Dynamic nonreversibility view of intrinsic brain organization and brain dynamic analysis of repetitive transcranial magnitude stimulation.

Intrinsic neural activities are characterized as endless spontaneous fluctuation over multiple time scales. However, how the intrinsic brain organization changes over time under local perturbation remains an open question. By means of statistical physics, we proposed an approach to capture whole-brain dynamics based on estimating time-varying nonreversibility and k-means clustering of dynamic varying nonreversibility patterns. We first used synthetic fMRI to investigate the effects of window parameters on the temporal variability of varying nonreversibility. Second, using real test-retest fMRI data, we examined the reproducibility, reliability, biological, and physiological correlation of the varying nonreversibility substates. Finally, using repetitive transcranial magnetic stimulation-fMRI data, we investigated the modulation effects of repetitive transcranial magnetic stimulation on varying nonreversibility substate dynamics. The results show that: (i) as window length increased, the varying nonreversibility variance decreased, while the sliding step almost did not alter it; (ii) the global high varying nonreversibility states and low varying nonreversibility states were reproducible across multiple datasets and different window lengths; and (iii) there were increased low varying nonreversibility states and decreased high varying nonreversibility states when the left frontal lobe was stimulated, but not the occipital lobe. Taken together, these results provide a thermodynamic equilibrium perspective of intrinsic brain organization and reorganization under local perturbation.

High-frequency repetitive transcranial magnetic stimulation promotes ipsilesional functional hyperemia and motor recovery in mice with ischemic stroke.

Neurovascular decoupling plays a significant role in dysfunction following an ischemic stroke. This study aimed to explore the effect of low- and high-frequency repetitive transcranial magnetic stimulation on neurovascular remodeling after ischemic stroke. To achieve this goal, we compared functional hyperemia, cerebral blood flow regulatory factors, and neurochemical transmitters in the peri-infract cortex 21 days after a photothrombotic stroke. Our findings revealed that low- and high-frequency repetitive transcranial magnetic stimulation increased the real-time cerebral blood flow in healthy mice and improved neurobehavioral outcomes after stroke. Furthermore, high-frequency (5-Hz) repetitive transcranial magnetic stimulation revealed stronger functional hyperemia recovery and increased the levels of post-synaptic density 95, neuronal nitric oxide synthase, phosphorylated-endothelial nitric oxide synthase, and vascular endothelial growth factor in the peri-infract cortex compared with low-frequency (1-Hz) repetitive transcranial magnetic stimulation. The magnetic resonance spectroscopy data showed that low- and high-frequency repetitive transcranial magnetic stimulation reduced neuronal injury and maintained excitation/inhibition balance. However, 5-Hz repetitive transcranial magnetic stimulation showed more significant regulation of excitatory and inhibitory neurotransmitters after stroke than 1-Hz repetitive transcranial magnetic stimulation. These results indicated that high-frequency repetitive transcranial magnetic stimulation could more effectively promote neurovascular remodeling after stroke, and specific repetitive transcranial magnetic stimulation frequencies might be used to selectively regulate the neurovascular unit.

Low intensity repetitive transcranial magnetic stimulation enhances remyelination by newborn and surviving oligodendrocytes in the cuprizone model of toxic demyelination.

In people with multiple sclerosis (MS), newborn and surviving oligodendrocytes (OLs) can contribute to remyelination, however, current therapies are unable to enhance or sustain endogenous repair. Low intensity repetitive transcranial magnetic stimulation (LI-rTMS), delivered as an intermittent theta burst stimulation (iTBS), increases the survival and maturation of newborn OLs in the healthy adult mouse cortex, but it is unclear whether LI-rTMS can promote remyelination. To examine this possibility, we fluorescently labelled oligodendrocyte progenitor cells (OPCs; Pdgfrα-CreER transgenic mice) or mature OLs (Plp-CreER transgenic mice) in the adult mouse brain and traced the fate of each cell population over time. Daily sessions of iTBS (600 pulses; 120 mT), delivered during cuprizone (CPZ) feeding, did not alter new or pre-existing OL survival but increased the number of myelin internodes elaborated by new OLs in the primary motor cortex (M1). This resulted in each new M1 OL producing ~ 471 µm more myelin. When LI-rTMS was delivered after CPZ withdrawal (during remyelination), it significantly increased the length of the internodes elaborated by new M1 and callosal OLs, increased the number of surviving OLs that supported internodes in the corpus callosum (CC), and increased the proportion of axons that were myelinated. The ability of LI-rTMS to modify cortical neuronal activity and the behaviour of new and surviving OLs, suggests that it may be a suitable adjunct intervention to enhance remyelination in people with MS.

