Adaptation motor learning of arm movements in patients with cerebellar disease.

OBJECTIVE--To design a test of motor learning using arm movements in normal subjects and patients with cerebellar disease. METHODS--Elbow angle was continuously displayed as a cursor (a dot) on a computer screen, and subjects made ballistic elbow flexion and extension movements to try to move the cursor between two targets on the screen. The relation between the arm movement and its visual feedback was changed, and the subjects reacted by adapting the amplitude of their movements in subsequent trials. RESULTS--The consecutive errors showed exponential learning curves during adaptation, which were quantified by their steepness. Ten patients with isolated cerebellar or olivopontocerebellar degeneration had less steep learning curves than normal subjects, indicating a failure of adaptation motor learning in cerebellar disease. The results show that this test may be useful for the analysis of motor learning.     

Role of cerebellum in learning postural tasks

For a long time, the cerebellum has been known to be a structure related to posture and equilibrium control. According to the anatomic structure of inputs and internal structure of the cerebellum, its role in learning was theoretically reasoned and experimentally proved. The hypothesis of an inverse internal model based on feedback-error learning mechanism combines feedforward control by the cerebellum and feedback control by the cerebral motor cortex. The cerebellar cortex is suggested to acquire internal models of the body and objects in the external world. During learning of a new tool the motor cortex receives feedback from the realized movement while the cerebellum produces only feedforward command. To realize a desired movement without feedback of the realized movement, the cerebellum needs to form an inverse model of the hand/ arm system. This suggestion was supported by FMRi data. The role of cerebellum in learning new postural tasks mainly concerns reorganization of natural synergies. A learned postural pattern in dogs has been shown to be disturbed after lesions of the cerebral motor cortex or cerebellar nuclei. In humans, learning voluntary control of center of pressure position is greatly disturbed after cerebellar lesions. However, motor cortex and basal ganglia are also involved in the feedback learning postural tasks.     

Basal ganglia contributions during the learning of a visuomotor rotation: Effect of dopamine,deep brain stimulation and reinforcement

It is commonly thought that visuomotor adaptation is mediated by the cerebellum while reinforcement learning is mediated by the basal ganglia. In contrast to this strict dichotomy, we demonstrate a role for the basal ganglia in visuomotor adaptation (error‐based motor learning) in patients with Parkinson's disease (PD) by comparing the degree of motor learning in the presence and absence of dopamine medication. We further show similar modulation of learning rates in the presence and absence of subthalamic deep brain stimulation. We also report that reinforcement is an essential component of visuomotor adaptation by demonstrating the lack of motor learning in patients with PD during the ON‐dopamine state relative to the OFF‐dopamine state in the absence of a reinforcement signal. Taken together, these results raise the possibility that the basal ganglia modulate the gain of visuomotor adaptation based on the reinforcement received at the end of the trial.     

Motor sequence learning and motor adaptation in primary cervical dystonia

Motor sequence learning and motor adaptation rely on overlapping circuits predominantly involving the basal ganglia and cerebellum. Given the importance of these brain regions to the pathophysiology of primary dystonia, and the previous finding of abnormal motor sequence learning in DYT1 gene carriers, we explored motor sequence learning and motor adaptation in patients with primary cervical dystonia. We recruited 12 patients with cervical dystonia and 11 healthy controls matched for age. Subjects used a joystick to move a cursor from a central starting point to radial targets as fast and accurately as possible. Using this device, we recorded baseline motor performance, motor sequence learning and a visuomotor adaptation task. Patients with cervical dystonia had a significantly higher peak velocity than controls. Baseline performance with random target presentation was otherwise normal. Patients and controls had similar levels of motor sequence learning and motor adaptation. Our patients had significantly higher peak velocity compared to controls, with similar movement times, implying a different performance strategy. The preservation of motor sequence learning in cervical dystonia patients contrasts with the previously observed deficit seen in patients with DYT1 gene mutations, supporting the hypothesis of differing pathophysiology in different forms of primary dystonia. Normal motor adaptation is an interesting finding. With our paradigm we did not find evidence that the previously documented cerebellar abnormalities in cervical dystonia have a behavioral correlate, and thus could be compensatory or reflect “contamination” rather than being directly pathological.     

