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Background | visceral pain | NEONATAL ASPHYXIA, COMPLICATIONS | China's "open childbirth policy" is anticipated to increase the number of women undergoing repeated cesarean section (C-section). C-section has typically been performed under epidural anesthesia due to its safety and controllability [The ability of extracellular vesicles (EVs) to transport specific components of proteins, lipids, RNA and DNA, as well as deliver various physiological information is well recognized [Here, this prospective and randomized clinical trial was designed to investigate the effects of intravenous remifentanil in parturients undergoing repeated C-section under epidural anesthesia. The primary outcome was the number of UEs. Secondary outcomes included the size and protein amount of UEs, the vital signs, visceral pain score, sedation score, score of maternal satisfaction, Apgar score, the incidence of neonatal asphyxia, umbilical arterial pH, and the presence of complications. | PMC9840320 |
Methods | PMC9840320 |
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Study setting | This prospective single-center and randomized clinical trial was approved by the ethical committee of The First Affiliated Hospital of Wenzhou Medical University on 21/09/2021 (Chairperson Pro. Jinglin Xia, NO.KY2021-119) and registered at chictr.org.cn (ChiCTR2100053635) on 26/11/2021. The study was conducted in the First Affiliated Hospital of Wenzhou Medical University between 01/12/2021 and 30/06/2022 according to the criteria of Declaration of Helsinki, and informed consent was obtained from each participant. | PMC9840320 |
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Patient enrollment | Parturients with singleton, full-term pregnancies, ASA physical status I or II, age 20–40 years, height 150–170 cm, weight 50–80 kg, and body mass index (BMI) less than 35 kg/m | PMC9840320 |
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Randomization and group allocation | Using a simple randomization procedure (1:1 ratio, | PMC9840320 |
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Anesthetic procedure | No premedication was administered, and parturients were required to abstain from food and liquid intake for at least 6 h and 2 h before surgery, respectively. Intravenous access was established and nasal oxygenation at a rate of 3 L/min was administered upon entering the operating room. As a preload prior to anesthesia, 10 mL/kg of Ringer's lactate was administered. The parturient was placed in a left lateral position, and an 18-gauge cannula needle was used to puncture the epidural space, followed by the insertion of an epidural catheter. After administering 3 mL of 2% lidocaine as a test dose via the epidural catheter, an initial bolus of 6 mL 0.5% ropivacaine was delivered, followed by a supplemental dose of 6–9 mL of the same local anesthetic solution to ensure the upper sensory block level of T6. The local anesthetic solution could be administered as needed, up to a safe maximum dose of 200 mg. If the sensory block level failed to reach T6 at 30 min after epidural administration, intravenous analgesics as rescue agents or general anesthesia would be considered and the parturient would be excluded from the study. The patient-controlled epidural analgesia package containing 150 mg ropivacaine and 3 mg morphine in 100 mL normal saline, with a bolus of 2 mL, a background flow of 2 mL/h, and a lockout interval of 15 min, was initiated for postoperative analgesia before transfer to the post-anesthesia care unit (PACU). | PMC9840320 |
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Vital signs recording | Mean arterial blood pressure (MAP), heart rate (HR), respiration rate (RR), and oxygen saturation (SpO | PMC9840320 |
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Visceral pain score | Visceral pain, pain | Visceral pain was defined as pain associated with uterine exteriorization and peritoneal traction. The intensity of pain was measured at time points T1-6 using a standard visual analogue scale (VAS) ranging from 0 to 10. | PMC9840320 |
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Evaluation of sedation | drowsiness, irritability, anxiety | The sedation level of the parturient was determined using the Ramsay sedation score system, where level 1 indicates anxiety or irritability; level 2 indicates cooperation, quietness, and well orientation; level 3 indicates drowsiness but responsiveness to instructions; level 4 indicates a rapid response to tapping the brow or strong sound stimulation; level 5 indicates delayed response to tapping the brow or strong sound stimulation, and level 6 indicates no response to tapping the brow or strong sound stimulation. | PMC9840320 |
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Maternal satisfaction with the anesthetic method | At 24 h postoperatively, maternal satisfaction with the anesthetic method was evaluated using a five-point scale (1 = completely dissatisfied, 2 = dissatisfied, 3 = neutral or undecided, 4 = satisfied, and5 = completely satisfied). | PMC9840320 |
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Evaluation of Apgar scores and neonatal asphyxia | neurological abnormalities | NEONATAL ASPHYXIA, NEONATAL ASPHYXIA | The neonatal Apgar scores were recorded at 1 min, 5 min, and 10 min after birth, and the occurrence of neonatal asphyxia was documented. Neonatal asphyxia was diagnosed using the following clinical criteria: neurological abnormalities or neonatal resuscitation required at birth, and/or an Apgar score < 7 at 5 min. | PMC9840320 |
Umbilical arterial pH and the isolation of exosomes | UEs | 6 mL of blood samples were obtained from the umbilical artery at 5 min after delivery. One portion of each sample was analyzed for pH. UEs were isolated from another portion of umbilical cord sample using ExoQuick exosome precipitation solution (System Biosciences, Palo Alto, CA, USA), a commercially available kit that gently precipitates exosomes ranging in size from 30 and 200 nm [ | PMC9840320 |
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Characterization of exosomes using nanoparticle tracking analysis (NTA) | NTA measurements were performed in a flow model using a NanoSight NS300 instrument (Malvern Panalytical, Malvern, United Kingdom) equipped with a 488 nm laser and sCMOS camera module (Malvern Panalytical, Malvern, United Kingdom). Each sample was subjected to NTA at least three times to calculate the mean values. To ensure the accuracy of results, all culture medium samples were identically diluted. | PMC9840320 |
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Exosome validation by transmission electron microscopy (TEM) | TEM | The morphology of the exosome was identified using TEM. Briefly, a suspension of freshly isolated exosomes was dropped onto a formvar carbon-coated copper electron microscopy grid (Plano, Wetzlar Germany). The grid was then negatively stained for 1 min with 2% uranyl acetate solution, washed with PBS, and dried at room temperature. Finally, images were acquired with an EM 900 transmission electron microscope (Zeiss, Germany) at a voltage of 80-90kv. | PMC9840320 |
