Therapeutic robots for post-stroke rehabilitation.

Stroke is a prevalent, severe, and disabling health-care issue on a global scale, inevitably leading to motor and cognitive deficits. It has become one of the most significant challenges in China, resulting in substantial social and economic burdens. In addition to the medication and surgical interventions during the acute phase, rehabilitation treatment plays a crucial role in stroke care. Robotic technology takes distinct advantages over traditional physical therapy, occupational therapy, and speech therapy, and is increasingly gaining popularity in post-stroke rehabilitation. The use of rehabilitation robots not only alleviates the workload of healthcare professionals but also enhances the prognosis for specific stroke patients. This review presents a concise overview of the application of therapeutic robots in post-stroke rehabilitation, with particular emphasis on the recovery of motor and cognitive function.

Kinect-based objective assessment of the acute levodopa challenge test in parkinsonism: a feasibility study.

INTRODUCTION: The acute levodopa challenge test (ALCT) is an important and valuable examination but there are still some shortcomings with it. We aimed to objectively assess ALCT based on a depth camera and filter out the best indicators. METHODS: Fifty-nine individuals with parkinsonism completed ALCT and the improvement rate (IR, which indicates the change in value before and after levodopa administration) of the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS III) was calculated. The kinematic features of the patients' movements in both the OFF and ON states were collected with an Azure Kinect depth camera. RESULTS: The IR of MDS-UPDRS III was significantly correlated with the IRs of many kinematic features for arising from a chair, pronation-supination movements of the hand, finger tapping, toe tapping, leg agility, and gait (rs = - 0.277 ~ - 0.672, P < 0.05). Moderate to high discriminative values were found in the selected features in identifying a clinically significant response to levodopa with sensitivity, specificity, and area under the curve (AUC) in the range of 50-100%, 47.22%-97.22%, and 0.673-0.915, respectively. The resulting classifier combining kinematic features of toe tapping showed an excellent performance with an AUC of 0.966 (95% CI = 0.922-1.000, P < 0.001). The optimal cut-off value was 21.24% with sensitivity and specificity of 94.44% and 87.18%, respectively. CONCLUSION: This study demonstrated the feasibility of measuring the effect of levodopa and objectively assessing ALCT based on kinematic data derived from an Azure Kinect-based system.

Early-onset and late-onset Parkinson's disease exhibit a different profile of gait and posture features based on the Kinect.

INTRODUCTION: Gait and posture abnormalities are the common disabling motor symptoms in Parkinson's disease (PD). This study aims to investigate the differential characteristics of gait and posture in early-onset PD (EOPD) and late-onset PD (LOPD) using the Kinect depth camera. METHODS: Eighty-eight participants, including two subgroups of 22 PD patients and two subgroups of 22 healthy controls (HC) matched for age, sex, and height, were enrolled. Gait and posture features were quantitatively assessed using a Kinect-based system. A two-way analysis of variance was used to compare the difference between different subgroups. RESULTS: EOPD had a significantly higher Gait score than LOPD (p = 0.031). Specifically, decreased swing phase (p = 0.034) was observed in the EOPD group. Although the Posture score was similar between the two groups, LOPD was characterized by an increased forward flexion angle of the trunk at the thorax (p = 0.042) and a decreased forward flexion angle of the head relative to the trunk (p = 0.009). Additionally, age-independent features were observed in both PD subgroups, and post hoc tests revealed that EOPD generally performed worse gait features. In comparison, LOPD was characterized by worse performance in posture features. CONCLUSIONS: EOPD and LOPD exhibit different profiles of gait and posture features. The phenotype-specific characteristics likely reflect the distinct neurodegenerative processes between them.

Considerable effects of lateralization and aging in intracortical excitation and inhibition.

