Intermittent theta burst stimulation of the left dorsolateral prefrontal cortex has no additional effect on the efficacy of virtual reality exposure therapy for acrophobia. A randomized double-blind placebo-controlled study.

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.

Theta-burst transcranial magnetic stimulation attenuates chronic ischemic demyelination and vascular cognitive impairment in mice.

Vascular cognitive impairment and dementia (VCID) is mainly caused by chronic cerebral hypoperfusion and subsequent white matter lesions. Noninvasive transcranial magnetic stimulation has been utilized in treating various neurological disorders. However, the function of theta-burst transcranial magnetic stimulation on VCID remains to be defined. We utilized 4-week bilateral carotid artery stenosis model of male mice to mimic VCID. Intermittent theta-burst stimulation (iTBS) or consecutive theta-burst stimulation (cTBS) was administered for 14 consecutive days. Through luxol fast blue staining, electron microscopy and immunofluorescence, we found that iTBS, not cTBS, significantly improved demyelination, axonal damage and ß-amyloid deposition, without affecting cerebral blood flow in VCID mice. At cellular levels, iTBS rescued the loss of mature oligodendrocytes, promoted precursor cell differentiation, and inhibited pro-inflammatory activation of astrocytes and microglia. Notably, iTBS attenuated cognitive deterioration in both short-term retention and long-term spatial memory of VCID mice as indicated by serial neurobehavioral tests. To explore the molecular involvement of iTBS, mRNA sequencing was carried out. By real-time PCR and combined RNA fluorescence in situ hybridization with immunofluorescence, iTBS was confirmed to increase Rxrg expression specifically in mature oligodendrocytes. Collectively, iTBS could ameliorate vascular cognitive dysfunction, probably via mitigating white matter lesions and neuroinflammation in the corpus callosum. Rxrg signaling in mature oligodendrocytes, which was increased by iTBS, might be a potential target for VCID treatment.

Procognitive Effects of Adjunctive D-Cycloserine to Intermittent Theta-Burst Stimulation in Major Depressive Disorder: Effets procognitifs de la D-cyclosérine en traitement complémentaire par la stimulation thêta-burst intermittente dans le trouble dépressif caractérisé.

OBJECTIVE: 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. METHOD: 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. RESULTS: 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. CONCLUSIONS: An intersectional strategy pairing iTBS with NMDA receptor agonism may restore cognitive function in MDD.

Intermittent theta burst stimulation in adolescents and young adults with depressive disorders: protocol of a randomized, sham-controlled study with a sequential Bayesian design for adaptive trials.

Intermittent theta burst stimulation (iTBS), a variant of repetitive transcranial magnetic stimulation (rTMS), is an established treatment for adults with major depressive disorder (MDD). Due to its favorable safety profile, iTBS is also a promising early intervention in the transition phase from adolescence to early adulthood, but this has not been systematically investigated to date. Thus, the EARLY-BURST trial investigates the efficacy and safety of iTBS over the left dorsolateral prefrontal cortex (lDLPFC) in treatment-seeking young patients (age 16-26 years) with depressive disorders (i.e. major depressive disorder, persistent depressive disorder, bipolar depression), allowing for relevant co-morbidities. Participants have not received antidepressant or antipsychotic medication during the last 12 months except for short-term (< 2 weeks) on-demand medication. The trial will employ a novel sequential Bayesian, randomized, double-blind, parallel-group, sham-controlled design. Up to 90 patients at two clinical sites (Munich, Augsburg) will be randomized 1:1 to the treatment groups, with sequential analyses starting after 26 patients in each group completed the treatment. The primary outcome will be the difference in depression severity at week 6 (post-treatment visit) between active iTBS and sham iTBS, assessed with the Montgomery-Åsberg Depression Rating Scale (MADRS). The trial is planned to be expanded towards a three-arm leapfrog design, contingent on securing additional funding. Thus, in addition to potentially providing evidence of iTBS's efficacy in adolescents and young adults with depressive disorders, the EARLY-BURST trial aims at setting the stage for subsequent platform trials in this dynamic research field, where novel adaptive study designs are required to meet the need for rapidly testing promising new vs established rTMS protocols.Trial registration: DRKS00033313.

