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Various studies showed a clear impairment of cerebellar patients to modulate grip force in anticipation of the loads resulting from movements with a grasped object. This failure corroborated the theory of internal feedforward models in the cerebellum. Cerebellar damage also impairs the coordination of multiple-joint movements and this has been related to deficient prediction and compensation of movement-induced torques. To study the effects of disturbed torque control on feedforward grip-force control, two self-generated load conditions with different demands on torque control-one with movement-induced and the other with isometrically generated load changes-were directly compared in patients with cerebellar degeneration. Furthermore the cerebellum is thought to be more involved in grip-force adjustment to self-generated loads than to externally generated loads. Consequently, an additional condition with externally generated loads was introduced to further test this hypothesis. Analysis of 23 patients with degenerative cerebellar damage revealed clear impairments in predictive feedforward mechanisms in the control of both self-generated load types. Besides feedforward control, the cerebellar damage also affected more reactive responses when the externally generated load destabilized the grip, although this impairment may vary with the type of load as suggested by control experiments. The present findings provide further support that the cerebellum plays a major role in predictive control mechanisms. However, this impact of the cerebellum does not strongly depend on the nature of the load and the specific internal forward model. Contributions to reactive (grip force) control are not negligible, but seem to be dependent on the physical characteristics of an externally generated load.

While high-resolution structural magnetic resonance imaging (MRI) combined with newer analysis methods has become a powerful tool in human cerebral lesion studies, comparatively few studies have used these advanced imaging techniques to study lesions of the human cerebellum and their associated symptoms. This review will summarize the methodology of MRI-based lesion-symptom mapping of the human cerebellum and discuss its potential for gaining insights into cerebellar function. The investigation of patients with defined focal lesions yields the greatest potential for obtaining meaningful correlations between lesion site and behavioral deficits. In smaller groups of patients overlay plots and subtraction analysis are good options. If larger groups of patients are available, different statistical techniques have been introduced to compare behavior and lesion site on a voxel-by-voxel basis. Although localization in degenerative cerebellar disorders is less accurate because of the diffuse nature of the disease, certain information about the supposed function of larger subdivisions of the cerebellum can be gained. Examples are given which show that lesion-symptom mapping allows to investigate the function of the intermediate zone and cerebellar nuclei. We conclude that meaningful correlations between lesion site and behavioral data can be obtained in patients with degenerative as well as focal cerebellar disorders.

When an object is repeatedly grasped and lifted, the balance between grip force (normal to the object's surface) and lift force (tangential to the object's surface) is programmed according to the mechanical object features within a few lifts. Information related to the mechanical object properties is easily transferred in between both hands, and the cerebellum may play an essential role for the integration and generalization of this information. Recently, we have shown that the transfer of weight-related information in between both hands is impaired in cerebellar degeneration (Nowak et al., Neuropsychologia, 43:20-27, 2005). Here, we investigated the role of the cerebellum for the inter-manual transfer of friction-related information. Healthy subjects and patients with either focal or generalized cerebellar disorders first repeatedly lifted an object with one hand followed by a series of lifts of the same object with the opposite hand. The experiments were performed with the object's grip surfaces covered with either silk or sandpaper. Patients and healthy subjects scaled grip force differentially to surface friction within a few lifts. However, the ability to transfer friction-related information from one hand to the other was disturbed in cerebellar patients. We interpret these data within the recent concept that the cerebellum is essential for the rapid integration and generalization of mechanical object features in between both hemispheres when handling objects in the environment.

Objective: This study established the relationship between kinematic and grip force parameters in prehension tasks, disease severity and cerebellar atrophy in patients with cerebellar degeneration., Methods: Prehension was tested in a condition during which the hand reached out, grasped, and lifted an object. Task complexity was modified by limiting the transport component to a single-joint movement, and introducing a bimanual condition., Results: Compared to controls the cerebellar patients showed disturbances in hand transport, in hand shaping and the most pronounced in time to peak grip force and the grip/load force coupling. Task-dependent changes did not differ between groups. Ataxia scores revealed significant correlations with hand transport and shaping measures only. Ataxia subscores correlated with volume reduction of appropriate longitudinal cerebellar zones. Volume reduction of the intermediate zone was associated with grip force coordination deficits., Conclusions: Results indicate that the cerebellum may have a more general role in motor control of grasping independent of task complexity. Temporal and coordinative measures of grip force appear to be most useful to assess the severity of grasping deficits in patients with cerebellar degeneration not detectable by clinical ataxia scales., Significance: To assess the severity and course of cerebellar disease grip force control in a standard prehension task is a sensitive quantitative measure.