Introduction: Findings based on the use of transcranial magnetic stimulation and electromyography (TMS-EMG) to determine the effects of motor lateralization and aging on intracortical excitation and inhibition in the primary motor cortex (M1) are inconsistent in the literature. TMS and electroencephalography (TMS-EEG) measures the excitability of excitatory and inhibitory circuits in the brain cortex without contamination from the spine and muscles. This study aimed to investigate the effects of motor lateralization (dominant and non-dominant hemispheres) and aging (young and older) and their interaction effects on intracortical excitation and inhibition within the M1 in healthy adults, measured using TMS-EMG and TMS-EEG. Methods: This study included 21 young (mean age = 28.1 ± 3.2 years) and 21 older healthy adults (mean age = 62.8 ± 4.2 years). A battery of TMS-EMG measurements and single-pulse TMS-EEG were recorded for the bilateral M1. Results: Two-way repeated-measures analysis of variance was used to investigate lateralization and aging and the lateralization-by-aging interaction effect on neurophysiological outcomes. The non-dominant M1 presented a longer cortical silent period and larger amplitudes of P60, N100, and P180. Corticospinal excitability in older participants was significantly reduced, as supported by a larger resting motor threshold and lower motor-evoked potential amplitudes. N100 amplitudes were significantly reduced in older participants, and the N100 and P180 latencies were significantly later than those in young participants. There was no significant lateralization-by-aging interaction effect in any outcome. Conclusion: Lateralization and aging have independent and significant effects on intracortical excitation and inhibition in healthy adults. The functional decline of excitatory and inhibitory circuits in the M1 is associated with aging.

Kinect-based objective assessment for early frailty identification in patients with Parkinson's disease.

BACKGROUND: Frailty is common in Parkinson's disease (PD) and increases vulnerability to adverse outcomes. Early detection of this syndrome aids in early intervention. AIMS: To objectively identify frailty at an early stage during routine motor tasks in PD patients using a Kinect-based system. METHODS: PD patients were recruited and assessed with the Fried criteria to determine their frailty status. Each participant was recorded performing the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS III) extremity tasks with a Kinect-based system. Statistically significant kinematic parameters were selected to discriminate the pre-frail from the non-frail group. RESULTS: Of the fifty-two participants, twenty were non-frail and thirty-two were pre-frail. Decreased frequency in finger tapping (P = 0.005), hand grasping (P = 0.002), toe tapping (P = 0.002), and leg agility (P = 0.019) alongside reduced hand grasping speed (P = 0.030), lifting (P < 0.001) and falling speed (P < 0.001) in leg agility were observed in the pre-frail group. Amplitude in leg agility (P = 0.048) and amplitude decrement rate (P = 0.046) in hand grasping showed marginally significant differences between two groups. Moderate discriminative values were found in frequency and speed of the extremity tasks to identify pre-frailty with sensitivity, specificity, and area under the curve (AUC) in the range of 45.00-85.00%, 68.75-100%, and 0.701-0.836, respectively. The combination of frequency and speed in extremity tasks showed moderate to high discriminatory ability, with AUC of 0.775 (95% CI 0.637-0.913, P < 0.001) for upper limb tasks and 0.909 (95% CI 0.832-0.987, P < 0.001) for lower limb tasks. When combining these features in both upper and lower limb tasks, the AUC increased to 0.942 (95% CI 0.886-0.999, P < 0.001). CONCLUSIONS: Our findings demonstrated the promise of utilizing Kinect-based kinematic data from MDS-UPDRS III tasks as early indicators of frailty in PD patients.

Feasibility of challenging treadmill speed-dependent gait and perturbation-induced balance training in chronic stroke patients with low ambulation ability: a randomized controlled trial.

