Central Motor Research Articles

Changes in thumb tapping rates and central motor conduction times are associated in persons with multiple sclerosis

IntroductionIn persons with multiple sclerosis, nerve conductivity can be reduced. The assessment is generally performed via motor evoked potentials (MEP). So far, a strongly associated motor performance surrogate for changes in the extracted central motor conduction time (CMCT) is missing.MethodsCMCT and performance in the nine-hole peg test and maximum thumb tapping frequencies over 10 s of 12 persons with multiple sclerosis were measured prior to and after training over 5 consecutive days. Each training consisted of 10,000 thumb taps at maximum effort with the dominant upper limb.ResultsThe dominant upper limb improved in maximum tapping frequency over 10 s (d = 0.79) and 10,000 taps (d = 1.04), the nine-hole peg test (d = 0.60), and CMCT (d = 0.52). The nondominant upper limb only improved in the nine-hole peg test (d = 0.38). Models of multiple linear regression predicted 0.78 (model 1, tapping performance as factors) and 0.87 (model 2, patient baseline characteristics as factors) of the variance in CMCT changes.DiscussionChanges in CMCT were well predictable, although the assessment of those surrogates is either not economic (model 1) or rather describing a potential of change (model 2). However, we were able to show moderate changes in CMCT within 5 days.

Roles of neural communication between the brain and thoracic ganglia in the selection and regulation of the cricket escape behavior

To survive a predator’s attack, prey animals must exhibit escape responses that are appropriately regulated in terms of their moving speed, distance, and direction. Insect locomotion is considered to be controlled by an interaction between the brain, which is involved in behavioral decision-making, and the thoracic ganglia (TG), which are primary motor centers. However, it remains unknown which descending and ascending signals between these neural centers are involved in the regulation of the escape behavior. We addressed the distinct roles of the brain and TG in the wind-elicited escape behavior of crickets by assessing the effects of partial ablation of the intersegmental communications on escape responses. We unilaterally cut the ventral nerve cord (VNC) at different locations, between the brain and TG, or between the TG and terminal abdominal ganglion (TAG), a primary sensory center of the cercal system. The partial ablation of ascending signals to the brain greatly reduced the jumping response rather than running, indicating that sensory information processing in the brain is essential for the choice of escape responses. The ablation of descending signals from the brain to the TG impaired locomotor performance and directional control of the escape responses, suggesting that locomotion in the escape behavior largely depends on the descending signals from the brain. Finally, the extracellular recording from the cervical VNC indicated a difference in the descending activities preceding the escape responses between running and jumping. Our results demonstrated that the brain sends the descending signals encoding the behavioral choice and locomotor regulation to the TG, while the TG seem to have other specific roles, such as in the preparation of escape movement.

Stepping in time: Alpha‐mu and beta oscillations during a walking synchronization task

Interpersonal behavioral synchrony is defined as the temporal coordination of action between two or more individuals. Humans tend to synchronize their movements during repetitive movement tasks such as walking. Mobile EEG technology now allows us to examine how this happens during gait. 18 participants equipped with foot accelerometers and mobile EEG walked with an experimenter in three conditions: With their view of the experimenter blocked, walking naturally, and trying to synchronize their steps with the experimenter. The experimenter walked following a headphone metronome to keep their steps consistent for all conditions. Step behavior and synchronization between the experimenter and participant were compared between conditions. Additionally, event-related spectral perturbations (ERSPs) were time-warped to the gait cycle in order to analyze alpha-mu (7.5-12.5 Hz) and beta (16-32 Hz) rhythms over the whole gait cycle. Step synchronization was significantly higher in the synchrony condition than in the natural condition. Likewise regarding ERSPs, right parietal channel (C4, C6, CP4, CP6) alpha-mu and central channel (C1, Cz, C2) beta power were suppressed from baseline in the walking synchrony condition compared to the natural walking condition. The natural and blocked conditions were not found to be significantly different in behavioral or spectral comparisons. Our results are compatible with the view that intentional synchronization employs systems associated with social interaction as well as the central motor system.

Assessment of Neurological Status in Patients with Cerebrovascular Diseases through the Nursing Outcome Classification: A Methodological Study.

