Allogeneic umbilical cord blood (UCB) has therapeutic potential for cerebral palsy (CP). Concomitant administration of recombinant human erythropoietin (rhEPO) may boost the efficacy of UCB, as it has neurotrophic effects. The objectives of this study were to assess the safety and efficacy of allogeneic UCB potentiated with rhEPO in children with CP. Children with CP were randomly assigned to one of three parallel groups: the pUCB group, which received allogeneic UCB potentiated with rhEPO; the EPO group, which received rhEPO and placebo UCB; and the Control group, which received placebo UCB and placebo rhEPO. All participants received rehabilitation therapy. The main outcomes were changes in scores on the following measures during the 6 months treatment period: the gross motor performance measure (GMPM), gross motor function measure, and Bayley scales of infant development-II (BSID-II) Mental and Motor scales (18). F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET/CT) and diffusion tensor images (DTI) were acquired at baseline and followed up to detect changes in the brain. In total, 96 subjects completed the study. Compared with the EPO (n = 33) and Control (n = 32) groups, the pUCB (n = 31) group had significantly higher scores on the GMPM and BSID-II Mental and Motor scales at 6 months. DTI revealed significant correlations between the GMPM increment and changes in fractional anisotropy in the pUCB group. 18F-FDG-PET/CT showed differential activation and deactivation patterns between the three groups. The incidence of serious adverse events did not differ between groups. In conclusion, UCB treatment ameliorated motor and cognitive dysfunction in children with CP undergoing active rehabilitation, accompanied by structural and metabolic changes in the brain.

Previous studies on repetitive transcranial magnetic stimulation (rTMS) suggested potential neurorestorative properties in Alzheimer’s disease (AD). This study aimed to investigate therapeutic effects of rTMS on an AD mouse model at high and low frequencies. The subject mice were allocated into the AD model group (AD induced by intracerebroventricular amyloid beta 42 oligomer [Aβ42] injection) and the saline-injected control group. Each group was subdivided according to rTMS treatment: high frequency (20 Hz), low frequency (1 Hz), and not rTMS-treated. Behavioural assessments with Y-maze test and novel object recognition task were performed; the results indicated cognition recovery by both the frequencies of rTMS after treatment in the AD model (Ps < 0.01). Tendency of further effects by high frequency compared to low frequency rTMS was also shown in Y-maze test. Neurotransmitter assay showed increment in dopamine concentration and upregulation of dopamine-receptor 4 (DR4) by rTMS in AD mice with higher response by high frequency stimulation (Ps < 0.05). Only high-frequency rTMS induced an elevation of brain-derived neurotrophic factor (BDNF) levels and enhanced the expression of Nestin and NeuN in the brain tissue (Ps < 0.05). Under in vitro conditions, Aβ42 incubated mouse hippocampal cell showed an increase in dopamine levels and BDNF by application of high-frequency rTMS treatment. In conclusion, rTMS might have a potential therapeutic effect on AD, and it seems to be related with dopaminergic activation. High frequency of stimulation seems to induce higher efficacy than that induced by low frequency, with elevated expressions of DR4 gene and neurogenic proteins.

Objective: Post-stroke cognitive impairment (PSCI) is resistant to treatment. Recent studies have widely applied repetitive transcranial magnetic stimulation (rTMS) to treat various brain dysfunctions, such as post-stroke syndromes. Nonetheless, a protocol for PSCI has not been established. Therefore, this study is aimed to evaluate the therapeutic effect of our high-frequency rTMS protocol for PSCI during the chronic phase of stroke.Methods: In this prospective study, ten patients with PSCI were enrolled and received high-frequency rTMS on the ipsilesional dorsolateral prefrontal cortex (DLPFC) for 10 sessions (5 days per week for 2 weeks). Cognitive and affective abilities were assessed at baseline and 2 and 14 weeks after rTMS initiation. To investigate the therapeutic mechanism of rTMS, the mRNA levels of pro-inflammatory cytokines (interleukin (IL)-6, IL-1β, transforming growth factor beta [TGF-β], and tumor necrosis factor alpha [TNF-α]) in peripheral blood samples were quantified using reverse transcription polymerase chain reaction, and cognitive functional magnetic resonance imaging (fMRI) was conducted at baseline and 14 weeks in two randomly selected patients after rTMS treatment.Results: The scores of several cognitive evaluations, i.e., the Intelligence Quotient (IQ) of Wechsler Adult Intelligence Scale, auditory verbal learning test (AVLT), and complex figure copy test (CFT), were increased after completion of the rTMS session. After 3 months, these improvements were sustained, and scores on the Mini-Mental Status Examination and Montreal Cognitive Assessment (MoCA) were also increased (p < 0.05). While the Geriatric Depression Scale (GeDS) did not show change among all patients, those with moderate-to-severe depression showed amelioration of the score, with marginal significance. Expression of pro-inflammatory cytokines was decreased immediately after the ten treatment sessions, among which, IL-1β remained at a lower level after 3 months. Furthermore, strong correlations between the decrease in IL-6 and increments in AVLT (r = 0.928) and CFT (r = 0.886) were found immediately after the rTMS treatment (p < 0.05). Follow-up fMRI revealed significant activation in several brain regions, such as the medial frontal lobe, hippocampus, and angular area.Conclusions: High-frequency rTMS on the ipsilesional DLPFC may exert immediate efficacy on cognition with the anti-inflammatory response and changes in brain network in PSCI, lasting at least 3 months.

