Effects and safety of high-frequency rTMS in subacute ischemic stroke patients.

OBJECTIVE: Although high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) has shown benefits in chronic stroke, its application in subacute ischemic stroke remains underexplored. This study aims to investigate the effects and safety of lesion-side HF-rTMS in subacute ischemic stroke. METHODS: Prospective lesion-side HF-rTMS was conducted on consecutive ischemic stroke patients within 3 days of onset from February 2019 to June 2022. Inclusion criteria required persistent paralysis (NIHSS score ≥ 1 for at least 7 days). Exclusion criteria comprised cortical infarction, disturbance of consciousness, and age over 80 years. A conventional rehabilitation group meeting the same criteria from June 2015 to January 2019 served as a comparison. We compared the two groups regarding clinical background and outcome. We also evaluated incidence of epilepsy and exacerbation of the NIHSS score in the rTMS group. RESULTS: Seventy-eight patients participated, with 50% in the HF-rTMS group. Median time from onset to HF-rTMS initiation was 9 (IQR 7-12) days. A favorable outcome (modified Rankin Scale score 0-2) at 3 months was more frequent in the rTMS group (80% vs. 44%, p = 0.002). HF-rTMS was independently associated with a favorable outcome at 3 months (OR = 5.60, 95% CI = 1.53-20.50, p = 0.009). No cases of epilepsy or exacerbation of NIHSS score were observed. CONCLUSIONS: HF-rTMS demonstrates potential effectiveness and safety in subacute ischemic stroke patients.

Upper-Limb Functional Recovery in Chronic Stroke Patients after COVID-19-Interrupted Rehabilitation: An Observational Study.

Background/Objectives: Upper-limb function of chronic stroke patients declined when outpatient rehabilitation was interrupted and outings restricted, owing to the novel coronavirus infection (COVID-19) pandemic. We investigated whether these patients recovered upper-limb function post-resumption of outpatient rehabilitation. Methods: In this observational study, 43 chronic stroke hemiparesis patients with impaired upper extremity function were scored for limb function via the Fugl-Meyer assessment of the upper extremity (FMA-UE) and the Action Research Arm Test (ARAT) after a structured interview, evaluation, and intervention. Scores at 6 and 3 months pre- and 3 months post-rehabilitation interruption were examined retrospectively; scores immediately and at 3 and 6 months post-resumption of care were examined prospectively. The amount of change for each time period and an analysis of covariance were performed with time as a factor, changes in the FMA-UE and the ARAT scores as dependent variables, and statistical significance at 5%. Results: The time of evaluation significantly impacted the total score, as well as part C and part D of FMA-UE and total, pinch, and gross movement of the ARAT. Post-hoc tests showed that the magnitude of change in limb-function scores from immediately to 3 months post-resumption was significantly higher than the change from 3 months pre- to immediately post-interruption for the total score and part D of the FMA-UE, as well as grip and gross movement of the ARAT (p < 0.05). Conclusions: Upper-limb functional decline in chronic stroke patients, caused by the COVID-19 pandemic-related therapy interruption and outing restrictions, was resolved approximately 3 months post-resumption of rehabilitation therapy. Our data can serve as reference standards for planning and evaluating treatment for chronic stroke patients with inactivity-related impaired upper-limb function.

Improved language function for post-stroke aphasia in the long term following repeated repetitive transcranial magnetic stimulation and intensive speech-language-hearing therapy: a case report.

BACKGROUND: There have been no papers reporting improvement in language function and changes in cerebral blood flow following repeated use of repetitive transcranial magnetic stimulation in combination with intensive speech-language-hearing therapy. This case report concerns the efficacy of repeated use of repetitive transcranial magnetic stimulation and intensive speech-language-hearing therapy for a certain patient suffering from aphasia following stroke, plus the findings of the cerebral blood flow measurements. CASE PRESENTATION: The patient was a 71-year-old right-handed Japanese male who developed fluent aphasia following a left middle cerebral artery stroke. He underwent repetitive transcranial magnetic stimulation and intensive speech-language-hearing therapy five times in total. The repetitive transcranial magnetic stimulation was applied to right inferior frontal gyrus at the frequency of 1 Hz plus 2 hours per day of intensive speech-language-hearing therapy. The patient's language function was evaluated in the short term and long term. Cerebral blood flow was measured with single photon emission computed tomography scan. As a result, in the short term, the patient's language function improved especially during the initial hospitalization. In the long term, it improved gradually and stabilized.Cerebral blood flow was increased in the right hemisphere. CONCLUSIONS: The findings of the study indicate that the repeated use of repetitive transcranial magnetic stimulation and intensive speech-language-hearing therapy may be effective in improving and preserving language function and increasing cerebral blood flow for aphasia following stroke.

