Intermittent Theta Burst Stimulation Attenuates Cognitive Deficits and Alzheimer's Disease-Type Pathologies via ISCA1-Mediated Mitochondrial Modulation in APP/PS1 Mice.

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.

Intermittent Theta-Burst Stimulation for Stroke: Primary Motor Cortex Versus Cerebellar Stimulation: A Randomized Sham-Controlled Trial.

BACKGROUND: Stroke survivors with impaired balance and motor function tend to have relatively poor functional outcomes. The cerebellum and primary motor cortex (M1) have been suggested as targets for neuromodulation of balance and motor recovery after stroke. This study aimed to compare the efficacy and safety of intermittent theta-burst stimulation (iTBS) to the cerebellum or M1 on balance and motor recovery in patients with stroke. METHODS: In this randomized, double-blind, sham-controlled clinical trial, patients with subacute stroke were randomly divided into 3 groups: M1-, cerebellar-, and sham-iTBS (n=12 per group; 15 sessions, 3 weeks). All outcomes were evaluated before intervention (T0), after 1 week of intervention (T1), after 3 weeks of intervention (T2), and at follow-up (T3). The primary outcome was the Berg balance scale score at T2. Secondary outcomes include the Fugl-Meyer assessment scale for lower extremities, the trunk impairment scale, the Barthel index, the modified Rankin Scale, the functional ambulation categories, and cortical excitability. RESULTS: A total of 167 inpatients were screened, 36 patients (age, 57.50±2.41 years; 10 women, 12 ischemic) were enrolled between December 2020 and January 2023. At T2, M1- or cerebellar-iTBS significantly improved Berg balance scale scores by 10.7 points ([95% CI, 2.7-18.6], P=0.009) and 14.2 points ([95% CI, 1.2-27.2], P=0.032) compared with the sham-iTBS group. Moreover, the cerebellar-iTBS group showed a significantly greater improvement in Fugl-Meyer assessment scale for lower extremities scores by 5.6 points than the M1-iTBS ([95% CI, 0.3-10.9], P=0.037) and by 7.8 points than the sham-iTBS ([95% CI, 1.1-14.5], P=0.021) groups at T2. The motor-evoked potential amplitudes of the M1- and cerebellar-iTBS groups were higher than those of the sham-iTBS group (P<0.001). CONCLUSIONS: Both M1- and cerebellar-iTBS could improve balance function. Moreover, cerebellar-iTBS, but not M1-iTBS, induced significant effects on motor recovery. Thus, cerebellar-iTBS may be a valuable new therapeutic option in stroke rehabilitation programs. REGISTRATION: URL: https://www.chictr.org.cn/; Unique identifier: ChiCTR2100047002.

The long-term effects of intermittent theta burst stimulation on Alzheimer's disease-type pathologies in APP/PS1 mice.

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 Aß 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 Aß load could be attributed to the inhibition of Aß production and facilitation of Aß 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 Aß production and facilitation of Aß degradation.

Prevalence and clinical predictors of spasticity after intracerebral hemorrhage.

BACKGROUND: Spasticity is a common complication of intracerebral hemorrhage (ICH). However, no consensus exists on the relation between spasticity and initial clinical findings after ICH. METHODS: This retrospective study enrolled adult patients with a history of ICH between January 2012 and October 2020. The modified Ashworth scale was used to assess spasticity. A trained image analyst traced all ICH lesions. Multivariable logistic regression was used to examine the association between ICH lesion sites and spasticity. RESULTS: We finally analyzed 304 patients (mean age 54.86 ± 12.93 years; 72.04% men). The incidence of spasticity in patients with ICH was 30.92%. Higher National Institutes of Health stroke scale (NIHSS) scores were associated with an increased predicted probability for spasticity (odds ratio, OR = 1.153 [95% confidence interval, CI 1.093-1.216], p < .001). Logistic regression analysis revealed that lower age, higher NIHSS scores, and drinking were associated with an increased risk of moderate-to-severe spasticity (OR = 0.965 [95% CI 0.939-0.992], p = .013; OR = 1.068 [95% CI 1.008-1.130], p = .025; OR = 4.809 [95% CI 1.671-13.840], p = .004, respectively). However, smoking and ICH in the thalamus were associated with a reduced risk of moderate-to-severe spasticity (OR = 0.200 [95% CI 0.071-0.563], p = .002; OR = 0.405 [95% CI 0.140-1.174], p = .046, respectively) compared with ICH in the basal ganglia. CONCLUSIONS: Our results suggest that ICH lesion locations are at least partly associated with post-stroke spasticity rather than the latter simply being a physiological reaction to ICH itself. The predictors for spasticity after ICH were age, NIHSS scores, past medical history, and ICH lesion sites.