Effects of Continuous Theta Burst Stimulation on Contralateral Primary Motor Cortex: A Concurrent TMS-EEG Study.

Continuous theta burst stimulation (cTBS) is a non-invasive brain stimulation technique. cTBS modulation is an effective treatment for motor dysfunction rehabilitation in post-stroke patients. However, there's currently a lack of research on the effects of cTBS stimulation on the contralesional hemisphere. To better understand the role of cTBS in motor rehabilitation, we investigated the neuroregulatory mechanisms of cTBS in the contralateral cortex using transcranial magnetic stimulation-evoked electroencephalography (TMS-EEG). In this randomized, sham-controlled, single-blind study, 18 healthy subjects received two separate stimulation conditions:cTBS or sham stimulation applied to the left M1. TMS-EEG measurements were taken before and immediately after stimulation. We investigated the TMS-evoked potentials (TEPs), evoked oscillatory responses (EOR), and phase synchronization index(PSI) of TMS-EEG. The effects of cTBS were analyzed using two-way repeated measures analysis of variance (RMANOVA). There was a significant "cTBS condition×time" interaction effect on the theta and gamma bands of EOR, as well as on inter-hemisphere PSI (inter-PSI) and global PSI in both cTBS stimulation conditions. (theta:F=4.526,p=0.041;gamma:F=5.574,p=0.024;inter-PSI:F=5.028,p=0.032;global PSI:F=5.129,p=0.030).After real cTBS modulation, the energy in the theta and gamma frequency bands was significantly higher than before (theta: F=5.747, p=0.022; gamma: F=5.545, p=0.024). The inter-PSI and global PSI significantly increased after real cTBS modulation (inter-PSI: F=6.209, p=0.018; global PSI: F=6.530, p=0.015). cTBS modulation significantly increased EOR and PSI in contralateral brain regions, thereby enhancing cortical excitability and cortical functional connectivity throughout the brain. This provides a theoretical basis for cTBS neuromodulation in stroke patients.

Continuous theta burst stimulation ameliorates cognitive deficits in microinfarcts mice via inhibiting glial activation and promoting paravascular CSF-ISF exchange.

Microinfarcts are widespread in the elderly, accompanied by varying degrees of cognitive decline. Continuous theta burst stimulation (cTBS) has been demonstrated to be neuroprotective on cognitive dysfunction, but the underlying cellular mechanism has been still not clear. In the present study, we evaluated the effects of cTBS on cognitive function and brain pathological changes in mice model of microinfarcts. The spatial learning and memory was assessed by Morris water maze (MWM), Glymphatic clearance efficiency was evaluated using in vivo two-photon imaging. The loss of neurons, activation of astrocytes and microglia, the expression and polarity distribution of the astrocytic aquaporin-4 (AQP4) were assessed by immunofluorescence staining. Our results showed that cTBS treatment significantly improved the spatial learning and memory, accelerated the efficiency of glymphatic clearance, up-regulated the AQP4 expression and improved the polarity distribution of AQP4 in microinfarcts mice. Besides, cTBS treatment increased the number of surviving neurons, whereas decreased the activated astrocytes and microglia. Our study suggested that cTBS accelerated glymphatic clearance and inhibited the excessive gliogenesis, which ultimately exerted neuroprotective effects on microinfarcts mice.

Increasing mind wandering with accelerated intermittent theta burst stimulation over the left dorsolateral prefrontal cortex.

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.

Continuous Theta Burst Stimulation Inhibits Oxidative Stress-Induced Inflammation and Autophagy in Hippocampal Neurons by Activating Glutathione Synthesis Pathway, Improving Cognitive Impairment in Sleep-Deprived Mice.