Background: Treadmill training shows advantages in the specificity, amount, and intensity of gait and balance practice for the rehabilitation of stroke patients. Objective: To investigate the feasibility and effectiveness of challenging treadmill speed-dependent gait and perturbation-induced balance training in chronic stroke patients with low ambulation ability. Methods: For this randomized controlled trial (Chinese Clinical Trials.gov registration number ChiCTR-IOR-16009536) with blinded testers, we recruited 33 ambulatory stroke participants with restricted community ambulation capacity and randomly assigned them into two groups: the experimental group with 2 week treadmill speed-dependent gait training combined with 2 week treadmill perturbation-induced balance training (EXP) or the control group with traditional gait and balance training (CON). Various variables were recorded during EXP training, including the rating of perceived exertion, heart rate, causes of pauses, treadmill speed, and perturbation intensity. Outcome measures were examined before training and at 2 and 4 weeks after training. They included gait velocity during five-meter walk test at comfortable and fast speed and reactive balance ability in the compensatory stepping test as primary outcome measures, as well as dynamic balance ability (timed up-and-go test and 5 times sit-to-stand test) and balance confidence as secondary outcome measures. Results: All participants completed the study. The treadmill speed and perturbation intensity significantly increased across training sessions in the EXP group, and no adverse effects occurred. The normal and fast gait velocities showed significant time and group interaction effects. They significantly increased after 2 and 4 weeks of training in the EXP group (p < 0.05) but not in the CON group (p > 0.05). Likewise, dynamic balance ability measured using the timed up-and-go test at a fast speed significantly improved after 2 and 4 weeks of training in the EXP group (p < 0.05) but not in the CON group (p > 0.05), although without a significant time and group interaction effect. Surprisingly, the reactive balance ability did not show improvement after treatment in the EXP group (p > 0.05). Conclusion: Challenging treadmill speed-dependent gait and treadmill perturbation-induced balance training is feasible and effective to improve ambulation function in chronic stroke patients with low ambulation ability.

Substantia Nigra Pars Reticulata Projections to the Pedunculopontine Nucleus Modulate Dyskinesia.

BACKGROUND: Long-term use of levodopa for Parkinson's disease (PD) treatment is often hindered by development of motor complications, including levodopa-induced dyskinesia (LID). The substantia nigra pars reticulata (SNr) and globus pallidus internal segment (GPi) are the output nuclei of the basal ganglia. Dysregulation of SNr and GPi activity contributes to PD pathophysiology and LID. OBJECTIVE: The objective of this study was to determine whether direct modulation of SNr GABAergic neurons and SNr projections to the pedunculopontine nucleus (PPN) regulates PD symptoms and LID in a mouse model. METHODS: We expressed Cre-recombinase activated channelrhodopsin-2 (ChR2) or halorhodopsin adeno-associated virus-2 (AAV2) vectors selectively in SNr GABAergic neurons of Vgat-IRES-Cre mice in a 6-hydroxydopamine model of PD to investigate whether direct optogenetic modulation of SNr neurons or their projections to the PPN regulates PD symptoms and LID expression. The forepaw stepping task, mouse LID rating scale, and open-field locomotion were used to assess akinesia and LID to test the effect of SNr modulation. RESULTS: Akinesia was improved by suppressing SNr neuron activity with halorhodopsin. LID was significantly reduced by increasing SNr neuronal activity with ChR2, which did not interfere with the antiakinetic effect of levodopa. Optical stimulation of ChR2 in SNr projections to the PPN recapitulated direct SNr stimulation. CONCLUSIONS: Modulation of SNr GABAergic neurons alters akinesia and LID expression in a manner consistent with the rate model of basal ganglia circuitry. Moreover, the projections from SNr to PPN likely mediate the antidyskinetic effect of increasing SNr neuronal activity, identifying a potential novel role for the PPN in LID. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Subject-independent EEG classification based on a hybrid neural network.