Microglial Cytokines Mediate Plasticity Induced by 10 Hz Repetitive Magnetic Stimulation.

Microglia, the resident immune cells of the CNS, sense the activity of neurons and regulate physiological brain functions. They have been implicated in the pathology of brain diseases associated with alterations in neural excitability and plasticity. However, experimental and therapeutic approaches that modulate microglia function in a brain region-specific manner have not been established. In this study, we tested for the effects of repetitive transcranial magnetic stimulation (rTMS), a clinically used noninvasive brain stimulation technique, on microglia-mediated synaptic plasticity; 10 Hz electromagnetic stimulation triggered a release of plasticity-promoting cytokines from microglia in mouse organotypic brain tissue cultures of both sexes, while no significant changes in microglial morphology or microglia dynamics were observed. Indeed, substitution of tumor necrosis factor α (TNFα) and interleukin 6 (IL6) preserved synaptic plasticity induced by 10 Hz stimulation in the absence of microglia. Consistent with these findings, in vivo depletion of microglia abolished rTMS-induced changes in neurotransmission in the mPFC of anesthetized mice of both sexes. We conclude that rTMS affects neural excitability and plasticity by modulating the release of cytokines from microglia.SIGNIFICANCE STATEMENT Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain stimulation technique that induces cortical plasticity. Despite its wide use in neuroscience and clinical practice (e.g., depression treatment), the cellular and molecular mechanisms of rTMS-mediated plasticity remain not well understood. Herein, we report an important role of microglia and plasticity-promoting cytokines in synaptic plasticity induced by 10 Hz rTMS in organotypic slice cultures and anesthetized mice, thereby identifying microglia-mediated synaptic adaptation as a target of rTMS-based interventions.

The neurorehabilitation of post-stroke dysphagia: Physiology and pathophysiology.

Swallowing is a complex process involving the precise contractions of numerous muscles of the head and neck, which act to process and shepherd ingested material from the oral cavity to its eventual destination, the stomach. Over the past five decades, information from animal and human studies has laid bare the complex network of neurones in the brainstem, cortex and cerebellum that are responsible for orchestrating each normal swallow. Amidst this complexity, problems can and often do occur that result in dysphagia, defined as impaired or disordered swallowing. Dysphagia is common, arising from multiple varied disease processes that can affect any of the neuromuscular structures involved in swallowing. Post-stroke dysphagia (PSD) remains the most prevalent and most commonly studied form of dysphagia and, as such, provides an important disease model to assess dysphagia physiology and pathophysiology. In this review, we explore the complex neuroanatomical processes that occur during normal swallowing and PSD. This includes how strokes cause dysphagia, the mechanisms through which natural neuroplastic recovery occurs, current treatments for patients with persistent dysphagia and emerging neuromodulatory treatments.

The alterations of repetitive transcranial magnetic stimulation on the energy landscape of resting-state networks differ across the human cortex.

Repetitive transcranial magnetic stimulation (rTMS) is a promising intervention tool for the noninvasive modulation of brain activity and behavior in neuroscience research and clinical settings. However, the resting-state dynamic evolution of large-scale functional brain networks following rTMS has rarely been investigated. Here, using resting-state fMRI images collected from 23 healthy individuals before (baseline) and after 1 Hz rTMS of the left frontal (FRO) and occipital (OCC) lobes, we examined the different effects of rTMS on brain dynamics across the human cortex. By fitting a pairwise maximum entropy model (pMEM), we constructed an energy landscape for the baseline and poststimulus conditions by fitting a pMEM. We defined dominant brain states (local minima) in the energy landscape with synergistic activation and deactivation patterns of large-scale functional networks. We calculated state dynamics including appearance probability, transitions and duration. The results showed that 1 Hz rTMS induced increased and decreased state probability, transitions and duration when delivered to the FRO and OCC targets, respectively. Most importantly, the shortest path and minimum cost between dominant brain states were altered after stimulation. The absolute sum of the costs from the source states to the destinations was lower after OCC stimulation than after FRO stimulation. In conclusion, our study characterized the dynamic trajectory of state transitions in the energy landscape and suggested that local rTMS can induce significant dynamic perturbation involving stimulated and distant functional networks, which aligns with the modern view of the dynamic and complex brain. Our results suggest low-dimensional mapping of rTMS-induced brain adaption, which will contribute to a broader and more effective application of rTMS in clinical settings.

