Quantitative but Not Qualitative Performance Changes in Predictive Motor Timing as a Result of Overtraining.

The possibilities of substantial long-term improvement of predictive timing might be sometimes seen as limited, with scanty information of neural substrates underlying the potential learning process. To address this issue, we have investigated the performance of 21 baseball professionals and 21 matched controls in a predictive motor timing task previously shown to engage the cerebellum. Baseball players, hypothesized as a model of overtraining of the prediction of future state of the surroundings, showed significantly higher quantitative performance than nonathletic controls, with a substantial part of the baseball players reaching levels far beyond the range observed in common population. Furthermore, the qualitative performance profile of baseball players under various conditions as target speed and acceleration modes did not differ from the profile of healthy controls. Our results suggest that regular exigent training has the potential to vastly improve predictive motor timing. Moreover, the quantitative but not qualitative difference in the performance profile allows us to hypothesize that the selective honing of the same cerebellar processes and networks as in non-trained individuals is the substrate for the quantitative performance improvement, without substantial engagement of further neural nodes.

Disruption in cerebellar and basal ganglia networks during a visuospatial task in cervical dystonia.

BACKGROUND: Although dystonia is traditionally conceptualized as a basal ganglia disorder, increasing interest has been directed at a different neural network node, the cerebellum, which may play a significant role in the pathophysiology of dystonia. Abnormal sensorimotor processing and disturbed motor schemes, possibly attributable to cerebellar changes, remain unclear. METHODS: We sought to characterize the extent of cerebellar dysfunction within the motor network using functional MRI activation analysis, connectivity analysis, and voxel-based morphometry in cervical dystonia patients (n = 25, 15 women, mean age 45.8 years) and healthy volunteers (n = 25, 15 women, mean age 44.7 years) in a visuospatial task requiring predictive motor timing. RESULTS: Cervical dystonia patients showed decreased activation in the posterior cerebellar lobules as well as in the premotor areas, the associative parietal cortex, and visual regions. Patients also had decreased cerebellar connectivity with bilateral basal ganglia structures and the dorsolateral prefrontal cortex. CONCLUSIONS: This promotes the view that dystonia results from miscommunication between the basal ganglia and cerebellar loops, thus providing new insights into the brain regions essential for the development of cervical dystonia. © 2017 International Parkinson and Movement Disorder Society.

Trial-to-trial Adaptation: Parsing out the Roles of Cerebellum and BG in Predictive Motor Timing.

We previously demonstrated that predictive motor timing (i.e., timing requiring visuomotor coordination in anticipation of a future event, such as catching or batting a ball) is impaired in patients with spinocerebellar ataxia (SCA) types 6 and 8 relative to healthy controls. Specifically, SCA patients had difficulties postponing their motor response while estimating the target kinematics. This behavioral difference relied on the activation of both cerebellum and striatum in healthy controls, but not in cerebellar patients, despite both groups activating certain parts of cerebellum during the task. However, the role of these two key structures in the dynamic adaptation of the motor timing to target kinematic properties remained unexplored. In the current paper, we analyzed these data with the aim of characterizing the trial-by-trial changes in brain activation. We found that in healthy controls alone, and in comparison with SCA patients, the activation in bilateral striatum was exclusively associated with past successes and that in the left putamen, with maintaining a successful performance across successive trials. In healthy controls, relative to SCA patients, a larger network was involved in maintaining a successful trial-by-trial strategy; this included cerebellum and fronto-parieto-temporo-occipital regions that are typically part of attentional network and action monitoring. Cerebellum was also part of a network of regions activated when healthy participants postponed their motor response from one trial to the next; SCA patients showed reduced activation relative to healthy controls in both cerebellum and striatum in the same contrast. These findings support the idea that cerebellum and striatum play complementary roles in the trial-by-trial adaptation in predictive motor timing. In addition to expanding our knowledge of brain structures involved in time processing, our results have implications for the understanding of BG disorders, such as Parkinson disease where feedback processing or reward learning is affected.

Linking Essential Tremor to the Cerebellum: Physiological Evidence.