The effect of Parkinson's disease and Huntington's disease on human visuomotor learning

Visuomotor adaptation is often driven by error‐based (EB) learning in which signed errors update motor commands. There are, however, visuomotor tasks where signed errors are unavailable or cannot be mapped onto appropriate motor command changes, rendering EB learning ineffective; and yet, healthy subjects can learn in these EB learning‐free conditions. While EB learning depends on cerebellar integrity, the neural bases of EB‐independent learning are poorly understood. As basal ganglia are involved in learning mechanisms that are independent of signed error feedback, here we tested whether patients with basal ganglia lesions, including those with Huntington's disease and Parkinson's disease, would show impairments in a visuomotor learning task that prevents the use of EB learning. We employed two visuomotor throwing tasks that were similar, but were profoundly different in the resulting visual feedback. This difference was implemented through the introduction of either a lateral displacement of the visual field via a wedge prism (EB learning) or a horizontal reversal of the visual field via a dove prism (non‐EB learning). Our results show that patients with basal ganglia degeneration had normal EB learning in the wedge prism task, but were profoundly impaired in the reversing prism task that does not depend on the signed error signal feedback. These results represent the first evidence that human visuomotor learning in the absence of EB feedback depends on the integrity of the basal ganglia.     

Source-based morphometry: the use of independent component analysis to identify gray matter differences with application to schizophrenia

We present a multivariate alternative to the voxel-based morphometry (VBM) approach called source-based morphometry (SBM), to study gray matter differences between patients and healthy controls. The SBM approach begins with the same preprocessing procedures as VBM. Next, independent component analysis is used to identify naturally grouping, maximally independent sources. Finally, statistical analyses are used to determine the significant sources and their relationship to other variables. The identified "source networks," groups of spatially distinct regions with common covariation among subjects, provide information about localization of gray matter changes and their variation among individuals. In this study, we first compared VBM and SBM via a simulation and then applied both methods to real data obtained from 120 chronic schizophrenia patients and 120 healthy controls. SBM identified five gray matter sources as significantly associated with schizophrenia. These included sources in the bilateral temporal lobes, thalamus, basal ganglia, parietal lobe, and frontotemporal regions. None of these showed an effect of sex. Two sources in the bilateral temporal and parietal lobes showed age-related reductions. The most significant source of schizophrenia-related gray matter changes identified by SBM occurred in the bilateral temporal lobe, while the most significant change found by VBM occurred in the thalamus. The SBM approach found changes not identified by VBM in basal ganglia, parietal, and occipital lobe. These findings show that SBM is a multivariate alternative to VBM, with wide applicability to studying changes in brain structure.     

The Marcus Gunn pupil.

BACKGROUND--Palatal tremor is divided into symptomatic palatal tremor (SPT) and essential palatal tremor (EPT) on the basis of clinical features. The inferior olive seems to be abnormal in SPT, but not EPT. Because the inferior olive is likely to be involved in several types of motor learning, it is hypothesised that motor learning would be abnormal in patients with SPT, but not those with EPT. METHODS--In six patients with SPT and four patients with EPT, two motor learning paradigms were studied--the classical conditioning of an acoustically elicited eyeblink with electrical supraorbital nerve shock and a test of adaptation of ballistic arm movements to a change of the gain. RESULTS--Classical conditioning was impaired unilaterally or bilaterally in the patients with SPT, depending on whether they had unilateral or bilateral abnormalities of the inferior olives, except for the two least affected patients. All but one of the patients with EPT had normal conditioning. On the adaptation test of arm movements, most of the patients with SPT had impaired learning of the arm contralateral to the hypertrophied inferior olive, regardless of whether the abnormality was unilateral or bilateral, but all patients with EPT had normal results. CONCLUSIONS--In SPT pseudohypertrophy of the inferior olive leads to defective cerebellar function, whereas in EPT the inferior olive functions normally.     