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Exosomal biomarkers measurement | tumor, ABM | TUMOR, LYSIS, SECONDARY | The total protein content of exosomes was extracted using a homemade cell lysis buffer, followed by protein precipitation using a 5 × protein loading buffer (ABM, Vancouver, Canada). After 5 min of heating in a water bath at 100 °C, the mixture was transferred to a polyvinylidene difluoride membrane (Millipore, Burlington, MA, USA). The PVDF membrane was blocked by incubating it for 1 h at room temperature in milk Tris-buffered saline with Tween20 solution. After that, the membrane was incubated for 15 h with primary antibodies against rabbit anti-mouse CD63 (1:1000; Abcam, USA) and tumor susceptibility gene 101 (TSG101; 1:1000; Abcam, USA). The membranes were then incubated for 1 h at room temperature with HRP-conjugated secondary antibodies (1:1500; Abcam, USA). Finally, the expression of proteins was determined using enhanced chemiluminescence reagents. | PMC9840320 |
Measurement of other outcomes | ADVERSE EVENTS, RESPIRATORY DEPRESSION | The adverse events that occurred during surgery and PACU stay were documented. Remifentanil infusion was stopped if the parturient developed respiratory depression, defined as SpO | PMC9840320 |
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Statistical analysis | The sample size was calculated using the OpenEpi software version 2.3.1 with the number of UEs as the primary outcome. In our preliminary study of 10 cases (n = 5 in each group), the mean number of UEs was 62 × 10Statistical analysis was performed with SPSS 26.0 software (SPSS Inc, Chicago, IL, USA). The Shapiro–Wilk test was used to examine the normality of the data. Continuous and normally distributed data were reported as mean ± standard deviation (SD), and an independent t-test was performed to compare data between the two groups. Repeated measures analysis of variance was used to compare repeated measured data between different time points within each group, non-normally distributed data were log-normally transformed if necessary before adopting the above statistical methods. Data with non-normal distribution were expressed as median (interquartile range, IQR) and analyzed using the Mann–Whitney U test. Moreover, categorical data were expressed as numbers (%), and Fisher’s exact test was employed to compare these data between the two groups. Statistical significance was defined as | PMC9840320 |
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Results | PMC9840320 |
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The vital signs of the parturients | CAVITY, UTERUS | As demonstrated in Fig. The vital signs of the parturients. T0 = immediately before anesthesia; T1 = skin incision; T2 = peritoneum incision; T3 = neonatal delivery; T4 = placental delivery; T5 = suture of the uterus; T6 = closure of the abdominal cavity; MAP, mean arterial blood pressure; HR, heart rate; SpO | PMC9840320 |
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Discussion | aching, visceral pain, blood loss, Visceral pain, shivering | NEONATAL RESPIRATORY DEPRESSION, BLOOD LOSS, CONTRACTION, ADVERSE EFFECTS, RESPIRATORY DEPRESSION | The primary finding of our present study was that the intravenous administration of remifentanil increased the number of UEs in parturients undergoing repeated C-section under epidural anesthesia. As expected, intravenous remifentanil might be considered as an effective adjunct to epidural ropivacaine for the relief of visceral pain and improvement of childbirth experience in parturients, with no significant adverse effects in neonates.Visceral pain is described as a dull, aching, ill-defined, and unpleasant feeling that is poorly localized and appears to come from deep within the body, and is frequently accompanied by malaise and strong autonomic reflexes [Remifentanil, a commonly used analgesic in obstetric anesthesia, could provide effective analgesia during monitored anesthesia care in a general patient population with minimal effects on respiration and hemodynamics at dose of 0.1 μg/kg/min [Due to its rapid metabolism, redistribution, or both, the neonatal concentration may not reach a sufficient level to induce fatal neonatal respiratory depression [Moreover, the Ramsay scores of the parturients who received remifentanil were increased significantly, and no subject developed respiratory depression (RR < 8 times/ min) without impairments in oxygen saturation and other vital signs. Continuous intravenous administration of remifentanil had little effect on uterine contraction, given that the dose of oxytocin administration and the total volume of blood loss were comparable between two groups. And, consistent with previous studies, no significant adverse effects on neonates were reported [Up to 85% of parturient undergoing C-section may experience shivering after spinal anesthesia due to an impairment of thermoregulation [Several limitations should be addressed. First, the maximum safe dose of intravenous remifentanil for C-section under epidural anesthesia is undetermined, and we should be aware that adverse outcomes are significant with bolus dose larger than 40 ug or the concomitant use of long-acting opioids [ | PMC9840320 |
Conclusion | pain | COMPLICATIONS | An intravenous bolus of 0.15 μg/kg followed by a continuous infusion of 0.075 μg/kg/min remifentanil increased the number of UEs in parturients undergoing repeated C-section under epidural anesthesia, effectively reduced visceral pain and improved birth experience of the parturients, without causing significant neonatal complications. | PMC9840320 |
Acknowledgements | The authors wish to thank all the parturients who participated in this study. | PMC9840320 |
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Authors’ contributions | Liangrong Wang helped with literature search, study design, and manuscript preparation. Juan Li helped with data acquisition, definition of intellectual content and manuscript editing. Xiaodan Yang helped with data acquisition and data analysis. Yicheng Xiong helped with the experimental studies and manuscript editing, Zilu Wang helped with data acquisition, data analysis, and statistical analysis. Li Li helped with experimental studies. Xinmiao Li and Hang Zhang helped with data acquisition, data interpretation and study design. Yong Chen helped with experimental studies and data interpretation. Xiangqing Xiong helped with concept, study design, funding acquisition, statistical analysis and manuscript review. All the authors participated in critical revision of the manuscript and provided final approval of the version to be submitted. | PMC9840320 |
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Funding | This study was supported by Wenzhou Municipal Science and Technology Bureau (No.Y20211139), Zhejiang Provincial Natural Science Foundation of China (LQ21H010002) and The Key Project of Scientific Research Fund of National Health Commission (WKJ-ZJ-2131). | PMC9840320 |
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Availability of data and materials | The datasets generated and analyzed during the current study are available from the corresponding author, on reasonable request. | PMC9840320 |
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Declarations | PMC9840320 |
