hospital for treatment from March 2020 to November 2021 were selected. According to the random number table method, they were divided into the control group (aerobic exercise training, 58 cases) and the observation group (i TBS combined with aerobic exercise training, 59 cases). The changes of glucose and lipid metabolism, cognitive function and auditory evoked potential P300 in the two groups were observed before and after the intervention. Results: Fasting blood glucose (FBG) and glycosylated hemoglobin (HbA1c) in the observation group were lower than those in the control group after intervention (P<0.05). After the intervention, there was no statistical difference in total cholesterol (TC), triacylglycerol (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) between the two groups (P>0.05 ). After the intervention, the Montreal scale (MoCA) and the total score of the observation group were higher than those of the control group (P<0.05). After intervention, the latency of the central zone (Cz) and the top zone (Pz) of the observation group were shorter than those of the control group, and the amplitudes of Cz and Pz were higher than those of the control group (P<0.05). Conclusion: i TBS combined with aerobic exercise training for elderly patients with T2DM and MCI can effectively reduce blood sugar, improve cognitive function and auditory evoked potential P300. [ABSTRACT FROM AUTHOR]

Aims: Limited understanding of neurobiological mechanisms of repetitive transcranial magnetic stimulation (rTMS) prevents us from choosing optimal therapeutic regimen for patients to improve therapeutic efficiency. Resting-state functional magnetic resonance imaging (rs-fMRI) has been demonstrated to obtain comparable functional readouts across species., Methods: Intermittent and continuous theta burst stimulation were used to stimulate ipsilesional and contralesional hemisphere, respectively, during the subacute phase after stroke. We used a rat middle cerebral artery occlusion stroke model. The amplitude of low-frequency fluctuations and functional connectivity analyses of rs-fMRI were chosen to detect neuron activity and functional connectivity. The expression of neuron activation marker c-Fos and axonal plasticity marker GAP43 was examined by an immunochemistry method to corroborate the results of rs-fMRI., Results: iTBS altered the long-term neuronal activity in bilateral sensorimotor cortex, whereas cTBS influenced immediate neuronal activity of bilateral sensorimotor cortex. In addition, cTBS enhanced interhemispheric and intrahemisheric functional connectivity in contralesional hemisphere, accompanied by axonal and dendritic remodeling in the perilesional cortical areas and contralesional homologous areas after large stroke., Conclusion: rTMS exerted complex effects on brain structural and functional connectivity in addition to affecting cortical excitability. cTBS promoted the compensatory effect of contralesional hemisphere after stroke with large lesions., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Background: Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive tool commonly used to drive neural plasticity in the young adult and aged brain. Recent data from mouse models have shown that even at subthreshold intensities (0.12 T), rTMS can drive neuronal and glial plasticity in the motor cortex. However, the physiological mechanisms underlying subthreshold rTMS induced plasticity and whether these are altered with normal ageing are unclear. Objective: To assess the effect of subthreshold rTMS, using the intermittent theta burst stimulation (iTBS) protocol on structural synaptic plasticity in the mouse motor cortex of young and aged mice. Methods: Longitudinal in vivo 2-photon microscopy was used to measure changes to the structural plasticity of pyramidal neuron dendritic spines in the motor cortex following a single train of subthreshold rTMS (in young adult and aged animals) or the same rTMS train administered on 4 consecutive days (in young adult animals only). Data were analysed with Bayesian hierarchical generalized linear regression models and interpreted with the aid of Bayes Factors (BF). Results: We found strong evidence (BF > 10) that subthreshold rTMS altered the rate of dendritic spine losses and gains, dependent on the number of stimulation sessions and that a single session of subthreshold rTMS was effective in driving structural synaptic plasticity in both young adult and aged mice. Conclusion: These findings provide further evidence that rTMS drives synaptic plasticity in the brain and uncovers structural synaptic plasticity as a key mechanism of subthreshold rTMS induced plasticity.