Nurses play an important role in healthcare, and the Nursing Outcomes Classification is a key tool for the standardization of care. This study aims to validate the nursing outcome “Neurological Status” for patients with cerebrovascular diseases. A methodological study was performed in four phases. In Phase 1, the relevance of the indicators was evaluated by seven specialists and the modified kappa coefficient and content validity index were calculated. In Phase 2, conceptual and operational definitions were formulated. In addition, their content was validated with a focus group in Phase 3. In Phase 4, the results were applied in clinical practice and convergence with the National Institute of Health Stroke Scale was verified. The reliability was measured by Cronbach’s alpha. Of the 22 initial indicators, 6 were excluded. The focus group suggested changes in the definitions and the exclusion of two indicators. In Phase 4, only 13 indicators were validated due to the impossibility of measuring intracranial pressure. A strong correlation between the two scales and agreement among all the indicators were observed. Following the specialists’ review, the nursing outcome was reliable and clinically validated with 13 indicators: consciousness, orientation, language, central motor control, cranial sensory and motor function, spinal sensory and motor function, body temperature, blood pressure, heart rate, eye movement pattern, pupil size, pupil reactivity, and breathing pattern.

The central moTOR of metabolism.

The protein kinase mechanistic target of rapamycin (mTOR) functions as a central regulator of metabolism, integrating diverse nutritional and hormonal cues to control anabolic processes, organismal physiology, and even aging. This review discusses the current state of knowledge regarding the regulation of mTOR signaling and the metabolic regulation of the four macromolecular building blocks of the cell: carbohydrate, nucleic acid, lipid, and protein by mTOR. We review the role of mTOR in the control of organismal physiology and aging through its action in key tissues and discuss the potential for clinical translation of mTOR inhibition for the treatment and prevention of diseases of aging.

Factors affecting postural instability after more than one-year bilateral subthalamic stimulation in Parkinson's disease: A cross-sectional study.

BackgroundBalance impairment in Parkinson’s disease is multifactorial and its changes due to subthalamic stimulation vary in different studies.ObjectiveWe aimed to analyze the combination of predictive clinical factors of balance impairment in patients with Parkinson’s disease treated with bilateral subthalamic stimulation for at least one year.MethodsWe recruited 24 patients with Parkinson’s disease treated with bilateral subthalamic stimulation and 24 healthy controls. They wore an Opal monitor (APDM Inc.) consisting of three-dimensional gyroscopes and accelerometers in the lumbar region. We investigated four stimulation conditions (bilateral stimulation OFF, bilateral stimulation ON, and unilateral right- and left-sided stimulation ON) with four tests: stance on a plain ground with eyes open and closed, stance on a foam platform with eyes open and closed. Age, disease duration, the time elapsed after implantation, levodopa, and stimulation responsiveness were analyzed. The distance of stimulation location from the subthalamic motor center was calculated individually in each plane of the three dimensions. We analyzed the sway values in the four stimulation conditions in the patient group and compared them with the control values. We explored factor combinations (with age as confounder) in the patient group predictive for imbalance with cluster analysis and a machine‐learning‐based multiple regression method.ResultsSway combined from the four tasks did not differ in the patients and controls on a group level. The combination of the disease duration, the preoperative levodopa responsiveness, and the stimulation responsiveness predicted individual stimulation-induced static imbalance. The more affected patients had more severe motor symptoms; primarily, the proprioceptive followed by visual sensory feedback loss provoked imbalance in them when switching on the stimulation.ConclusionsThe duration of the disease, the severity of motor symptoms, the levodopa responsiveness, and additional sensory deficits should be carefully considered during preoperative evaluation to predict subthalamic stimulation-induced imbalance in Parkinson’s disease.