Sleep deprivation (SD) has been reported to have a negative impact on cognitive function. Continuous theta burst stimulation (cTBS) shows certain effects in improving sleep and neurological diseases, and its molecular or cellular role in SD-induced cognition impairment still need further exploration. In this study, C57BL/6 mice were subjected to 48 h of SD and cTBS treatment, and cTBS treatment significantly improved SD-triggered impairment of spatial learning and memory abilities in mice. Additionally, cTBS reduced malondialdehyde levels, increased superoxide dismutase activities, and inhibited the production of inflammatory cytokines, alleviating oxidative stress and inflammation levels in hippocampal tissues of SD model mice. cTBS decreased LC3II/LC3I ratio, Beclin1 protein levels, and LC3B puncta intensity, and elevated p62 protein levels to suppress excessive autophagy in hippocampal tissues of SD-stimulated mice. Then, we proved that inhibiting oxidative stress alleviated inflammation, autophagy, and death of hippocampal neuron cells through an in vitro cellular model for oxidative stress, and cTBS treatment promoted the production of glutathione (GSH), the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and the mRNA expression of GSH synthesis-related genes to enhance antioxidant capacity in hippocampal tissues of SD mice. An Nrf2 inhibitor ML385 or a GSH synthesis inhibitor BSO reversed the alleviating effects of cTBS treatment on oxidative stress-associated damage of hippocampal tissues and cognitive impairment in SD model mice. Altogether, our study demonstrated that cTBS mitigates oxidative stress-associated inflammation and autophagy through activating the Nrf2-mediated GSH synthesis pathway, improving cognitive impairment in SD mice.

Efficacy of Cortical-Hippocampal Target Intermittent Theta Burst Stimulation (iTBS) on Associative Memory of Schizophrenia: A Double-Blind, Randomized Sham-Controlled Trial.

Objective: The objective of our study was to evaluate whether intermittent theta burst stimulation(iTBS) applied to the regions with the strongest cortico-hippocampal connectivity within the lateral parietal cortical (LPC) or dorsolateral prefrontal cortical (DLPFC) areas in individuals with schizophrenia could enhance associative memory. Methods: We randomized 96 participants with schizophrenia to receive either active iTBS applied to the right DLPFC, left LPC or sham iTBS for 20 days. Clinical and cognitive assessments were performed at baseline and at the end of treatment. The primary outcome was change in associative memory. The secondary outcome was change in other cognitive functions and psychiatric symptoms. Results: In comparison to the sham group, iTBS targeting the right DLPFC or left LPC in schizophrenia did not yield significant improvements in auditory-auditory associative memory (F=1.27, p=0.294), auditory-visual associative memory (F=0.49, p=0.617), or visual-visual associative memory (F=1.094, p=0.347). Furthermore, after adjusting for variables such as education, disease duration, and negative symptoms, no significant changes were observed in any of these three memory domains. Conclusion: Although our study suggests that iTBS applied to the cortical-hippocampal did not lead to a significant change in associative memory. However, further investigation combining hippocampal-targeted iTBS with functional magnetic resonance imaging (fMRI) is warranted to elucidate the regulatory effects of iTBS on hippocampal function. Trial Registration: clinicaltrials.gov NCT03608462.

Repetitive Transcranial Magnetic Stimulation (rTMS) in Major Depression.

Major depressive disorder (MDD) is a psychiatric disorder with several effective therapeutic approaches, being antidepressants and psychotherapies the first-line treatments. Nonetheless, due to side effects, limited efficacy, and contraindications for these treatments, alternative treatment options are required. Neurostimulation is a non-pharmacological and non-psychotherapeutic approach that has been under study for diverse neuropsychiatric conditions in the form of electrical or magnetic stimulation of the brain. Repetitive transcranial magnetic stimulation (rTMS) is a neurostimulation method designed to generate magnetic fields and deliver magnetic pulses to stimulate the brain cortex. The magnetic pulses produce electrical currents in the brain which are not intense enough to provoke seizures, differentiating this method from other forms of neurostimulation that produce seizures. Although the exact rTMS mechanisms of action are not completely understood, rTMS seems to cause its beneficial effects through changes in neuroplasticity. Devices and protocols for rTMS are still evolving, becoming more efficient over time. There are still some challenges to be addressed, including further refinement of parameters (coil/device type, location, intensity, frequency, number of sessions, and duration of treatment); treatment cost and burden for patients; and treatment resistance. However, the efficacy, tolerability, and safety of some rTMS protocols have been demonstrated in different double-blind sham-controlled randomized controlled trials and meta-analyses for treatment-resistant depression.

The efficacy and safety of continuous theta burst stimulation for auditory hallucinations: a systematic review and meta-analysis of randomized controlled trials.

