Dagmar Timmann

Consensus paper: roles of the cerebellum in motor control--the diversity of ideas on cerebellar involvement in movement.

Considerable progress has been made in developing models of cerebellar function in sensorimotor control, as well as in identifying key problems that are the focus of current investigation. In this consensus paper, we discuss the literature on the role of the cerebellar circuitry in motor control, bringing together a range of different viewpoints. The following topics are covered: oculomotor control, classical conditioning (evidence in animals and in humans), cerebellar control of motor speech, control of grip forces, control of voluntary limb movements, timing, sensorimotor synchronization, control of corticomotor excitability, control of movement-related sensory data acquisition, cerebro-cerebellar interaction in visuokinesthetic perception of hand movement, functional neuroimaging studies, and magnetoencephalographic mapping of cortico-cerebellar dynamics. While the field has yet to reach a consensus on the precise role played by the cerebellum in movement control, the literature has witnessed the emergence of broad proposals that address cerebellar function at multiple levels of analysis. This paper highlights the diversity of current opinion, providing a framework for debate and discussion on the role of this quintessential vertebrate structure.

The human cerebellum contributes to motor, emotional and cognitive associative learning. A review

In this review results of human lesion studies are compared examining associative learning in the motor, emotional and cognitive domain. Motor and emotional learning were assessed using classical eyeblink and fear conditioning. Cerebellar patients were significantly impaired in acquisition of conditioned eyeblink and fear-related autonomic and skeletal responses. An additional finding was disordered timing of conditioned eyeblink responses. Cognitive learning was examined using stimulus-stimulus-response paradigms, with an experimental set-up closely related to classical conditioning paradigms. Cerebellar patients were impaired in the association of two visual stimuli, which could not be related to motor performance deficits. Human lesion and functional brain imaging studies in healthy subjects are in accordance with a functional compartmentalization of the cerebellum for different forms of associative learning. The medial zone appears to contribute to fear conditioning and the intermediate zone to eyeblink conditioning. The posterolateral hemispheres (that is lateral cerebellum) appear to be of additional importance in fear conditioning in humans. Future studies need to examine the reasonable assumption that the posterolateral cerebellum contributes also to higher cognitive forms of associative learning. Human cerebellar lesion studies provide evidence that the cerebellum is involved in motor, emotional and cognitive associative learning. Because of its simple and homogeneous micro-circuitry a common computation may underly cerebellar involvement in these different forms of associative learning. The overall task of the cerebellum may be the ability to provide correct predictions about the relationship between sensory stimuli.

Cerebellar contributions to cognitive functions: A progress report after two decades of research

Accumulating evidence from both human lesion and functional neuroimaging studies appears to support the hypothesis that the cerebellum contributes to non-motor functions. Along similar lines, cognitive, affective and behavioural changes in psychiatric disorders, such as autism, schizophrenia and dyslexia, have been linked to structural cerebellar abnormalities. The aim of this special issue was to evaluate the current knowledge base after more than 20 years of controversial discussion. The contributions of the special issue cover the most important cognitive domains, i.e., attention, memory and learning, executive control, language and visuospatial function. The available empirical evidence suggests that cognitive changes in patients with cerebellar dysfunction are mild and clearly less severe than the impairments observed after lesions to neocortical areas to which the cerebellum is closely connected via different cerebro-cerebellar loops. Frequently cited early findings, e.g., with respect to a specific cerebellar involvement in attention, have not been replicated or might be confounded by motor or working memory demands of the respective attention task. On the other hand, there is now convincing evidence for a cerebellar involvement in the mediation of a range of cognitive domains, most notably verbal working memory. Verbal working memory problems may partly underlie the compromised performance of cerebellar lesion patients on at least some complex cognitive tasks. Although investigations have moved from anecdotical case reports to hypothesis-driven controlled clinical group studies based on sound methods which are complemented by state-of-the-art functional neuroimaging studies, the empirical evidence available so far does not yet allow a convincing theory of the mechanisms of a cerebellar involvement in cognitive function. Future studies are clearly needed to further elucidate the nature of the processes linked to cerebellar mediation of cognitive processes and their possible link to motor theories of cerebellar function, e.g., its role in prediction and/or timing.