To evaluate the effectiveness of intensive rehabilitation to support recovery of neurological function after brain tumor surgery and assess long-term satisfaction. This retrospective study included patients with neurological impairment after brain tumor surgery who underwent intensive rehabilitation therapy between December 2013 and May 2017. To assess effectiveness of rehabilitation, functional outcomes (motor, cognition, and activities of daily living [ADL]) were compared between brain tumor group and a control group enrolling stroke patients who received equivalent rehabilitation during the study period. Long-term satisfaction with rehabilitation was evaluated by surveying family caregivers. This study included 21 patients with benign brain tumor, 14 with malignant brain tumor, and 108 with stroke. Significant and similar improvement in motor, cognition, and ADL function were noted in both the brain tumor group and the stroke group. Malignancy status did not influence the extent of functional improvement. According to medical records and surveys, 9 (69.2%) patients with malignant tumor and 2 (11.8%) with benign tumor had expired by the time of the survey. Most family caregivers confirmed that rehabilitation was effective for functional improvement (>60%), expressing overall satisfaction and stating they would recommend such therapy to patients with similar conditions (approximately 70%). Intensive rehabilitation may help promote functional improvement following brain tumor surgery regardless of malignancy compared with stroke patients. Family caregivers expressed overall satisfaction with rehabilitation at long-term follow-up. These findings support the provision of intensive rehabilitation therapy for neurologic function recovery following brain tumor surgery.

Stroke is one of the leading causes of death and disability worldwide, and its incidence is increasing. To overcome impairment from stroke, translational research for developing new therapeutic technologies has been conducted and middle cerebral artery occlusion (MCAo) in rat is the representative model. Since recovery from neurological impairment in contralateral limbs caused by brain damage is the major goal of treatment, behavioral tests that assess the relevant function are used. To determine therapeutic effect, obtaining reliable results of behavioral assessment is a prerequisite. However, studies on the reliability of behavioral tests in the MCAo rat model and necessity of prior training have not yet been reported. In this study, the authors investigate relative and absolute inter-rater reliabilities of modified neurological severity score (mNSS), cylinder test, and grid-walking test before training and repeated training every week until the reliability of results reached a satisfactory level. The training included repeated learning of the scoring system and decreasing disagreements among the raters. For MCAo modeling, adult male Sprague-Dawley rats were subjected to 90 min of transient MCAo. Six raters conducted behavioral tests via observation of video-recording on sham-operated and MCAo model rats at 3 or 7 days after the intervention. An independent experimenter randomly numbered each video clip to blind the experiment. The results of reliabilities were unacceptable before training and improved to a satisfactory level after 6 weeks of training in all of the tests. In conclusion, mNSS, cylinder test, and grid-walking test on the MCAo rat model are reliable evaluation methods after conducting appropriate training.

Background: Concomitant administration of allogeneic umbilical cord blood (UCB) infusion and erythropoietin (EPO) showed therapeutic efficacy in children with cerebral palsy (CP). However, no clinical studies have investigated the effects of UCB and EPO combination therapy using a 2 × 2 four-arm factorial blinded design with four arms. This randomized placebo-controlled trial aimed to identify the synergistic and individual efficacies of UCB cell and EPO for the treatment of CP. Methods: Children diagnosed with CP were randomly segregated into four groups: (A) UCB+EPO, (B) UCB+placebo EPO, (C) placebo UCB+EPO, and (D) placebo UCB+placebo EPO. Based on the UCB unit selection criteria of matching for ≥ 4/6 of human leukocyte antigen (HLA)-A, -B, and DRB1 and total nucleated cell (TNC) number of ≥ 3 × 10⁷/kg, allogeneic UCB was intravenously infused and 500 IU/kg human recombinant EPO was administered six times. Functional measurements, brain imaging studies, and electroencephalography were performed from baseline until 12 months post-treatment. Furthermore, adverse events were closely monitored. Results: Eighty-eight of 92 children enrolled (3.05 ± 1.22 years) completed the study. Change in gross motor performance measure (GMPM) was greater in group A than in group D at 1 month (△2.30 vs. △0.71, P = 0.025) and 12 months (△6.85 vs. △2.34, P = 0.018) post-treatment. GMPM change ratios were calculated to adjust motor function at the baseline. Group A showed a larger improvement in the GMPM change ratio at 1 month and 12 months post-treatment than group D. At 12 months post-treatment, the GMPM change ratios were in the order of groups A, B, C, and D. These results indicate synergistic effect of UCB and EPO combination better than each single therapy. In diffusion tensor imaging, the change ratio of fractional anisotropy at spinothalamic radiation was higher in group A than group D in subgroup of age ≥ 3 years. Additionally, higher TNC and more HLA-matched UCB units led to better gross motor outcomes in group A. Adverse events remained unchanged upon UCB or EPO administration. Conclusions: These results indicate that the efficacy of allogeneic UCB cell could be potentiated by EPO for neurological recovery in children with CP without harmful effects. Trial registration: ClinicalTrials.gov, NCT01991145, registered 25 November 2013.