Cognitive enhancing effect of rTMS combined with tDCS in patients with major depressive disorder: a double-blind, randomized, sham-controlled study.

BACKGROUND: Cognitive dysfunction is one of the common symptoms in patients with major depressive disorder (MDD). Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) have been studied separately in the treatment of cognitive dysfunction in MDD patients. We aimed to investigate the effectiveness and safety of rTMS combined with tDCS as a new therapy to improve neurocognitive impairment in MDD patients. METHODS: In this brief 2-week, double-blind, randomized, and sham-controlled trial, a total of 550 patients were screened, and 240 MDD inpatients were randomized into four groups (active rTMS + active tDCS, active rTMS + sham tDCS, sham rTMS + active tDCS, sham rTMS + sham tDCS). Finally, 203 patients completed the study and received 10 treatment sessions over a 2-week period. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was performed to assess patients' cognitive function at baseline and week 2. Also, we applied the 24-item Hamilton Depression Rating Scale (HDRS-24) to assess patients' depressive symptoms at baseline and week 2. RESULTS: After 10 sessions of treatment, the rTMS combined with the tDCS group showed more significant improvements in the RBANS total score, immediate memory, and visuospatial/constructional index score (all p < 0.05). Moreover, post hoc tests revealed a significant increase in the RBANS total score and Visuospatial/Constructional in the combined treatment group compared to the other three groups but in the immediate memory, the combined treatment group only showed a better improvement than the sham group. The results also showed the RBANS total score increased significantly higher in the active rTMS group compared with the sham group. However, rTMS or tDCS alone was not superior to the sham group in terms of other cognitive performance. In addition, the rTMS combined with the tDCS group showed a greater reduction in HDRS-24 total score and a better depression response rate than the other three groups. CONCLUSIONS: rTMS combined with tDCS treatment is more effective than any single intervention in treating cognitive dysfunction and depressive symptoms in MDD patients. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR2100052122).

Effects of a novel regimen of repetitive transcranial magnetic stimulation (rTMS) on neural remodeling and motor function in adult male mice with ischemic stroke.

Neuroinflammation caused by excessive microglial activation plays a key role in the pathogenesis of ischemic stroke. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive neuromodulatory technique that has recently been reported to regulate microglial functions and exert anti-inflammatory effects. The intermittent burst stimulation (iTBS) regimen in rTMS improves neuronal excitability. However, whether iTBS exerts its anti-inflammatory effects by stimulating neurons and thereby modulating microglial polarization remains unclear. Motor function was assessed after 1 week of rTMS (iTBS regimen) treatment in adult male mice with occlusion/reperfusion of the middle cerebral artery (MCAO/r) injury. We also investigated the molecular biological alterations associated with microglial polarization using a cell proliferation assay, multiplex cytokine bioassays, and immunofluorescence staining. iTBS regimen can improve balance and motor coordination function, increase spontaneous movement, and improve walking function in mice with early cerebral ischemia injury. Expression levels of IL-1ß, TNF-α, and IL-10 increased significantly in mice with MCAO injury. Especially, rTMS significantly increased the number of proliferating cells in the infarcted cortex. The fluorescence intensity of MAP2 in the peri-infarct area of MCAO injured mice was low, but the signal was broader. Compared with MCAO group, the fluorescence intensity of MAP2 in rTMS group was significantly increased. rTMS inhibited pro-inflammatory M1 activation (Iba1+/CD86+) and improved anti-inflammatory M2 activation (Iba1+/CD206+) in the peri-infarct zone, thus significantly changing the phenotypic ratio M1/M2. rTMS improves motor dysfunction and neuroinflammation after cerebral I/R injury in mice by regulating microglial polarization.

Cognitive Effects Following Offline High-Frequency Repetitive Transcranial Magnetic Stimulation (HF-rTMS) in Healthy Populations: A Systematic Review and Meta-Analysis.