Proteomic analysis reveals rattlesnake venom modulation of proteins associated with cardiac tissue damage in mouse hearts

Snake envenomation is a common but neglected disease that affects millions of people around the world annually. Among venomous snake species in Brazil, the tropical rattlesnake (Crotalus durissus terrificus) accounts for the highest number of fatal envenomations and is responsible for the second highest number of bites. Snake venoms are complex secretions which, upon injection, trigger diverse physiological effects that can cause significant injury or death. The components of C. d. terrificus venom exhibit neurotoxic, myotoxic, hemotoxic, nephrotoxic, and cardiotoxic properties which present clinically as alteration of central nervous system function, motor paralysis, seizures, eyelid ptosis, ophthalmoplesia, blurred vision, coagulation disorders, rhabdomyolysis, myoglobinuria, and cardiorespiratory arrest. In this study, we focused on proteomic characterization of the cardiotoxic effects of C. d. terrificus venom in mouse models. We injected venom at half the lethal dose (LD50) into the gastrocnemius muscle. Mouse hearts were removed at set time points after venom injection (1 h, 6 h, 12 h, or 24 h) and subjected to trypsin digestion prior to high-resolution mass spectrometry. We analyzed the proteomic profiles of >1300 proteins and observed that several proteins showed noteworthy changes in their quantitative profiles, likely reflecting the toxic activity of venom components. Among the affected proteins were several associated with cellular deregulation and tissue damage. Changes in heart protein abundance offer insights into how they may work synergistically upon envenomation. SignificanceVenom of the tropical rattlesnake (Crotalus durissus terririficus) is known to be neurotoxic, myotoxic, nephrotoxic and cardiotoxic. Although there are several studies describing the biochemical effects of this venom, no work has yet described its proteomic effects in the cardiac tissue of mice. In this work, we describe the changes in several mouse cardiac proteins upon venom treatment. Our data shed new light on the clinical outcome of the envenomation by C. d. terrificus, as well as candidate proteins that could be investigated in efforts to improve current treatment approaches or in the development of novel therapeutic interventions in order to reduce mortality and morbidity resulting from envenomation.

Partial Restoration of Spinal Cord Neural Continuity via Sural Nerve Transplantation Using a Technique of Spinal Cord Fusion.

BackgroundSpinal cord injury (SCI) can cause paralysis and serious chronic morbidity, and there is no effective treatment. Based on our previous experimental results of spinal cord fusion (SCF) in mice, rats, beagles, and monkeys, we developed a surgical protocol of SCF for paraplegic human patients. We designed a novel surgical procedure of SCF, called sural nerve transplantation (SNT), for human patients with lower thoracic SCI and distal cord dysfunction.MethodsWe conducted a clinical trial (ChiCTR2000030788) and performed SNT in 12 fully paraplegic patients due to SCI between T1 and T12. We assessed pre- and postoperative central nerve pain, motor function, sensory function, and autonomic nerve function. Conduction of action potentials across the sural nerve transplant was evaluated. Neural continuity was also examined by diffusion tensor imaging (DTI).ResultsAmong the 12 paraplegic patients enrolled in this clinical trial, seven patients demonstrated improved autonomic nerve functions. Seven patients had clinically significant relief of their symptoms of cord central pain. One patient, however, developed postoperative cord central pain (VAS: 4). Five patients had varying degrees of recovered sensory and/or motor functions below the single neurologic level 1 month after surgery. One patient showed recovery of electrophysiologic, motor-evoked potentials 6 months after the operation. At 6 months after surgery, DTI indicated fusion and nerve connections of white cord and sural nerves in seven patients.ConclusionSNT was able to fuse the axonal stumps of white cord and sural nerve and at least partially improve the cord central pain in most patients. Although SNT did not restore the spinal cord continuity in white matter in some patients, SNT could restore spinal cord continuity in the cortico-trunco-reticulo-propriospinal pathway, thereby restoring in part some motor and sensory functions. SNT may therefore be a safe, feasible, and effective method to treat paraplegic patients with SCI. Future clinical trials should be performed to optimize the type/technique of nerve transplantation, reduce surgical damage, and minimize postoperative scar formation and adhesion, to avoid postoperative cord central pain.Clinical Trial Registration[http://www.chictr.org.cn/showproj.aspx?proj=50526], identifier [ChiCTR2000030788].

Cortical Correlates of Gait Compensation Strategies in Parkinson Disease.