A brain-computer interface (BCI) based on the electroencephalograph (EEG) signal is a novel technology that provides a direct pathway between human brain and outside world. For a traditional subject-dependent BCI system, a calibration procedure is required to collect sufficient data to build a subject-specific adaptation model, which can be a huge challenge for stroke patients. In contrast, subject-independent BCI which can shorten or even eliminate the pre-calibration is more time-saving and meets the requirements of new users for quick access to the BCI. In this paper, we design a novel fusion neural network EEG classification framework that uses a specially designed generative adversarial network (GAN), called a filter bank GAN (FBGAN), to acquire high-quality EEG data for augmentation and a proposed discriminative feature network for motor imagery (MI) task recognition. Specifically, multiple sub-bands of MI EEG are first filtered using a filter bank approach, then sparse common spatial pattern (CSP) features are extracted from multiple bands of filtered EEG data, which constrains the GAN to maintain more spatial features of the EEG signal, and finally we design a convolutional recurrent network classification method with discriminative features (CRNN-DF) to recognize MI tasks based on the idea of feature enhancement. The hybrid neural network proposed in this study achieves an average classification accuracy of 72.74 ± 10.44% (mean ± std) in four-class tasks of BCI IV-2a, which is 4.77% higher than the state-of-the-art subject-independent classification method. A promising approach is provided to facilitate the practical application of BCI.

Kinect-based objective evaluation of bradykinesia in patients with Parkinson's disease.

Objective: To quantify bradykinesia in Parkinson's disease (PD) with a Kinect depth camera-based motion analysis system and to compare PD and healthy control (HC) subjects. Methods: Fifty PD patients and twenty-five HCs were recruited. The Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS III) was used to evaluate the motor symptoms of PD. Kinematic features of five bradykinesia-related motor tasks were collected using Kinect depth camera. Then, kinematic features were correlated with the clinical scales and compared between groups. Results: Significant correlations were found between kinematic features and clinical scales (P < 0.05). Compared with HCs, PD patients exhibited a significant decrease in the frequency of finger tapping (P < 0.001), hand movement (P < 0.001), hand pronation-supination movements (P = 0.005), and leg agility (P = 0.003). Meanwhile, PD patients had a significant decrease in the speed of hand movements (P = 0.003) and toe tapping (P < 0.001) compared with HCs. Several kinematic features exhibited potential diagnostic value in distinguishing PD from HCs with area under the curve (AUC) ranging from 0.684-0.894 (P < 0.05). Furthermore, the combination of motor tasks exhibited the best diagnostic value with the highest AUC of 0.955 (95% CI = 0.913-0.997, P < 0.001). Conclusion: The Kinect-based motion analysis system can be applied to evaluate bradykinesia in PD. Kinematic features can be used to differentiate PD patients from HCs and combining kinematic features from different motor tasks can significantly improve the diagnostic value.

A sequential learning model with GNN for EEG-EMG-based stroke rehabilitation BCI.

Introduction: Brain-computer interfaces (BCIs) have the potential in providing neurofeedback for stroke patients to improve motor rehabilitation. However, current BCIs often only detect general motor intentions and lack the precise information needed for complex movement execution, mainly due to insufficient movement execution features in EEG signals. Methods: This paper presents a sequential learning model incorporating a Graph Isomorphic Network (GIN) that processes a sequence of graph-structured data derived from EEG and EMG signals. Movement data are divided into sub-actions and predicted separately by the model, generating a sequential motor encoding that reflects the sequential features of the movements. Through time-based ensemble learning, the proposed method achieves more accurate prediction results and execution quality scores for each movement. Results: A classification accuracy of 88.89% is achieved on an EEG-EMG synchronized dataset for push and pull movements, significantly outperforming the benchmark method's performance of 73.23%. Discussion: This approach can be used to develop a hybrid EEG-EMG brain-computer interface to provide patients with more accurate neural feedback to aid their recovery.

Dystonia-like behaviors and impaired sensory-motor integration following neurotoxic lesion of the pedunculopontine tegmental nucleus in mice.