High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) is a commonly used form of rTMS to treat neuropsychiatric disorders. Emerging evidence suggests that 'offline' HF-rTMS may have cognitive enhancing effects, although the magnitude and moderators of these effects remain unclear. We conducted a systematic review and meta-analysis to clarify the cognitive effects of offline HF-rTMS in healthy individuals. A literature search for randomised controlled trials with cognitive outcomes for pre and post offline HF-rTMS was performed across five databases up until March 2022. This study was registered on the PROSPERO international prospective protocol for systematic reviews (PROSPERO 2020 CRD 42,020,191,269). The Risk of Bias 2 tool was used to assess the risk of bias in randomised trials. Separate analyses examined the cognitive effects of excitatory and inhibitory forms of offline HF-rTMS on accuracy and reaction times across six cognitive domains. Fifty-three studies (N = 1507) met inclusion criteria. Excitatory offline HF-rTMS showed significant small sized effects for improving accuracy (k = 46, g = 0.12) and reaction time (k = 44, g = -0.13) across all cognitive domains collapsed. Excitatory offline HF-rTMS demonstrated a relatively greater effect for executive functioning in accuracy (k = 24, g = 0.14). Reaction times were also improved for the executive function (k = 21, g = -0.11) and motor (k = 3, g = -0.22) domains following excitatory offline HF-rTMS. The current review was restricted to healthy individuals and future research is required to examine cognitive enhancement from offline HF-rTMS in clinical cohorts.

Repetitive transcranial magnetic stimulation ameliorates cognitive deficits in mice with radiation-induced brain injury by attenuating microglial pyroptosis and promoting neurogenesis via BDNF pathway.

BACKGROUND: Radiation-induced brain injury (RIBI) is a common and severe complication during radiotherapy for head and neck tumor. Repetitive transcranial magnetic stimulation (rTMS) is a novel and non-invasive method of brain stimulation, which has been applied in various neurological diseases. rTMS has been proved to be effective for treatment of RIBI, while its mechanisms have not been well understood. METHODS: RIBI mouse model was established by cranial irradiation, K252a was daily injected intraperitoneally to block BDNF pathway. Immunofluorescence staining, immunohistochemistry and western blotting were performed to examine the microglial pyroptosis and hippocampal neurogenesis. Behavioral tests were used to assess the cognitive function and emotionality of mice. Golgi staining was applied to observe the structure of dendritic spine in hippocampus. RESULTS: rTMS significantly promoted hippocampal neurogenesis and mitigated neuroinflammation, with ameliorating pyroptosis in microglia, as well as downregulation of the protein expression level of NLRP3 inflammasome and key pyroptosis factor Gasdermin D (GSDMD). BDNF signaling pathway might be involved in it. After blocking BDNF pathway by K252a, a specific BDNF pathway inhibitor, the neuroprotective effect of rTMS was markedly reversed. Evaluated by behavioral tests, the cognitive dysfunction and anxiety-like behavior were found aggravated with the comparison of mice in rTMS intervention group. Moreover, the level of hippocampal neurogenesis was found to be attenuated, the pyroptosis of microglia as well as the levels of GSDMD, NLRP3 inflammasome and IL-1ß were upregulated. CONCLUSION: Our study indicated that rTMS notably ameliorated RIBI-induced cognitive disorders, by mitigating pyroptosis in microglia and promoting hippocampal neurogenesis via mediating BDNF pathway.

Efficacy and acceptability of noninvasive brain stimulation for treating posttraumatic stress disorder symptoms: A network meta-analysis of randomized controlled trials.