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Ethics approval and consent to participate | Ethical clearance was obtained from the ethical committee of The First Affiliated Hospital of Wenzhou Medical University on 29/09/2021 (Chairperson Pro. Jinglin Xia, NO.KY2021-119) and registered at chictr.org.cn (ChiCTR2100053635) on 26/11/2021. The study was conducted according to the criteria of Declaration of Helsinki, and informed consent was obtained from each included parturient. | PMC9840320 |
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Consent for publication | Not applicable. | PMC9840320 |
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Competing interests | The authors declare that they have no competing interests. | PMC9840320 |
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References | PMC9840320 |
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Introduction | HC, malignant cerebral infarction | In malignant cerebral infarction decompressive hemicraniectomy has demonstrated beneficial effects, but the optimum size of hemicraniectomy is still a matter of debate. Some surgeons prefer a large-sized hemicraniectomy with a diameter of more than 14 cm (HC > 14). We investigated whether this approach is associated with reduced mortality and an improved long-term functional outcome compared to a standard hemicraniectomy with a diameter of less than 14 cm (HC ≤ 14). | PMC10345046 |
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Methods | DEcompressive, malignant INfarction | COMPLICATIONS | Patients from the DESTINY (DEcompressive Surgery for the Treatment of malignant INfarction of the middle cerebral arterY) registry who received hemicraniectomy were dichotomized according to the hemicraniectomy diameter (HC ≤ 14 cm vs. HC > 14 cm). The primary outcome was modified Rankin scale (mRS) score ≤ 4 after 12 months. Secondary outcomes were in-hospital mortality, mRS ≤ 3 and mortality after 12 months, and the rate of hemicraniectomy-related complications. The diameter of the hemicraniectomy was examined as an independent predictor of functional outcome in multivariable analyses. | PMC10345046 |
Results | infarct, HC | INFARCT, COMPLICATIONS | Among 130 patients (32.3% female, mean (SD) age 55 (11) years), the mean hemicraniectomy diameter was 13.6 cm. 42 patients (32.3%) had HC > 14. There were no significant differences in the primary outcome and mortality by size of hemicraniectomy. Rate of complications did not differ (HC ≤ 14 27.6% vs. HC > 14 36.6%, p = 0.302). Age and infarct volume but not hemicraniectomy diameter were associated with outcome in multivariable analyses. | PMC10345046 |
Conclusion | MIDDLE CEREBRAL ARTERY INFARCT | In this post-hoc analysis, large hemicraniectomy was not associated with an improved outcome or lower mortality in unselected patients with malignant middle cerebral artery infarction. Randomized trials should further examine whether individual patients could benefit from a large-sized hemicraniectomy. | PMC10345046 |
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Clinical trial registration information | German Clinical Trials Register (URL: | PMC10345046 |
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Supplementary Information | The online version contains supplementary material available at 10.1007/s00415-023-11766-3. | PMC10345046 |
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Keywords | Open Access funding enabled and organized by Projekt DEAL. | PMC10345046 |
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Introduction | malignant cerebral infarction | BRAIN EDEMA | In malignant cerebral infarction space-occupying brain edema is associated with a mortality of up to 80% despite intensive care treatment [The volume gained by hemicraniectomy directly correlates with the diameter of the bone flap. Current recommendations are based on in vitro models which calculated a minimum diameter of 12 cm to create an additional volume of at least 80 ml [ | PMC10345046 |
Methods | stroke, DEcompressive, infratentorial infarction, malignant INfarction, hemispheric syndrome, infarction | STROKE, INFARCTION | Between January 2010 and July 2016 patients with large ischemic infarction were prospectively included into the DEcompressive Surgery for the Treatment of malignant INfarction of the middle cerebral arterY—Registry (DESTINY-R) study in 30 neurological and neurosurgical departments in Germany and Austria.A detailed description of the study design has been published previously [For this analysis patients who fulfilled the following inclusion criteria were selected from the complete study cohort: (1) ischemic infarction of at least 50% of the middle cerebral artery territory confirmed by computed tomography (CT) or magnetic resonance imaging (MRI) with corresponding clinical signs of a severe hemispheric syndrome, with or without additional infarction of the ipsilateral anterior or posterior cerebral artery territory, (2) hemicraniectomy performed according to the decision of the treating physician independent of study participation, (3) available postoperative imaging data measuring hemicraniectomy diameter, and (4) completed follow-up assessment of functional outcome conducted after 12 months. Patients with concomitant acute contralateral and/or infratentorial infarction or additional acute traumatic brain injury were excluded. The timing of hemicraniectomy and choice of the surgical technique (including the diameter of the bone flap, type of duraplasty) were left to the discretion of the treating neurosurgeon with a reference to the current guidelines [After study inclusion, sociodemographic factors, clinical parameters (stroke severity on admission, level of consciousness on admission and before neurosurgery), pre-morbid functional status, vascular risk factors as well as surgical and medical treatment data were documented in a case report form [ | PMC10345046 |
Clinical outcome analysis | The primary outcome was defined as the functional status according to the modified Rankin Scale score (mRS) after 12 months. Clinical outcome was dichotomized as mRS 0–4 versus 5 and 6 according to the definition of the pooled analysis of the three European hemicraniectomy RCTs [ | PMC10345046 |
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Neuroimaging analysis | Neuroradiological parameters were processed centrally and blinded to functional outcome on the basis of CT or MRI scans on admission and after neurosurgery using To simplify the measurement of the hemicraniectomy diameter on postoperative imaging data, the bone flap was considered as an ellipse oriented in sagittal axis (see Fig. Non-contrast computed tomography CT scan in representative slices after alignment (rotation angles ϕAll patients were dichotomized in two groups based on the diameter of the bone flap according to the larger major axis defining diameter ≤ 14 cm as “standard hemicraniectomy” (HC ≤ 14) and > 14 cm as “large hemicraniectomy” (HC > 14) [ | PMC10345046 |
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Statistical analysis | Statistics were performed using the SPSS 26 software package (SPSS Inc., Chicago, Illinois, USA). Descriptive analyses were calculated for all variables. Student´s t test, Mann–Whitney U test, or χ | PMC10345046 |
