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Motor skills and powerful movements seen in a variety of sports are acquired through repetitive practice and experience. Motor learning is the process of acquiring motor skills and involves the establishment of appropriate motor programs within the neuronal circuits of the brain. The cerebellum has been implicated as an important area of plasticity for motor learning. Purkinje cells(PCs) have great ability to express a characteristic type of activity dependent synaptic plasticity. Following the simultaneous activation of two major excitatory inputs to a PC, parallel fibers(PFs) and a climbing fiber, long-term depression(LTD) occurs in PF-PC synapses and is regarded as the cellular basis for the memory mechanism of the cerebellar neuronal circuit. LTD represents a persistent reduction in the efficacy of PF induced excitatory postsynaptic potentials(EPSPs). PF activation releases glutamate, which activates glutamate receptors in the dendritic spine of the PCs. mGluR1, a subtype of the metabotropic glutamate receptors, is highly expressed in the PCs. In addition, delta 2 ionotropic glutamate receptor(GluR δ 2) is expressed in only PCs throughout the brain. Our recent studies demonstrate that these glutamate receptors play a key role in the induction of LTD and motor learning. The present review will be expressed in terms of the involvement of these types of glutamate receptors in LTD and motor coordination during locomotion. Mice null mutant for mGluR1 exhibit characteristic cerebellar symptoms such as ataxia and motor discoordination, and also lack the LTD. Although the mGluR1 is abundantly expressed in PCs. mGluR1 is also expressed by many types of neurons in the nervous system. Hence, we returned the missing mGluR1 only into PCs with a PC-specific L7 promotor. The cell-selective rescue of mGluR1 in PCs off mGluR1 null mutant mice restored both LTD and motor coordination. GluR δ 2 is classified as an ionotropic glutamate receptor. In GluR δ 2(-/-) mice, LTD is deficient and motor coordination is also impaired. In addition, GluR δ 2(-/-) mice show abnormal synaptogenesis between PFs and PCs during development. Therefore, it is unclear whether GluR δ 2 is functional in the adult cerebellum because impairment of motor behavior may be attributed to abnormal development. Application of a blocking antibody is useful to resolve the developmental side-effects, which are inherent in conventional knockout mice. Using an antibody specific for the putative ligand-binding region of GluR δ 2, we demonstrated that GluR δ 2 is involved in LTD and motor learning in adult mice. [ABSTRACT FROM AUTHOR]

Postural control circuitry performs the essential function of maintaining balance and body position in response to perturbations that are either self-generated (e.g. reaching to pick up an object) or externally delivered (e.g. being pushed by another person). Human studies have shown that anticipation of predictable postural disturbances can modulate such responses. This indicates that postural control could involve higher-level neural structures associated with predictive functions, rather than being purely reactive. However, the underlying neural circuitry remains largely unknown. To enable studies of predictive postural control circuits, we developed a novel task for mice . In this task, modeled after human studies, a dynamic platform generated reproducible translational perturbations. While mice stood bipedally atop a perch to receive water rewards, they experienced backward translations that were either unpredictable or preceded by an auditory cue. To validate the task, we investigated the effect of the auditory cue on postural responses to perturbations across multiple days in three mice. These preliminary results serve to validate a new postural control model, opening the door to the types of neural recordings and circuit manipulations that are currently possible only in mice.