Cerebellar Motor Function in Spina Bifida Meningomyelocele

Spina bifida meningomyelocele (SBM), a congenital neurodevelopmental disorder, involves dysmorphology of the cerebellum, and its most obvious manifestations are motor deficits. This paper reviews cerebellar neuropathology and motor function across several motor systems well studied in SBM in relation to current models of cerebellar motor and timing function. Children and adults with SBM have widespread motor deficits in trunk, upper limbs, eyes, and speech articulators that are broadly congruent with those observed in adults with cerebellar lesions. The structure and function of the cerebellum are correlated with a range of motor functions. While motor learning is generally preserved in SBM, those motor functions requiring predictive signals and precise calibration of the temporal features of movement are impaired, resulting in deficits in smooth movement coordination as well as in the classical cerebellar triad of dysmetria, ataxia, and dysarthria. That motor function in individuals with SBM is disordered in a manner phenotypically similar to that in adult cerebellar lesions, and appears to involve similar deficits in predictive cerebellar motor control, suggests that age-based cerebellar motor plasticity is limited in individuals with this neurodevelopmental disorder.     

Procedural learning in Parkinson's disease and cerebellar degeneration

We compared procedural learning, translation of procedural knowledge into declarative knowledge, and use of declarative knowledge in age-matched normal volunteers (n = 30), patients with Parkinson's disease (n = 20), and patients with cerebellar degeneration (n = 15) by using a serial reaction time task. Patients with Parkinson's disease achieved procedural knowledge and used declarative knowledge of the task to improve performance, but they required a larger number of repetitions of the task to translate procedural knowledge into declarative knowledge. Patients with cerebellar degeneration did not show performance improvement due to procedural learning, failed to achieve declarative knowledge, and showed limited use of declarative knowledge of the task to improve their performance. Both basal ganglia and cerebellum are involved in procedural learning, but their roles are different. The normal influence of the basal ganglia on the prefrontal cortex may be required for timely access of information to and from the working memory buffer, while the cerebellum may index and order events in the time domain and be therefore essential for any cognitive functions involving sequences.     

Modulation of gamma and theta spectral amplitude and phase synchronization is associated with the development of visuo-motor learning

The formation of new motor memories, which is fundamental for efficient performance during adaptation to a visuo-motor rotation, occurs when accurate planning is achieved mostly with feedforward mechanisms. The dynamics of brain activity underlying the switch from feedback to feedforward control is still matter of debate. Based on the results of studies in declarative learning, it is likely that phase synchronization of low and high frequencies as well as their temporal modulation in power amplitude underlie the formation of new motor memories during visuo-motor adaptation. High-density EEG (256 electrodes) was recorded in 17 normal human subjects during adaptation to a visuo-motor rotation of 60° in four incremental steps of 15°. We found that initial learning is associated with enhancement of gamma power in a right parietal region during movement execution as well as gamma/theta phase coherence during movement planning. Late stages of learning are instead accompanied by an increase of theta power over that same right parietal region during movement planning, which is correlated with the degree of learning and retention. Altogether, these results suggest that the formation of new motor memories and, thus, the switch from feedback to feedforward control is associated with the modulation of gamma and theta spectral activities, with respect to their amplitude and phase, during movement planning and execution. Specifically, we propose that gamma/theta phase coupling plays a pivotal role in the integration of a new representation into motor memories.     

Pathways for control of face and neck musculature by the basal ganglia and cerebellum

The basal ganglia are believed to influence movement via thalamo-cortical projections. However, the basal ganglia may also affect brainstem areas involved in movement control such as the red nucleus. The red nucleus receives input from the cerebellum and projects to motor neurons and premotor neurons in the contralateral brainstem and spinal cord. Are there pathways that allow output from the basal ganglia to influence processing in the red nucleus? This study uses the bidirectional tracer, WGA-HRP, to demonstrate that regions of the cat red nucleus receive input from the basal ganglia as well as from the cerebellum. Output from the entopeduncular nucleus, the feline equivalent of the internal segment of the globus pallidus, provides a modest direct input to the red nucleus as well as a more substantial indirect input via projections to the zona incerta and the fields of Forel. Regions of the red nucleus with input from the basal ganglia also receive input from the cerebellar dentate nucleus and lateral regions of interpositus. The regions of the red nucleus receiving basal gangliar input project to the contralateral facial nucleus and upper segments of the cervical spinal cord. Therefore, the red nucleus provides a junction where output from the basal ganglia can interact with output of the cerebellum for movement control of the head and face. The pathway may provide a substrate for a variety of movement disorders that are seen with diseases of the basal ganglia such as cervical dystonia and Parkinson's facies.     