Effects and safety of high-frequency rTMS in acute intracerebral hemorrhage patients: A pilot study.

OBJECTIVE: Although high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) in chronic intracerebral hemorrhage (ICH) is beneficial, it has been poorly investigated in rTMS for acute ICH. Our aim is to investigate the effects and safety of rTMS in acute spontaneous ICH. METHODS: We prospectively performed HF-rTMS on consecutive patients with ICH within 24 h from onset between April 2019 and August 2021. The inclusion criterion was (1) persistent paralysis, with an NIHSS scale of 1 or higher for at least 3 days after onset. The exclusion criteria were (1) cortical, subcortical, and cerebellar ICH, (2) disturbance of consciousness, and (3) over 80 years of age. For the purpose of comparison, we used a conventional rehabilitation group whose patients met the same criteria between April 2016 and March 2019. We evaluated incidence of epilepsy and exacerbation of the NIHSS score in the rTMS group. We also compared the two groups regarding clinical background and outcome. RESULTS: Enrolled in the study were a total of 44 patients. Of the patients, 22 (50%) were in the rTMS group. The median (IQR) time from onset to the start of rTMS was 9 (6-12) days. There were no cases of epilepsy or exacerbation of NIHSS after the start of rTMS. Favorable outcome (modified Rankin Scale score of between 0 and 2) at 3 months was frequently observed in the rTMS group (73% vs 27%, p = 0.006). HF-rTMS was independently associated with favorable outcome at 3 months (OR = 11.5, 95% CI = 2.194-60.447, p = 0.004). CONCLUSIONS: HF-rTMS may be safe and effective in acute ICH patients.

Changes in motor paralysis involving upper extremities of outpatient chronic stroke patients from temporary rehabilitation interruption due to spread of COVID-19 infection: An observational study on pre- and post-survey data without a control group.

BACKGROUND: Outpatient rehabilitation was temporarily suspended because of coronavirus disease (COVID-19), and there was a risk that patients' activities of daily living (ADLs) would decrease and physical functions unmaintained. Therefore, we investigated the ADLs and motor functions of chronic stroke patients whose outpatient rehabilitation was temporarily interrupted. METHODS: In this observational study, the Fugl-Meyer Assessment of the Upper Extremity (FMA-UE), Action Research Arm Test (ARAT), and Barthel Index (BI) scores of 49 stroke hemiplegic patients at 6 and 3 months before rehabilitation interruptions were retrospectively determined and were prospectively investigated on resumption of outpatient rehabilitation. Presence or absence of symptoms and difficulties caused by the interruption period (IP) was investigated using a binomial method. Deltas were analyzed using a generalized linear model (GLM) according to the survey period. Age, sex, severity of FMA-UE immediately post-resumption and post-onset period were used as covariates. For survey items showing significant model fit, the 95% confidence interval of minimum detectable change (MDC95) was calculated, and the amount of change was compared. Questionnaire responses were tested via proportion ratio. Statistical significance was set at 5%. RESULTS: The FMA-UE part A and total scores were significantly model fit depending on periods. The estimated FMA-UE total score decreased by 1.64 (z = -2.38, p = 0.02) during the 3-month IP. No fits were observed by GLM in other parts of the FMA-UE, ARAT, or BI. The calculated MDC95 was 3.58 for FMA-UE part A and 4.50 for FMA-UE overall. Answers to questions regarding sleep disturbance and physical pain were significantly biased toward "no" in the psychosomatic function items (p<0.05). There was no bias in the distribution of answers to questions regarding joint stiffness, muscle weakness, muscle stiffness, and difficulty in moving arms and hands. All 16 questions regarding activities and participation items were significantly biased toward answers "no" (p<0.05). CONCLUSIONS: The FMA-UE part A and total scores were affected. Patients complained of subjective symptoms related to upper limb paralysis after the IP. Since ADLs of patients were maintained, the therapist can recommend that patients not receiving outpatient treatments be evaluated in relation to the shoulder, elbow, and forearm and instructed on self-training to maintain motor function.