Background: Janus kinase (JAK) inhibitors, such as baricitinib, are widely used to treat rheumatoid arthritis (RA). Clinical studies show that baricitinib is more effective at reducing pain than other similar drugs. Here, we aimed to elucidate the molecular mechanisms underlying the pain relief conferred by baricitinib, using a mouse model of arthritis., Methods: We treated collagen antibody-induced arthritis (CAIA) model mice with baricitinib, celecoxib, or vehicle, and evaluated the severity of arthritis, histological findings of the spinal cord, and pain-related behaviours. We also conducted RNA sequencing (RNA-seq) to identify alterations in gene expression in the dorsal root ganglion (DRG) following baricitinib treatment. Finally, we conducted in vitro experiments to investigate the direct effects of baricitinib on neuronal cells., Results: Both baricitinib and celecoxib significantly decreased CAIA and improved arthritis-dependent grip-strength deficit, while only baricitinib notably suppressed residual tactile allodynia as determined by the von Frey test. CAIA induction of inflammatory cytokines in ankle synovium, including interleukin (IL)-1β and IL-6, was suppressed by treatment with either baricitinib or celecoxib. In contrast, RNA-seq analysis of the DRG revealed that baricitinib, but not celecoxib, restored gene expression alterations induced by CAIA to the control condition. Among many pathways changed by CAIA and baricitinib treatment, the interferon-alpha/gamma, JAK-signal transducer and activator of transcription 3 (STAT3), and nuclear factor kappa B (NF-κB) pathways were considerably decreased in the baricitinib group compared with the celecoxib group. Notably, only baricitinib decreased the expression of colony-stimulating factor 1 (CSF-1), a potent cytokine that causes neuropathic pain through activation of the microglia-astrocyte axis in the spinal cord. Accordingly, baricitinib prevented increases in microglia and astrocytes caused by CAIA. Baricitinib also suppressed JAK/STAT3 pathway activity and Csf1 expression in cultured neuronal cells., Conclusions: Our findings demonstrate the effects baricitinib has on the DRG in relation to ameliorating both inflammatory and neuropathic pain., (© 2024. The Author(s).)

Hand-gripping training is important for improving the fundamental functions of human physical activity. Bernstein's idea of "repetition without repetition" suggests that motor control function should be trained under changing states. The randomness level of load should be visualized for self-administered screening when repeating various training tasks under changing states. This study aims to develop a sensing methodology of random loads applied to both the agonist and antagonist skeletal muscles when performing physical tasks. We assumed that the time-variability and periodicity of the applied load appear in the time-series feature of muscle deformation data. In the experiment, 14 participants conducted the gripping tasks with a gripper, ball, balloon, Palm clenching, and paper. Crumpling pieces of paper (paper exercise) involves randomness because the resistance force of the paper changes depending on the shape and layers of the paper. Optical myography during gripping tasks was measured, and time-series features were analyzed. As a result, our system could detect the random movement of muscles during training.

The central nervous system predictively controls posture against external disturbances; however, the detailed mechanisms remain unclear. We tested the hypothesis that the cerebellar vermis plays a substantial role in acquiring predictive postural control by using a standing task with floor disturbances in rats. The intact, lesioned, and sham groups of rats sequentially underwent 70 conditioned floor-tilting trials, and kinematics were recorded. Six days before these recordings, only the lesion group underwent focal suction surgery targeting vermal lobules IV-VIII. In the naïve stage of the sequential trials, the upright postures and fluctuations due to the disturbance were mostly consistent among the groups. Although the pattern of decrease in postural fluctuation due to learning corresponded among the groups, the learning rate estimated from the lumbar displacement was significantly lower in the lesion group than in the intact and sham groups. These results suggest that the cerebellar vermis contributes to predictive postural controls., (© 2024. The Author(s).)

Patients with cerebellar stroke display relatively mild ataxic gaits. These motor deficits often improve dramatically; however, the neural mechanisms of this improvement have yet to be elucidated. Previous studies in mouse models of gait ataxia, such as ho15J mice and cbln1-null mice, have shown that they have a dysfunction of parallel fiber-Purkinje cell synapses in the cerebellum. However, the effects of cerebellar stroke on the locomotor kinematics of wild-type mice are currently unknown. Here, we performed a kinematic analysis of gait ataxia caused by a photothrombotic stroke in the medial, vermal, and intermediate regions of the cerebellum of wild-type mice. We used the data and observations from this analysis to develop a model that will allow locomotive prognosis and indicate potential treatment regimens following a cerebellar stroke. Our analysis showed that mice performed poorly in a ladder rung test after a stroke. During walking on a treadmill, the mice with induced cerebellar stroke had an increased duty ratio of the hindlimb caused by shortened duration of the swing phase. Overall, our findings suggest that photothrombotic cerebellar infarction and kinematic gait analyses will provide a useful model for quantification of different types of acute management of cerebellar stroke in rodents., (© 2023. Springer Nature Limited.)