Background: Intermittent theta burst stimulation (iTBS) is a newer form of repetitive transcranial magnetic stimulation (rTMS) for patients with treatment resistant depression (TRD). Applying multiple daily iTBS sessions may enable patients to achieve remission more rapidly. Objective: We compared the efficacy and tolerability of a twice-daily versus once-daily iTBS protocol in patients with TRD. We hypothesized that twice-daily iTBS would result in a greater improvement in depression scores compared to once-daily iTBS. Methods: 208 participants (131 females) with TRD were randomized to receive either iTBS (600 pulses) delivered twice-daily with a 54-min interval between treatments or once-daily (1200 pulses) with 1 sham treatment with the same interval between treatments, to ensure equal levels of daily therapeutic contact and blinding of patients and raters. The primary outcome measure was change in depression scores on the Hamilton Rating Scale for Depression (HRSD-17) after 10 days of treatment and 30 days of treatments. Results: HRSD-17 scores improved in both the twice-daily and once-daily iTBS groups; however, these improvements did not significantly differ between the two groups at either the 10-day or 30-day timepoints. Response and remission rates were low (

IntroductionIntermittent theta-burst stimulation (iTBS) is a non-invasive brain stimulation paradigm that has demonstrated promising therapeutic benefits for a variety of neuropsychiatric disorders. It has recently garnered widespread favor among researchers and clinicians, owing to its comparable potentiation effects as conventional high-frequency repetitive transcranial magnetic stimulation (rTMS), but administered in a much shorter time frame. However, there is still a lack of agreement over the optimal stimulation intensity, particularly when targeting the prefrontal regions. The objective of this study was to systematically investigate the influence of different stimulation intensities of iTBS, applied over the left dorsolateral prefrontal cortex (DLPFC), on brain activity and executive function in healthy adults.MethodsTwenty young healthy adults were enrolled in this randomized cross-over experiment. All participants received a single session iTBS over the left DLPFC at intensities of 50, 70, or 100% of their individual resting motor threshold (RMT), each on separate visits. Functional near-infrared spectroscopy (fNIRS) was used to measure changes of hemoglobin concentrations in prefrontal areas during the verbal fluency task (VFT) before and after stimulation.ResultsAfter stimulation, iTBS to the left DLPFC with 70% RMT maintained the concentration change of oxyhemoglobin (HbO) in the target area during the VFT. In contrast, 50% [t(17) = 2.203, P = 0.042, d = 0.523] and 100% iTBS [t(17) = 2.947, P = 0.009, d = 0.547] significantly decreased change of HbO concentration, indicating an inverse U-shape relationship between stimulation intensity and prefrontal hemodynamic response in healthy young adults. Notably, improved VFT performance was only observed after 70% RMT stimulation [t(17) = 2.511, P = 0.022, d = 0.592]. Moreover, a significant positive correlation was observed between task performance and the difference in HbO concentration change in the targeted area after 70% RMT stimulation (r = 0.496, P = 0.036) but not after 50 or 100% RMT stimulation.ConclusionThe linear relationship between stimulation intensity and behavioral outcomes reported in previous conventional rTMS studies may not be translated to iTBS. Instead, iTBS at 70% RMT may be more efficacious than 100% RMT.

The present study aims to investigate the efficacy of intermittent theta burst stimulation (iTBS) on post-stroke dysphagia and its effect on the motor cortical excitability of the suprahyoid muscle. A total of 40 patients with post-stroke dysphagia were randomly divided into the iTBS and the sham stimulation groups, with the conduction of motor cortical iTBS and sham stimulation of the supraglottal muscle on the affected side, respectively. Swallowing function was assessed before (T0), immediately after (T1), and two weeks after (T2) cessation of the intervention using the water-swallowing test (WST), standard swallowing assessment (SSA), Murray secretion scale (MSS), and Penetration–Aspiration Scale (PAS). The bilateral motor evoked potentials (MEP) of the suprahyoid muscle were recorded. After the intervention, the PAS, WST, SSA, and MSS scores were significantly improved in both groups (p < 0.05). The iTBS group showed a greater change in the PAS score than the sham stimulation group at T1 (p < 0.05) and a greater change in the WST and MSS scores at T2 (p < 0.05). The amplitude of the MEP wave of the suprahyoid muscle in the affected hemisphere was significantly higher in the iTBS group at T1 and in the healthy hemisphere at T2 (p < 0.05). The feasibility of applying iTBS to the affected hemisphere for the treatment of post-stroke dysphagia was directly analyzed for the first time. ITBS combined with conventional swallowing therapy could be adopted as a rehabilitation strategy to improve post-stroke dysphagia. [ABSTRACT FROM AUTHOR]

