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Non-invasive cerebellar stimulation (NICS) aims to modulate cerebello-cerebral loops and cerebro-spinal loops, both for research and clinical applications. It is of paramount importance to establish and validate morphological and functional tools to quantify cerebellar reserve, defined as the capacity for restoration and compensation to pathology of the cerebellum. Using NICS without efforts to estimate cerebellar reserve will end up in conflicting results due to the very high heterogeneity of cerebellar disorders encountered in daily practice.

Cerebellar reserve refers to the capacity of the cerebellum to compensate for tissue damage or loss of function resulting from many different etiologies. When the inciting event produces acute focal damage (e.g., stroke, trauma), impaired cerebellar function may be compensated for by other cerebellar areas or by extracerebellar structures (i.e., structural cerebellar reserve). In contrast, when pathological changes compromise cerebellar neuronal integrity gradually leading to cell death (e.g., metabolic and immune-mediated cerebellar ataxias, neurodegenerative ataxias), it is possible that the affected area itself can compensate for the slowly evolving cerebellar lesion (i.e., functional cerebellar reserve). Here, we examine cerebellar reserve from the perspective of the three cornerstones of clinical ataxiology: control of ocular movements, coordination of voluntary axial and appendicular movements, and cognitive functions. Current evidence indicates that cerebellar reserve is potentiated by environmental enrichment through the mechanisms of autophagy and synaptogenesis, suggesting that cerebellar reserve is not rigid or fixed, but exhibits plasticity potentiated by experience. These conclusions have therapeutic implications. During the period when cerebellar reserve is preserved, treatments should be directed at stopping disease progression and/or limiting the pathological process. Simultaneously, cerebellar reserve may be potentiated using multiple approaches. Potentiation of cerebellar reserve may lead to compensation and restoration of function in the setting of cerebellar diseases, and also in disorders primarily of the cerebral hemispheres by enhancing cerebellar mechanisms of action. It therefore appears that cerebellar reserve, and the underlying plasticity of cerebellar microcircuitry that enables it, may be of critical neurobiological importance to a wide range of neurological/neuropsychiatric conditions.

We here provide neural evidence that the cerebellar circuit can predict future inputs from present outputs, a hallmark of an internal forward model. Recent computational studies hypothesize that the cerebellum performs state prediction known as a forward model. To test the forward-model hypothesis, we analyzed activities of 94 mossy fibers (inputs to the cerebellar cortex), 83 Purkinje cells (output from the cerebellar cortex to dentate nucleus), and 73 dentate nucleus cells (cerebellar output) in the cerebro-cerebellum, all recorded from a monkey performing step-tracking movements of the right wrist. We found that the firing rates of one population could be reconstructed as a weighted linear sum of those of preceding populations. We then went on to investigate if the current outputs of the cerebellum (dentate cells) could predict the future inputs of the cerebellum (mossy fibers). The firing rates of mossy fibers at time t + t_1 could be well reconstructed from as a weighted sum of firing rates of dentate cells at time t, thereby proving that the dentate activities contained predictive information about the future inputs. The average goodness-of-fit (R^2) decreased moderately from 0.89 to 0.86 when t_1 was increased from 20 to 100 ms, hence indicating that the prediction is able to compensate the latency of sensory feedback. The linear equations derived from the firing rates resembled those of a predictor known as Kalman filter composed of prediction and filtering steps. In summary, our analysis of cerebellar activities supports the forward-model hypothesis of the cerebellum.

The cerebellum is endowed with the capacity for compensation and restoration after pathological injury, a property known as cerebellar reserve. Such capacity is attributed to two unique morphological and physiological features of the cerebellum. First, mossy fibers that convey peripheral and central information run mediolaterally over a wide area of the cerebellum, resulting in the innervation of multiple microzones, commonly known as cerebellar functional units. Thus, a single microzone receives redundant information that can be used in pathological conditions. Secondly, the circuitry is characterized by a co-operative interplay among various forms of synaptic plasticity. Recent progress in understanding the mechanisms of redundant information and synaptic plasticity has allowed outlining therapeutic strategies potentiating these neural substrates to enhance the cerebellar reserve, taking advantage of the unique physiological properties of the cerebellum which appears as a modular and potentially reconfiguring brain structure.