ObjectiveGait impairment in persons with Parkinson disease is common and debilitating. Compensation strategies (eg, external cues) are an essential part of rehabilitation, but their underlying mechanisms remain unclear. Using electroencephalography (EEG), we explored the cortical correlates of 3 categories of strategies: external cueing, internal cueing, and action observation.MethodsEighteen participants with Parkinson disease and gait impairment were included. We recorded 126‐channel EEG during both stance and gait on a treadmill under 4 conditions: (1) uncued, (2) external cueing (listening to a metronome), (3) internal cueing (silent rhythmic counting), and (4) action observation (observing another person walking). To control for the effects of sensory processing of the cues, we computed relative power changes as the difference in power spectral density between walking and standing for each condition.ResultsRelative to uncued gait, the use of all 3 compensation strategies induced a decrease of beta band activity in sensorimotor areas, indicative of increased cortical activation. Parieto‐occipital alpha band activity decreased with external and internal cueing, and increased with action observation. Only internal cueing induced a change in frontal cortical activation, showing a decrease of beta band activity compared to uncued gait.InterpretationThe application of compensation strategies resulted in changed cortical activity compared to uncued gait, which could not be solely attributed to sensory processing of the cueing modality. Our findings suggest there are multiple routes to control gait, and different compensation strategies seem to rely on different cortical mechanisms to achieve enhanced central motor activation in persons with Parkinson disease. ANN NEUROL 2022;91:329–341

Neurophysiological outcomes following mesenchymal stem cell therapy in multiple sclerosis

ObjectiveTo report on neurophysiological outcomes derived from transcranial magnetic stimulation (TMS) following autologous mesenchymal stem cells (aMSCs) therapy in patients with multiple sclerosis (MS). Methods20 adults with confirmed MS were recruited to participate in a phase II randomized control trial to assess the safety and potential benefits of aMSCs infusion. At Week 0, patients were randomly assigned to receive either aMSCs (n = 9) or a placebo infusion (n = 11). At Week 24, the placebo group received the aMSCs infusion. Blind assessments were performed at Weeks 0, 24 and 48. Outcomes consisted of TMS measures of corticomotor excitability and motor conduction along with measures of motor impairments and disability. ResultsPost-infusion, no change was detected in measures of corticomotor excitability or measures of intra- or interhemispheric inhibition. The latency of motor evoked potentials and central motor conduction time were significantly prolonged. These changes in motor conduction were associated with declines in hand dexterity post-infusion. ConclusionClinical and neurophysiological measures showed no improvement following aMSCs therapy in this cohort of MS patients. SignificanceAlthough promising, stem cell therapy remains elusive regarding its benefits in influencing disease activity in MS patients.

Post-Stroke Treatment with Neuromuscular Functional Electrostimulation of Antagonistic Muscles and Kinesiotherapy Evaluated with Electromyography and Clinical Studies in a Two-Month Follow-Up.

The aim of this study was to determine the sustained influence of personalized neuromuscular functional electrical stimulation (NMFES) combined with kinesiotherapy (mainly, proprioceptive neuromuscular facilitation (PNF)) on the activity of muscle motor units acting antagonistically at the wrist and the ankle in a large population of post-stroke patients. Clinical evaluations of spasticity (Ashworth scale), manual muscle testing (Lovett scale), and surface electromyography recordings at rest (rEMG) and during attempts of maximal muscle contraction (mcEMG) were performed three times in 120 post-stroke patients (T0: up to 7 days after the incidence; T1: after 21 days of treatment; T2: after 60 days of treatment). Patients (N = 120) were divided into two subgroups—60 patients received personalized NMFES and PNF treatment (NMFES+K), and the other 60 received only PNF (K). The NMFES+K therapy resulted in a decrease in spasticity and an increase in muscle strength of mainly flexor muscles, in comparison with the K group. A positive correlation between the increase of rEMG amplitudes and high Ashworth scale scores and a positive correlation between low amplitudes of mcEMG and low Lovett scale scores were found in the wrist flexors and calf muscles on the paretic side. Negative correlations were found between the rEMG and mcEMG amplitudes in the recordings. The five-grade alternate activity score of the antagonists’ actions improved in the NMFES+K group. These improvements in the results of controlled NMFES treatment combined with PNF in patients having experienced an ischemic stroke, in comparison to the use of kinesiotherapy alone, might justify the application of conjoined rehabilitation procedures based on neurophysiological approaches. Considering the results of clinical and neurophysiological studies, we suppose that NMFES of the antagonistic muscle groups acting at the wrist and the ankle may evoke its positive effects in post-stroke patients by the modulation of the activity more in the spinal motor centers, including the level of Ia inhibitory neurons, than only at the muscular level.