A pilot study verifying the effectiveness of high-frequency repetitive transcranial magnetic stimulation in combination with intensive speech-language-hearing therapy in patients with chronic aphasia.

BACKGROUND: A lot of research on the effectiveness of repetitive transcranial magnetic stimulation (rTMS) in patients with aphasia in the chronic stage deals with low-frequency stimulation, and reports on high-frequency stimulation (HF-rTMS) are scarce. OBJECTIVE: The purpose of this study was to evaluate retrospectively the effectiveness of high-frequency rTMS in combination with intensive speech-language-hearing therapy (ST) following the identification of the stimulation site using functional magnetic resonance imaging (fMRI) before, after the procedure and at 3 months in patients with aphasia in the chronic stage. METHODS: 20 patients with aphasia in the chronic stage who met the eligibility criteria for rTMS therapy and who underwent HF-rTMS for the first time were included in the present study. All patients received fMRI before hospitalization, and the stimulation site was decided accordingly. RESULTS: There was a significant improvement in all patients, rTMS to the left hemisphere, fluent and non-fluent groups by the evaluation of pre- and post- treatment by hospitalization. All groups had a significant improvement in total Standard Language Test of Aphasia score at 3 months when compared with the time of hospitalization. CONCLUSIONS: The current study indicates that HF-rTMS in combination with intensive ST is an effective therapeutic approach for patients with aphasia in the chronic stage.

Prediction of Motor Recovery in the Upper Extremity for Repetitive Transcranial Magnetic Stimulation and Occupational Therapy Goal Setting in Patients With Chronic Stroke: A Retrospective Analysis of Prospectively Collected Data.

Recovery from motor paralysis is facilitated by affected patients' recognition of the need for and practice of their own exercise goals. Neurorehabilitation has been proposed and used for the treatment of motor paralysis in stroke, and its effect has been verified. If an expected score for the neurorehabilitation effect can be calculated using the Fugl-Meyer Motor Assessment (FMA), a global assessment index, before neurorehabilitation, such a score will be useful for optimizing the treatment application criteria and for setting a goal to enhance the treatment effect. Therefore, this study verified whether the responsiveness to a treatment method, the NovEl intervention using repetitive transcranial magnetic stimulation and occupational therapy (NEURO), in patients with post-stroke upper extremity (UE) motor paralysis could be predicted by the pretreatment FMA score. No control group was established in this study for NEURO treatment. To analyze the recovery of the motor function in the UE, delta-FMA was calculated from the pre- and post-FMA scores obtained during NEURO treatment. The probability of three levels of treatment responsiveness was evaluated in association with delta-FMA score (<5, 5 ≤ delta-FMA <10, and ≥10 as non-responders; responders; and hyper-responders, respectively) according to the reported minimal clinically important difference (MCID). The association of the initial FMA scores with post-FMA scores, from the status of the treatment responsiveness, was determined by multinomial logistic regression analysis. Finally, 1,254 patients with stroke, stratified by FMA scores were analyzed. About 45% of the patients who had FMA scores ranging from 30 to 40 before treatment showed improvement over the MCID by NEURO treatment (odds ratio = 0.93, 95% CI = 0.92-0.95). Furthermore, more than 25% of the patients with more severe initial values, ranging from 26 to 30, improved beyond the MCID calculated in the acute phase (odds ratio = 0.87, 95% CI = 0.85-0.89). These results suggest that the evaluated motor function score of the UE before NEURO treatment can be used to estimate the possibility of a patient recovering beyond MCID in the chronic phase. This study provided clinical data to estimate the effect of NEURO treatment by the pretreatment FMA-UE score.