Humans learn motor skills (MSs) through practice and experience and may then retain them for recruitment, which is effective as a rapid response for novel contexts. For an MS to be recruited for novel contexts, its recruitment range must be extended. In addressing this issue, we hypothesized that an MS is dynamically modulated according to the feedback context to expand its recruitment range into novel contexts, which do not involve the learning of an MS. The following two sub-issues are considered. We previously demonstrated that the learned MS could be recruited in novel contexts through its modulation, which is driven by dynamically regulating the synergistic redundancy between muscles according to the feedback context. However, this modulation is trained in the dynamics under the MS learning context. Learning an MS in a specific condition naturally causes movement deviation from the desired state when the MS is executed in a novel context. We hypothesized that this deviation can be reduced with the additional modulation of an MS, which tunes the MS-produced muscle activities by using the feedback gain signals driven by the deviation from the desired state. Based on this hypothesis, we propose a feedback gain signal-driven tuning model of a learned MS for its robust recruitment. This model is based on the neurophysiological architecture in the cortico-basal ganglia circuit, in which an MS is plausibly retained as it was learned and is then recruited by tuning its muscle control signals according to the feedback context. In this study, through computational simulation, we show that the proposed model may be used to neurophysiologically describe the recruitment of a learned MS in novel contexts.

The terminology of cerebellar dysmetria embraces a ubiquitous symptom in motor deficits, oculomotor symptoms, and cognitive/emotional symptoms occurring in cerebellar ataxias. Patients with episodic ataxia exhibit recurrent episodes of ataxia, including motor dysmetria. Despite the consensus that cerebellar dysmetria is a cardinal symptom, there is still no agreement on its pathophysiological mechanisms to date since its first clinical description by Babinski. We argue that impairment in the predictive computation for voluntary movements explains a range of characteristics accompanied by dysmetria. Within this framework, the cerebellum acquires and maintains an internal forward model, which predicts current and future states of the body by integrating an estimate of the previous state and a given efference copy of motor commands. Two of our recent studies experimentally support the internal-forward-model hypothesis of the cerebellar circuitry. First, the cerebellar outputs (firing rates of dentate nucleus cells) contain predictive information for the future cerebellar inputs (firing rates of mossy fibers). Second, a component of movement kinematics is predictive for target motions in control subjects. In cerebellar patients, the predictive component lags behind a target motion and is compensated with a feedback component. Furthermore, a clinical analysis has examined kinematic and electromyography (EMG) features using a task of elbow flexion goal-directed movements, which mimics the finger-to-nose test. Consistent with the hypothesis of the internal forward model, the predictive activations in the triceps muscles are impaired, and the impaired predictive activations result in hypermetria (overshoot). Dysmetria stems from deficits in the predictive computation of the internal forward model in the cerebellum. Errors in this fundamental mechanism result in undershoot (hypometria) and overshoot during voluntary motor actions. The predictive computation of the forward model affords error-based motor learning, coordination of multiple degrees of freedom, and adequate timing of muscle activities. Both the timing and synergy theory fit with the internal forward model, microzones being the elemental computational unit, and the anatomical organization of converging inputs to the Purkinje neurons providing them the unique property of a perceptron in the brain. We propose that motor dysmetria observed in attacks of ataxia occurs as a result of impaired predictive computation of the internal forward model in the cerebellum.