Prevalence and factors influencing the occurrence of spasticity in stroke patients: a retrospective study.

BACKGROUND: To describe the prevalence and clinical characteristics of stroke patients without spasticity, and simultaneously analyse the factors related to post-stroke non-spasticity. METHODS: In this retrospective study, information on patients hospitalized in the department of rehabilitation, Daping Hospital, over the past eight years was collected. Demographic information and clinical characteristics were statistically analysed. RESULTS: A total of 819 stroke patients with an average age of 61.66±13.72 years old were analysed, including 561 males (68.5%), and 258 females (31.5%). In this study, 201 (24.5%) patients developed spasticity, and 618 (75.5%) patients had no spasticity. Patients without spasticity were older than those with spasticity. Patients with ischemic stroke and mild functional impairment were also less likely to have spasticity. Post-stroke spasticity may be related to age [odd ratio (OR): 0.982; 95% CI:0.965 to 0.999; P = 0.042), hemorrhagic stroke (OR: 1.643; 95% CI: 1.029 to 2.626; P = 0.038), National Institute of Health Stroke Scale (NIHSS) Scores (OR: 1.132; 95% CI: 1.063 to 1.204; P = 0.000]. CONCLUSION: Most stroke patients do not have spasticity, especially the elderly, patients with ischemic stroke, and those with mild functional impairment, suggesting that not all upper motor nerve injuries lead to increased muscle tension. For young individuals, patients with hemorrhagic stroke, and those with moderate to severe functional impairment, close follow-up is necessary to identify the occurrence of spasticity early on and then formulate corresponding rehabilitation strategies for prompt intervention.

Repetitive Transcranial Magnetic Stimulation Decreases Serum Amyloid-ß and Increases Ectodomain of p75 Neurotrophin Receptor in Patients with Alzheimer's Disease.

BACKGROUND: This study investigated the impact of repetitive transcranial magnetic stimulation (rTMS) on serum levels of Amyloid-ß (Aß) as well as the ectodomain of p75 neurotrophin receptor (p75ECD) in patients with Alzheimer's disease (AD). METHODS: A total of 46 patients diagnosed with AD between June 1, 2020 and December 31, 2021 were randomized to undergo either 20 Hz rTMS treatment of the left dorsolateral prefrontal cortex (DLPFC) or sham procedure. Cognitive function and activity of daily living were evaluated. Neuropsychological tests and blood samples were gathered at baseline and at 2, 3, 4, and 6 weeks after rTMS therapy. RESULTS: There were no evident differences between rTMS group and sham group in serum Aß40, Aß42, total Aß, ApoE, and p75ECD standards at baseline (p > 0.05). Serum levels of Aß40, Aß42, as well as total Aß, were significantly lower in the rTMS group at 3, 4 and 6 weeks relative to the sham group (p < 0.05). Serum p75ECD levels in the rTMS group were significantly higher than those of the sham group at 3, 4 and 6 weeks (p < 0.05). Levels of serum Aß40 (r: -0.78, -0.83, -0.68, respectively), Aß42 (r: -0.76, -0.76, -0.61, respectively) and total Aß (r: -0.74, -0.81, -0.66, respectively) were negatively correlated with MoCA, MMSE and MBI scores, while serum p75ECD levels (r: 0.84, 0.90, 0.72, respectively) were positively correlated (p < 0.01). The level of serum Aß40 (r = 0.77), Aß42 (r = 0.69) as well as total Aß (r = 0.73) were positively correlated with ADAS-cog score, while p75ECD levels (r = -0.86) were negatively correlated (p < 0.01). CONCLUSIONS: The results of this study suggest that rTMS may decrease serum Aß levels and increase serum p75ECD levels in patients with AD, offering insight into a potential underpinning mechanism of rTMS.

p75NTR Ectodomain Ameliorates Cognitive Deficits and Pathologies in a Rapid Eye Movement Sleep Deprivation Mice Model.