Anxiety disorders are among the most common mental disorders. Treatment guidelines recommend pharmacotherapy and cognitive behavioral therapy as standard treatment. Although cognitive behavioral therapy is an effective therapeutic approach, not all patients benefit sufficiently from it. In recent years, non-invasive brain stimulation techniques, such as transcranial magnetic stimulation, have been investigated as promising adjuncts in the treatment of affective disorders. The aim of this study is to investigate whether a combination of intermittent theta burst stimulation (iTBS) and virtual reality exposure therapy leads to a significantly greater reduction in acrophobia than virtual reality exposure with sham stimulation. In this randomized double-blind placebo-controlled study, 43 participants with acrophobia received verum or sham iTBS over the left dorsolateral prefrontal cortex prior to two sessions of virtual reality exposure therapy. Stimulation of the left dorsolateral prefrontal cortex with iTBS was motivated by an experimental study showing a positive effect on extinction memory retention. Acrophobic symptoms were assessed using questionnaires and two behavioral approach tasks one week before, after treatment and six months after the second diagnostic session. The results showed that two sessions of virtual reality exposure therapy led to a significant reduction in acrophobic symptoms, with an overall remission rate of 79 %. However, there was no additional effect of iTBS of the left dorsolateral prefrontal cortex on the therapeutic effects. Further research is needed to determine how exactly a combination of transcranial magnetic stimulation and exposure therapy should be designed to enhance efficacy. • Two sessions of virtual reality exposure therapy led to a significant reduction in acrophobic symptoms. • The overall remission rate at follow-up was 79 %. • Intermittent theta burst stimulation over the left dorsolateral prefrontal cortex showed no additional effect. • The expectancy of being in the verum iTBS group was a predictor of short-term treatment response. [ABSTRACT FROM AUTHOR]

Background: Intermittent theta burst stimulation (iTBS) is known to improve cognitive impairment caused by Alzheimer's disease and Parkinson's disease, but studies are lacking with respect to the efficacy of iTBS on poststroke cognitive impairment (PSCI). Objective: This study was conducted to investigate the effect of left dorsolateral prefrontal cortex (DLPFC) iTBS on improving cognitive function in stroke patients. Methods: Fifty‐eight patients with PSCI are randomly divided into iTBS (n = 28) and sham stimulation groups (n = 30). Both groups receive routine cognitive‐related rehabilitation. The iTBS group is treated with iTBS intervention of the left DLPFC, and the sham stimulation group is treated with the same parameters at the same site for 2 weeks. Outcome measures are assessed at baseline (T0) and immediately after the last intervention (T1) by mini‐mental state examination (MMSE), Oxford cognitive screen, and event‐related potential P300. Results: There are no differences in baseline clinical characteristics between the two groups. After intervention, the MMSE scores and P300 amplitude increase significantly for both groups, and the P300 incubation period reduces significantly. The change value of the iTBS group is significantly higher than that of sham stimulation group (p <.05). Compared with the sham stimulation group, the iTBS group has more significant changes in semantic comprehension and executive function (p <.05). Conclusion: iTBS can effectively and safely improve overall cognitive impairment in stroke patients, including semantic understanding and executive function, and it also has a positive impact on memory function. Future randomized controlled studies with large samples and long‐term follow‐up should be conducted to further validate the results of the present study [ABSTRACT FROM AUTHOR]

Neurodegeneration implies progressive neuronal loss and neuroinflammation further contributing to pathology progression. It is a feature of many neurological disorders, most common being Alzheimer's disease (AD). Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive stimulation which modulates excitability of stimulated brain areas through magnetic pulses. Numerous studies indicated beneficial effect of rTMS in several neurological diseases, including AD, however, exact mechanism are yet to be elucidated. We aimed to evaluate the effect of intermittent theta burst stimulation (iTBS), an rTMS paradigm, on behavioral, neurochemical and molecular level in trimethyltin (TMT)-induced Alzheimer's-like disease model. TMT acts as a neurotoxic agent targeting hippocampus causing cognitive impairment and neuroinflammation, replicating behavioral and molecular aspects of AD. Male Wistar rats were divided into four experimental groups–controls, rats subjected to a single dose of TMT (8 mg/kg), TMT rats subjected to iTBS two times per day for 15 days and TMT sham group. After 3 weeks, we examined exploratory behavior and memory, histopathological and changes on molecular level. TMT-treated rats exhibited severe and cognitive deficit. iTBS-treated animals showed improved cognition. iTBS reduced TMT-induced inflammation and increased anti-inflammatory molecules. We examined PI3K/Akt/mTOR signaling pathway which is involved in regulation of apoptosis, cell growth and learning and memory. We found significant downregulation of phosphorylated forms of Akt and mTOR in TMT-intoxicated animals, which were reverted following iTBS stimulation. Application of iTBS produces beneficial effects on cognition in of rats with TMT-induced hippocampal neurodegeneration and that effect could be mediated via PI3K/Akt/mTOR signaling pathway, which could candidate this protocol as a potential therapeutic approach in neurodegenerative diseases such as AD. [ABSTRACT FROM AUTHOR]