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Discussion | herniation, malignant infarction, osmotherapy, deaths, infarct | MUSCLE RELAXATION, INFARCT, MIDDLE CEREBRAL ARTERY INFARCT, COMPLICATIONS | Despite early prophylactic hemicraniectomy almost 20% of patients who suffer a malignant middle cerebral artery infarction still die. Most deaths occur early and are due to herniation which raises the question if some patients might benefit from a larger hemicraniectomy or if a larger hemicraniectomy in general could be beneficial [Mortality in this study population was similar compared to patients treated with hemicraniectomy in the pooled analysis of RCTs in younger patients with malignant infarction [Since infarct volume can predict outcome after decompressive hemicraniectomy [In RCTs, the rates of hemicraniectomy-related complications were comparatively lower (9% and 7%, respectively) [In our cohort osmotherapy and muscle relaxation were applied more frequently in the standard hemicraniectomy group. Although both treatments had no impact on functional outcome in multivariable analyses, the increased use of osmotherapy and muscle relaxation in patients with smaller hemicraniectomies may be indicative of a poorer control of intracranial pressure compared to patients with larger bone flaps.Despite the strengths of a prospective multicenter registry, our study is not without limitations: it is a non-randomized study and the decision of timing, diameter, and technique of the hemicraniectomy was left at the discretion of the treating neurosurgeon. Hemicraniectomy with duraplasty as a procedure was not standardized [In conclusion, our results do not provide evidence that large hemicraniectomy is beneficial regarding functional outcome or mortality as compared to standard hemicraniectomy in unselected patients with malignant middle cerebral artery infarction treated by hemicraniectomy. Although our results indicate that standard hemicraniectomy may be associated with less complications and is sufficient in most cases, selected patients may still benefit from a larger diameter hemicraniectomy to achieve the best possible outcome. This relevant question should be addressed in a randomized controlled trial. | PMC10345046 |
Supplementary Information | Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 32 KB) | PMC10345046 |
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Acknowledgements | The authors thank Victoria Rücker, PhD (Institute of Clinical Epidemiology and Biometry, University Würzburg) for her support in data analysis. | PMC10345046 |
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Author contributions | EJ, TG | EJ and HN conceived, designed and supervised the study. H-PM and JK analyzed radiologic data. Analyses of clinical data were performed by DL and HN. The first draft of the manuscript was written by DL and all authors commented on previous versions of the manuscript. Data collection was performed by NH, GT, DM, TG, KEW, JS-A, HH, JBK, SW, H-HS, KW, SH, AG, HS, SP, CD, JW, EJ and HN. All authors read and approved the final manuscript. | PMC10345046 |
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Funding | Open Access funding enabled and organized by Projekt DEAL. The authors report no targeted funding. | PMC10345046 |
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Data availability | Original data are available and will be shared by request from a qualified investigator. | PMC10345046 |
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Declarations | PMC10345046 |
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Conflicts of interest | Edema, Stroke | EDEMA, STROKE, BRAIN INFARCTION | D. Lehrieder, H.P. Müller, J. Kassubek, G. Thomalla, D. Michalski, T. Gattringer, K.E. Wartenberg, J. Schultze-Amberger, H. Huttner, J.B. Kuramatsu, S. Wunderlich, H.H. Steiner, K. Weissenborn, S. Heck, H. Schneider, C. Dohmen, J. Woitzik and H. Neugebauer report no disclosures relevant to the manuscript; N. Hecht is Berlin Institute of Health Clinical Fellow, funded by Stiftung Charité; S. Poli is coordinating investigator of Automatic PredICtion of Edema after Stroke (APICES) study (ClinicalTrials.gov unique identifier: NCT04057690); A. Günther reports honoria from Pfizer, Bristol-Myers-Squibb, Boeringer Ingelheim, Daiichi Sankyo, Occlutech, Ipsen Pharma and Merz outside the submitted work; E. Jüttler reports honoria from Pfizer, Bristol-Myers-Squibb, Boehringer Ingelheim, Daiichi Sankyo and Stryker outside the submitted work. He was Principle Investigator of DESTINY and DESTINY II, Co-Investigator of the pooled analyses of randomized hemicraniectomy trials and Co-author of guidelines on intracranial pressure treatment and treatment of space-occupying brain infarction. | PMC10345046 |
Ethical approval | FRANKLIN | The trial was registered in the German Registry for Clinical Studies (DRKS00000624). The ethics committee of the Charité – Universitätsmedizin Berlin, Campus Benjamin Franklin (EA4/108/09) and the local ethics committees of all participating centers approved this registry. Written informed consent was obtained from all patients or legal representatives. | PMC10345046 |
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References | PMC10345046 |
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Objective | CMDs | DISORDERS | Edited by: Yuka Kotozaki, Iwate Medical University, JapanReviewed by: José Ignacio Ramírez Manent,Balearic Islands Health Research Institute (IdISBa), Spain;Alicia Salamanca-Sanabria, Singapore Institute for Clinical Sciences (A*STAR), SingaporeTo prevent the exacerbation of mental health burdens, a growing body of research has recommended a balanced approach that emphasizes both the delivery of mental health treatments to individuals with common mental disorders (CMDs) and the strengthening of protective factors for CMDs among nonclinical populations. This randomized controlled trial (RCT) evaluated the efficacy of a smartphone-delivered multicomponent lifestyle medicine (LM) intervention, Lifestyle Hub, for improving mental health among a nonclinical population of Chinese adults. | PMC10824847 |
Methods | Anxiety | DISORDER | A total of 106 participants with Patient Health Questionnaire-9 total score < 10 and Generalized Anxiety Disorder 7-Item Scale <8 were randomly assigned to either the Lifestyle Hub intervention group (LH, | PMC10824847 |
Results | depressive, insomnia, anxiety | The linear mixed effect model based on the intention-to-treat principle indicated that Lifestyle Hub significantly improved overall mental health, depressive symptoms, anxiety symptoms, stress, insomnia severity, overall health-promoting behaviors, dietary quality, and stress management compared to the WL group at immediate post-intervention ( | PMC10824847 |
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Introduction | CMDs, anxiety, Common mental disorders, CMD, depressive, depression | Common mental disorders (CMDs), such as depression and anxiety, are significant public health concerns worldwide. Recent studies indicated that the prevalence of depression and anxiety among the general population ranged between 32% and 38% across the globe (Considering the sound evidentiary support for the relationship between lifestyles and the onset and development of CMDs, there has been a growing interest in the lifestyle medicine (LM) approach as one of the potential options for managing CMD symptoms in clinical populations and promoting mental health in nonclinical populations (Recent meta-analytic reviews revealed that multicomponent LM interventions comprising exercise, diet and nutrition, sleep management, and/or stress management were efficacious for improving depressive (The utilization of smartphones has emerged as a promising approach for augmenting the dissemination and reach of LM interventions. With an estimated 80% of the world population being smartphone users (Given the potential merit of smartphone-delivered interventions in managing CMDs, a pioneering smartphone-delivered LM intervention, Lifestyle Hub, was developed ( | PMC10824847 |