The neurotrophin receptor p75 (p75NTR) is a circadian rhythm regulator and mediates cognitive deficits induced by sleep deprivation (SD). The soluble extracellular domain of p75NTR (p75ECD) has been shown to exert a neuroprotective function in Alzheimer's disease (AD) and depression animal models. Nevertheless, the role of p75ECD in SD-induced cognitive dysfunction is unclear. In the present study we administrated p75ECD-Fc (10, 3 mg/kg), a recombinant fusion protein of human p75ECD and fragment C of immunoglobulin IgG1, to treat mice via intraperitoneal injection. The results revealed that peripheral supplementation of high-dose p75ECD-Fc (10 mg/kg) recovered the balance between Aß and p75ECD in the hippocampus and rescued the cognitive deficits in SD mice. We also found that p75ECD-Fc ameliorated other pathologies induced by SD, including neuronal apoptosis, synaptic plasticity impairment and neuroinflammation. The current study suggests that p75ECD-Fc is a potential candidate for SD and peripheral supplementation of p75ECD-Fc may be a prospective preventive measure for cognitive decline in SD.

Cerebellar Intermittent Theta-Burst Stimulation Reduces Upper Limb Spasticity After Subacute Stroke: A Randomized Controlled Trial.

Objective: This study aims to explore the efficacy of cerebellar intermittent theta-burst stimulation (iTBS) on upper limb spasticity in subacute stroke patients. Methods: A total of 32 patients with upper limb spasticity were enrolled and randomly assigned to treatment with cerebellar iTBS or sham stimulation before conventional physical therapy daily for 2 weeks. The primary outcomes included the modified Ashworth scale (MAS), the modified Tardieu scale (MTS), and the shear wave velocity (SWV). The secondary outcomes were the H-maximum wave/M-maximum wave amplitude ratio (Hmax/Mmax ratio), motor-evoked potential (MEP) latency and amplitude, central motor conduction time (CMCT), and the Barthel Index (BI). All outcomes were evaluated at baseline and after 10 sessions of intervention. Results: After the intervention, both groups showed significant improvements in the MAS, MTS, SWV, and BI. In addition, patients treated with cerebellar iTBS had a significant increase in MEP amplitude, and patients treated with sham stimulation had a significant decrease in Hmax/Mmax ratio. Compared with the sham stimulation group, the MAS, MTS, and SWV decreased more in the cerebellar iTBS group. Conclusion: Cerebellar iTBS is a promising adjuvant tool to reinforce the therapeutic effect of conventional physical therapy in upper limb spasticity management after subacute stroke (Chinese Clinical Trial Registry: ChiCTR1900026516).

Cerebellar Theta Burst Stimulation on Walking Function in Stroke Patients: A Randomized Clinical Trial.

Objectives: The objective of this study was to explore the efficacy of cerebellar intermittent theta burst stimulation (iTBS) on the walking function of stroke patients. Methods: Stroke patients with walking dysfunction aged 25-80 years who had suffered their first unilateral stroke were included. A total of 36 patients [mean (SD) age, 53 (7.93) years; 10 women (28%)] were enrolled in the study. All participants received the same conventional physical therapy, including transfer, balance, and ambulation training, during admission for 50 min per day during 2 weeks (10 sessions). Every session was preceded by 3 min procedure of cerebellar iTBS applyed over the contralesional cerebellum in the intervention group or by a similar sham iTBS in control group. The groups were formed randomly and the baseline characteristics showed no significant difference. The primary outcome measure was Fugl-Meyer Assessment-Lower Extremity scores. Secondary outcomes included walking performance and corticospinal excitability. Measures were performed before the intervention beginning (T0), after the first (T1) and the second (T2) weeks. Results: The Fugl-Meyer Assessment for lower extremity scores slightly improved with time in both groups with no significant difference between the groups and over the time. The walking performance significantly improved with time and between group. Two-way mixed measures ANOVA showed that there was significant interaction between time and group in comfortable walking time (F 2,68 = 6.5242, P = 0.0080, η2 partial = 0.276, ε = 0.641), between-group comparisons revealed significant differences at T1 (P = 0.0072) and T2 (P = 0.0133). The statistical analysis of maximum walking time showed that there was significant interaction between time and groups (F 2,68 = 5.4354, P = 0.0115, η2 partial = 0.198, ε = 0.734). Compared with T0, the differences of maximum walking time between the two groups at T1 (P = 0.0227) and T2 (P = 0.0127) were statistically significant. However, both the Timed up and go test and functional ambulation category scale did not yield significant differences between groups (P > 0.05). Conclusion: Our results revealed that applying iTBS over the contralesional cerebellum paired with physical therapy could improve walking performance in patients after stroke, implying that cerebellar iTBS intervention may be a noninvasive strategy to promote walking function in these patients. This study was registered at ChiCTR, number ChiCTR1900026450.