Background: The recovery of balance function is a critical segment in the rehabilitation treatment of stroke. The cerebellum is considered as the key structure involved in balance and motor control. The cerebellar vermis plays an important role in integrating vision, proprioception, and sensory skin input and may be a candidate stimulation target for regulating the motor network related with balance. However, evidence that the intermittent theta burst stimulation (iTBS) of cerebellar vermis can promote the recovery of balance function after stroke remains insufficient. Therefore, this study aims to explore the efficacy of the cerebellar vermis iTBS for the treatment of balance function in patients with stroke. Methods and Analysis: Forty patients with stroke will be recruited in this prospective, randomized, sham-controlled trial. Participants will be randomized in a 1:1 ratio to receive either 15 sessions of cerebellar vermis iTBS (600 pulses) or sham stimulation. Additionally, a routine rehabilitation therapy follows the intervention. The primary outcome is the Berg Balance Scale, and the secondary outcomes are the Fugl–Meyer assessment of the lower extremity and modified Barthel index. The above outcomes will be assessed before intervention and at the end of each week. Pre- and post-iTBS resting-state functional magnetic resonance imaging (rs-fMRI) will be acquired, and the regional homogeneity, fractional amplitude of low-frequency fluctuation and functional connectivity will be calculated and analyzed. Discussion: This protocol holds promise as a potential method to improve balance function in patients with stroke. If the outcomes of patients improve after the intervention, the study will provide new insights into improving balance function. Ethics and Dissemination: This study has been approved by the Medical Research Ethics Committee of Wuxi Mental Health Center (Wuxi Tongren Rehabilitation Hospital). Results will be disseminated through (open-access) peer-reviewed publications, networks of scientists, professionals, and the public and presented at conferences. Clinical Trial Registration Number: www.chictr.org.cn, identifier ChiCTR2100052590. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether a four-week course of neuronavigated intermittent theta burst stimulation (iTBS) of the left dorsolateral prefrontal cortex is superior to the non-neuronavigated F3-EEG method of positioning. Methods: We conducted a single-center, two-arm, randomized and double-blinded study (clinicaltrials.gov NCT03953521). 37 inpatients with an at least moderate depressive episode were randomized to receive either neuronavigated or 10-20-EEG-system based F3 guided iTBS. Both groups received twenty week daily sessions of iTBS while continuing to receive standard-of-care treatment by their ward physicians. For navigated iTBS, we used magnetic resonance imaging to target the border between the anterior and middle third of the middle frontal gyrus considered to represent the left dorsolateral prefrontal cortex (lDLPFC).Differences in the treatment arms were blinded by completely mimicking the procedures of the respective other treatment group. Rating physicians were not involved in the treatment procedure.Primary outcome was defined as the change of the 21-item version of the Hamilton Depression Score (HAMD) from baseline to end of treatment at week 4. Secondary outcomes included HAMD score during the treatment, Patient Health Questionnaire-9, WHO Quality of Life-BREF and Clinical Global Impression. For primary outcome, we used a planned group comparison for the absolute change in the HAMD. For secondary outcome measures we calculated analyses of variance (ANOVAs) with the within-subjects factor time (primary: baseline vs. week 4; secondary: all visits) and the between-subjects factor group (navigated vs. F3 guided group). We also did planned contrasts between both groups for all variables and all treatment and follow-up visits with the aim not to oversee any group differences. For group contrasts we used Student T-tests for metric and chi-square tests for categorial variables. Significance threshold was set to 5% uncorrected for multiple comparisons. Results: Enrolment of 80 patients with interim analysis was planned. Interim analysis was performed after 37 patients (intention to treat). 6 patients dropped out, leaving 31 for analysis. With respect to primary outcome criteria, absolute change in the HAMD did not differ significantly between groups. In accordance, relative change and number of responders and remitters were not significantly different. Overall number of responders was 53% and of remitters was 60%. On a descriptive level, the results favor the clinical effects of the F3 group for the absolute and relative change in the HAMD and the number of responders. Number of remitters were exactly the same for both groups. Therefore, we decided to stop the trial due to the added burden of magnetic resonance imaging and neuronavigated treatment in relation to the effect. Secondary outcomes did also not differ significantly between groups. Patients did not differ in their baseline characteristics nor with respect to intake of medication during the trial period and all had access to the same therapeutic interventions. Conclusion: We noticed a high antidepressive effect of add-on iTBS treatment to standard inpatient treatment but failed to demonstrate a clinical superiority of neuronavigated localization. The non-navigated, F3 guided iTBS treatment used as a control group may be sophisticated enough to dilute potential added benefits, and the difference between the localization approaches is either negligible or too small to justify the additional efforts of navigation. The effects of concomitant treatment may mask effects, but our patient population reflects clinical reality in an inpatient setting. Further prospective studies are warranted to compare neuronavigated with surface-based approaches.