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Methods | PMC10824847 |
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Study design | MAY | To assess the efficacy of Lifestyle Hub in improving mental health, a two-arm RCT was conducted between February and May 2020. A total of 106 eligible participants were randomly assigned to either the intervention group receiving the 8-week smartphone-delivered multicomponent LM intervention (Lifestyle Hub; LH) or the WL control group. This study was approved by the Survey and Behavioral Research Ethics Committee (Reference no. SBRE-19-303), The Chinese University of Hong Kong. The trial was registered with | PMC10824847 |
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Eligibility criteria | depressive symptoms | Participants were eligible if they (1) were Hong Kong residents; (2) aged 18 years or older; (3) were able to read Chinese and type in Chinese or English; (4) had an internet-enabled mobile device (iOS or Android operating system); and (5) were willing to provide informed consent and comply with the trial protocol. Participants were excluded if they (1) had a Patient Health Questionnaire-9 (PHQ-9) total score ≥ 10, indicating the presence of at least a moderate level of depressive symptoms ( | PMC10824847 |
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Recruitment and study procedure | anxiety, depressive symptoms | Participants were recruited via the university mass mailing system, social networking websites (i.e., Facebook and Instagram), and print media. Prospective participants were required to complete a set of online questionnaires for screening purposes, which included (1) the PHQ-9 measuring depressive symptoms and current suicidality; (2) the GAD-7 measuring anxiety symptoms, (3) a self-report checklist on eligibility criteria, and (4) a demographics questionnaire. Eligible participants were invited to participate in this study via text messaging or telephone calls by a research assistant. Besides, they were instructed to download an in-house smartphone application (Given the nature of the study design, blinding of participants and research personnel was not possible. However, the data analyst was blinded to the group assignment. The research assistant instructed the participants in the LH group to download Lifestyle Hub, and each LH participant was provided with a unique account via text messages. The LH participants were informed that Lifestyle Hub is a self-help intervention such that no therapeutic support would be provided throughout the trial period. However, they could contact the research assistant for technical assistance (e.g., log-in problems). Participants assigned to the WL group were informed that they would be given access to Lifestyle Hub upon the completion of the immediate post-intervention assessment at Week 9. A research compensation of HK$100 (approximately USD12.8) was offered to the participants in both groups after they completed all the required assessments. | PMC10824847 |
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The LH intervention group | breathing exerciseExplain | SESSION | The detailed intervention content has been published elsewhere (Overview of the intervention structure and content of Lifestyle Hub.Overview of Introduction to lifestyle medicineA brief assessment of physical activityIntroduction to low-intensity exercise with demonstration videosExplain the association between physical activity and mental healthIntroduction to calories (with gamified tests)Tips for healthy eatingExplain the relationship between food micronutrients and mental healthSMART goal-settingSetting up mid-term and short-term goalsDaily lifestyle tasks (physical activity and diet)Introduction to low-intensity exercise with demonstration videos (i.e., flexibility and balancing exercise)Introduction to food nutrition labelsIntroduction to progressive muscle relaxationExplain the association between sleep and mental healthSetting up short-term goalsDaily lifestyle tasks (physical activity and diet)Progressive muscle relaxationIntroduction to moderate-intensity exercise with demonstration videos (i.e., cardiovascular and muscle training)Wake-up and wind-down routineSleep hygiene and sleep–wake regularityStimulus controlWorry timeProblem-solving strategiesSetting up short-term goalsDaily lifestyle tasks (physical activity and diet)Wake-up and wind-down routine practiceWorry time and problem-solving practiceIntroduction to yoga and abdominal breathing exerciseExplain the association between mindfulness and mental healthIntroduction to positive psychologySetting up short-term goalsDaily lifestyle tasks (physical activity and diet)Mindfulness and abdominal breathing practiceGratitude journalRevision of all session contentReview of Review self-setting goals and lifestyle modification progressSetting long-term goalsSetting up long-term goalsDaily practice of lifestyle modificationsTo facilitate intervention delivery and participant understanding, the eight 60-min weekly sessions were divided into 45 submodules (i.e., 5–6 submodules per session), and the content was structured to progress from low to high intensity. Each weekly session began with a review of the previous session to consolidate participant learning outcomes (except for Session 1). Subsequently, new intervention content was introduced through animated videos (8–15 min each with video scripts supplemented), gamified mini quizzes, texts, audios, and/or infographics. Each weekly session was concluded with a smart goal-setting submodule to facilitate short/long-term lifestyle modifications and self-monitoring of intervention progress. The motivational interviewing approach was adopted to promote lifestyle modifications and guide participants to accomplish their lifestyle goals ( | PMC10824847 |
The WL control group | Participants allocated to the WL control group were advised to maintain their usual lifestyle routines and were given access to Lifestyle Hub upon the completion of the immediate post-intervention assessment at Week 9. | PMC10824847 |
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Outcome measures | anxiety, Functional disability, insomnia, Insomnia, depressive symptoms, Depression | SHEEHAN, SECONDARY | Self-report outcome measures were collected at baseline (Week 0), immediate post-intervention (Week 9), and 1-month post-intervention (LH only; Week 13). The primary outcome was overall mental health conditions as assessed by the Chinese version of Depression Anxiety Stress Scales-21 (DASS-21) (The secondary outcomes included depressive symptoms, anxiety symptoms, stress levels, insomnia severity, functional disability, HRQOL, HPBs, and intervention acceptability. The Chinese version of the Insomnia Severity Index (ISI) (Functional disability was measured by the Chinese version of the Sheehan Disability Scale (SDS) on an 11-point Likert scale (HRQOL was measured by the Hong Kong version of the Short Form (Six-Dimension) Health Survey (SF-6D) (HPBs were assessed using the Chinese version of the Health-Promoting Lifestyle Profile (HPLP-II) (The Chinese version of the Credibility-Expectancy Questionnaire (CEQ) was adopted to evaluate intervention acceptability ( | PMC10824847 |