INTRODUCTION: Despite its high lifetime prevalence rate and the elevated disability caused by posttraumatic stress disorder (PTSD), treatments exhibit modest efficacy. In consideration of the abnormal connectivity between the dorsolateral prefrontal cortex (DLPFC) and amygdala in PTSD, several randomized controlled trials (RCTs) addressing the efficacy of different noninvasive brain stimulation (NIBS) modalities for PTSD management have been undertaken. However, previous RCTs have reported inconsistent results. The current network meta-analysis (NMA) aimed to compare the efficacy and acceptability of various NIBS protocols in PTSD management. METHODS: We systematically searched ClinicalKey, Cochrane Central Register of Controlled Trials, Embase, ProQuest, PubMed, ScienceDirect, Web of Science, and ClinicalTrials.gov to identify relevant RCTs. The targeted RCTs was those comparing the efficacy of NIBS interventions, such as transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), and transcutaneous cervical vagal nerve stimulation, in patients with PTSD. The NMA was conducted using a frequentist model. The primary outcomes were changes in the overall severity of PTSD and acceptability (to be specific, rates of dropouts for any reason). RESULTS: We identified 14 RCTs that enrolled 686 participants. The NMA demonstrated that among the investigated NIBS types, high-frequency rTMS over bilateral DLPFCs was associated with the greatest reduction in overall PTSD severity. Further, in comparison with the sham controls, excitatory stimulation over the right DLPFC with/without excitatory stimulation over left DLPFC were associated with significant reductions in PTSD-related symptoms, including depression and anxiety symptoms, and overall PTSD severity. CONCLUSIONS: This NMA demonstrated that excitatory stimulation over the right DLPFC with or without excitatory stimulation over left DLPFC were associated with significant reductions in PTSD-related symptoms. TRIAL REGISTRATION: PROSPERO CRD42023391562.

Efficacy of rTMS for poststroke epilepsy and its effects on patients' cognitive function and depressive status.

OBJECTIVE: This study aimed to investigate the efficacy of rTMS in the treatment of poststroke epilepsy and the effect of rTMS on patients' cognitive function and depressive status. METHODS: One hundred and twenty-one poststroke epilepsy patients with mild cognitive impairment and depressive status admitted to the Department of Neurology of the Second People's Hospital of Nanning from January 1, 2017, to April 31, 2023, were selected and divided into the rTMS treatment group (treated group) and the control group. MMSE scores and HAMD scores were recorded before and after treatment. The frequency of EEG spiky waves recorded before and after treatment within 24 h and the frequency of any clinical seizure form (the number of clinical seizures within 1 month after treatment) and changes in observed indices before and after treatment were calculated. The differences between the data of the two groups were analyzed, to further assess the efficacy of rTMS in the treatment of poststroke epilepsy and the rTMS' effects on cognition and depression. RESULTS: Compared with drug treatment alone, rTMS significantly decreased clinical seizures and epileptiform discharges after stroke, especially in patients with lesions in the frontal, temporal, and parietal lobes. Compared with drug treatment alone, rTMS treatment can effectively reduce cognitive impairment and mood disorders, such as depression, especially for patients with lesions in the frontal and temporal lobes. The results of this experiment suggest that rTMS treatment does not increase adverse effects. CONCLUSION: rTMS reduces clinical seizures while improving cognitive impairment and depression in patients with epilepsy. Therefore, we suggest that low-frequency rTMS can be used as an adjunctive treatment for patients with epilepsy and provide some ideas and references for the treatment of epilepsy with cognitive impairment and depression.

Recovered grasping performance after stroke depends on interhemispheric frontoparietal connectivity.

Activity changes in the ipsi- and contralesional parietal cortex and abnormal interhemispheric connectivity between these regions are commonly observed after stroke, however, their significance for motor recovery remains poorly understood. We here assessed the contribution of ipsilesional and contralesional anterior intraparietal cortex (aIPS) for hand motor function in 18 recovered chronic stroke patients and 18 healthy control subjects using a multimodal assessment consisting of resting-state functional MRI, motor task functional MRI, online-repetitive transcranial magnetic stimulation (rTMS) interference, and 3D movement kinematics. Effects were compared against two control stimulation sites, i.e. contralesional M1 and a sham stimulation condition. We found that patients with good motor outcome compared to patients with more substantial residual deficits featured increased resting-state connectivity between ipsilesional aIPS and contralesional aIPS as well as between ipsilesional aIPS and dorsal premotor cortex. Moreover, interhemispheric connectivity between ipsilesional M1 and contralesional M1 as well as ipsilesional aIPS and contralesional M1 correlated with better motor performance across tasks. TMS interference at individual aIPS and M1 coordinates led to differential effects depending on the motor task that was tested, i.e. index finger-tapping, rapid pointing movements, or a reach-grasp-lift task. Interfering with contralesional aIPS deteriorated the accuracy of grasping, especially in patients featuring higher connectivity between ipsi- and contralesional aIPS. In contrast, interference with the contralesional M1 led to impaired grasping speed in patients featuring higher connectivity between bilateral M1. These findings suggest differential roles of contralesional M1 and aIPS for distinct aspects of recovered hand motor function, depending on the reorganization of interhemispheric connectivity.