Metacognition is the ability to adaptively control one's behavior by referring to one's own cognitive processes. It is thought to contribute to learning in situations where there is insufficient information available from the environment. Information-seeking behavior is a type of metacognition in which one confirms the necessary information only when one does not have the necessary and sufficient information to accomplish a task. The rats were required to respond to a nose poke hole on one wall of the experimental box for a certain period of time and then move to the opposite side at a specific time. Unfortunately, they were unable to match the timing when responding to the hole on one side. Therefore, they had to look back and confirm that now was the right time. The results obtained by analyzing these looking-back movements using a motion capture system showed that this behavior occurred frequently and rapidly in situations of insufficient information, such as in the early stages of learning, but was hardly observed and became slower as learning progressed. These results suggest that rats can adjust their behavior in response to a lack of information more flexibly than previously assumed., (© 2023. Springer Nature Limited.)

Mammalian locomotion is generated by central pattern generators (CPGs) in the spinal cord, which produce alternating flexor and extensor activities controlling the locomotor movements of each limb. Afferent feedback signals from the limbs are integrated by the CPGs to provide adaptive control of locomotion. Responses of CPG-generated neural activity to afferent feedback stimulation have been previously studied during fictive locomotion in immobilized cats. Yet, locomotion in awake, behaving animals involves dynamic interactions between central neuronal circuits, afferent feedback, musculoskeletal system, and environment. To study these complex interactions, we developed a model simulating interactions between a half-center CPG and the musculoskeletal system of a cat hindlimb. Then, we analyzed the role of afferent feedback in the locomotor adaptation from a dynamic viewpoint using the methods of dynamical systems theory and nullcline analysis. Our model reproduced limb movements during regular cat walking as well as adaptive changes of these movements when the foot steps into a hole. The model generates important insights into the mechanism for adaptive locomotion resulting from dynamic interactions between the CPG-based neural circuits, the musculoskeletal system, and the environment., Competing Interests: The 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., (Copyright © 2022 Kim, Aoi, Fujiki, Danner, Markin, Ausborn, Rybak, Yanagihara, Senda and Tsuchiya.)

Humans and animals learn the internal model of bodies and environments from their experience and stabilize posture against disturbances based on the predicted future states according to the internal model. We evaluated the mechanism of predictive control during standing, by using rats to construct a novel experimental system and comparing their behaviors with a mathematical model. In the experiments, rats ( n = 6) that were standing upright using their hindlimbs were given a sensory input of light, after a certain period, the floor under them tilted backward. Initially, this disturbance induced a large postural response, including backward rotation of the center-of-mass angle and hindlimb segments. However, the rats gradually adjusted to the disturbance after experiencing 70 sequential trials, and a reduction in the amplitude of postural response was noted. We simulated the postural control of the rats under disturbance using an inverted pendulum model and model predictive control (MPC). MPC is a control method for predicting the future state using an internal model of the control target. It provides control inputs that optimize the predicted future states. Identification of the predictive and physiological parameters so that the simulation corresponds to the experiment, resulted in a value of predictive horizon (0.96 s) close to the interval time in the experiment (0.9-1.15 s). These results suggest that the rats predict posture dynamics under disturbance based on the timing of the sensory input and that the central nervous system provides plasticity mechanisms to acquire the internal model for MPC., Competing Interests: The 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., (Copyright © 2021 Konosu, Funato, Matsuki, Fujita, Sakai and Yanagihara.)

Impairment of inferior olivary neurons (IONs) affects whole-body movements and results in abnormal gait and posture. Because IONs are activated by unpredicted motion rather than regular body movements, the postural dysfunction caused by ION lesions is expected to involve factors other than simple loss of feedback control. In this study, we measured the postural movements of rats with pharmacological ION lesions (IO rats) trained to stand on their hindlimbs. The coordination of body segments as well as the distribution and frequency characteristics of center of mass (COM) motion were analyzed. We determined that the lesion altered the peak properties of the power spectrum density of the COM, whereas changes in coordination and COM distribution were minor. To investigate how the observed properties reflected changes in the control system, we constructed a mathematical model of the standing rats and quantitatively identified the control system. We found an increase in linear proportional control and a decrease in differential and nonlinear control in IO rats compared with intact rats. The dystonia-like changes in body stiffness explain the nature of the linear proportional and differential control, and a disorder in the internal model is one possible cause of the decrease in nonlinear control., (© 2021. The Author(s).)