High-resolution structural magnetic resonance imaging (MRI) has become a powerful tool in human cerebellar lesion studies. Structural MRI is helpful to analyse the localisation and extent of cerebellar lesions and to determine possible extracerebellar involvement. Functionally meaningful correlations between a cerebellar lesion site and behavioural data can be obtained both in subjects with degenerative as well as focal cerebellar disorders. In this review, examples are presented which demonstrate that MRI-based lesion-symptom mapping is helpful to study the function of cerebellar cortex and cerebellar nuclei. Behavioural measures were used which represent two main areas of cerebellar function, that is, motor coordination and motor learning. One example are correlations with clinical data which are in good accordance with the known functional compartmentalisation of the cerebellum in three sagittal zones: In patients with cerebellar cortical degeneration ataxia of stance and gait was correlated with atrophy of the medial (and intermediate) cerebellum, oculomotor disorders with the medial, dysarthria with the intermediate and limb ataxia with atrophy of the intermediate and lateral cerebellum. Similar findings were obtained in patients with focal lesions. In addition, in patients with acute focal lesions, a somatotopy in the superior cerebellar cortex was found which is in close relationship to animal data and functional MRI data in healthy control subjects. Finally, comparison of data in patients with acute and chronic focal lesions revealed that lesion site appears to be critical for motor recovery. Recovery after lesions to the nuclei of the cerebellum was less complete. Another example which extended knowledge about functional localisation within the cerebellum is classical conditioning of the eyeblink response, a simple form of motor learning. In healthy subjects, learning rate was related to the volume of the cortex of the posterior cerebellar lobe. In patients with focal cerebellar lesions, acquisition of eyeblink conditioning was significantly reduced in lesions including the cortex of the superior posterior lobe, but not the inferior posterior lobe. Disordered timing of conditioned eyeblink responses correlated with lesions of the anterior lobe. Findings are in good agreement with the animal literature. Different parts of the cerebellar cortex may be involved in acquisition and timing of conditioned eyeblink responses in humans. These examples demonstrate that MRI-based lesion-symptom mapping is helpful to study the contribution of functionally relevant cerebellar compartments in motor control and recovery in patients with cerebellar disease. In addition, information about the function of cerebellar cortex and nuclei can be gained.

Given the well established role of the cerebellum in motor control, deficient motor performance during life time appears to be common in cerebellar agenesis. However, behavioural data on motor performance in living subjects with cerebellar agenesis are scarce. Dexterity during object manipulation was comparatively investigated in a 63-year old female with cerebellar agenesis and three healthy age- and gender-matched control subjects. Participants performed a transport task with an instrumented object and caught a weight that was dropped into a hand-held receptacle either expectedly from the opposite hand or unexpectedly from the experimenter's hand. Compared to healthy subjects, the subject with cerebellar agenesis generated greater grasping forces. For the transport task the patient showed a clear impairment of the predictive adjustment of grasping forces to the differential loading requirements of movement direction. For the weight-catching task, the patient established an accurate reactive mode of control when the weight was dropped unexpectedly. In case the weight was dropped expectedly from the opposite hand, predictive control mechanisms were severely disturbed in the subject with cerebellar agenesis. These data highlight the role of the cerebellum for predictive force control and are interpreted within the concept of internal models reflecting the causal relationship between actions and their consequences.

Predictive control of grasping forces when manipulating objects in the environment is suggested to reflect internal models that capture the causal relationship between actions and their consequences. The anatomical correlate of predictive control of grasping within the central nervous system is not completely understood. One structure which has been related to the neural representation of internal models is the cerebellum. Given its stereotyped cytoarchitecture, the widespread connections with cortical and subcortical sensory-motor structures and the neural activity of cerebellar Purkinje cells during sensory-motor tasks, the cerebellum has long been considered to play a major role in the establishment and maintenance of sensory-motor representations related to voluntary movement. Such representations are necessary to predict the consequences of our own movements. Here we review theoretical concepts, electrophysiological, imaging and behavioural data suggesting the cerebellum to be the anatomical and functional correlate of internal models relevant for predictive control of grasping.