Statistical analysis | Sample size estimation was conducted using G*Power 3 (The R version 4.1.2 ( | PMC10824847 |
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Results | PMC10824847 |
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Participant characteristics | In sum, 546 prospective participants completed the online screening for eligibility, of which 348 were excluded due to a variety of reasons (CONSORT flow diagram.Baseline characteristics.Data were presented as mean ( | PMC10824847 |
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Intervention dropout | The study attrition rates (i.e., the number of dropouts throughout the entire study period) of the LH and WL groups were 20.8% ( | PMC10824847 |
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Intervention usage | At Week 9, the 44 LH participants who completed the immediate post-intervention assessment had a mean Lifestyle Hub utilization of 11 days ( | PMC10824847 |
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Intervention acceptability | The paired-samples | PMC10824847 |
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Discussion | depression, insomnia, anxiety, depressive symptoms | RECRUITMENT | This RCT examined the efficacy and acceptability of a smartphone-delivered multicomponent LM intervention, Lifestyle Hub, for improving mental health among a nonclinical population of Chinese adults. The results indicated that Lifestyle Hub had small to moderate effects (The findings regarding the improvement in depressive symptoms (Contrary to the hypothesis, Lifestyle Hub did not result in a significant improvement in health responsibility compared to the WL control group at immediate post-intervention. This finding is noteworthy, as our previous RCT found a moderate to large between-group improvement in health responsibility at immediate post-intervention (Furthermore, our results demonstrated nonsignificant group-by-time interaction in functional impairment, HRQOL, spiritual growth, and physical activity level between the LH and WL groups, while the previous RCT found significant improvements in these outcomes with small to large effect sizes (In our study, the LH group demonstrated a significantly higher (20.8%) study attrition rate than the WL control group (5.7%). Despite a higher attrition rate relative to our previous RCT (While this RCT has contributed to the body of evidence supporting the efficacy of the LM approach in improving mental health in nonclinical populations, the results should be considered in light of the following potential limitations. Despite utilizing open recruitment strategies to enhance the generalizability of the sample, the included sample was predominantly female (77.4%) and those with higher educational attainment (75.5%). Moreover, the lack of blinding of participants might threaten the internal validity of the study findings. In addition, the potential improvements in outcomes may be masked by the floor effect, given a nonclinical sample was targeted in this RCT. Besides, the medium- and long-term effects of Lifestyle Hub are unclear, considering that the only follow-up assessment was conducted at 1-month post-intervention. Further investigation into the durability of the Lifestyle Hub is needed since the LM approach stresses long-term benefits (This RCT represents a pioneer attempt to investigate the efficacy of a smartphone-delivered multicomponent LM intervention for improving mental health among a nonclinical population. Several research endeavors are important to be considered in future literature. First, future trials that include participants with a variety of diagnostic profiles (e.g., depression, anxiety, and /or insomnia) are warranted to establish the transdiagnostic potential of the LM approach. Additionally, it is crucial for upcoming causal research to understand the direct impacts of LM on CMDs and the underlying mechanisms of change. Concurrently, identifying the potential moderators and mediators as well as delineating the direct and indirect effects of LM on CMDs are also important (In summary, smartphone-delivered multicomponent LM intervention may serve as an efficacious, safe, and acceptable option for improving overall mental health conditions, insomnia severity, overall HPBs, dietary quality, and stress management in nonclinical adult populations. Future research is needed to investigate the long-term efficacy of Lifestyle Hub and how to maximize the benefits of smartphone-delivered LM interventions at the population level. | PMC10824847 |
Data availability statement | The datasets presented in this article are not readily available because the data underlying this article will be shared on reasonable request to the corresponding author. Requests to access the datasets should be directed to FY-YH, | PMC10824847 |
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Ethics statement | The studies involving humans were approved by Survey and Behavioral Research Ethics Committee, The Chinese University of Hong Kong. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. | PMC10824847 |
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Author contributions | VWW and FY-YH designed the study protocol, developed the intervention, performed the data analysis, and contributed to the writing of the manuscript. JTT and N-KS assisted in developing the intervention and data collection and contributed to the writing of the manuscript. CN and JS verified the intervention content and contributed to the writing and reviewing of the manuscript. All authors contributed to the article and approved the submitted version.The authors wish to thank all the participants in the study and the members of the Public Mental Health Laboratory, The Chinese University of Hong Kong for their contributions to this research. | PMC10824847 |
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Abbreviations | Anxiety, CMD, Insomnia, Health-Promoting Behaviors, Depression Anxiety Stress Scales-21 | SHEEHAN, DISORDER | CMD, Common Mental Disorder; CEQ, Credibility-Expectancy Questionnaire; DASS-21, Depression Anxiety Stress Scales-21; GAD-7, Generalized Anxiety Disorder 7-Item Scale; HPBs, Health-Promoting Behaviors; HRQOL, Health-Related Quality of Life; ISI, Insomnia Severity Index; LMM, Linear Mixed-Effects Model; LM, Lifestyle Medicine; PHQ-9, Patient Health Questionnaire-9; RCT, Randomized Controlled Trial; SDS, Sheehan Disability Scale; WL, Waitlist. | PMC10824847 |
Conflict of interest | CN had served as a consultant for Lundbeck, Grunbiotics, Servier, Janssen-Cilag, Wyeth, and Eli Lilly, received research grant support from Wyeth and Lundbeck, and speaker honoraria from Servier, Lundbeck, Bristol-Myers Squibb, Organon, Eli Lilly, GlaxoSmithKline, Janssen-Cilag, Astra-Zenaca, Wyeth, and Pfizer, none related to this publication.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | PMC10824847 |
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Publisher’s note | All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. | PMC10824847 |