Objective: Auditory hallucinations are the most frequently occurring psychotic symptom in schizophrenia. Continuous theta burst stimulation (cTBS) has been used as an adjuvant treatment for auditory hallucinations. This meta-analysis focused on randomized controlled clinical trials (RCTs) to assess the efficacy of adjuvant cTBS on auditory hallucinations in schizophrenia. Methods: We performed a comprehensive search of four international databases from their inception to January 14, 2024, to identify relevant RCTs that assessed the effects of adjuvant cTBS on auditory hallucinations. The key words included "auditory hallucinations", "continuous theta burst stimulation" and "transcranial magnetic stimulation". Inclusion criteria included patients with auditory hallucinations in schizophrenia or schizoaffective disorder. The Revised Cochrane risk-of-bias tool for randomized trials (RoB1) were used to evaluate the risk of bias and the Review Manager Software Version 5.4 was employed to pool the data. Results: A total of 4 RCTs involving 151 patients with auditory hallucinations were included in the analysis. The Cochrane risk of bias of these studies presented "low risk" in all items. Preliminary analysis showed no significant advantage of adjuvant cTBS over sham stimulation in reducing hallucinations [4 RCTs, n = 151; SMD: -0.45 (95%CI: -1.01, 0.12), P = 0.13; I2 = 61%]. Subgroup analysis revealed that patients treated with adjuvant cTBS for more than 10 stimulation sessions and total number of pulses more than 6000 [3 RCTs, n = 87; SMD: -4.43 (95%CI: -8.22, -0.63), P = 0.02; I2 = 47%] had a statistically significant improvement in hallucination symptoms. Moreover, the rates of adverse events and discontinuation did not show any significant difference between the cTBS and sham group. Conclusions: Although preliminary analysis did not revealed a significant advantage of adjuvant cTBS over sham stimulation, subgroup analysis showed that specific parameters of cTBS appear to be effective in the treatment of auditory hallucinations in schizophrenia. Further large-scale studies are needed to determine the standard protocol of cTBS for treating auditory hallucinations. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42024534045.

Efficiency and safety of continuous theta burst stimulation for primary insomnia: A randomized clinical trial.

OBJECTIVES: Primary insomnia is a substantial public health burden, but current treatments for this disorder have limited effectiveness and adherence. Herein, we aimed to investigate the efficacy and safety of continuous theta burst stimulation (cTBS) for the treatment of primary insomnia. METHODS: This two-armed, randomized, sham-controlled trial was conducted at Peking University Sixth Hospital and local community clinics. A total of 46 patients with primary insomnia were recruited and randomly allocated to either the cTBS group or sham group. Forty-one patients completed 10 sessions of cTBS or sham intervention and follow-up assessments. RESULTS: After the intervention, the severity of insomnia was significantly lower in the cTBS group than in the sham group, with a large effect size (Cohen's d = -1.938). Additionally, 52.4 % of patients in the cTBS group achieved a response (Insomnia Severity Index score reduction ≥8), whereas only 4 % of patients in the sham group achieved a response. The duration of objective total sleep time and slow-wave sleep were higher in the cTBS group than in the sham group. The degree of anxiety was lower in the cTBS group than in the sham group. There were no significant differences in depression, sleepiness, or cognitive function between the cTBS and sham groups. During follow-up, the sleep quality of the cTBS group significantly improved and remained stable at the 6-month follow-up. CONCLUSION: In this randomized clinical trial, cTBS improved insomnia symptoms and was generally well tolerated, thus supporting the further development of cTBS for the treatment of primary insomnia.

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

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

Transcranial magnetic stimulation for the rehabilitation of patients with addiction: current status and future prospects.