Oligodendrocyte and Extracellular Matrix Contributions to Central Nervous System Motor Function: Implications for Dystonia.

The quest to elucidate nervous system function and dysfunction in disease has focused largely on neurons and neural circuits. However, fundamental aspects of nervous system development, function, and plasticity are regulated by nonneuronal elements, including glial cells and the extracellular matrix (ECM). The rapid rise of genomics and neuroimaging techniques in recent decades has highlighted neuronal-glial interactions and ECM as a key component of nervous system development, plasticity, and function. Abnormalities of neuronal-glial interactions have been understudied but are increasingly recognized to play a key role in many neurodevelopmental disorders. In this report, we consider the role of myelination and the ECM in the development and function of central nervous system motor circuits and the neurodevelopmental disease dystonia. © 2022 International Parkinson and Movement Disorder Society.

Cortical excitability changes as a marker of cognitive impairment in Parkinson’s disease

Cognitive impairment of different severity with eventual progression to dementia in Parkinson’s disease (PD) appears during the course of the disease. In this study, transcranial magnetic stimulation (TMS) was used to assess cortical excitability changes in PD patients with varying cognitive impairment. We aimed to identify the TMS parameters that could serve as a non-invasive marker of cognitive impairment in patients with PD. Consecutive PD patients were recruited in the study. Detailed neuropsychological assessment was carried out to identify PD without cognitive impairment (PD-nC), PD with mild cognitive impairment (PD-MCI) and PD with dementia (PDD). Twenty patients of PDD (2 females and 18 males), 20 PD-MCI (4 females and 16 males), 18 PD-nC (5 females, 13 males) and 18 healthy controls (4 females, and 14 males) were included in the study. All the participants underwent TMS with recording of resting motor threshold, central motor conduction time, silent period, short interval intracortical inhibition (SICI) and intracortical facilitation (ICF). All the groups were age matched. The SICI was present in all; however, significantly greater inhibition was noted in PDD (Mean±SD; 0.11 ± 0.08) followed by PD-MCI (0.31 ± 0.17), PD-nC (0.49 ± 0.26) and controls (0.61 ± 0.23; p < 0.001). The ICF was significantly reduced in PDD (Mean±SD; 0.15 ± 0.18), PD-MCI (0.55 ± 0.31), PD-nC (0.96 ± 0.59), when compared to healthy controls (1.81 ± 0.83; p < 0.001). Patients with PD-nC, PD-MCI and PDD had graded reduction in ICF and increasing intracortical inhibition as the disease progressed from PD-nC through PD-MCI to PDD. This suggests progressive overactivity of GABAergic transmission, glutaminergic deficiency with consequent reduction of cholinergic transmission leading to dementia.

Research progress on improving motor function of spastic cerebral palsy with integrated traditional Chinese and western medicine

Cerebral palsy is a common central nervous system disease syndrome in childhood. The lesions are in the brain and involve the limbs, which seriously affects the growth and development of children. The central motor and postural development disorders are the main causes of physical disability in children. The disease is slow growing and has a high chance of long-term disability. At present, the treatment methods for cerebral palsy are becoming more and more mature, and the treatment methods are diversified. Clinically, the treatment of cerebral palsy with integrated traditional Chinese and western medicine has achieved remarkable results. This article summarizes the research methods of integrated traditional Chinese and western medicine to improve the motor function of cerebral palsy.

Association between masticatory movement and oral and physical function in healthy older women.

This study examined the association between masticatory movement and oral and physical function in healthy older women using clinical assessments considering central motor control. A total of 107 independent older women (mean age, 74.37 ± 4.46 years; age range, 66-84 years) living in the community participated in this cross-sectional study. The subjects selected were those aged 65 years or older with at least 28 teeth and without oral dysfunction, temporomandibular joint (TMJ) disease, cerebrovascular disease, or neuromuscular disease. The following items of oral and physical function were measured: masticatory path pattern, masticatory performance, oral diadochokinesis (ODK), tongue pressure, single-leg stance with eyes open (SLS), stepping test, and grip strength. Logistic regression analysis adjusting for age was performed to investigate the association between masticatory movement and other items. In total, 30.8% of subjects were classified into the abnormal group regarding masticatory path pattern, having a significantly lower value than that of the normal group in masticatory performance (unadjusted p = 0.021). After adjusting for age, the masticatory path pattern was significantly associated with masticatory performance ( p = 0.032); ODK /pa/ ( p < 0.001), /ta/ ( p = 0.022), and /ka/ ( p = 0.016); and stepping test ( p = 0.018). Tongue pressure, SLS, and grip strength were not significantly associated with masticatory path pattern. Masticatory movement in older women was associated with masticatory performance, tongue and lip motor skills, and physical agility, which might be influenced by central motor control.