Control of isometric grip forces during manipulation of objects is an essential feature of all skilled manual performances. Recent studies suggested that the anticipation of movement-induced loads may be a cerebellar function. We analysed grip force adjustments to fluctuations of inertial loads during discrete vertical movements with a grasped object in five patients with cerebellar atrophy and five healthy control subjects. Normally grip force is precisely adapted to the load fluctuations, in particular to the maximum load force, which occurs early in upward and late in downward movements. Both groups produced similar accelerations of the grasped object and consequently similar maximum loads. However, cerebellar patients established increased static grip forces during stationary holding of the object and increased force ratios between grip and load force at the time of maximum acceleration. These findings are congruent with earlier studies analysing grip and load force coupling in patients with cerebellar lesions. In contrast to earlier studies, we found no significant differences in the timing of grip force onset and grip force maximum relative to the onset of movement and maximum acceleration, respectively, between normal controls and four of five cerebellar patients. However, a regression analysis between grip and load forces during the load increase and decrease phases of the movement suggested deficits in the close temporospatial coupling between the two forces in all cerebellar patients. Our findings give further support to the notion that the cerebellum plays a crucial role in the forward control of grip force magnitude and timing during voluntary object manipulation. Compared to earlier studies, the increase in grip forces may be interpreted as a general control strategy to compensate for motor deficits, whereas impairments of temporal grip force regulation may occur at different degrees of dysfunction during the progression of cerebellar atrophy.

Abstract: In a recent study using voxel based lesion symptom mapping (VLSM) in cerebellar patients following stroke we found associations of prehensile deficits to lesions of the cerebellar cortex and dentate nucleus (DN). Associations to lesions of the interposed nucleus (IN), which has been shown to contribute to prehension in monkeys, could not be established. One possible reason was that the IN was largely unaffected in the stroke patients. To further address the question of IN involvement in prehension we performed VLSM in patients with surgical cerebellar lesions (n =20), exhibiting high lesion overlap in the medial and intermediate cerebellum including the IN. Prehensile deficits were quantified by analyses of movement kinematics and finger forces. In the patient population prehensile deficits comprised lower movement velocity in reaching and increased lift-off time in grasping. These were associated with lesions of the intermediate and lateral cerebellar cortex together with their output nuclei. Specifically, IN lesions were linked to increased lift-off time in grasping and not to slower reaching movements. Thus, our data support IN contribution particularly for the fluent production of grip forces during dexterous prehension in humans. [Copyright &y& Elsevier]

Abstract: The existence of forward internal models is a fundamental principle in theories of predictive motor control. There are indications that internal models are represented in the cerebellum. So far, no conclusive data exist on automated procedures involving predictive motor behavior. In particular, it is unknown whether single or multiple task-specific internal models handle the broad range of behavioral situations in which they occur. Using H2 15O PET in eight subjects, we examined predictive motor control in an automated grip force–load force coupling task at three differing load force levels. In the experimental condition, subjects pulled a grasped object against an isometric resistance while simultaneously producing anticipatory grip forces. There were three control conditions (pull force isolated; grip force isolated; motor rest). A 2 × 2 factorial design was chosen to reveal the interaction effect of grip force–pull force coupling. The factors were pull force (with/without) and grip force (with/without). Grip and load forces were well matched between experimental and control conditions. Conjunction inference and interaction analyses identified force coupling related activity in the ipsilateral posterior cerebellum that was independent of force levels. Interaction effects were also identified in the anterior cingulate and frontal association regions, the right caudate nucleus, and the left lingual gyrus. These data demonstrate the existence of modular representations for predictive force coupling, with the ipsilateral cerebellum playing a major role. Moreover, the data implicate that the representations for predictive force control are applicable to a range of different environmental affordances. [Copyright &y& Elsevier]