This review surveys physiological, behavioral, and morphological evidence converging to the view of the cerebro-cerebellum as loci of internal forward models. The cerebro-cerebellum, the phylogenetically newest expansion in the cerebellum, receives convergent inputs from cortical, subcortical, and spinal sources, and is thought to perform the predictive computation for both motor control, motor learning, and cognitive functions. This predictive computation is known as an internal forward model. First, we elucidate the theoretical foundations of an internal forward model and its role in motor control and motor learning within the framework of the optimal feedback control model. Then, we discuss a neural mechanism that generates various patterns of outputs from the cerebro-cerebellum. Three lines of supporting evidence for the internal-forward-model hypothesis are presented in detail. First, we provide physiological evidence that the cerebellar outputs (activities of dentate nucleus cells) are predictive for the cerebellar inputs [activities of mossy fibers (MFs)]. Second, we provide behavioral evidence that a component of movement kinematics is predictive for target motion in control subjects but lags behind a target motion in patients with cerebellar ataxia. Third, we provide morphological evidence that the cerebellar cortex and the dentate nucleus receive separate MF projections, a prerequisite for optimal estimation. Finally, we speculate that the predictive computation in the cerebro-cerebellum could be deployed to not only motor control but also to non-motor, cognitive functions. This review concludes that the predictive computation of the internal forward model is the unifying algorithmic principle for understanding diverse functions played by the cerebro-cerebellum.

Summary Sensory processing is essential for motor control. Climbing fibers from the inferior olive transmit sensory signals to Purkinje cells, but how the signals are represented in the cerebellar cortex remains elusive. To examine the olivocerebellar organization of the mouse brain, we perform quantitative Ca2+ imaging to measure complex spikes (CSs) evoked by climbing fiber inputs over the entire dorsal surface of the cerebellum simultaneously. The surface is divided into approximately 200 segments, each composed of ∼100 Purkinje cells that fire CSs synchronously. Our in vivo imaging reveals that, although stimulation of four limb muscles individually elicits similar global CS responses across nearly all segments, the timing and location of a stimulus are derived by Bayesian inference from coordinated activation and inactivation of multiple segments on a single trial basis. We propose that the cerebellum performs segment-based, distributed-population coding that represents the conditional probability of sensory events.

It is widely accepted that the cerebellum acquires and maintain internal models for motor control. An internal model simulates mapping between a set of causes and effects. There are two candidates of cerebellar internal models, forward models and inverse models. A forward model transforms a motor command into a prediction of the sensory consequences of a movement. In contrast, an inverse model inverts the information flow of the forward model. Despite the clearly different formulations of the two internal models, it is still controversial whether the cerebro-cerebellum, the phylogenetically newer part of the cerebellum, provides inverse models or forward models for voluntary limb movements or other higher brain functions. In this article, we review physiological and morphological evidence that suggests the existence in the cerebro-cerebellum of a forward model for limb movement. We will also discuss how the characteristic input–output organization of the cerebro-cerebellum may contribute to forward models for non-motor higher brain functions.

The visuomotor transformation during a goal-directed movement may involve a coordinate transformation from visual ‘extrinsic’ to muscle-like ‘intrinsic’ coordinate frames, which might be processed via a multilayer network architecture composed of neural basis functions. This theory suggests that the postural change during a goal-directed movement task alters activity patterns of the neurons in the intermediate layer of the visuomotor transformation that recieves both visual and proprioceptive inputs, and thus influence the multi-voxel pattern of the blood oxygenation level dependent signal. Using a recently developed multi-voxel pattern decoding method, we found extrinsic, intrinsic and intermediate coordinate frames along the visuomotor cortical pathways during a visuomotor control task. The presented results support the hypothesis that, in human, the extrinsic coordinate frame was transformed to the muscle-like frame over the dorsal pathway from the posterior parietal cortex and the dorsal premotor cortex to the primary motor cortex.