Abstract Background Intermittent theta burst stimulation (iTBS) is known to improve cognitive impairment caused by Alzheimer's disease and Parkinson's disease, but studies are lacking with respect to the efficacy of iTBS on poststroke cognitive impairment (PSCI). Objective This study was conducted to investigate the effect of left dorsolateral prefrontal cortex (DLPFC) iTBS on improving cognitive function in stroke patients. Methods Fifty‐eight patients with PSCI are randomly divided into iTBS (n = 28) and sham stimulation groups (n = 30). Both groups receive routine cognitive‐related rehabilitation. The iTBS group is treated with iTBS intervention of the left DLPFC, and the sham stimulation group is treated with the same parameters at the same site for 2 weeks. Outcome measures are assessed at baseline (T0) and immediately after the last intervention (T1) by mini‐mental state examination (MMSE), Oxford cognitive screen, and event‐related potential P300. Results There are no differences in baseline clinical characteristics between the two groups. After intervention, the MMSE scores and P300 amplitude increase significantly for both groups, and the P300 incubation period reduces significantly. The change value of the iTBS group is significantly higher than that of sham stimulation group (p

Neurodegeneration implies progressive neuronal loss and neuroinflammation further contributing to pathology progression. It is a feature of many neurological disorders, most common being Alzheimer’s disease (AD). Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive stimulation which modulates excitability of stimulated brain areas through magnetic pulses. Numerous studies indicated beneficial effect of rTMS in several neurological diseases, including AD, however, exact mechanism are yet to be elucidated. We aimed to evaluate the effect of intermittent theta burst stimulation (iTBS), an rTMS paradigm, on behavioral, neurochemical and molecular level in trimethyltin (TMT)-induced Alzheimer’s-like disease model. TMT acts as a neurotoxic agent targeting hippocampus causing cognitive impairment and neuroinflammation, replicating behavioral and molecular aspects of AD. Male Wistar rats were divided into four experimental groups–controls, rats subjected to a single dose of TMT (8 mg/kg), TMT rats subjected to iTBS two times per day for 15 days and TMT sham group. After 3 weeks, we examined exploratory behavior and memory, histopathological and changes on molecular level. TMT-treated rats exhibited severe and cognitive deficit. iTBS-treated animals showed improved cognition. iTBS reduced TMT-induced inflammation and increased anti-inflammatory molecules. We examined PI3K/Akt/mTOR signaling pathway which is involved in regulation of apoptosis, cell growth and learning and memory. We found significant downregulation of phosphorylated forms of Akt and mTOR in TMT-intoxicated animals, which were reverted following iTBS stimulation. Application of iTBS produces beneficial effects on cognition in of rats with TMT-induced hippocampal neurodegeneration and that effect could be mediated via PI3K/Akt/mTOR signaling pathway, which could candidate this protocol as a potential therapeutic approach in neurodegenerative diseases such as AD.