INTRODUCTION: Substance use disorders (SUDs) are severe conditions that remain extremely challenging to treat in clinical practice. With high rates of non-response to current treatment options and several SUDs with no approved interventions, novel therapies are needed. Repetitive transcranial magnetic stimulation (rTMS) can non-invasively modulate the neurocircuitry of brain-based disorders, and investigation into its therapeutic potential for SUDs is growing rapidly. AREAS COVERED: In this review, we summarize the clinical research to date evaluating its safety and efficacy for various SUDs. We highlight the investigations comparing different stimulation parameters to present our current understanding on optimal stimulation parameters. Additionally, we cover key research avenues in the use of neuroimaging to guide treatment, cue-induction paradigms, and adjunctive or combination treatments that may optimize outcomes. EXPERT OPINION: Evidence of rTMS as an effective treatment for certain SUDs has emerged and is preliminary for others. There are a growing number of studies showing benefit and meta-analyses suggesting that rTMS can significantly reduce substance craving and consumption. However, the optimal approach has not been determined, and there is a great deal of heterogeneity in rTMS protocols and mixed outcomes. Further research into strategies for enhancing precision will be crucial in moving the field forward.

Optimizing antidepressant benefits: Effect of theta burst stimulation treatment in physically active people with treatment-resistant depression.

Theta burst stimulation (TBS) is a promising therapy for treatment-resistant major depressive disorder (MDD), but a significant proportion of individuals do not respond adequately, necessitating alternative approaches. This study explores whether individuals meeting minimum recommended physical activity levels demonstrate better responses to TBS compared to physically inactive individuals. Using data from a randomized controlled trial (n = 43), participants were categorized as physically active or inactive based on baseline International Physical Activity Questionnaire (IPAQ) scores. Depression scores (Hamilton Rating Scale for Depression, 17-item; HRSD-17) were assessed at baseline, 4, and 6 weeks of TBS treatment. A significant Time X Group effect adjusted for age and baseline depression was observed. Physically active individuals consistently exhibited lower depression scores across time points. At 4 and 6 weeks, there was a significant increase in between-group differences, indicating that the physically active group derived greater benefits from treatment. At 6 weeks, a significantly higher proportion of responders (≥50 % HRSD-17 reduction) were observed in the physically active compared to inactive group. Physical activity significantly contributed to regression and logistic models predicting treatment response. These findings support the potential role of baseline physical activity in enhancing TBS therapy for MDD.

Combined biomaterial scaffold and neuromodulation strategy to promote tissue repair and corticospinal connectivity after spinal cord injury in a rodent model.

Spinal cord injury (SCI) damages the trauma site, leading to progressive and secondary structural defects rostral and caudal to the injury. Interruption of ascending and descending pathways produce motor, sensory, and autonomic impairments, driving the need for effective therapies. In this study, we address lesion site repair and promoting descending projections using a combined biomaterial-neuromodulation strategy in a rat model of cervical contusion SCI. To promote tissue repair, we used Chitosan fragmented physical hydrogel suspension (Cfphs), a biomaterial formulation optimized to mitigate inflammation and support tissue remodeling. To promote descending projections, we targeted the corticospinal motor system with dual motor cortex-trans-spinal direct current neuromodulation to promote spared corticospinal tract (CST) axon sprouting rostral and caudal to SCI. Cfphs, injected into the lesion site acutely, was followed by 10 days of daily neuromodulation. Analysis was made at the chronic phase, 8-weeks post-SCI. Compared with SCI only, Cfphs alone or in combination with neuromodulation prevented cavity formation, by promoting tissue remodeling at the injury site, abrogated astrogliosis surrounding the newly formed tissue, and enabled limited CST axon growth into the remodeled injury site. Cfphs alone significantly reduced CST axon dieback and was accompanied by preserving more CST axon gray matter projections rostral to SCI. Cfphs + neuromodulation produced sprouting rostral and caudal to injury. Our findings show that our novel biomaterial-neuromodulation combinatorial strategy achieves significant injury site tissue remodeling and promoted CST projections rostral and caudal to SCI.

Improving social cognition following theta burst stimulation over the right inferior frontal gyrus in autism spectrum: an 8-week double-blind sham-controlled trial.