In this paper, we examined the age-related changes in control of preprogramed movement, with emphasis on its accuracy. Forty-nine healthy subjects participated in this study, and were divided into three groups depending on their ages: the young group (20-39 years) (n = 16), the middle-age group (40-59 years) (n = 16), and the elderly group (60-79 years) (n = 17). We asked the subjects to perform step-tracking movements of the wrist joint with a manipulandum, and recorded the movements. We evaluated the accuracy of control of preprogramed movement in the three groups in terms of the primary submovement, which was identified as the first segment of the step-tracking movement based on the bell-shaped velocity profile, and calculated the distance between the end position of the primary submovement and the target (i.e. error). The error in the young group was found to be significantly smaller than that in the middle-age and elderly groups, i.e., the error was larger for the higher age groups. These results suggest that young subjects have better control of preprogramed movement than middle-age or elderly subjects. Finally, we examined the temporal property of the primary submovement and its age-related changes. The duration of the primary submovement tended to be longer for the aged groups, although significance was reached only for the elderly group. In particular, the ratio of the duration of the primary submovement to total movement time tended to be lower for the aged groups, suggesting that the proportion of additional movements that are required to compensate for the incomplete control in the preprogramed movement, which are under feedback control, was higher for the aged groups. Consequently, our results indicate that the distance between the end point of the primary submovement and the target center (i.e. error) in the step-tracking movement is a useful parameter to evaluate the age-related changes in control of preprogramed movement.

Background: In order to optimize outcomes of novel therapies for cerebellar ataxias (CAs), it is desirable to start these therapies while declined functions are restorable: i.e. while the so-called cerebellar reserve remains. Objective: In this mini-review, we tried to define and discuss the cerebellar reserve from physiological and morphological points of view. Method: The cerebellar neuron circuitry is designed to generate spatiotemporally organized outputs, regardless of the region. Therefore, the cerebellar reserve may be defined as a mechanism to restore its proper input-output organization of the cerebellar neuron circuitry, when it is damaged. Then, the following four components are essential for recruitment of the cerebellar reserve: operational local neuron circuitry; proper combination of mossy fiber inputs to be integrated; climbing fiber inputs to instruct favorable reorganization of the integration; deep cerebellar nuclei to generate reorganized outputs. Results: We discussed three topics related to these resources, 1) principles of generating organized cerebellar outputs, 2) redundant mossy fiber inputs to the cerebellum, 3) plasticity of the cerebellar neuron circuitry. Conclusion: To make most of the cerebellar reserve, it is desirable to start any intervention as early as possible when the cerebellar cell loss is minimal or even negligible. Therefore, an ideal future therapy for degenerative cerebellar diseases should start before consuming the cerebellar reserve at all. In the meantime, our real challenge is to establish a reliable method to identify the decrease in the cerebellar reserve as early as possible.

Once people have a well-trained motor skill, their performance becomes stabilized and achieving substantial improvement is difficult. Recently, we have shown that even a plateaued hand motor skill can be upgraded with short-period electrical stimulation to the hand prior to the task. Here, we identify the neuronal substrates underlying the improvement of the plateaued skill by examining the enhanced functional connectivity in the sensory-motor regions that are associated with motor learning. We measured brain activity using functional magnetic resonance imaging and performed psychophysiological interaction analysis. We recruited seven right-handed very-well trained participants, whose motor performance of continuously rotating two balls with their right hands became stabilized at higher performance levels. We prepared two experiments, in each of which they repeated an experimental run 16 times. In each run, they performed this cyclic rotation as many times as possible in 16 s. In the thenar-stimulation experiment, we applied 60-s stimulation to the thenar muscle before each of the 5th - 12th runs, and the others were preceded by ineffective sham stimulation. In the control experiment, the sham was always provided. Thenar stimulation enabled the participants to perform the movements at higher cycles. In association with this performance improvement, we found enhanced activity couplings between the primary motor cortex and the sensorimotor territory of the putamen and between the cerebellum and the primary sensorimotor cortices, without any quantitative activity increase. Neither behavioral change nor these increased activity couplings were observed in the control.Thus, in contrast to the stable neuronal states in the cortico-subcortical motor circuits when the well-learned task is repeated at the later stages of motor skill learning, plastic changes in the motor circuits seem to be required when the plateaued skill is upgraded, and the stimulation may entail a state of readiness for the plastic change that allows subsequent performance improvement.

Holmes proposed not only the term ataxia, but also opposite clinical signs related to muscle recruitment, which have escaped clinical attention; (1) asthenia, representing delay in initiating muscle contraction and slowness in attaining exertion of full power, and (2) adventitiousness, representing adventitious movements. Recent physiological studies have shown that cerebellar outputs are modified by release or facilitation of Purkinje cell-mediated inhibition on dentate neurons. We believe that asthenia and adventitiousness, which correlate with deficits in the control of disinhibition and inhibition, respectively, deserve more attention in clinical examination.