Disrupting the Dorsolateral Prefrontal Cortex Attenuates the Difference in Decision-Making for Altruistic Punishment Between the Gain and Loss Contexts.

Altruistic punishment is a primary response to social norms violations; its neural mechanism has also attracted extensive research attention. In the present studies, we applied a low-frequency repetitive transcranial magnetic stimulation (rTMS) to the bilateral dorsolateral prefrontal cortex (DLPFC) while participants engaged in a modified Ultimatum Game (Study 1) and third-party punishment game (Study 2) to explore how the bilateral DLPFC disruption affects people's perception of violation of fairness norms and altruistic punishment decision in the gain and loss contexts. Typically, punishers intervene more often against and show more social outrage towards Dictators/Proposers who unfairly distribute losses than those who unfairly share gains. We found that disrupting the function of the left DLPFC in the second-party punishment and the bilateral DLPFC in the third-party punishment with rTMS effectively obliterated this difference, making participants punish unfairly shared gains as often as they usually would punish unfairly shared losses. In the altruistic punishment of maintaining the social fairness norms, the inhibition of the right DLPFC function will affect the deviation of individual information integration ability; the inhibition of the left DLPFC function will affect the assessment of the degree of violation of fairness norms and weaken impulse control, leading to attenuate the moderating effect of gain and loss contexts on altruistic punishment. Our findings emphasize that DLPFC is closely related to altruistic punishment and provide causal neuroscientific evidence.

Theta burst stimulation add on to dialectical behavioral therapy in borderline-personality-disorder: methods and design of a randomized, single-blind, placebo-controlled pilot trial.

Specialized psychotherapeutic treatments like dialectical behavioral therapy (DBT) are recommended as first treatment for borderline personality disorder (BPD). In recent years, studies have emerged that focus on repetitive transcranial magnetic stimulation (rTMS) in BPD. Both have independently demonstrated efficacy in the treatment of BPD. Intermitted theta burst stimulation (iTBS), a modified design of rTMS, is thought to increase the excitability of neurons and could be a supplement to psychotherapy in addition to being a standalone treatment. However, no studies to date have investigated the combination of DBT and rTMS/iTBS. This study protocol describes the methods and design of a randomized, single-blinded, sham-controlled clinical pilot study in which BPD patients will be randomly assigned to either iTBS or sham during four consecutive weeks (20 sessions in total) in addition to standardized DBT treatment. The stimulation will focus on the unilateral stimulation of the left dorsolateral prefrontal cortex (DLPFC), which plays an important role in the control of impulsivity and risk-taking. Primary outcome is the difference in borderline symptomatology, while secondary target criteria are depressive symptoms, general functional level, impulsivity and self-compassion. Statistical analysis of therapy response will be conducted by Mixed Model Repeated Measurement using a 2 × 2-factorial between-subjects design with the between-subject factor stimulation (TMS vs. Sham) and the within-subject factor time (T0 vs. T1). Furthermore, structural magnetic resonance imaging (MRI) will be conducted and analyzed. The study will provide evidence and insight on whether iTBS has an enhancing effect as add-on to DBT in BPD.Trial registration: drks.de (DRKS00020413) registered 13/01/2020.

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.

Accelerated sequential bilateral theta-burst stimulation in major depression: an open trial.