Normal sexual dimorphism in the human basal ganglia

Male and female brains differ in both structure and function. Investigating this sexual dimorphism in healthy subjects is an important first step to ultimately gain insight into sex-specific differences in behavior and risk for neuropsychiatric disorders. The basal ganglia are among the main regions containing sex steroid receptors in the brain and play a central role in cognitive (dys)functioning. However, little is known about sexual dimorphism of different basal ganglia nuclei. The aim of the present study was to investigate sex-specific differences in basal ganglia morphology using MRI. We applied automatic volumetry on anatomical MRI data of two large cohorts of healthy young adults (n = 463 and n = 541) and assessed the volume of four major nuclei of the basal ganglia: caudate nucleus, globus pallidus, nucleus accumbens, and putamen, while controlling for total gray matter volume, total white matter volume, and age of the participant. No significant sex differences were found for caudate nucleus and nucleus accumbens, but males showed significantly larger volumes for globus pallidus and putamen, as confirmed in both cohorts. These results show that sexual dimorphism is neither a general effect in the basal ganglia nor confined to just one specific nucleus, and will aid the interpretation of differences in basal ganglia (dys)function between males and females.     

Tissue factor localization in non-human primate cerebral tissue.

Tissue factor (TF), the principal procoagulant of human brain, resides in specific regions of the non-human primate central nervous system. Immunohistochemical studies employing murine anti-human TF monoclonal antibodies (MoAbs) detected TF antigen in the cortex, basal ganglia, cerebellum, and cervical spinal cord in three normal baboon subjects. Although significantly less prominent than human cortical gray matter, a distinct partition of TF in gray matter > white matter was noted. The gray matter predilection of TF was confirmed in primate temporal and parietal lobe cortex by both sandwich ELISA and one-stage coagulation assay. Variation in the relative quantity of TF antigen was observed by ELISA among the three subjects studied. Procoagulant activity followed the pattern of TF antigen (cortical gray matter > basal ganglia > or = cerebellum > cortical white matter), and was 96.5-98.5% inhibitable by a function inhibiting anti-human TF MoAb combination. TF antigen was associated with the microvasculature of all cerebral tissues studied, and spared capillaries most selectively in the cerebral cortex, basal ganglia, and cerebellum. These findings suggest a highly specific ordering of TF antigen and related procoagulant activity in the central nervous system of the baboon, confined primarily to gray matter parenchyma, and to the non-capillary microvasculature.     

Structural and functional bases for individual differences in motor learning

People vary in their ability to learn new motor skills. We hypothesize that between‐subject variability in brain structure and function can explain differences in learning. We use brain functional and structural MRI methods to characterize such neural correlates of individual variations in motor learning. Healthy subjects applied isometric grip force of varying magnitudes with their right hands cued visually to generate smoothly‐varying pressures following a regular pattern. We tested whether individual variations in motor learning were associated with anatomically colocalized variations in magnitude of functional MRI (fMRI) signal or in MRI differences related to white and grey matter microstructure. We found that individual motor learning was correlated with greater functional activation in the prefrontal, premotor, and parietal cortices, as well as in the basal ganglia and cerebellum. Structural MRI correlates were found in the premotor cortex [for fractional anisotropy (FA)] and in the cerebellum [for both grey matter density and FA]. The cerebellar microstructural differences were anatomically colocalized with fMRI correlates of learning. This study thus suggests that variations across the population in the function and structure of specific brain regions for motor control explain some of the individual differences in skill learning. This strengthens the notion that brain structure determines some limits to cognitive function even in a healthy population. Along with evidence from pathology suggesting a role for these regions in spontaneous motor recovery, our results also highlight potential targets for therapeutic interventions designed to maximize plasticity for recovery of similar visuomotor skills after brain injury. Hum Brain Mapp, 2011. © 2010 Wiley‐Liss, Inc.     