A region of cerebellar lobules V and VI makes strong loop connections with the primary motor (M1) and premotor (PM) cortical areas and is assumed to play essential roles in limb motor control. To examine its functional role, we compared the activities of its input, intermediate, and output elements, i.e., mossy fibers (MFs), Golgi cells (GoCs), and Purkinje cells (PCs), in three monkeys performing wrist movements in two different forearm postures. The results revealed distinct steps of information processing. First, MF activities displayed temporal and directional properties that were remarkably similar to those of M1/PM neurons, suggesting that MFs relay near copies of outputs from these motor areas. Second, all GoCs had a stereotyped pattern of activity independent of movement direction or forearm posture. Instead, GoC activity resembled an average of all MF activities. Therefore, inhibitory GoCs appear to provide a filtering function that passes only prominently modulated MF inputs to granule cells. Third, PCs displayed highly complex spatiotemporal patterns of activity, with coordinate frames distinct from those of MF inputs and directional tuning that changed abruptly before movement onset. The complexity of PC activities may reflect rapidly changing properties of the peripheral motor apparatus during movement. Overall, the cerebellar cortex appears to transform a representation of outputs from M1/PM into different movement representations in a posture-dependent manner and could work as part of a forward model that predicts the state of the peripheral motor apparatus.

To examine whether mossy fibers (MFs) in the cerebellar hemisphere show delay activity, we recorded MF activity during a wrist movement task with a random instructed delay period in two monkeys. Among 155 task-related MFs, 70 MFs (45%) demonstrated significant delay activity. Those MFs were widely distributed in the cerebellar hemisphere. Some of the activities were evoked by instruction cue presentation, whereas other activity started in anticipation of the upcoming go signal. For most MFs, the delay activities showed directional tuning. These patterns of the activity were in common with those of neurons in the cerebral motor cortices.

Background: Fundamental cytological changes of amyotrophic lateral sclerosis (ALS) were looked for by comparing relatively preserved Onuf’s nucleus (ON) and severely affected neighboring motor neuron groups (dorsolateral alpha motoneurons (DL) and other anterior horn neurons (OAH)). The second sacral segments from 11 ALS patients and 5 controls were initially quadruple-labeled for phosphorylated and non-phosphorylated TAR DNA-binding protein of 43 kDa (TDP43), and p62 with DAPI to identify TDP43-related changes. After digital recording of these fluorescence data encompassing the entire specimen at a high resolution, the same sections were stained with Kluver-Barrera method to obtain their exact bright-field counterparts. This novel approach facilitated exact identification of ON. Furthermore, this cell to cell comparison enabled to correlate quantitative indices of the neuronal cell bodies: perimeter, area and circularity index (CI) i.e. the ratio of (perimeter/2π) divided by the square root of (area/π), which decreases with dendritic retraction, overall number of neurons and inclusions. Results: In addition to known preservation of ON neuron number relative to DL and OAH, size reduction of ON neurons was not significant even in the advanced stage. Significant size reduction in DL was counteracted in the presence of TDP43-positive inclusions. Early increase of neuronal size in OAH was further enhanced by the presence of TDP43-positive inclusions. Even with these heterogeneous cytopathological changes, a decrease in CI was consistent in all groups at an early phase and was correlated with neuronal loss. Conclusions: Among variable cytological changes of ALS, a decrease in CI is a consistent early feature shared between non-atrophic ON neurons and other anterior horn neurons with either decreased (DL) or even increased (OAH) size and profounder neuronal loss. This decrease in CI, representative of dendritic retraction, is fundamental to ALS pathogenesis, not necessarily linked to cell size and pathological inclusions.