Dose-response of rPMS for upper Limb hemiparesis after stroke.

INTRODUCTION: Repetitive peripheral magnetic stimulation (rPMS) therapy is an innovative and minimally invasive neurorehabilitative technique and has been shown to facilitate neural plasticity. However, there is at present no research that clarifies the dose-response of rPMS therapy on the recovery of upper limb hemiparesis after stroke. This trial aims to clarify the dose-response of rPMS therapy combined with intensive occupational therapy (OT) for chronic stroke patients with moderate to severe upper limb hemiparesis. METHODS AND ANALYSIS: This multicenter, prospective, assessor-blinded, randomized controlled study with 3 parallel groups will be conducted from January 20, 2020 to September 30, 2022. Fifty patients will be randomly assigned in a ratio of 1:2:2 to the control group, the group receiving daily 2400 pulses of rPMS, or the group receiving daily 4800 pulses of rPMS, respectively. From the day after admission (Day 1), rPMS therapy and intensive OT will be initiated. The primary outcome is the change in the motor function of the affected upper extremity (Fugl-Meyer Assessment) between the time of admission (Day 0) and the day after 2 weeks of treatment (Day 14). Secondary outcomes will include the changes in spasticity, active range of motion, motor evoked potential, and activity of daily living. ETHICS AND DISSEMINATION: The study was approved by the Jikei University Certified Review Board for all institutions (reference number: JKI19-020). Results of the primary and secondary outcomes will be published in a peer-reviewed journal and presented at international congresses. The results will also be disseminated to patients. TRIAL REGISTRATION NUMBER: jRCTs032190191.

Diffusion Tensor Imaging Evaluation of Neural Network Development in Patients Undergoing Therapeutic Repetitive Transcranial Magnetic Stimulation following Stroke.

We aimed to investigate plastic changes in cerebral white matter structures using diffusion tensor imaging following a 15-day stroke rehabilitation program. We compared the detection of cerebral plasticity between generalized fractional anisotropy (GFA), a novel tool for investigating white matter structures, and fractional anisotropy (FA). Low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) of 2400 pulses applied to the nonlesional hemisphere and 240 min intensive occupation therapy (OT) daily over 15 days. Motor function was evaluated using the Fugl-Meyer assessment (FMA) and Wolf Motor Function Test (WMFT). Patients underwent diffusion tensor magnetic resonance imaging (MRI) on admission and discharge, from which bilateral FA and GFA values in Brodmann area (BA) 4 and BA6 were calculated. Motor function improved following treatment (p < 0.001). Treatment increased GFA values for both the lesioned and nonlesioned BA4 (p < 0.05, p < 0.001, resp.). Changes in GFA value for BA4 of the lesioned hemisphere were significantly inversely correlated with changes in WMFT scores (R2 = 0.363, p < 0.05). Our findings indicate that the GFA may have a potentially more useful ability than FA to detect changes in white matter structures in areas of fiber intersection for any such future investigations.

Impact of orthotic therapy for improving activities of daily living in individuals with spinal cord injury: a retrospective cohort study.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To determine the impact of leg orthotic therapy for improving activities of daily living after spinal cord injury. SETTING: Participating acute care and rehabilitation hospitals across Japan. METHODS: We retrospectively identified individuals with spinal cord injury admitted to eight participating hospitals in 2015-2016 from the Japan Rehabilitation Database. Data for 293 individuals were analyzed. Propensity score analysis by inverse probability weighting (IPW) was applied to adjust for potential bias and create two comparable groups. Outcomes were compared between the leg orthotic group and the non-leg orthotic group, using IPW. The primary outcome was motor Functional Independence Measure® (FIM) effectiveness score and the secondary outcome was motor FIM score at discharge. FIM was measured on hospital admission and discharge. RESULTS: Leg orthoses were prescribed for 26% of the 293 individuals. Those prescribed leg orthoses had significantly higher motor FIM effectiveness scores than those who were not, before and after IPW (motor FIM effectiveness: 0.54 vs. 0.35, p < 0.01 and 0.45 vs. 0.36, p = 0.02). Discharge motor FIM was significantly higher in individuals who were prescribed leg orthoses than in those who were not, before and after IPW (discharge motor FIM: 64.5 vs. 52.2, p < 0.01 and 58.9 vs. 53.5, p = 0.02). CONCLUSIONS: Leg orthoses may improve activities of daily living in individuals with spinal cord injury after the acute phase.