Consensus Paper: Language and the Cerebellum: an Ongoing Enigma

In less than three decades, the concept “cerebellar neurocognition” has evolved from a mere afterthought to an entirely new and multifaceted area of neuroscientific research. A close interplay between three main strands of contemporary neuroscience induced a substantial modification of the traditional view of the cerebellum as a mere coordinator of autonomic and somatic motor functions. Indeed, the wealth of current evidence derived from detailed neuroanatomical investigations, functional neuroimaging studies with healthy subjects and patients and in-depth neuropsychological assessment of patients with cerebellar disorders shows that the cerebellum has a cardinal role to play in affective regulation, cognitive processing, and linguistic function. Although considerable progress has been made in models of cerebellar function, controversy remains regarding the exact role of the “linguistic cerebellum” in a broad variety of nonmotor language processes. This consensus paper brings together a range of different viewpoints and opinions regarding the contribution of the cerebellum to language function. Recent developments and insights in the nonmotor modulatory role of the cerebellum in language and some related disorders will be discussed. The role of the cerebellum in speech and language perception, in motor speech planning including apraxia of speech, in verbal working memory, in phonological and semantic verbal fluency, in syntax processing, in the dynamics of language production, in reading and in writing will be addressed. In addition, the functional topography of the linguistic cerebellum and the contribution of the deep nuclei to linguistic function will be briefly discussed. As such, a framework for debate and discussion will be offered in this consensus paper.

Imaging the deep cerebellar nuclei: a probabilistic atlas and normalization procedure.

The deep cerebellar nuclei (DCN) are a key element of the cortico-cerebellar loop. Because of their small size and functional diversity, it is difficult to study them using magnetic resonance imaging (MRI). To overcome these difficulties, we present here three related methodological advances. First, we used susceptibility-weighted imaging (SWI) at a high-field strength (7T) to identify the dentate, globose, emboliform and fastigial nucleus in 23 human participants. Due to their high iron content, the DCN are visible as hypo-intensities. Secondly, we generated probabilistic maps of the deep cerebellar nuclei in MNI space using a number of common normalization techniques. These maps can serve as a guide to the average location of the DCN, and are integrated into an existing probabilistic atlas of the human cerebellum (Diedrichsen et al., 2009). The maps also quantify the variability of the anatomical location of the deep cerebellar nuclei after normalization. Our results indicate that existing normalization techniques do not provide satisfactory overlap to analyze the functional specialization within the DCN. We therefore thirdly propose a ROI-driven normalization technique that utilizes both information from a T1-weighted image and the hypo-intensity from a T2*-weighted or SWI image to ensure overlap of the nuclei. These techniques will promote the study of the functional specialization of subregions of the DCN using MRI.

Adaptation to Visuomotor Rotation and Force Field Perturbation Is Correlated to Different Brain Areas in Patients With Cerebellar Degeneration

Although it is widely agreed that the cerebellum is necessary for learning and consolidation of new motor tasks, it is not known whether adaptation to kinematic and dynamic errors is processed by the same cerebellar areas or whether different parts play a decisive role. We investigated arm movements in a visuomotor (VM) rotation and a force field (FF) perturbation task in 14 participants with cerebellar degeneration and 14 age- and gender-matched controls. Magnetic resonance images were used to calculate the volume of cerebellar areas (medial, intermediate, and lateral zones of the anterior and posterior lobes) and to identify cerebellar structure important for the two tasks. Corroborating previous studies, cerebellar participants showed deficits in adaptation to both tasks compared with controls (P < 0.001). However, it was not possible to draw conclusions from the performance in one task on the performance in the other task because an individual participant could show severe impairment in one task and perform relatively well in the other (rho = 0.1; P = 0.73). We found that atrophy of distinct cerebellar areas correlated with impairment in different tasks. Whereas atrophy of the intermediate and lateral zone of the anterior lobe correlated with impairment in the FF task (rho = 0.72, 0.70; P = 0.003, 0.005, respectively), atrophy of the intermediate zone of the posterior lobe correlated with adaptation deficits in the VM task (rho = 0.64; P = 0.015). Our results suggest that adaptation to the different tasks is processed independently and relies on different cerebellar structures.

The involvement of the human cerebellum in eyeblink conditioning

Besides its known importance for motor coordination, the cerebellum plays a major role in associative learning. The form of cerebellum-dependent associative learning, which has been examined in greatest detail, is classical conditioning of eyeblink responses. The much advanced knowledge of anatomical correlates, as well as cellular and molecular mechanisms involved in eyeblink conditioning in animal models are of particular importance because there is general acceptance that findings in humans parallel the animal data. The aim of the present review is to give an update of findings in humans. Emphasis is put on human lesion studies, which take advantage of the advances of high-resolution structural magnetic resonance imaging (MRI). In addition, findings of functional brain imaging in healthy human subjects are reviewed. The former helped to localize areas involved in eyeblink conditioning within the cerebellum, the latter was in particular helpful in delineating extracerebellar neural substrates, which may contribute to eyeblink conditioning. Human lesion studies support the importance of cortical areas of the ipsilateral superior cerebellum both in the acquisition and timing of conditioned eyeblink responses (CR). Furthermore, the ipsilateral cerebellar cortex seems to be also important in extinction of CRs. Cortical areas, which are important for CR acquisition, overlap with areas related to the control of the unconditioned eyeblink response. Likewise, cortical lesions are followed by increased amplitudes of unconditioned eyeblinks. These findings are in good accordance with the animal literature. Knowledge about contributions of the cerebellar nuclei in humans, however, is sparse. Due to methodological limitations both of human lesion and functional MRI studies, at present no clear conclusions can be drawn on the relative contributions of the cerebellar cortex and nuclei.