White matter volume loss drives cortical reshaping after thalamic infarcts

ObjectiveThe integration of somatosensory, ocular motor and vestibular signals is necessary for self-location in space and goal-directed action. We aimed to detect remote changes in the cerebral cortex after thalamic infarcts to reveal the thalamo-cortical connections necessary for multisensory processing and ocular motor control. MethodsThirteen patients with unilateral ischemic thalamic infarcts presenting with vestibular, somatosensory, and ocular motor symptoms were examined longitudinally in the acute phase and after six months. Voxel- and surface-based morphometry were used to detect changes in vestibular and multisensory cortical areas and known hubs of central ocular motor processing. The results were compared with functional connectivity data in 50 healthy volunteers. ResultsPatients with paramedian infarcts showed impaired saccades and vestibular perception, i.e., tilts of the subjective visual vertical (SVV). The most common complaint in these patients was double vision or vertigo / dizziness. Posterolateral thalamic infarcts led to tilts of the SVV and somatosensory deficits without vertigo. Tilts of the SVV were higher in paramedian compared to posterolateral infarcts (median 11.2° vs 3.8°). Vestibular and ocular motor symptoms recovered within six months. Somatosensory deficits persisted. Structural longitudinal imaging showed significant volume reduction in subcortical structures connected to the infarcted thalamic nuclei (vestibular nuclei region, dentate nucleus region, trigeminal root entry zone, medial lemniscus, superior colliculi). Volume loss was evident in connections to the frontal, parietal and cingulate lobes. Changes were larger in the ipsilesional hemisphere but were also detected in homotopical regions contralesionally. The white matter volume reduction led to deformation of the cortical projection zones of the infarcted nuclei. ConclusionsWhite matter volume loss after thalamic infarcts reflects sensory input from the brainstem as well the cortical projections of the main affected nuclei for sensory and ocular motor processing. Changes in the cortical geometry seem not to reflect gray matter atrophy but rather reshaping of the cortical surface due to the underlying white matter atrophy.

Passive Proprioceptive Training Alters the Sensitivity of Muscle Spindles to Imposed Movements.

Humans rely on precise proprioceptive feedback from our muscles, which is important in both the acquisition and execution of movements, to perform daily activities. Somatosensory input from the body shapes motor learning through central processes, as demonstrated for tasks using the arm, under active (self-generated) and passive conditions. Presently, we investigated whether passive movement training of the ankle increased proprioceptive acuity (psychophysical experiment) and whether it changed the peripheral proprioceptive afferent signal (microneurography experiment). In the psychophysical experiment, the ankle of 32 healthy human participants was moved passively using pairs of ramp-and-hold movements in different directions. In a pretraining test, participants made judgements about the movement direction in a two-alternative forced choice paradigm. Participants then underwent passive movement training, but only half were cued for learning, where a reference position was signaled by a sound and the participant had to learn to recognize this position; they then completed a post-training test. In a paradigm using the same setup, nine healthy participants underwent microneurography recordings of Ia muscle afferents from the peroneal nerve, where all were cued during training. In the psychophysical experiment, proprioceptive acuity improved with training only in the cued group. In the microneurography experiment, we found that muscle afferent firing was modulated, via an increase in the dynamic index, after training. We suggest that changes in muscle afferent input from the periphery can contribute to and support central perceptual and motor learning, as shown under passive conditions using ankle movements, which may be exploited for movement rehabilitation.

Molecularly confirmed pontocerebellar hypoplasia in a large family from Slovakia with four severely affected children.