Callosal tissue loss in multiple system atrophy—A one‐year follow‐up study

Multiple system atrophy (MSA) is a neurodegenerative disease not only affecting the basal ganglia, brainstem, cerebellum, and intermediolateral cell columns of the spinal cord but also the cerebral cortex. Clinically, cerebellar (MSA‐C) and parkinsonian variants of MSA (MSA‐P) are distinguished. We investigated 14 MSA patients (10 MSA‐C, 4 MSA‐P, men: 7, women: 7; age: 61.1 ± 3.3 years) and 14 matched controls (men: 7, women: 7; age: 58.6 ± 5.1 years) with voxel‐based morphometry (VBM) to analyze gray and white matter differences both at baseline and at follow‐up, 1 year later. Baseline comparisons between patients and controls confirmed significantly less gray matter in MSA in the cerebellum and cerebral cortex, and significantly less white matter in the cerebellar peduncles and brainstem. Comparisons of tissue‐loss profiles (i.e., baseline versus follow‐up) between patients and controls, revealed white matter reduction in MSA along the middle cerebellar peduncles, reflecting degeneration of the ponto‐cerebellar tract as a particularly prominent and progressive morphological alteration in MSA. Comparisons between baseline and follow‐up, separately performed in patients and controls, revealed additional white matter reduction in MSA along the corpus callosum at follow‐up. This was replicated through additional shape‐based analyses indicating a reduced callosal thickness in the anterior and posterior midbody, extending posteriorly into the isthmus. Callosal atrophy may possibly reflect a disease‐specific pattern of neurodegeneration and cortical atrophy, fitting well with the predominant impairment of motor functions in the MSA patients. © 2010 Movement Disorder Society     

Saccadic adaptation in Chiari type II malformation

BACKGROUND: Saccadic adaptation corrects errors in saccadic amplitude. Experimentally-induced saccadic adaptation provides a method for studying motor learning. The cerebellum is a major participant in saccadic adaptation. Chiari type II malformation (CII) is a developmental deformity of the cerebellum and brainstem that is associated with spina bifida. We investigated the effects of CII on saccadic adaptation. METHOD: We measured eye movements using an infrared eye tracker in 21 subjects with CII (CII group) and 39 typically developing children (control group), aged 8-19 years. Saccadic adaptation was induced experimentally using targets that stepped horizontally 120 to the right and then stepped backward 3 degrees during saccades. RESULTS: Saccadic adaptation was achieved at the end of the adaptation phase in participants in each group. Saccadic amplitude gain decreased by 6.9% in the CII group and 9.3% in the control group. The groups did not differ significantly (p = 0.27). Amplitude gain reduction was significantly less in the CII participants who had multiple shunt revisions. Regression analyses revealed no effects of spinal lesion level, presence of nystagmus, or cerebellar vermis dysmorphology on saccadic adaptation. CONCLUSION: The neural circuits involved in saccadic adaptation appear to be functionally intact in CII.     

Source‐based morphometry of gray matter volume in men with first‐episode schizophrenia

Objectives: There is a lot of variability between the results of studies reporting the pattern of gray matter volume changes in schizophrenia. Methodological issues may play an important role in this heterogeneity. The aim of the present study was to replicate the better performance of multivariate “source‐based morphometry” (SBM) over the mass‐univariate approach. Experimental design: Voxel‐based morphometry of Jacobian‐modulated gray matter volume images, using voxel and cluster level inference, and SBM were performed in a group of first‐episode schizophrenia patients (N = 49) and healthy controls (N = 127). Results: Using SBM we were able to find a significant reduction of gray matter volume in fronto‐temporo‐cerebellar areas whereas no significant results were obtained using voxel‐based morphometry. Conclusion: Multivariate analysis of gray matter volume seems to be a suitable method for characterization of the pattern of changes at the beginning of the illness in schizophrenia subjects. Hum Brain Mapp, 2010. © 2009 Wiley‐Liss, Inc.     