Essential tremor (ET), clinically characterized by postural and kinetic tremors, predominantly in the upper extremities, originates from pathological activity in the dynamic oscillatory network comprising the majority of nodes in the central motor network. Evidence indicates dysfunction in the thalamus, the olivocerebellar loops, and intermittent cortical engagement. Pathology of the cerebellum, a structure with architecture intrinsically predisposed to oscillatory activity, has also been implicated in ET as shown by clinical, neuroimaging, and pathological studies. Despite electrophysiological studies assessing cerebellar impairment in ET being scarce, their impact is tangible, as summarized in this review. The electromyography-magnetoencephalography combination provided the first direct evidence of pathological alteration in cortico-subcortical communication, with a significant emphasis on the cerebellum. Furthermore, complex electromyography studies showed disruptions in the timing of agonist and antagonist muscle activation, a process generally attributed to the cerebellum. Evidence pointing to cerebellar engagement in ET has also been found in electrooculography measurements, cerebellar repetitive transcranial magnetic stimulation studies, and, indirectly, in complex analyses of the activity of the ventral intermediate thalamic nucleus (an area primarily receiving inputs from the cerebellum), which is also used in the advanced treatment of ET. In summary, further progress in therapy will require comprehensive electrophysiological and physiological analyses to elucidate the precise mechanisms leading to disease symptoms. The cerebellum, as a major node of this dynamic oscillatory network, requires further study to aid this endeavor.

Salience network and olanzapine in schizophrenia: implications for treatment in anorexia nervosa.

UNLABELLED: The salience network (SN), a set of brain regions composed of the anterior fronto-insular cortex (aFI) and the anterior cingulate cortex (ACC), is usually involved in interoception, self-regulating, and action selection. Accumulating evidence indicates that dysfunctions in this network are associated with various pathophysiological deficits in both schizophrenia and eating disorders, stemming mainly from dysfunctional information processing of internal or external stimuli. In addition, the metabolic side effects of some antipsychotics (APs), as well as their pharmacological mechanisms of action, also suggest a link between the functional and neurophysiological changes in the brain in both schizophrenia and in eating disorders. Nevertheless, there is still a knowledge gap in explicitly and directly linking the metabolic side effects associated with AP treatment with the dysfunction in SN associated with processing of food-related information in schizophrenia. Here we provide neuroimaging evidence for such a link, by presenting data on a group of schizophrenia patients who followed 16 weeks of olanzapine treatment and undertook a passive viewing task while their brain activity was recorded. In response to food-related dynamic stimuli (video clips), we observed a decreased activity in SN (aFI and ACC) after the treatment, which also correlated with ghrelin plasma concentration and a measure of dietary restraint. Taken together with past findings regarding the role of SN in both schizophrenia and eating disorders, our results suggest that enhancing the reactivity in the SN has the potential to be a treatment strategy in people with anorexia nervosa. CLINICAL TRIAL REGISTRATION NUMBER: NCT 00290121.

The mechanisms of movement control and time estimation in cervical dystonia patients.

Traditionally, the pathophysiology of cervical dystonia has been regarded mainly in relation to neurochemical abnormities in the basal ganglia. Recently, however, substantial evidence has emerged for cerebellar involvement. While the absence of neurological "cerebellar signs" in most dystonia patients may be considered at least provoking, there are more subtle indications of cerebellar dysfunction in complex, demanding tasks. Specifically, given the role of the cerebellum in the neural representation of time, in the millisecond range, dysfunction to this structure is considered to be of greater importance than dysfunction of the basal ganglia. In the current study, we investigated the performance of cervical dystonia patients on a computer task known to engage the cerebellum, namely, the interception of a moving target with changing parameters (speed, acceleration, and angle) with a simple response (pushing a button). The cervical dystonia patients achieved significantly worse results than a sample of healthy controls. Our results suggest that the cervical dystonia patients are impaired at integrating incoming visual information with motor responses during the prediction of upcoming actions, an impairment we interpret as evidence of cerebellar dysfunction.

The neural substrate of predictive motor timing in spinocerebellar ataxia.

The neural mechanisms involved in motor timing are subcortical, involving mainly cerebellum and basal ganglia. However, the role played by these structures in predictive motor timing is not well understood. Unlike motor timing, which is often tested using rhythm production tasks, predictive motor timing requires visuo-motor coordination in anticipation of a future event, and it is evident in behaviors such as catching a ball or shooting a moving target. We examined the role of the cerebellum and striatum in predictive motor timing in a target interception task in healthy (n = 12) individuals and in subjects (n = 9) with spinocerebellar ataxia types 6 and 8. The performance of the healthy subjects was better than that of the spinocerebellar ataxia. Successful performance in both groups was associated with increased activity in the cerebellum (right dentate nucleus, left uvula (lobule V), and lobule VI), thalamus, and in several cortical areas. The superior performance in the controls was related to activation in thalamus, putamen (lentiform nucleus) and cerebellum (right dentate nucleus and culmen-lobule IV), which were not activated either in the spinocerebellar subjects or within a subgroup of controls who performed poorly. Both the cerebellum and the basal ganglia are necessary for the predictive motor timing. The degeneration of the cerebellum associated with spinocerebellar types 6 and 8 appears to lead to quantitative rather than qualitative deficits in temporal processing. The lack of any areas with greater activity in the spinocerebellar group than in controls suggests that limited functional reorganization occurs in this condition.