Introduction: The pedunculopontine nucleus (PPTg) is a vital interface between the basal ganglia and cerebellum, participating in modulation of the locomotion and muscle tone. Pathological changes of the PPTg have been reported in patients and animal models of dystonia, while its effect and mechanism on the phenotyping of dystonia is still unknown. Methods: In this study, a series of behavioral tests focusing on the specific deficits of dystonia were conducted for mice with bilateral and unilateral PPTg excitotoxic lesion, including the dystonia-like movements evaluation, different types of sensory-motor integrations, explorative behaviors and gait. In addition, neural dysfunctions including apoptosis, neuroinflammation, neurodegeneration and neural activation of PPTg-related motor areas in the basal ganglia, reticular formations and cerebellum were also explored. Results: Both bilateral and unilateral lesion of the PPTg elicited dystonia-like behaviors featured by the hyperactivity of the hindlimb flexors. Moreover, proprioceptive and auditory sensory-motor integrations were impaired in bilaterally lesioned mice, while no overt alterations were found for the tactile sensory-motor integration, explorative behaviors and gait. Similar but milder behavioral deficits were found in the unilaterally lesioned mice, with an effective compensation was observed for the auditory sensory-motor integration. Histologically, no neural loss, apoptosis, neuroinflammation and neurodegeneration were found in the substantia nigra pars compacta and caudate putamen (CPu) following PPTg lesion, while reduced neural activity was found in the dorsolateral part of the CPu and striatal indirect pathway-related structures including subthalamic nucleus, globus pallidus internus and substantia nigra pars reticular. Moreover, the neural activity was decreased for the reticular formations such as pontine reticular nucleus, parvicellular reticular nucleus and gigantocellular reticular nucleus, while deep cerebellar nuclei were spared. Conclusion: In conclusion, lesion of the PPTg could elicit dystonia-like behaviors through its effect on the balance of the striatal pathways and the reticular formations.

Cortical activation and functional connectivity during locomotion tasks in Parkinson's disease with freezing of gait.

Background: Freezing of gait (FoG) is a severely disabling symptom in Parkinson's disease (PD). The cortical mechanisms underlying FoG during locomotion tasks have rarely been investigated. Objectives: We aimed to compare the cerebral haemodynamic response during FoG-prone locomotion tasks in patients with PD and FoG (PD-FoG), patients with PD but without FoG (PD-nFoG), and healthy controls (HCs). Methods: Twelve PD-FoG patients, 10 PD-nFoG patients, and 12 HCs were included in the study. Locomotion tasks included normal stepping, normal turning and fast turning ranked as three difficulty levels based on kinematic requirements and probability of provoking FoG. During each task, we used functional near-infrared spectroscopy to capture concentration changes of oxygenated haemoglobin (ΔHBO2) and deoxygenated haemoglobin (ΔHHB) that reflected cortical activation, and recorded task performance time. The cortical regions of interest (ROIs) were prefrontal cortex (PFC), supplementary motor area (SMA), premotor cortex (PMC), and sensorimotor cortex (SMC). Intra-cortical functional connectivity during each task was estimated based on correlation of ΔHBO2 between ROIs. Two-way multivariate ANOVA with task performance time as a covariate was conducted to investigate task and group effects on cerebral haemodynamic responses of ROIs. Z statistics of z-scored connectivity between ROIs were used to determine task and group effects on functional connectivity. Results: PD-FoG patients spent a nearly significant longer time completing locomotion tasks than PD-nFoG patients. Compared with PD-nFoG patients, they showed weaker activation (less ΔHBO2) in the PFC and PMC. Compared with HCs, they had comparable ΔHBO2 in all ROIs but more negative ΔHHB in the SMC, whereas PD-nFoG showed SMA and PMC hyperactivity but more negative ΔHHB in the SMC. With increased task difficulty, ΔHBO2 increased in each ROI except in the PFC. Regarding functional connectivity during normal stepping, PD-FoG patients showed positive and strong PFC-PMC connectivity, in contrast to the negative PFC-PMC connectivity observed in HCs. They also had greater PFC-SMC connectivity than the other groups. However, they exhibited decreased SMA-SMC connectivity when task difficulty increased and had lower SMA-PMC connectivity than HCs during fast turning. Conclusion: Insufficient compensatory cortical activation and depletion of functional connectivity during complex locomotion in PD-FoG patients could be potential mechanisms underlying FoG. Clinical trial registration: Chinese clinical trial registry (URL: http://www.chictr.org.cn, registration number: ChiCTR2100042813).