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References | PMC10824847 |
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Subject terms | stroke | STROKE, CORTEX | Upregulation of neuroplasticity might help maximize stroke recovery. One intervention that appears worthy of investigation is aerobic exercise. This study aimed to determine whether a single bout of moderate intensity aerobic exercise can enhance neuroplasticity in people with stroke. Participants were randomly assigned (1:1) to a 20-min moderate intensity exercise intervention or remained sedentary (control). Transcranial magnetic stimulation measured corticospinal excitability of the contralesional hemisphere by recording motor evoked potentials (MEPs). Intermittent Theta Burst Stimulation (iTBS) was used to repetitively activate synapses in the contralesional primary motor cortex, initiating the early stages of neuroplasticity and increasing excitability. It was surmised that if exercise increased neuroplasticity, there would be a greater facilitation of MEPs following iTBS. Thirty-three people with stroke participated in this study (aged 63.87 ± 10.30 years, 20 male, 6.13 ± 4.33 years since stroke). There was an interaction between Time*Group on MEP amplitudes ( | PMC10475034 |
Introduction | stroke, disabilityA, Stroke | STROKE, STROKE | Stroke remains a leading global cause of adult disabilityA topical question in stroke recovery is whether it is possible to re-open, or prolong, the spontaneous period of enhanced neuroplasticity seen after stroke. Ability to do so might lead to greater recovery. A mouse model of stroke has provided some evidence to suggest this may be possibleThe aim of this pilot study was to investigate whether moderate intensity exercise could increase neuroplasticity in people with stroke. We specifically investigated people who were several months after stroke to avoid the initial, brief, spontaneous period of enhanced neuroplasticity that emerges early after stroke | PMC10475034 |
Methods | PMC10475034 |
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Participants | stroke, seizures, seizure | STROKE, RECRUITMENT, NEUROLOGICAL DISEASE | People who had experienced stroke at least three months prior, were community ambulators, medically stable and over the age of 18 years were invited to participate. Recruitment occurred via advertisement in a university health clinic and distributing information to willing volunteers in a research database. Exclusion criteria were previous diagnosis of another neurological disease, recent craniotomy or neurosurgical intervention, any concurrent medication known to modify seizure threshold, presence of contraindications to transcranial magnetic stimulation (TMS; such as metallic implants in the skull, history of seizures or implanted permanent pacemaker)Whilst this was a pilot study, a power calculation was performed based on an estimated effect size. To achieve a power of 80%, an allowable difference of 0.5, and population variance of 0.9 at | PMC10475034 |
Study design and protocol | A single-blinded, randomized, parallel group, controlled study was conducted to explore physiological effects of cardiovascular exercise on the brain. Participants were allocated to either the intervention or control group following consent using a random number generator. Allocation was concealed prior to enrolment, with intervention personnel and participants unaware of the allocation until all baseline measures were complete. All experimental work was completed in a single session that involved baseline neurophysiological measures of corticospinal excitability, an exercise or rest condition (randomized 1:1), and a neuroplasticity assessment. The measure of neuroplasticity was performed using iTBS and assessments of corticospinal excitability (Fig. Experimental protocol. Following screening and randomization, procedures are shown with top describing the intervention arm, and bottom the control arm. Abbreviations: iTBS, intermittent theta burst stimulation; MEPs, motor evoked potentials. | PMC10475034 |
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Baseline assessment | stroke | STROKE | Participant demographics and clinical characteristics including age, sex, time since stroke, levels of physical activity and resting motor threshold (RMT) were obtained. Prior physical activity was assessed using the International Physical Activity Questionnaire—Short Form (IPAQ-SF) | PMC10475034 |
Electromyography (EMG) | SKIN | Surface EMG was used to record MEPs from the first dorsal interosseous (FDI) muscle of the non-paretic hand, with adhesive disposable EMG electrodes positioned in a belly-tendon montage (22 × 34 mm, FIAB, Florence, Italy). Skin overlying the FDI muscle was cleaned using an alcohol wipe prior to electrode application. A ground strap was placed on the wrist. Participants were seated in a standard chair with the contralesional arm resting on their lap in a pronated position. | PMC10475034 |
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Stimulation | CORTEX | Stimulation was delivered using a Neuro-MS/D rTMS device (Neurosoft Ltd. Ivanova, Russia) that was connected to an oil cooled figure eight coil (wing diameter 70 mm). Single pulses were delivered every five seconds to the contralesional motor cortex region. The coil was held tangentially to the scalp with the handle positioned at a 45-degree posterolateral angle. The optimal position (over the scalp) for evoking MEPs in the resting FDI muscle was located by systematically moving the coil in small increments, then marked with a permanent marker to ensure consistency for subsequent stimulation. An automated algorithm obtained RMT, defined as the lowest stimulus intensity to evoke a MEP of 0.05 mV in the relaxed FDI muscle in at least 5 out of 10 consecutive stimulations. Corticospinal excitability was measured by recording MEPs at 120% RMT and measuring peak-to-peak amplitudes. Blocks of 20 MEPs were completed at each time point (pre-activity, post-activity, 0 min post-iTBS, 5 min post-iTBS, 10 min post-iTBS and 15 min post-iTBS) to ensure reliability of MEP amplitude | PMC10475034 |
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iTBS | iTBS was delivered following the control or intervention. The standard 600 pulses iTBS paradigm was used, consisting of three low intensity, high frequency pulses (50 Hz), applied every 200 ms for two seconds, then repeated every 10 s for a total of 190 seconds | PMC10475034 |
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Cardiovascular exercise | Participants allocated to the intervention (exercise) group completed 20 min of moderate intensity continuous aerobic exercise on a Monark RT2 recumbent exercise bike. Participants were monitored to ensure they stayed within 60–80% of maximum heart rate which was calculated using the formula: 208–(0.7 × age) | PMC10475034 |
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Control condition | Those allocated to the control group were seated in a quiet room and watched a documentary of the same duration (20 min) on a television. The documentary was interesting, but not overstimulating. It was ensured participants did not move around but stayed awake and engaged in a sedentary position. | PMC10475034 |