A Pilot Study on the Repetitive Transcranial Magnetic Stimulation of Aß and Tau Levels in Rhesus Monkey Cerebrospinal Fluid.

Previous studies have demonstrated that a non-invasive light-flickering regime and auditory tone stimulation could affect Aß and tau metabolism in the brain. As a non-invasive technique, repetitive transcranial magnetic stimulation (rTMS) has been applied for the treatment of neurodegenerative disorders. This study explored the effects of rTMS on Aß and tau levels in rhesus monkey cerebrospinal fluid (CSF). This is a single-blind, self-controlled study. Three different frequencies (low frequency, 1 Hz; high frequencies, 20 Hz and 40 Hz) of rTMS were used to stimulate the bilateral-dorsolateral prefrontal cortex (DLPFC) of the rhesus monkey. A catheterization method was used to collect CSF. All samples were subjected to liquid chip detection to analyze CSF biomarkers (Aß42, Aß42/Aß40, tTau, pTau). CSF biomarker levels changed with time after stimulation by rTMS. After stimulation, the Aß42 level in CSF showed an upward trend at all frequencies (1 Hz, 20 Hz, and 40 Hz), with more significant differences for the high-frequencies (p < 0.05) than for the low frequency. After high-frequency rTMS, the total Tau (tTau) level of CSF immediately increased at the post-rTMS timepoint (p < 0.05) and gradually decreased by 24 h. Moreover, the results showed that the level of phosphorylated Tau (pTau) increased immediately after 40 Hz rTMS (p < 0.05). The ratio of Aß42/Aß40 showed an upward trend at 1 Hz and 20 Hz (p < 0.05). There was no significant difference in the tau levels with low-frequency (1 Hz) stimulation. Thus, high-frequencies (20 Hz and 40 Hz) of rTMS may have positive effects on Aß and tau levels in rhesus monkey CSF, while low-frequency (1 Hz) rTMS can only affect Aß levels.

Extremely low frequency electromagnetic fields promote cognitive function and hippocampal neurogenesis of rats with cerebral ischemia.

Extremely low frequency electromagnetic fields (ELF-EMF) can improve the learning and memory impairment of rats with Alzheimer's disease, however, its effect on cerebral ischemia remains poorly understood. In this study, we established rat models of middle cerebral artery occlusion/reperfusion. One day after modeling, a group of rats were treated with ELF-EMF (50 Hz, 1 mT) for 2 hours daily on 28 successive days. Our results showed that rats treated with ELF-EMF required shorter swimming distances and latencies in the Morris water maze test than those of untreated rats. The number of times the platform was crossed and the time spent in the target quadrant were greater than those of untreated rats. The number of BrdU+/NeuN+ cells, representing newly born neurons, in the hippocampal subgranular zone increased more in the treated than in untreated rats. Up-regulation in the expressions of Notch1, Hes1, and Hes5 proteins, which are the key factors of the Notch signaling pathway, was greatest in the treated rats. These findings suggest that ELF-EMF can enhance hippocampal neurogenesis of rats with cerebral ischemia, possibly by affecting the Notch signaling pathway. The study was approved by the Institutional Ethics Committee of Sichuan University, China (approval No. 2019255A) on March 5, 2019.

Cerebellar Theta-Burst Stimulation Combined With Physiotherapy in Subacute and Chronic Stroke Patients: A Pilot Randomized Controlled Trial.

BACKGROUND: Intermittent theta-burst stimulation (iTBS) has been suggested to improve poststroke rehabilitation. The cerebellum is considered crucial for motor control. However, the effects of cerebellar iTBS with routine physical therapy on balance and motor recovery in subacute and chronic stroke patients have not been explored. OBJECTIVE: To measure the short-term effects of cerebellar iTBS with physiotherapy on the balance and functional outcomes in subacute and chronic stroke patients with hemiparesis. METHODS: Thirty hemiparetic patients were recruited for this randomized, double-blinded, sham-controlled trial, and randomized into either the treatment or sham group. Both groups participated in physiotherapy 5 times per week for 2 weeks, and cerebellar iTBS or sham iTBS was performed daily, immediately before physiotherapy. The primary outcome was the Berg balance scale (BBS) score. Secondary outcomes included the trunk impairment scale (TIS) score, Fugl-Meyer assessment scale score for lower extremities (FMA-LE), Barthel index (BI), and corticospinal excitability, as measured by transcranial magnetic stimulation. The outcomes were measured before and 1 week and 2 weeks after the intervention. RESULTS: Compared with those at baseline, significant increases were identified in all clinical scores (BBS, TIS, FMA-LE, and BI) in both groups after the 2-week intervention. The BBS and TIS scores improved more in the iTBS group than in the sham group. CONCLUSIONS: Cerebellar iTBS with physiotherapy promotes balance and motor recovery in poststroke patients. Therefore, this method can be used in low-cost, fast, and efficient protocols for stroke rehabilitation (Chinese Clinical Trial Registry: ChiCTR1900026450).