Efficacy of faecal microbiota transplantation in patients with progressive supranuclear palsy-Richardson's syndrome: a phase 2, single centre, randomised clinical trial.

Background: Faecal microbiota transplantation (FMT) has demonstrated efficacy in treating gastrointestinal (GI) diseases, such as Clostridium difficile infection (CDI) and inflammatory bowel disease (IBD). GI dysfunction is a frequent and occasionally dominating symptom of progressive supranuclear palsy-Richardson's syndrome (PSP-RS). However, it is not known whether FMT has clinical efficacy for PSP-RS. Methods: This 36-week, randomised, placebo-controlled, parallel-group, phase 2 clinical trial was performed at a university tertiary referral hospital in China. From August 15 2021 to December 31 2021, a total of 68 newly diagnosed patients with PSP-RS (male 40 [59%], female 28 [41%]) who had never received any antiparkinsonian medications were enrolled and randomly assigned to receive either healthy donor FMT (n = 34, FMT group) or a mixture of 0.9% saline and food colouring (E150c) as sham transplantation (n = 34, placebo group) through transendoscopic enteral tubing (TET). Two days after oral antibiotics, participants received 1 week of transplantation. After an interval of 4 weeks, retransplantation was performed. Then, the last transplantation was given after another interval of 4 weeks, and the participants were followed up for 24 weeks (week 36). Clinicaltrials.gov identifier: ChiCTR-2100045397. Findings: Among 68 patients who were randomised (mean age, 67.2 (SD 5.1); 40 [59%] were male, 28 [41%] were female), 63 participants completed the trial. Efficacy analyses were performed on the intention-to-treat (ITT) analysis set. At week 16, the mean PSP Rating Scale (PSPRS) scores (the primary outcome) improved from 40.1 (SD 7.6) to 36.9 (SD 5.9) in the FMT group, whereas the scores changed from 40.1 (SD 6.9) to 41.7 (SD 6.2) in the placebo group, for a treatment benefit of 4.3 (95% CI, 3.2-5.4) (P < 0.0001). After 3-cycle intervention, symptoms of constipation, depression, and anxiety (the secondary outcome) improved significantly at week 16 in the FMT group compared with the placebo group, the majority of which were maintained at the 24-week follow-up (week 36). Interpretation: Our findings suggest that, compared with placebo, FMT treatment significantly improved motor and nonmotor symptoms in patients with PSP-RS, as well as reduced intestinal inflammation and enhanced the intestinal barrier by regulating the intestinal microbiota composition. Funding: The National Natural Science Foundation of China (No. 82122022, 82171248, 81873791, and 82230084), Natural Science Foundation of Henan Province for Excellent Young Scholars (no. 202300410357), and Henan Province Young and Middle-Aged Health Science and Technology Innovation Talent Project (YXKC2020033).

Genetic spectrum and clinical features in a cohort of Chinese patients with isolated dystonia.

Dystonia is a genetically and phenotypically heterogeneous disorder that occurs in isolation (isolated dystonia) or in combination with other movement disorders. To determine the genetic spectrum in isolated dystonia, we enrolled 88 patients with isolated dystonia for whole-exome sequencing (WES). Seventeen mutations, including nine novel ones, were identified in 19 of the 88 patients, providing a 21.59% positive molecular diagnostic rate. Eleven distinct genes were involved, of which TOR1A and THAP1 accounted for 47.37% (9/19) of the positive cases. A novel missense variant, p.S225R in TOR1A, was found in a patient with adolescence-onset generalized dystonia. Cellular experiments revealed that p.S255R results in the abnormal aggregation of Torsin-1A encoding by TOR1A. In addition, we reviewed the clinical and genetic features of the isolated dystonia patients carrying TOR1A, THAP1, ANO3, and GNAL mutations in the Chinese population. Our results expand the genetic spectrum and clinical profiles of patients with isolated dystonia and demonstrate WES as an effective strategy for the molecular diagnosis of isolated dystonia.