The basal ganglia in human learning.

For many years, the basal ganglia were described in anatomy courses as strictly motor structures. Certainly, some of the most obvious and debilitating symptoms shown by persons with basal ganglia disorders are problems in motor control. However, the basal ganglia are not limited to motoric aspects of behavior: recent research shows that they are involved in most areas of cognitive and emotional functioning, consistent with their anatomical connections with all areas of the cortex. This review will focus on the roles of the basal ganglia in human learning, particularly sequence learning and category learning. Current areas of research that are discussed include the differing roles of different basal ganglia regions, patterns of interaction between the cortex and basal ganglia, differences in positive and negative association learning, effects of dopaminergic medication on learning, whether basal ganglia-mediated learning is implicit or explicit, and how the basal ganglia learning systems interact with other learning systems, particularly within the medial temporal lobe.     

Motor sequence learning and movement disorders

PURPOSE OF REVIEW: New insights into the psychophysiological determinants of performance changes and brain plasticity associated with motor sequence learning have recently been gained through behavioral and imaging studies in healthy individuals. In addition, using a variety of motor sequential paradigms in groups of patients affected by a movement disorder, major advances have been achieved in our understanding of the pathophysiological mechanisms underlying Parkinson's and Huntington's diseases, as well as primary forms of dystonia. RECENT FINDINGS: This review begins by describing the latest findings in normal participants with regards to the dynamic alterations in neural networks observed across the different phases of motor sequence learning. It then focuses on the hotly debated issue of motor memory consolidation, highlighting the results of novel studies that investigated the role of both day and night sleep, the neural substrates and the developmental evolution mediating this process. Finally, this paper addresses current work looking at motor sequence learning in movement disorders that helps to better comprehend the functional contribution of basal ganglia structures to this type of memory, to assess the impact of such diseases on related patterns of brain activation, as well as to identify the neuronal compensatory mechanisms educed by these basal ganglia disorders. SUMMARY: Such advances have major implications, not only for optimizing ways to learn new skilled behaviors in real-life situations, but also for guiding therapeutic approaches in patients with movement disorders.     

Cerebellar abnormalities in Huntington's disease: A role in motor and psychiatric impairment?

The cerebellum has received limited attention in Huntington's disease (HD), despite signs of possible cerebellar dysfunction, including motor incoordination and impaired gait, which are currently attributed to basal ganglia atrophy and disrupted fronto‐striatal circuits. This study is the first to investigate a potential contribution of macro‐ and microstructural cerebellar damage to clinical manifestations of HD. T1‐ and diffusion‐weighted 3T magnetic resonance imaging (MRI) scans were obtained from 12 controls and 22 early‐stage HD participants. Manual delineation and voxel‐based morphometry were used to assess between‐group differences in cerebellar volume, and diffusion metrics were compared between groups within the cerebellar gray and white matter. Associations between these imaging measures and clinical scores were examined within the HD group. Reduced paravermal volume was detected in HD compared with controls using voxel‐based morphometry (P < 0.05), but no significant volumetric differences were found using manual delineation. Diffusion abnormalities were detected in both cerebellar gray matter and white matter. Smaller cerebellar volumes, although not significantly reduced, were significantly associated with impaired gait and psychiatric morbidity and of borderline significance with pronate/supinate‐hand task performance. Abnormal cerebellar diffusion was associated with increased total motor score, impaired saccade initiation, tandem walking, and timed finger tapping. In conclusion, atrophy of the paravermis, possibly encompassing the cerebellar nuclei, and microstructural abnormalities within the cerebellum may contribute to HD neuropathology. Aberrant cerebellar diffusion and reduced cerebellar volume together associate with impaired motor function and increased psychiatric symptoms in stage I HD, potentially implicating the cerebellum more centrally in HD presentation than previously recognized. © 2014 International Parkinson and Movement Disorder Society