BackgroundThe recovery of balance function is a critical segment in the rehabilitation treatment of stroke. The cerebellum is considered as the key structure involved in balance and motor control. The cerebellar vermis plays an important role in integrating vision, proprioception, and sensory skin input and may be a candidate stimulation target for regulating the motor network related with balance. However, evidence that the intermittent theta burst stimulation (iTBS) of cerebellar vermis can promote the recovery of balance function after stroke remains insufficient. Therefore, this study aims to explore the efficacy of the cerebellar vermis iTBS for the treatment of balance function in patients with stroke.Methods and AnalysisForty patients with stroke will be recruited in this prospective, randomized, sham-controlled trial. Participants will be randomized in a 1:1 ratio to receive either 15 sessions of cerebellar vermis iTBS (600 pulses) or sham stimulation. Additionally, a routine rehabilitation therapy follows the intervention. The primary outcome is the Berg Balance Scale, and the secondary outcomes are the Fugl–Meyer assessment of the lower extremity and modified Barthel index. The above outcomes will be assessed before intervention and at the end of each week. Pre- and post-iTBS resting-state functional magnetic resonance imaging (rs-fMRI) will be acquired, and the regional homogeneity, fractional amplitude of low-frequency fluctuation and functional connectivity will be calculated and analyzed.DiscussionThis protocol holds promise as a potential method to improve balance function in patients with stroke. If the outcomes of patients improve after the intervention, the study will provide new insights into improving balance function.Ethics and DisseminationThis study has been approved by the Medical Research Ethics Committee of Wuxi Mental Health Center (Wuxi Tongren Rehabilitation Hospital). Results will be disseminated through (open-access) peer-reviewed publications, networks of scientists, professionals, and the public and presented at conferences.Clinical Trial Registration Numberwww.chictr.org.cn, identifier ChiCTR2100052590.

Background: Intermittent theta burst stimulation (iTBS) is an effective stimulus for long-term potentiation (LTP)-like plasticity. However, iTBS-induced effects varied greatly between individuals. Ample evidence suggested that an initial decrease in local γ-aminobutyric acid (GABA) or enhancement in N -methyl-D-aspartate (NMDA) facilitation neurotransmission is of vital importance for allowing LTP-like plasticity to occur. Therefore, we aimed to investigate whether the individual level of GABA or NMDA receptor-mediated activity before stimulation is correlated with the after-effect in cortical excitability induced by iTBS. Methods: Fifteen healthy volunteers were recruited for the present study. We measured short-interval intracortical inhibitory (SICI), long-interval intracortical inhibitory (LICI), and intracortical facilitation (ICF), which index GABAA receptor-, GABAB receptor-, and glutamate receptor-mediated activity, respectively, in the cortex before conducting iTBS. After iTBS intervention, the changes of motor-evoked potential (MEP) amplitude were taken as a measure for cortical excitability in response to iTBS protocol. Results: There was a significant negative correlation between the amount of SICI measured before iTBS and the after-effect of iTBS-induced LTP-like plasticity at the time points of 5, 10, and 15 min after inducing iTBS. A multiple linear regression model indicated that SICI was a good predictor of the after-effect in cortical excitability induced by iTBS at 5, 10, and 15 min following stimulation. Conclusion: The present study found that GABAA receptor-mediated activity measured before stimulation is negatively correlated with the after-effect of cortical excitability induced by iTBS. SICI, as the index of GABAA receptor-mediated activity measured before stimulation, might be a good predictor of iTBS-induced LTP-like plasticity for a period lasting 15 min following stimulation. [ABSTRACT FROM AUTHOR]

Objective: Intermittent theta burst stimulation (iTBS) has been widely used as a neural modulation approach in stroke rehabilitation. Concurrent use of transcranial magnetic stimulation and electroencephalography (TMS-EEG) offers a chance to directly measure cortical reactivity and oscillatory dynamics and allows for investigating neural effects induced by iTBS in all stroke survivors including individuals without recordable MEPs. Here, we used TMS-EEG to investigate aftereffects of iTBS following stroke. Methods: We studied 22 stroke survivors (age: 65.2 ± 11.4 years; chronicity: 4.1 ± 3.5 months) with upper limb motor deficits. Upper-extremity component of Fugl-Meyer motor function assessment and action research arm test were used to measure motor function of stroke survivors. Stroke survivors were randomly divided into two groups receiving either Active or Sham iTBS applied over the ipsilesional primary motor cortex. TMS-EEG recordings were performed at baseline and immediately after Active or Sham iTBS. Time and time-frequency domain analyses were performed for quantifying TMS-evoked EEG responses. Results: At baseline, natural frequency was slower in the ipsilesional compared with the contralesional hemisphere (P = 0.006). Baseline natural frequency in the ipsilesional hemisphere was positively correlated with upper limb motor function following stroke (P = 0.007). After iTBS, natural frequency in the ipsilesional hemisphere was significantly increased (P < 0.001). Conclusions: This is the first study to investigate the acute neural adaptations after iTBS in stroke survivors using TMS-EEG. Our results revealed that natural frequency is altered following stroke which is related to motor impairments. iTBS increases natural frequency in the ipsilesional motor cortex in stroke survivors. Our findings implicate that iTBS holds the potential to normalize natural frequency in stroke survivors, which can be utilized in stroke rehabilitation. [ABSTRACT FROM AUTHOR]