Irisin exhibits neuroprotection by preventing mitochondrial damage in Parkinson's disease.

Exercise has been proposed as an effective non-pharmacological management for Parkinson's disease (PD) patients. Irisin, a recently identified myokine, is increased by exercise and plays pivotal roles in energy metabolism. However, it remains unknown whether irisin has any protective effects on PD. Here, we found that serum irisin levels of PD patients were markedly elevated after 12-week regular exercise, which had a positive correlation with improved balance function scored by Berg Balance Scale. Treatment with exogenous irisin could improve motor function, and reduce dopaminergic neurodegeneration in PD models. Meanwhile, irisin could reduce cell apoptosis by renovating mitochondrial function in PD models, which was reflected in decreased oxidative stress, increased mitochondrial complex I activity and mitochondrial content, increased mitochondrial biogenesis, and repaired mitochondrial morphology. Furthermore, irisin regulated the aforementioned aspects by upregulating downstream Akt signaling pathway and ERK1/2 signaling pathway through integrin receptors rather than directly targeting mitochondria. With the use of small-molecule inhibitors, it was found that irisin can reduce apoptosis, restore normal mitochondrial biogenesis, and improve mitochondrial morphology and dynamic balance in PD models by activating Akt signaling pathway and ERK1/2 signaling pathway. And irisin reduced oxidative stress via activating ERK1/2 signaling pathway. The results revealed that exogenous irisin conferred neuroprotection relieving apoptosis and oxidative stress, restraining mitochondrial fragmentation, and promoting mitochondrial respiration and biogenesis in PD models, and irisin exerted the aforementioned effects by activating Akt signaling pathway and ERK1/2 signaling pathway. Thus, peripherally delivered irisin might be a promising candidate for therapeutic targeting of PD.

How to Avoid Misdiagnosing Spontaneous Cervical Spinal Epidural Hematoma as Ischemic Stroke: 3 Case Reports and Literature Review.

When spontaneous cervical spinal epidural hematoma (SCEH) presents with hemiparesis, it can be misdiagnosed with ischemic stroke (IS), and the treatment of IS such as thrombolysis may deteriorate the symptoms of patients with SCEH, leading to worse sequelae or even death. We reported 3 SCEH patients who were initially suspected as IS in our center between Jun 2020 and April 2022 and analyzed their clinical characteristics together with 48 patients reported in the literature from Jan 1995 to April 2022. Two of the 3 SCEH patients had neck symptoms, while none of them presented cranial nerve symptoms. Cranial computed tomography (CT) scans were negative; however, abnormal signals in the cervical spinal canal were observed during cranial computed tomography angiography (CTA) and subsequent cervical CT confirmed the diagnosis of SCEH. All of them avoid mistreatment with recombinant tissue plasminogen activator (rt-PA). Subsequently, we analyzed the clinical characteristics of a total of 51 patients. Thirteen of them developed symptoms during activity. Neck pain was an important sign of SCEH because 35 patients had neck pain or neck discomfort. Sensory impairment was reported in a small proportion of patients (11/51), which varied a lot in the patients. Some special manifestations highly suggested spinal cord lesions and provided evidence for the early differential diagnosis of SCEH and stroke, but the incidence of which was quite low: ipsilateral Horner syndrome in 2 patients, Brown-Séquard syndrome in 2 cases, and Lhermitte's sign in 1 case. Only a minority (8/51) of the patients were correctly diagnosed at the emergency unit using cervical CT. Six patients were correctly diagnosed when performing CTA. A large portion of the cases (21/51) were first misdiagnosed as IS, but no responsible lesions were found on cranial magnetic resonance imaging (MRI), and subsequent cervical MRI confirmed the diagnosis. Sixteen patients were diagnosed with SCEH after the deterioration of symptoms. A total of 13 patients received rt-PA, and 10 of them had symptoms aggravation after thrombolysis. For patients with acute onset of hemiparesis but without cranial nerve symptoms, especially those accompanied by clinical features such as neck pain, ipsilateral Horner syndrome, Brown-Séquard syndrome, and Lhermitte's sign, SCEH should be highly suspected rather than stroke. Careful differential diagnosis should be performed with a comprehensive medical history and thorough physical examination. Cervical CT scan is a reasonable choice for quick differential diagnosis prior to administering potentially harmful therapy, especially rt-PA.