Studies that evaluate human emotions from biological signals have been actively conducted, with many using images or sounds to induce emotions passively. However, few studies utilized the action of working to elicit emotions (especially positive ones) actively. Hence, in this study, emotions were examined during working (a puzzle was used in this study) from the psychological viewpoint of the Profile of Mood States 2nd Edition and the physiological viewpoint of electroencephalograms (EEGs). As a result, different time-dependent changes of power change rate in the theta band in the frontal region were observed between the presence and absence of the emotion "fatigue-inertia." Those in the alpha band in the frontal region were observed between the existence and nonexistence of the emotion "vigor-activity." Therefore, it is suggested that we can evaluate the emotion of a subject while working by a spatiotemporal pattern of band power obtained by EEG.

Changing gait is crucial for adaptive and smooth animal locomotion. Although it remains unclear what makes animals decide on a specific gait, energy efficiency is an important factor. It has been reported that the relationship of oxygen consumption with speed is U-shaped for each horse gait and that different gaits have different speeds at which oxygen consumption is minimized. This allows the horse to produce energy-efficient locomotion in a wide speed range by changing gait. However, the underlying mechanisms causing oxygen consumption to be U-shaped and the speeds for the minimum consumption to be different between different gaits are unclear. In the present study, we used a neuromusculoskeletal model of the rat to examine the mechanism from a dynamic viewpoint. Specifically, we constructed the musculoskeletal part of the model based on empirical anatomical data on rats and the motor control model based on the physiological concepts of the spinal central pattern generator and muscle synergy. We also incorporated the posture and speed regulation models at the levels of the brainstem and cerebellum. Our model achieved walking through forward dynamic simulation, and the simulated joint kinematics and muscle activities were compared with animal data. Our model also achieved trotting by changing only the phase difference of the muscle-synergy-based motor commands between the forelimb and hindlimb. Furthermore, the speed of each gait varied by changing only the extension phase duration and amplitude of the muscle synergy-based motor commands and the reference values for the regulation models. The relationship between cost of transport (CoT) and speed was U-shaped for both the generated walking and trotting, and the speeds for the minimum CoT were different for the two gaits, as observed in the oxygen consumption of horses. We found that the resonance property and the posture and speed regulations contributed to the CoT shape and difference in speeds for the minimum CoT. We further discussed the energy efficiency of gait based on the simulation results., (Copyright © 2020 Toeda, Aoi, Fujiki, Funato, Tsuchiya and Yanagihara.)

Central pattern generators (CPGs) in the spinal cord generate rhythmic neural activity and control locomotion in vertebrates. These CPGs operate under the control of sensory feedback that affects the generated locomotor pattern and adapt it to the animal's biomechanics and environment. Studies of the effects of afferent stimulation on fictive locomotion in immobilized cats have shown that brief stimulation of peripheral nerves can reset the ongoing locomotor rhythm. Depending on the phase of stimulation and the stimulated nerve, the applied stimulation can either shorten or prolong the current locomotor phase and the locomotor cycle. Here, we used a mathematical model of a half-center CPG to investigate the phase-dependent effects of brief stimulation applied to CPG on the CPG-generated locomotor oscillations. The CPG in the model consisted of two half-centers mutually inhibiting each other. The rhythmic activity in each half-center was based on a slowly inactivating, persistent sodium current. Brief stimulation was applied to CPG half-centers in different phases of the locomotor cycle to produce phase-dependent changes in CPG activity. The model reproduced several results from experiments on the effect of afferent stimulation of fictive locomotion in cats. The mechanisms of locomotor rhythm resetting under different conditions were analyzed using dynamic systems theory methods., (Copyright © 2019 Fujiki, Aoi, Tsuchiya, Danner, Rybak and Yanagihara.)

Objective: To sample 40 physician organizations stratified on the basis of longitudinal cost of care measures for qualitative interviews in order to describe the range of care delivery structures and processes that are being deployed to influence the total costs of caring for patients., Data Sources: Three years of physician organization-level total cost of care data (n = 156 in California) from the Integrated Healthcare Association's value-based pay-for-performance program., Study Design: We fit total cost of care data using mixture and K-means clustering algorithms to segment the population of physician organizations into sampling strata based on 3-year cost trajectories (ie, cost curves)., Principal Findings: A mixture of multivariate normal distributions can classify physician organization cost curves into clusters defined by total cost level, shape, and within-cluster variation. K-means clustering does not accommodate differing levels of within-cluster variation and resulted in more clusters being allocated to unstable cost curves. A mixture of regressions approach focuses overly on anomalous trajectories and is sensitive to model coding., Conclusions: Statistical clustering can be used to form sampling strata when longitudinal measures are of primary interest. Many clustering algorithms are available; the choice of the clustering algorithm can strongly impact the resulting strata because various algorithms focus on different aspects of the observed data., (© Health Research and Educational Trust.)