Pontocerebellar hypoplasia type 1 (PCH1) is characterized by a central and peripheral motor dysfunction associated with anterior horn cell degeneration, similar to spinal muscular atrophy (SMA). We analysed three probands (later discovered to be siblings) suspected to have severe SMA, however, not confirmed by genetic test. Clinical-exome analysis (Illumina) was performed to identify causative variants, followed by Sanger sequencing confirmation in probands and other 10 family members. Homozygous pathogenic variant c.92G>C (p.(Gly31Ala)) in the Exosome Component 3 (EXOSC3) gene was found in all 3 probands, thus confirming the diagnosis of a severe form of PCH1B. The parents and six siblings were carriers, while one sibling was homozygous for a reference allele. This variant is frequent in the Czech Roma population, where it is considered a founder mutation. Haplotype analysis in this largest reported PCH1B family showed that our patients inherited from their father (of Roma origin) a haplotype identical to that found in the Czech Roma population, thus indicating these alleles have a common origin. This EXOSC3 variant is rare among the general population but most likely frequent also among Roma people in Slovakia. PCH1B should be considered for a differential diagnosis in infants manifesting SMA-like phenotype, especially if of Roma origin (Tab. 1, Fig. 1, Ref. 22). Text in PDF www.elis.sk Keywords: pontocerebellar hypoplasia, PCH1B, EXOSC3, SMA plus syndromes, pathogenic sequence variant.

Autophagy-Related Activation of Hepatic Stellate Cells Reduces Cellular miR-29a by Promoting Its Vesicular Secretion.

Background & AimsLiver fibrosis arises from long-term chronic liver injury, accompanied by an accelerated wound healing response with interstitial accumulation of extracellular matrix (ECM). Activated hepatic stellate cells (HSC) are the main source for ECM production. MicroRNA29a (miR-29a) is a crucial antifibrotic miRNA that is repressed during fibrosis, resulting in up-regulation of collagen synthesis.MethodsIntracellular and extracellular miRNA levels of primary and immortalized myofibroblastic HSC in response to profibrogenic stimulation by transforming growth factor β (TGFβ) or platelet-derived growth factor-BB (PDGF-BB) or upon inhibition of vesicular transport and autophagy processes were determined by quantitative polymerase chain reaction. Autophagy flux was studied by electron microscopy, flow cytometry, immunoblotting, and immunocytochemistry. Hepatic and serum miR-29a levels were quantified by using both liver tissue and serum samples from a cohort of chronic hepatitis C virus patients and a murine CCl4 induced liver fibrosis model.ResultsIn our study, we show that TGFβ and PDGF-BB resulted in decrease of intracellular miR-29a and a pronounced increase of vesicular miR-29a release into the supernatant. Strikingly, miR-29a vesicular release was accompanied by enhanced autophagic activity and up-regulation of the autophagy marker protein LC3. Moreover, autophagy inhibition strongly prevented miR-29a secretion and repressed its targets’ expression such as Col1A1. Consistently, hepatic miR-29a loss and increased LC3 expression in myofibroblastic HSC were associated with increased serum miR-29a levels in CCl4-treated murine liver fibrosis and specimens of hepatitis C virus patients with chronic liver disease.ConclusionsWe provide evidence that activation-associated autophagy in HSC induces release of miR-29a, whereas inhibition of autophagy represses fibrogenic gene expression in part through attenuated miR-29a secretion.

Effects of cortical intermittent theta burst stimulation combined with precise root stimulation on motor function after spinal cord injury: a case series study

Activation and reconstruction of the spinal cord circuitry is important for improving motor function following spinal cord injury. We conducted a case series study to investigate motor function improvement in 14 patients with chronic spinal cord injury treated with 4 weeks of unilateral (right only) cortical intermittent theta burst stimulation combined with bilateral magnetic stimulation of L3-L4 nerve roots, five times a week. Bilateral resting motor evoked potential amplitude was increased, central motor conduction time on the side receiving cortical stimulation was significantly decreased, and lower extremity motor score, Berg balance score, spinal cord independence measure-III score, and 10 m-walking speed were all increased after treatment. Right resting motor evoked potential amplitude was positively correlated with lower extremity motor score after 4 weeks of treatment. These findings suggest that cortical intermittent theta burst stimulation combined with precise root stimulation can improve nerve conduction of the corticospinal tract and lower limb motor function recovery in patients with chronic spinal cord injury.