Mesencephalic astrocyte-derived neurotrophic factor (MANF) prevents the neuroinflammation induced dopaminergic neurodegeneration.

BACKGROUND: The excessive activation of the microglia leads to the release of inflammatory factors that contribute to neuronal cell loss and neurodegeneration in Parkinson's Disease (PD). Mesencephalic astrocyte-derived neurotrophic factor (MANF) that belongs to a newly found neurotrophic factors (NTFs) family has been reported to promote neuronal survival in the PD models. However, the effects of the MANF on neuroinflammation in PD remain unclear. METHODS: AAV8-MANF virus was constructed to determine whether the high expression of MANF can protect the neuroinflammation-induced dopaminergic neurodegeneration in rats with 6-OHDA-induced PD. Rotarod performance test, immunofluorescent staining and western bolt were employed to evaluate the behavioral dysfunction, dopaminergic neurodegeneration, microglia activation, and signal activation. 6-OHDA treated SH-SY5Y cells and LPS treated BV-2 cells were used as the in vitro model for MANF neuroprotective and neuroinflammation mechanisms. Cell vitality and apoptosis were evaluated with MTT, CCK-8 and flow cytometric analysis. The AKT/GSK3ß-Nrf2 signaling and the TNF-α/IL6 expression were measured by Western Blot. RESULTS: Our findings indicated that the elevated MANF expression by the AAV8-MANF administration ameliorated the motor dysfunction and protected the dopaminergic neurons in the 6-OHDA treated rats. The upregulated CD11b in the rat SN caused by the 6-OHDA administration was significantly attenuated by the pretreatment of the AAV8-MANF. Furthermore, the levels of p-AKT, p-GSK3ß, BCL-2, and Nrf-2 were upregulated by the high expression of the MANF. Under the oxidative stress of the 6-OHDA, the MANF significantly reduced the apoptotic effect of the TNF-α on the SH-SY5Y cells. In the LPS treated BV-2 cells, the MANF reduced the production of the TNF-α and IL-6, via enhancing the Nrf-2, p-Akt, p-GSK3ß, and p-NF-κß level. CONCLUSIONS: These results suggested that the MANF prevented the dopaminergic neurodegeneration caused by the microglia activation in PD via activation of the AKT/GSK3ß-Nrf-2 signaling axis.

Dystonia and the pedunculopontine nucleus: Current evidences and potential mechanisms.

Being a major component of the midbrain locomotion region, the pedunculopontine nucleus (PPN) is known to have various connections with the basal ganglia, the cerebral cortex, thalamus, and motor regions of the brainstem and spinal cord. Functionally, the PPN is associated with muscle tone control and locomotion modulation, including motor initiation, rhythm and speed. In addition to its motor functions, the PPN also contribute to level of arousal, attention, memory and learning. Recent studies have revealed neuropathologic deficits in the PPN in both patients and animal models of dystonia, and deep brain stimulation of the PPN also showed alleviation of axial dystonia in patients of Parkinson's disease. These findings indicate that the PPN might play an important role in the development of dystonia. Moreover, with increasing preclinical evidences showed presence of dystonia-like behaviors, muscle tone changes, impaired cognitive functions and sleep following lesion or neuromodulation of the PPN, it is assumed that the pathological changes of the PPN might contribute to both motor and non-motor manifestations of dystonia. In this review, we aim to summarize the involvement of the PPN in dystonia based on the current preclinical and clinical evidences. Moreover, potential mechanisms for its contributions to the manifestation of dystonia is also discussed base on the dystonia-related basal ganglia-cerebello-thalamo-cortical circuit, providing fundamental insight into the targeting of the PPN for the treatment of dystonia in the future.