Differential effect of reward and punishment on procedural learning.

Reward and punishment are potent modulators of associative learning in instrumental and classical conditioning. However, the effect of reward and punishment on procedural learning is not known. The striatum is known to be an important locus of reward-related neural signals and part of the neural substrate of procedural learning. Here, using an implicit motor learning task, we show that reward leads to enhancement of learning in human subjects, whereas punishment is associated only with improvement in motor performance. Furthermore, these behavioral effects have distinct neural substrates with the learning effect of reward being mediated through the dorsal striatum and the performance effect of punishment through the insula. Our results suggest that reward and punishment engage separate motivational systems with distinctive behavioral effects and neural substrates.

Predictive motor timing performance dissociates between early diseases of the cerebellum and Parkinson's disease.

There is evidence that both the basal ganglia and the cerebellum play a role in the neural representation of time in a variety of behaviours, but whether one of them is more important is not yet clear. To address this question in the context of predictive motor timing, we tested patients with various movement disorders implicating these two structures in a motor-timing task. Specifically, we investigated four different groups: (1) patients with early Parkinson's disease (PD); (2) patients with sporadic spinocerebellar ataxia (SCA); (3) patients with familial essential tremor (ET); and (4) matched healthy controls. We used a predictive motor-timing task that involved mediated interception of a moving target, and we assessed the effect of movement type (acceleration, deceleration and constant), speed (slow, medium and fast) and angle (0 degrees , 15 degrees and 30 degrees) on performance (hit, early error and late error). The main results showed that PD group and arm ET subgroup did not significantly differ from the control group. SCA and head ET subjects (severe and mild cerebellar damage, respectively) were significantly worse at interception than the other two groups. Our findings support the idea that the basal ganglia play a less significant role in predictive motor timing than the cerebellum. The fact that SCA and ET subjects seemed to have a fundamental problem with predictive motor timing suggests that the cerebellum plays an essential role in integrating incoming visual information with the motor output in a timely manner, and that ET is a heterogeneous entity that deserves increased attention from clinicians.

Neural changes in control implementation of a continuous task.

It is commonly agreed that control implementation, being a resource-consuming endeavor, is not exerted continuously or in simple tasks. However, most research in the field was done using tasks that varied the need for control on a trial-by-trial basis (e.g., Stroop, flanker) in a discrete manner. In this case, the anterior cingulate cortex (ACC) was found to monitor the need for control, whereas regions in the prefrontal cortex (PFC) were found to be involved in control implementation. Whether or not the same control mechanism would be used in continuous tasks was an open question. In our study, we found that in a continuous task, the same neural substrate subserves control monitoring (ACC) but that the neural substrate of control implementation changes over time. Early in the task, regions in the PFC were involved in control implementation, whereas later the control was taken over by subcortical structures, specifically the caudate. Our results suggest that humans possess a flexible control mechanism, with a specific structure dedicated to monitoring the need for control and with multiple structures involved in control implementation.

Cortical control of motor sequences.

The neural substrate of sequence learning is well known. However, we lack a clear understanding of the detailed functional properties of many of the areas involved. The reason for this discrepancy lies, in part, in the fact that two types of processes, implicit and explicit, subserve motor sequence learning, and these often interact with each other. The most significant recent advances have been the elucidation of the very complex relationships between medial motor areas and the temporal and ordinal control of sequences, and the demonstration that motor cortex is an important site for sequence storage and production. The challenge for the future will be to develop a coherent and internally consistent theory of sequence control.

Functional imaging of the cerebellum and basal ganglia during predictive motor timing in early Parkinson's disease.

BACKGROUND AND PURPOSE: The basal ganglia and the cerebellum have both emerged as important structures involved in the processing of temporal information. METHODS: We examined the roles of the cerebellum and striatum in predictive motor timing during a target interception task in healthy individuals (HC group; n = 21) and in patients with early Parkinson's disease (early stage PD group; n = 20) using functional magnetic resonance imaging. RESULTS: Despite having similar hit ratios, the PD failed more often than the HC to postpone their actions until the right moment and to adapt their behavior from one trial to the next. We found more activation in the right cerebellar lobule VI in HC than in early stage PD during successful trials. Successful trial-by-trial adjustments were associated with higher activity in the right putamen and lobule VI of the cerebellum in HC. CONCLUSIONS: We conclude that both the cerebellum and striatum are involved in predictive motor timing tasks. The cerebellar activity is associated exclusively with the postponement of action until the right moment, whereas both the cerebellum and striatum are needed for successful adaptation of motor actions from one trial to the next. We found a general ''hypoactivation'' of basal ganglia and cerebellum in early stage PD relative to HC, indicating that even in early stages of the PD there could be functional perturbations in the motor system beyond striatum.