Theta burst stimulation (TBS) is approved and widely used in the treatment of treatment resistant-major depression. More recently, accelerated protocols delivering multiple treatments per day have been shown to be efficacious and potentially enhance outcomes compared to once daily protocols. Meanwhile, bilateral treatment protocols have also been increasingly tested to enhance outcomes. Here, we examined the efficacy and safety of accelerated bilateral TBS in major depressive disorder (MDD). In this open label pilot study, 25 patients with MDD (60%: women; mean age (SD): 45.24 (12.22)) resistant to at least one antidepressant, received bilateral TBS, consisting of 5 sequential bilateral intermittent TBS (iTBS) (600 pulses) and continuous TBS (cTBS) (600 pulses) treatments delivered to the left and right dorsolateral prefrontal cortex (DLPFC), respectively, daily for 5 days at 120% resting motor threshold. Outcome measures were post-treat treatment changes at day 5 and 2-weeks in Hamilton Depression Rating Scale (HDRS-17) scores and response (≥ 50% reduction from the baseline scores) and remission (≤ 7) rates. There was a significant reduction in HDRS scores at day 5 (p < 0.001) and 2-weeks post treatment (p < 0.001). The response rates increased from 20% at day 5 to 32% at 2-weeks post treatment suggesting delayed clinical effects. However, reduction in symptom scores between two post treatment endpoints was non-significant. 60% of patients could not tolerate the high intensity stimulation. No major adverse events occurred. Open label uncontrolled study with small sample size. These preliminary findings suggest that accelerated bilateral TBS may be clinically effective and safe for treatment resistant depression. Randomized sham-controlled trials are needed to establish the therapeutic role of accelerated bilateral TBS in depression.Trial registration: ClinicalTrials.gov, NCT10001858.

Low-frequency repetitive transcranial magnetic stimulation alters the individual functional dynamical landscape.

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive approach to modulate brain activity and behavior in humans. Still, how individual resting-state brain dynamics after rTMS evolves across different functional configurations is rarely studied. Here, using resting state fMRI data from healthy subjects, we aimed to examine the effects of rTMS to individual large-scale brain dynamics. Using Topological Data Analysis based Mapper approach, we construct the precise dynamic mapping (PDM) for each participant. To reveal the relationship between PDM and canonical functional representation of the resting brain, we annotated the graph using relative activation proportion of a set of large-scale resting-state networks (RSNs) and assigned the single brain volume to corresponding RSN-dominant or a hub state (not any RSN was dominant). Our results show that (i) low-frequency rTMS could induce changed temporal evolution of brain states; (ii) rTMS didn't alter the hub-periphery configurations underlined resting-state brain dynamics; and (iii) the rTMS effects on brain dynamics differ across the left frontal and occipital lobe. In conclusion, low-frequency rTMS significantly alters the individual temporo-spatial dynamics, and our finding further suggested a potential target-dependent alteration of brain dynamics. This work provides a new perspective to comprehend the heterogeneous effect of rTMS.

Inappropriate study inclusion in meta-analysis of sham-controlled rTMS for treatment-resistant depression.

Dr. Vida and colleagues have published an important meta-analysis on a critical topic in psychiatry: the efficacy of double-blind, sham-controlled rTMS in treatment-resistant depression (TRD) [1]. The primary reported finding was a significant effect of rTMS on remission and response (RR 2.25 and 2.78 respectively) compared to sham rTMS. A close evaluation of the studies included in this meta-analysis raises concerns about the accuracy of these findings.

A randomized sham-controlled trial of high-dosage accelerated intermittent theta burst rTMS in major depression: study protocol.

BACKGROUND: Intermittent theta burst stimulation (iTBS), a novel form of repetitive transcranial magnetic stimulation (rTMS), can be administered in 1/10th of the time of standard rTMS (~ 3 min vs. 37.5 min) yet achieves similar outcomes in depression. The brief nature of the iTBS protocol allows for the administration of multiple iTBS sessions per day, thus reducing the overall course length to days rather than weeks. This study aims to compare the efficacy and tolerability of active versus sham iTBS using an accelerated regimen in patients with treatment-resistant depression (TRD). As a secondary objective, we aim to assess the safety, tolerability, and treatment response to open-label low-frequency right-sided (1 Hz) stimulation using an accelerated regimen in those who do not respond to the initial week of treatment. METHODS: Over three years, approximately 230 outpatients at the Centre for Addiction and Mental Health and University of British Columbia Hospital, meeting diagnostic criteria for unipolar MDD, will be recruited and randomized to a triple blind sham-controlled trial. Patients will receive five consecutive days of active or sham iTBS, administered eight times daily at 1-hour intervals, with each session delivering 600 pulses of iTBS. Those who have not achieved response by the week four follow-up visit will be offered a second course of treatment, regardless of whether they initially received active or sham stimulation. DISCUSSION: Broader implementation of conventional iTBS is limited by the logistical demands of the current standard course consisting of 4-6 weeks of daily treatment. If our proposed accelerated iTBS protocol enables patients to achieve remission more rapidly, this would offer major benefits in terms of cost and capacity as well as the time required to achieve clinical response. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04255784.