Comparison of the catalytic activities of three isozymes of carnitine palmitoyltransferase 1 expressed in COS7 cells.

The enzyme carnitine palmitoyltransferase 1 (CPT1) catalyzes the transfer of an acyl group from acyl-CoA to carnitine to form acylcarnitine, and three isozymes of it, 1a, 1b, and 1c, have been identified. Interestingly, the 1c isozyme was reported to show no enzymatic activity, but it was not clearly demonstrated whether this inactivity was due to its dysfunction or due to its poor expression. In the present study, we (a) expressed individual CPT1 isozymes in COS7 cells, (b) evaluated quantitatively their expression levels by Western blotting using the three bacterially expressed CPT1 isozymes as standards, and (c) evaluated their catalytic activities. With these experiments, we successfully demonstrated that the absence of the enzymatic activity of the 1c isozyme was due to its dysfunction. In addition, experiments on the preparation of standard CPT1 isozymes revealed that the 1c isozyme did not show the standard relationship between migration in an SDS-PAGE gel and molecular size. We further tried to determine why the 1c isozyme was inert by preparing chimeric CPT1 between 1a and 1c, but no clear conclusion could be drawn because one of the chimeric CPT1s was not sufficiently expressed.

Comparison of two expression systems using COS7 cells and yeast cells for expression of heart/muscle-type carnitine palmitoyltransferase 1.

Carnitine palmitoyltransferase 1 (CPT1), catalyzing the transfer of the acyl group from acyl-CoA to carnitine to form acylcarnitine, is located at the outer mitochondrial membrane. Because it is easily inactivated by solubilization, expression systems using living cells are essential for its functional characterization. COS7 cells or yeast cells are often utilized for this purpose; however, the advantages/disadvantages of the use of these cells or the question as to how the CPT1 enzyme expressed by these cells differs are still uncertain. In this study, we characterized the heart/muscle-type isozyme of rat CPT1 (CPT1b) expressed by these two cellular expression systems. The mitochondrial fraction prepared from yeast cells expressing CPT1b showed 25% higher CPT1 activity than that obtained from COS7 cells. However, the expression level of CPT1b in the former was 3.8 times lower than that in the latter; and thus, under the present experimental conditions, the specific activity of CPT1b expressed in yeast cells was estimated to be approximately five times higher than that expressed in COS7 cells. Possible reasons for this difference are discussed.

Properties of signal intensities observed with individual probes of GeneChip Rat Gene 1.0 ST Array, an affymetric microarray system.

For proper evaluation of the results of microarray experiments, it is important to understand how the signal intensities of individual probes are determined. Our previous studies revealed that signal intensities of individual probes in the Agilent array system (code G4131F) are largely dependent upon the location of the probes in the mRNA. In the present study, we examined the properties of signal intensities of individual probes in an Affymetrix array system (GeneChip Rat Gene 1.0 ST Array), in which a random primer fused to the T7 promoter sequence is employed. Distinct from the Agilent array system, individual probes used in this Affymetrix array system did not show the probe-location effects, but gave relatively diverse signal intensities. However, the diversities of the signal intensities of these individual probes were not due to experimental error.

Differential effects of cold exposure on gene expression profiles in white versus brown adipose tissue.

The thermogenic function of brown adipose tissue (BAT) is known to be markedly elevated when animals are exposed to the cold, and intensive studies have been carried out to understand the molecular basis enabling effective thermogenesis in cold-exposed animals. In this study, we used microarray analysis to examine the effects of cold exposure of animals on their gene expression profiles in white adipose tissue (WAT), which seems to function as a counterpart tissue of BAT. The results indicate that the effects of cold exposure on the gene expression profiles of WAT were much more moderate than the effects on those of BAT. Possible reasons for the different responses of BAT and WAT to cold exposure are discussed.