[Effects of Trunk Control Training on Dynamic Sitting Balance and Trunk Function in Hemiplegia Patients after Acute Stroke].

OBJECTIVE: To investigate the effect of trunk control training on trunk function, balance, mobility and functional independence in hemiplegia patients after acute stroke, and to compare the therapeutic effects with conventional stroke rehabilitation. METHODS: The study was designed as a randomized controlled trial. The subjects and evaluators were blinded and the therapist was unblinded. Subjects were randomly assigned to either the experimental group or the control group using a computer-generated random number table, the experimental group ( n=15) received30 min of high-intensity trunk control training plus 15 min of low-intensity conventional stroke rehabilitation (45 min, once1 d for 5 d). The control group ( n=15) received only 45 min low-intensity conventional stroke rehabilitation, once 1 d for 5 d. Trunk function was the primary outcome, which was evaluated by the Trunk Impairment Scale (TIS). The secondary outcome included balance, mobility and functional independence, which were assessed by the Brunel Balance Assessment (BBA), the Modified Rivermead Mobility Index (MRMI) and the modified Barthel Index (MBI). Subjects were assessed before and after the intervention. RESULTS: After 5 d of treatment, the scores of TIS general table, TIS static sitting balance sub table, TIS coordination sub table, BBA, MRMI and MBI were increased, but there was no statistically significant difference between the two groups (all P>0.05). The trunk control training group improved dynamic sitting balance more significantly, the score of TIS dynamic sitting balance sub table increased more than that in the control group, with a statistically significant difference ( P<0.05). CONCLUSION: The results of this study indicate that trunk control training has improved trunk function, balance, mobility, and activities of daily living in hemiplegia patients after acute stroke, and trunk control training improves dynamic sitting balance more effectively than conventional stroke rehabilitation.

Effects of kinesiology taping on trunk function, balance, and mobility in stroke patients: a pilot feasibility study.

[Purpose] This study aimed to explore whether trunk kinesiology taping (KT) can improve trunk function, mobility, and balance in post-stroke patients with hemiparesis. [Participants and Methods] We conducted a single-group pre-post design pilot feasibility study. Thirteen individuals with post-stroke hemiplegia were recruited for this study. All patients received therapeutic trunk KT on the skin, representing the direction of fibres of the trunk muscles underneath. We used the Trunk Impairment Scale (TIS) and Trunk Control Test (TCT) to measure trunk function, Fugl-Meyer assessment (FMA) for balance, limits of stability (LOS) to evaluate balance, and the modified Rivermead mobility index (MRMI) to assess mobility in post-stroke patients. All measures were assessed before and immediately after the intervention. [Results] No adverse effects were found and all patients completed the trial. Compared to the baseline, TIS scores were significantly increased after KT, whereas no changes in TCT score were detected. The directional control of LOS was significantly improved, while no significant changes were seen in the other parameters of LOS, FMA-balance, and MRMI scores. [Conclusion] The results of this investigation show that trunk KT has immediate effects that improve certain trunk functional and balance parameters in stroke patients.

Exogenous neural stem cell transplantation for cerebral ischemia.

Cerebral ischemic injury is the main manifestation of stroke, and its incidence in stroke patients is 70-80%. Although ischemic stroke can be treated with tissue-type plasminogen activator, its time window of effectiveness is narrow. Therefore, the incidence of paralysis, hypoesthesia, aphasia, dysphagia, and cognitive impairment caused by cerebral ischemia is high. Nerve tissue regeneration can promote the recovery of the aforementioned dysfunction. Neural stem cells can participate in the reconstruction of the damaged nervous system and promote the recovery of nervous function during self-repair of damaged brain tissue. Neural stem cell transplantation for ischemic stroke has been a hot topic for more than 10 years. This review discusses the treatment of ischemic stroke with neural stem cells, as well as the mechanisms of their involvement in stroke treatment.