To investigate the adaptive locomotion mechanism in animals, a split-belt treadmill has been used, which has two parallel belts to produce left-right symmetric and asymmetric environments for walking. Spinal cats walking on the treadmill have suggested the contribution of the spinal cord and associated peripheral nervous system to the adaptive locomotion. Physiological studies have shown that phase resetting of locomotor commands involving a phase shift occurs depending on the types of sensory nerves and stimulation timing, and that muscle activation patterns during walking are represented by a linear combination of a few numbers of basic temporal patterns despite the complexity of the activation patterns. Our working hypothesis was that resetting the onset timings of basic temporal patterns based on the sensory information from the leg, especially extension of hip flexors, contributes to adaptive locomotion on the split-belt treadmill. Our hypothesis was examined by conducting forward dynamic simulations using a neuromusculoskeletal model of a rat walking on a split-belt treadmill with its hindlimbs and by comparing the simulated motions with the measured motions of rats.

Purpose: Joint pain is the most common symptom of osteoarthritis (OA); however, its mechanism remains unclarified. The present study investigated hindlimb motion during locomotion on the treadmill using a three-dimensional (3D) motion analysis system with high-speed cameras to evaluate whether this method can be used as an indication of joint pain in a mouse model of surgically induced OA., Methods: We resected the medial meniscus and medial collateral ligament in 8-week old C57BL/6 male mice and performed locomotion recording 6 months post-operatively. Additionally, we performed the same recording after oral administration of the selective cyclooxygenase-2 inhibitor to determine whether alteration of the parameters were associated with joint pain., Results: OA development, characterized by cartilage degeneration and osteophyte formation, was markedly enhanced in the OA group. There was no significant difference between the sham and OA groups in basic gait parameters, including stance duration, swing duration and gait cycle. However, when we divided the gait cycle into four phases and calculated the joint ranges of motion in each phase, the range of motion of the knee joint during the stepping-in phase and the swing duration were significantly decreased in the OA group. These significant differences between the sham and OA groups were diminished by the oral administration of a selective cyclooxygenase-2 inhibitor to the OA group., Conclusion: The present method may be useful to evaluate joint pain in experimental mice and contribute to elucidating the molecular mechanisms of pain in the OA knee joint in combination with genetically modified mice.

Patients and rodents with cerebellar damage display ataxic gaits characterized by impaired coordination of limb movements. Here, gait ataxia in mice with a null mutation of the gene for the cerebellin 1 precursor protein (cbln1-null mice) was investigated by kinematic analysis of hindlimb movements during locomotion. The Cbln1 protein is predominately produced and secreted from cerebellar granule cells. The cerebellum of cbln1-null mice is characterized by an 80% reduction in the number of parallel fiber-Purkinje cell synapses compared with wild-type mice. Our analyses identified prominent differences in the temporal parameters of locomotion between cbln1-null and wild-type mice. The cbln1-null mice displayed abnormal hindlimb movements that were characterized by excessive toe elevation during the swing phase, and by severe hyperflexion of the ankles and knees. When recombinant Cbln1 protein was injected into the cerebellum of cbln1-null mice, the step cycle and stance phase durations increased toward those of wild-type mice, and the angular excursions of the knee during a cycle period showed a much closer agreement with those of wild-type mice. These findings suggest that dysfunction of the parallel fiber-Purkinje cell synapses might underlie the impairment of hindlimb movements during locomotion in cbln1-null mice.