Quantitative evaluation of motor functions of patients with cerebellar ataxia is vital for evidence-based treatments and has been a focus in previous investigations of movement kinematics. Due to redundancy of the musculoskeletal system, muscle activities contain more information than the movement kinematics. Therefore, it is preferable to analyze causal anomalies of muscle activities to evaluate motor functions in patients. Here we propose a new method to evaluate the motor functions at the level of muscle activities and movement kinematics. Nineteen patients and 10 control subjects performed two movement tasks of the wrist joint, a step-tracking task and a pursuit task, with a manipulandum. The movements of the wrist joint and activities of the four wrist prime movers were recorded. We developed a linear model for the wrist joint to approximate the causal relationship between muscle activities and movement kinematics in terms of the wrist joint torque. We used a canonical correlation analysis to verify the causality between the muscle activities and the movement kinematics in the model. We found that the activities of the four muscles were related almost entirely to the position and velocity, with negligible correlation with the acceleration of the wrist joint. Moreover, the ratio of the weights for position- and velocity-related torque components characterized the contents of the muscle activities in terms of the movement kinematics. Next, we compared the ratios for the two movement tasks between the controls and patients. In control subjects, the ratios indicated clear task-specific changes that conformed to the functional requirements of the tasks. In contrast, in patients, the task-specific changes diminished highly significantly. The present results indicate that this ability to accommodate motor commands to the task requirements provides a novel quantitative parameter to characterize motor functions in patients with cerebellar ataxia.

What aspects of movement are represented in the primary motor cortex (M1): relatively low-level parameters like muscle force, or more abstract parameters like handpath? To examine this issue, the activity of neurons in M1 was recorded in a monkey trained to perform a task that dissociates three major variables of wrist movement: muscle activity, direction of movement at the wrist joint, and direction of movement in space. A substantial group of neurons in M1 (28 out of 88) displayed changes in activity that were muscle-like. Unexpectedly, an even larger group of neurons in M1 (44 out of 88) displayed changes in activity that were related to the direction of wrist movement in space independent of the pattern of muscle activity that generated the movement. Thus, both “muscles” and “movements” appear to be strongly represented in M1.

An increasing number of projects in neuroscience require statistical analysis of high-dimensional data, as, for instance, in the prediction of behavior from neural firing or in the operation of artificial devices from brain recordings in brain–machine interfaces. Although prevalent, classical linear analysis techniques are often numerically fragile in high dimensions due to irrelevant, redundant, and noisy information. We developed a robust Bayesian linear regression algorithm that automatically detects relevant features and excludes irrelevant ones, all in a computationally efficient manner. In comparison with standard linear methods, the new Bayesian method regularizes against overfitting, is computationally efficient (unlike previously proposed variational linear regression methods, is suitable for data sets with large numbers of samples and a very high number of input dimensions) and is easy to use, thus demonstrating its potential as a drop-in replacement for other linear regression techniques. We evaluate our technique on synthetic data sets and on several neurophysiological data sets. For these neurophysiological data sets we address the question of whether EMG data collected from arm movements of monkeys can be faithfully reconstructed from neural activity in motor cortices. Results demonstrate the success of our newly developed method, in comparison with other approaches in the literature, and, from the neurophysiological point of view, confirms recent findings on the organization of the motor cortex. Finally, an incremental, real-time version of our algorithm demonstrates the suitability of our approach for real-time interfaces between brains and machines.

In the last few years, a lot of publications suggested that disabling cerebellar ataxias may develop through immune-mediated mechanisms. In this consensus paper, we discuss the clinical features of the main described immune-mediated cerebellar ataxias and address their presumed pathogenesis. Immune-mediated cerebellar ataxias include cerebellar ataxia associated with anti-GAD antibodies, the cerebellar type of Hashimoto's encephalopathy, primary autoimmune cerebellar ataxia, gluten ataxia, Miller Fisher syndrome, ataxia associated with systemic lupus erythematosus, and paraneoplastic cerebellar degeneration. Humoral mechanisms, cell-mediated immunity, inflammation, and vascular injuries contribute to the cerebellar deficits in immune-mediated cerebellar ataxias., SCOPUS: re.j, info:eu-repo/semantics/published