Dystonia and the cerebellum: a new field of interest in movement disorders?

Although dystonia has traditionally been regarded as a basal ganglia dysfunction, recent provocative evidence has emerged of cerebellar involvement in the pathophysiology of this enigmatic disease. This review synthesizes the data suggesting that the cerebellum plays an important role in dystonia etiology, from neuroanatomical research of complex networks showing that the cerebellum is connected to a wide range of other central nervous system structures involved in movement control to animal models indicating that signs of dystonia are due to cerebellum dysfunction and completely disappear after cerebellectomy, and finally to clinical observations in secondary dystonia patients with various types of cerebellar lesions. We propose that dystonia is a large-scale dysfunction, involving not only cortico-basal ganglia-thalamo-cortical pathways, but the cortico-ponto-cerebello-thalamo-cortical loop as well. Even in the absence of traditional "cerebellar signs" in most dystonia patients, there are more subtle indications of cerebellar dysfunction. It is clear that as long as the cerebellum's role in dystonia genesis remains unexamined, it will be difficult to significantly improve the current standards of dystonia treatment or to provide curative treatment.

Similar circuits but different connectivity patterns between the cerebellum, basal ganglia, and supplementary motor area in early Parkinson's disease patients and controls during predictive motor timing.

BACKGROUND AND PURPOSE: The cerebellum, basal ganglia (BG), and other cortical regions, such as supplementary motor area (SMA) have emerged as important structures dealing with various aspects of timing, yet the modulation of functional connectivity between them during motor timing tasks remains unexplored. METHODS: We used dynamic causal modeling to investigate the differences in effective connectivity (EC) between these regions and its modulation by behavioral outcome during a motor timing prediction task in a group of 16 patients with early Parkinson's disease (PD) and 17 healthy controls. Behavioral events (hits and errors) constituted the driving input connected to the cerebellum, and the modulation in connectivity was assessed relative to the hit condition (successful interception of target). RESULTS: The driving input elicited response in the target area, while modulatory input changed the specific connection strength. The neuroimaging data revealed similar structure of intrinsic connectivity in both groups with unidirectional connections from cerebellum to both sides of the BG, from BG to the SMA, and then from SMA to the cerebellum. However, the type of intrinsic connection was different between two groups. In the PD group, the connection between the SMA and cerebellum was inhibitory in comparison to the HC group, where the connection was activated. Furthermore, the modulation of connectivity by the performance in the task was different between the two groups, with decreased connectivity between the cerebellum and left BG and SMA and a more pronounced symmetry of these connections in controls. In the same time, there was an increased EC between the cerebellum and both sides of BG with more pronounced asymmetry (stronger connection with left BG) in patients. In addition, in the PD group the modulatory input strengthened inhibitory connectivity between the SMA and the cerebellum, while in the HC group the excitatory connection was slightly strengthened. CONCLUSIONS: Our findings indicate that although early PD subjects and controls use similar functional circuits to maintain a successful outcome in predictive motor timing behavior, the type and strength of EC and its modulation by behavioral performance differ between these two groups. These functional differences might represent the first step of cortical reorganization aimed at maintaining a normal performance in the brain affected by early Parkinson's disease and may have implications for the neuro-rehabilitation field.

Essential tremor, the cerebellum, and motor timing: towards integrating them into one complex entity.