The control of bipedal posture in humans is subject to non-ideal conditions such as delayed sensation and heartbeat noise. However, the controller achieves a high level of functionality by utilizing body dynamics dexterously. In order to elucidate the neural mechanism responsible for postural control, the present study made use of an experimental setup involving rats because they have more accessible neural structures. The experimental design requires rats to stand bipedally in order to obtain a water reward placed in a water supplier above them. Their motions can be measured in detail using a motion capture system and a force plate. Rats have the ability to stand bipedally for long durations (over 200 s), allowing for the construction of an experimental environment in which the steady standing motion of rats could be measured. The characteristics of the measured motion were evaluated based on aspects of the rats' intersegmental coordination and power spectrum density (PSD). These characteristics were compared with those of the human bipedal posture. The intersegmental coordination of the standing rats included two components that were similar to that of standing humans: center of mass and trunk motion. The rats' PSD showed a peak at approximately 1.8 Hz and the pattern of the PSD under the peak frequency was similar to that of the human PSD. However, the frequencies were five times higher in rats than in humans. Based on the analysis of the rats' bipedal standing motion, there were some common characteristics between rat and human standing motions. Thus, using standing rats is expected to be a powerful tool to reveal the neural basis of postural control.

Background: The belief that there is inefficiency, or the potential to improve patient health at current levels of spending, is driving the push for greater value in health care. Previous studies demonstrate overuse of a narrow set of services, suggesting provider inefficiency, but existing studies neither quantify inefficiency more broadly nor assess its variation across physician organizations (POs)., Data and Methods: We used data on quality of care and total cost of care from 129 California POs participating in a statewide value-based pay-for-performance program. We estimated a production function with quality as the output and cost as the input, using a stochastic frontier model, to develop a measure of relative efficiency for each PO. To validate the efficiency measure, we examined correlations of PO efficiency estimates with indicators representing overuse of services., Results: The estimated production function showed that PO quality was positively associated with costs, although there were diminishing marginal returns to spending. A certain minimum level of spending was associated with high quality even among efficient POs. Most strikingly, however, POs had substantial variation in efficiency, producing widely differing levels of quality for the same cost., Conclusions: Differences among POs in the efficiency with which they produce quality suggest opportunities for improvements in care delivery that increase quality without increasing spending.

Key Points: Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disease caused by a gene defect, leading to movement disorder such as cerebellar ataxia. It remains largely unknown which functional defect contributes to the cerebellar ataxic phenotype in SCA1. In this study, we report progressive dysfunction of metabotropic glutamate receptor (mGluR) signalling, which leads to smaller slow synaptic responses, reduced dendritic Ca 2+ signals and impaired synaptic plasticity at cerebellar synapses, in the early disease stage of SCA1 model mice. We also show that enhancement of mGluR signalling by a clinically available drug, baclofen, leads to improvement of motor performance in SCA1 mice. SCA1 is an incurable disease with no effective treatment, and our results may provide mechanistic grounds for targeting mGluRs and a novel drug therapy with baclofen to treat SCA1 patients in the future., Abstract: Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disease that presents with cerebellar ataxia and motor learning defects. Previous studies have indicated that the pathology of SCA1, as well as other ataxic diseases, is related to signalling pathways mediated by the metabotropic glutamate receptor type 1 (mGluR1), which is indispensable for proper motor coordination and learning. However, the functional contribution of mGluR signalling to SCA1 pathology is unclear. In the present study, we show that SCA1 model mice develop a functional impairment of mGluR signalling which mediates slow synaptic responses, dendritic Ca 2+ signals, and short- and long-term synaptic plasticity at parallel fibre (PF)-Purkinje cell (PC) synapses in a progressive manner from the early disease stage (5 postnatal weeks) prior to PC death. Notably, impairment of mGluR-mediated dendritic Ca 2+ signals linearly correlated with a reduction of PC capacitance (cell surface area) in disease progression. Enhancement of mGluR signalling by baclofen, a clinically available GABA B receptor agonist, led to an improvement of motor performance in SCA1 mice and the improvement lasted ∼1 week after a single application of baclofen. Moreover, the restoration of motor performance in baclofen-treated SCA1 mice matched the functional recovery of mGluR-mediated slow synaptic currents and mGluR-dependent short- and long-term synaptic plasticity. These results suggest that impairment of synaptic mGluR cascades is one of the important contributing factors to cerebellar ataxia in early and middle stages of SCA1 pathology, and that modulation of mGluR signalling by baclofen or other clinical interventions may be therapeutic targets to treat SCA1., (© 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.)