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MRI acquisition and analysis | BLIND | Anatomical MRI was available for a subset of participants (n = 26). Images were acquired with a Siemens 3 T MAGNETOM Skyra scanner (Siemens, Erlangen, Germany) with a 64-channel head coil. The scan protocol was: T1-weighted image MPRAGE (voxel 1 mm x 1 mm x 1 mm, repetition time (TR) = 2300 ms, echo time (TE) = 2.98 ms, flip angle = 9°); T2-weighted fluid-attenuated inversion recovery (FLAIR; voxel 1 mm × 0.5 mm × 0.5 mm, TR = 5000 ms, TE = 393 ms). Image processing was carried out using FSL (FMRIB Software Library, Oxford, UK). Non-brain tissue was removed using BET. T1 and T2 images were then registered using FLIRT and lesion masks manually traced by an experienced investigator blind to allocation. Lesion masks were used to obtain lesion volume. A weighted lesion load was also obtained as a measure of injury to the ipsilesional descending motor pathways | PMC10475034 |
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Data analysis | All statistical analyses were completed using SPSS (IBM Corp., Released 2020, IBM SPSS Statistics for Windows, Version 27.0, Armonk, NY, USA). Significance level was set at | PMC10475034 |
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Results | PMC10475034 |
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Participant demographics and clinical characteristics | stroke | STROKE | There were no adverse outcomes reported and all participants completed the study. A total of 33 stroke survivors participated, with 16 randomized to exercise and 17 randomized to the control group. MRI data was available for a subset of 26 participants (11 in exercise and 15 in control). No differences in patient demographics and clinical characteristics were identified between groups (Table Participant demographics and clinical characteristics.IPAQ-SF, International Physical Activity Questionnaire Short Form; MEP, motor evoked potential; MSO, Maximum Stimulator Output; mV, millivolt; n, number; RMT, resting motor threshold.*MRI data only available for 11 participants in the exercise group and 15 participants in the control group.Individual MRI data showing level of greatest cross-sectional area of lesion. Lesion is shown in red. | PMC10475034 |
Effect of exercise on iTBS response | stroke, Stroke | STROKE, STROKE | Linear mixed model analyses revealed a significant effect of Group (FResults for test of fixed effects.df, degrees of freedom; RMT, resting motor threshold; IPAQ-SF, International Physical Activity Questionnaire Short Form.Bold indicates statistical significance.Effect of exercise on iTBS response. X-axis shows time that motor evoked potentials were recorded, and Y-axis provides motor evoked potentials normalized to baseline (values > 1 indicate facilitation of motor evoked potentials by iTBS). Error bars are shown as shaded regions (SEM). The exercise condition appeared to promote a stronger facilitation of motor evoked potentials following iTBS. Abbreviations: iTBS, intermittent theta burst stimulation.There was a non-significant trend for the interaction between Time*Group*Time Since Stroke (FExploration of the effect of time since stroke on modifying iTBS response following exercise. Top figures show grand average iTBS responses on the Y-axis (values > 1 indicate facilitation of motor evoked potentials by iTBS) and time since stroke on the X-axis for exercise and control groups respectively. For the exercise group ( | PMC10475034 |
Discussion | stroke | ADVERSE EVENTS, STROKE | This study aimed to investigate whether moderate intensity aerobic exercise could enhance neuroplasticity in people with stroke. Our measure of neuroplasticity was the change in MEP amplitude after administering iTBS. We observed a stronger iTBS response for people allocated to the exercise group, compared to those in the control group. These preliminary findings might suggest that moderate intensity aerobic exercise could be used to enhance neuroplasticity in people with stroke. Given no adverse events were noted, it appears this is a safe method to modify brain activity. Therefore, moderate intensity exercise might be a clinically feasible method to prime the brain for enhanced stroke recovery in people who are months to years post stroke. | PMC10475034 |
Exercise can increase neuroplasticity | stroke | STROKE, CORTEX | That iTBS response was greater in the exercise group might indicate increased potential for neuroplasticity after moderate intensity exercise. There is evidence that iTBS can induce an effect that resembles long-term potentiation in the human cortex. Pharmacological studies found that administration of NMDA receptor antagonists blocked after-effects of iTBS, suggesting increases in excitability following iTBS might be due to short-term changes in efficacy of synaptic connectionsAlthough not evaluated here, BDNF is one possible mechanism that may underpin increased neuroplasticity following exercise. BDNF appears to have a role in regulating synaptic plasticity through both structural and functional effects that act on excitatory and inhibitory synapses in many brain regionsOur findings are well aligned with previous studies. For example, in a small sample of 16 patients with stroke, a 20-min bout of high-intensity interval cycling led to a greater long-term potentiation like effect measured with paired-associative stimulation | PMC10475034 |
Time since stroke and effects of exercise on neuroplasticity | stroke, human stroke, post-stroke | STROKE | A noteworthy finding from this study was the possible role of time post-stroke on neuroplasticity following aerobic exercise. While this outcome should be interpreted cautiously, given it was exploratory, and the sub-group analysis was performed on a small sample, it remains possible that chronicity might influence effects of exercise. Our results appear to suggest a greater response in those who were approximately 2–7.5 years post stroke. While it is unclear why the effect of exercise appeared weaker earlier after stroke (< 2 years), a possible explanation might be that we have interfered with the spontaneous upregulation in neuroplasticity thought to occur after stroke. The precise temporal characteristics of this upregulation in neuroplasticity are not clear, but its occurrence has been physiologically observed in the contralesional hemisphere in human stroke survivors | PMC10475034 |
Alternative explanations | Although the exercise group did exhibit a stronger response to iTBS, it is noteworthy that there was no iTBS facilitation of MEPs in the control group. This was not unexpected. Nonresponse to iTBS is commonly reported in the literature | PMC10475034 |
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Clinical implications | stroke | STROKE | Persistent disability after stroke is an unresolved problem. While much recovery happens in the weeks to months following stroke, likely underpinned by a spontaneous upregulation in neuroplasticity | PMC10475034 |
Limitations and future directions | Findings from this study should be considered with respect to several limitations. First, consistent with the pilot nature of this work, the sample size was relatively small. Future studies should seek to replicate these findings in a larger patient group. Second, there are many factors known to affect response to brain stimulation protocols | PMC10475034 |
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