BACKGROUND: The right inferior frontal gyrus (RIFG) is a potential beneficial brain stimulation target for autism. This randomized, double-blind, two-arm, parallel-group, sham-controlled clinical trial assessed the efficacy of intermittent theta burst stimulation (iTBS) over the RIFG in reducing autistic symptoms (NCT04987749). METHODS: Conducted at a single medical center, the trial enrolled 60 intellectually able autistic individuals (aged 8-30 years; 30 active iTBS). The intervention comprised 16 sessions (two stimulations per week for eight weeks) of neuro-navigated iTBS or sham over the RIFG. Fifty-seven participants (28 active) completed the intervention and assessments at Week 8 (the primary endpoint) and follow-up at Week 12. RESULTS: Autistic symptoms (primary outcome) based on the Social Responsiveness Scale decreased in both groups (significant time effect), but there was no significant difference between groups (null time-by-treatment interaction). Likewise, there was no significant between-group difference in changes in repetitive behaviors and exploratory outcomes of adaptive function and emotion dysregulation. Changes in social cognition (secondary outcome) differed between groups in feeling scores on the Frith-Happe Animations (Week 8, p = 0.026; Week 12, p = 0.025). Post-hoc analysis showed that the active group improved better on this social cognition than the sham group. Dropout rates did not vary between groups; the most common adverse event in both groups was local pain. Notably, our findings would not survive stringent multiple comparison corrections. CONCLUSIONS: Our findings suggest that iTBS over the RIFG is not different from sham in reducing autistic symptoms and emotion dysregulation. Nonetheless, RIFG iTBS may improve social cognition of mentalizing others' feelings in autistic individuals.

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

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment in major depressive disorder (MDD). However, intermittent theta-burst stimulation (iTBS) and rTMS protocols using 10 Hz stimulation frequency might differ in their effect on neuroplasticity and on clinical symptoms. This study compares the effect of iTBS and a novel 10 Hz-rTMS with shortened single session duration, on motor excitability and neuroplasticity and on clinical symptoms in MDD. METHODS: 30 patients with MDD received either iTBS or the novel 10 Hz-rTMS daily over three weeks to the left dorsolateral prefrontal cortex. Before and after the interventions, motor excitability, short-latency intracortical inhibition and long-term-potentiation-like plasticity in the motor cortex and clinical symptoms were measured by use of transcranial magnetic stimulation. RESULTS: After the intervention, the level of neuroplasticity increased and clinical symptoms of depression were reduced in both groups, though both effects were significantly stronger after the novel 10 Hz-rTMS. Importantly, the changes in neuroplasticity and clinical symptoms were correlated: the stronger neuroplasticity increased, the stronger was the improvement of clinical symptoms. LIMITATIONS: Short intervention period of 3 weeks. Clinical symptoms were measured by self-assessment only and are therefore preliminary. CONCLUSIONS: The novel 10 Hz-rTMS is more effective in increasing neuroplasticity in MDD and potentially also in reducing clinical symptoms than iTBS. This might be due to a differential mode of action on neuroplasticity and to the stimulation frequency of 10 Hz (within the alpha range) being more suitable to reset the brain's activity and to support neuroplastic changes.

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

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

A computational model elucidating mechanisms and variability in theta burst stimulation responses.

Theta burst stimulation (TBS) is a form of repetitive transcranial magnetic stimulation (rTMS) with unknown underlying mechanisms and highly variable responses across subjects. To investigate these issues, we developed a simple computational model. Our model consisted of two neurons linked by an excitatory synapse that incorporates two mechanisms: short-term plasticity (STP) and spike-timing-dependent plasticity (STDP). We applied a variable-amplitude current through I-clamp with a TBS time pattern to the pre- and post-synaptic neurons, simulating synaptic plasticity. We analyzed the results and provided an explanation for the effects of TBS, as well as the variability of responses to it. Our findings suggest that the interplay of STP and STDP mechanisms determines the direction of plasticity, which selectively affects synapses in extended neurons and underlies functional effects. Our model describes how the timing, number, and intensity of pulses delivered to neurons during rTMS contribute to induced plasticity. This not only successfully explains the different effects of intermittent TBS (iTBS) and continuous TBS (cTBS), but also predicts the results of other protocols such as 10 Hz rTMS. We propose that the variability in responses to TBS can be attributed to the variable span of neuronal thresholds across individuals and sessions. Our model suggests a biologically plausible mechanism for the diverse responses to TBS protocols and aligns with experimental data on iTBS and cTBS outcomes. This model could potentially aid in improving TBS and rTMS protocols and customizing treatments for patients, brain areas, and brain disorders.