Functional localization in the human cerebellum based on voxelwise statistical analysis: a study of 90 patients.

The aim of the present study was to examine somatotopy in the cerebellar cortex and a possible differential role of the cerebellar cortex and nuclei in functional outcome. Clinical findings and 3D MRI-based cerebellar lesions site were compared in a group of 90 patients with focal cerebellar lesion using International Cooperative Ataxia Rating Scale (ICARS) and voxel-based lesion-symptom mapping (VLSM). Separate analysis was performed in patients with acute and chronic ischemic lesions (n=43) and patients with acute and chronic surgical lesions (n=47). Thirty-eight patients were included after resection of a cerebellar tumor in childhood or adolescence. The most significant lesion symptom correlations were observed in the subgroup with acute ischemic lesions. Limb ataxia was significantly correlated with lesions of the interposed (NI) and part of the dentate nuclei (ND), ataxia of posture and gait with lesions of the fastigial nuclei (NF) including NI. Correlations with cortical lesions were less significant and present in the superior cerebellum only. Upper limb ataxia was correlated with lesions of vermal, paravermal and hemispheral lobules IV-V and VI, lower limb ataxia with lesions of vermal, paravermal and hemispheral lobules III and VI, dysarthria with lesions of paravermal and hemispheral lobules V and VI and ataxia of posture and gait with lesions of vermal and paravermal lobules II, III and IV. In the subgroups with chronic focal lesions, similar correlations were observed with lesions of the cerebellar nuclei, but significantly less correlations with lesions of the cerebellar cortex. Functional localization based on VLSM backs findings in previous animal and functional brain images studies in healthy human subjects. The lesion site appears to be critical for motor recovery. Lesions affecting the cerebellar nuclei are not fully compensated at any age and independent of the pathology in humans.

The influence of focal cerebellar lesions on the control and adaptation of gait

Cerebellar ataxic gait is influenced greatly by balance disorders, most likely caused by lesions of the medial zone of the cerebellum. The contributions of the intermediate and lateral zone to the control of limb dynamics for gait and the adaptation of locomotor patterns are less well understood. In this study, we analysed locomotion and goal-directed leg movements in 12 patients with chronic focal lesions after resection of benign cerebellar tumours. The extent of the cortical lesion and possible involvement of the cerebellar nuclei was determined by 3D-MR imaging. The subjects (age range 13-39 years, mean 20.3; seven female; ICARS score: mean 5.7, SD 6.3) performed three tasks: goal-directed leg placement, walking and walking with additional weights on the shanks. Based on the performance on the first two tasks, patients were categorized as impaired or unimpaired for leg placement and for dynamic balance control in gait. The subgroup with impaired leg placement but not the subgroup with impaired balance showed abnormalities in the adaptation of locomotion to additional loads. A detailed analysis revealed specific abnormalities in the temporal aspects of intra-limb coordination for leg placement and adaptive locomotion. These findings indicate that common neural substrates could be responsible for intra-limb coordination in both tasks. Lesion-based MRI subtraction analysis revealed that the interposed and the adjacent dentate nuclei were more frequently affected in patients with impaired compared to unimpaired leg placement, whereas the fastigial nuclei (and to a lesser degree the interposed nuclei) were more frequently affected in patients with impaired compared with unimpaired dynamic balance control. The intermediate zone appears thus to be of particular importance for multi-joint limb control in both goal-directed leg movements and in locomotion. For locomotion, our results indicate an influence of the intermediate zone on dynamic balance control as well as on the adaptation to changes in limb dynamics.

Comparison of three clinical rating scales in Friedreich ataxia (FRDA).

To test the validity and reliability of the scale for the assessment and rating of ataxia (SARA) in Friedreich ataxia (FRDA). SARA is limited to eight items and can be performed rapidly. Ninety‐six patients with a molecular genetic diagnosis of FRDA were rated using three different clinical scales, the FRDA Rating Scale (FARS), the International Cooperative Ataxia Rating Scale (ICARS), and SARA. Despite considerable discrepancies in scale size and subscale structure, SARA total scores were significantly correlated with ICARS (r = 0.953, P < 0.0001) and FARS (r = 0.938, P < 0.0001) total scores. SARA total scores also correlated with the activities of daily living (ADL, r = 0.929, P < 0.0001). Although originally developed for the use in dominantly inherited ataxias, which are primarily ataxias of the cerebellar type, SARA can also be used successfully to assess afferent ataxia, which is the predominant form in FRDA. Because SARA is characterized by high interrater reliability and practicability, SARA is applicable and well suited forclinical trials of FRDA.