Essential tremor (ET) is the most common movement disorder in humans. It is characterized by a postural and kinetic tremor most commonly affecting the forearms and hands. Isolated head tremor has been found in 1-10% of patients, suggesting that ET may be a composite of several phenotypes. The exact pathophysiology of ET is still unknown. ET has been repeatedly shown as a disorder of mild cerebellar degeneration, particularly in postmortem studies. Clinical observations, electrophysiological, volumetric and functional imaging studies all reinforce the fact that the cerebellum is involved in the generation of ET. However, crucial debate exists as to whether ET is a neurodegenerative disease. Data suggesting that it is neurodegenerative include postmortem findings of pathological abnormalities in the brainstem and cerebellum, white matter changes on diffusion tensor imaging, and clinical studies demonstrating an association with cognitive and gait changes. There is also conflicting evidence against ET as a neurodegenerative disease: the improvement of gait abnormalities with ethanol administration, lack of gray matter volume loss on voxel-based morphometry, failure to confirm the prominent presence of Lewy bodies in the locus ceruleus, and other pathological findings. To clarify this issue, future research is needed to describe the mechanism of cellular changes in the ET brain and to understand the order in which they occur. The cerebellum has been shown to be involved in the timing of movement and sensation, acting as an internal timing system that provides the temporal representation of salient events spanning hundreds of milliseconds. It has been reported that cerebellar timing function is altered in patients with ET, showing an increased variability of rhythmic hand movements as well as diminished performance during predictive motor timing task. Based on current knowledge and observations, we argue that ET is essentially linked with cerebellar degeneration, or at least cerebellar dysfunction, together with disturbance of motor timing. We explain the context of our current understanding on this topic, highlighting possible clinical consequences for patients suffering from ET and future research directions.

Neural correlates of cue-unique outcome expectations under differential outcomes training: an fMRI study.

In conditional discriminative choice learning, one learns the relations between discriminative/cue stimuli, associated choices, and their outcomes. When each correct cue-choice occurrence is followed by a cue-unique trial outcome (differential outcomes, DO, procedure), learning is faster and more accurate than when all correct cue-choice occurrences are followed by a common outcome (CO procedure)--differential outcomes effect (DOE). Superior DO performance is theorized to be mediated by the additional learning of cue-unique outcome expectations that "enrich" the prospective code available over the delay between cue and choice. We anticipated that such learned expectations comprise representations of expected outcomes. Here, we conducted an event-related functional MR imaging (fMRI) analysis of healthy adults who trained concurrently in two difficult but similar perceptual discrimination tasks under DO and CO procedures, respectively, and displayed the DOE. Control participants performed related tasks that differentially biased them towards delay-period retrospection versus prospection. Indeed, when differential outcomes were sensory-perceptual events (visual vs. auditory), delay-period expectations were experienced as sensory-specific imagery of the respectively expected outcome content, generated by sensory-specific cortices. Visual-specific imagery additionally activated stimulus-specific representations in prefrontal, lateral and medial frontal, fusiform and cerebellar regions, whereas auditory-specific imagery recruited claustrum/insula. Posterior parietal cortex (PPC), BA 39, was non-modality specific in mediating delay-period cue-unique outcome expectations. Greater hippocampal involvement in retrospection than prospection contrasted against the PPC's role in prospection. Time course analyses of hippocampal versus PPC responses suggest the DOE derives from an earlier transition from retrospection to prospection, which taps into long-term associative memory--more enduring.

Strategic modulation of cognitive control.

The neural substrate of cognitive control is thought to comprise an evaluative component located in the anterior cingulate cortex (ACC) and an executive component in the prefrontal cortex (PFC). The control mechanism itself is mainly local, triggered by response conflict (monitored by the ACC) and involving the allocation of executive resources (recruited by the PFC) in a trial-to-trial fashion. However, another way to achieve control would be to use a strategic mechanism based on long-term prediction of upcoming events and on a chronic response strategy that ignores local features of the task. In the current study, we showed that such a strategic control mechanism was based on a functional dissociation or complementary relationship between the ACC and the PFC. When information in the environment was available to make predictions about upcoming stimuli, local task features (e.g., response conflict) were no longer used as a control signal. We suggest that having separate control mechanisms based on local or global task features allows humans to be persistent in pursuing their goals, yet flexible enough to adapt to changes in the environment.

Frames of reference during implicit and explicit learning.

There is a significant overlap between the processes and neural substrates of spatial cognition and those subserving memory and learning. However, for procedural learning, which often is spatial in nature, we do not know how different forms of spatial knowledge, such as egocentric and allocentric frames of reference, are utilized nor whether these frames are differentially engaged during implicit and explicit processes. To address this issue, we trained human subjects on a movement sequence presented on a bi-dimensional (2D) geometric frame. We then systematically manipulated the geometric frame (allocentric) or the sequence of movements (egocentric) or both, and retested the subjects on their ability to transfer the sequence knowledge they had acquired in training and also determined whether the subjects had learned the sequence implicitly or explicitly. None of the subjects (implicit or explicit) showed evidence of transfer when both frames of reference were changed which suggests that spatial information is essential. Both implicit and explicit subjects transferred when the egocentric frame was maintained indicating that this representation is common to both processes. Finally, explicit subjects were also able to benefit from the allocentric frame in transfer, which suggests that explicit procedural knowledge may have two tiers comprising egocentric and allocentric representations.