Michael Küper

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.

Involvement of the cerebellar cortex and nuclei in verbal and visuospatial working memory: A 7 T fMRI study

The first aim of the present study was to extend previous findings of similar cerebellar cortical areas being involved in verbal and spatial n-back working memory to the level of the cerebellar nuclei. The second aim was to investigate whether different areas of the cerebellar cortex and nuclei contribute to different working memory tasks (n-back vs. Sternberg tasks). Young and healthy subjects participated in two functional magnetic resonance imaging (fMRI) studies using a 7 T MR scanner with its increased signal-to-noise ratio. One group of subjects (n=21) performed an abstract and a verbal version of an n-back task contrasting a 2-back and 0-back condition. Another group of subjects (n=23) performed an abstract and a verbal version of a Sternberg task contrasting a high load and a low load condition. A block design was used. For image processing of the dentate nuclei, a recently developed region of interest (ROI) driven normalization method of the dentate nuclei was applied (Diedrichsen et al., 2011). Whereas activated areas of the cerebellar cortex and dentate nuclei were not significantly different comparing the abstract and verbal versions of the n-back task, activation in the abstract and verbal Sternberg tasks was significantly different. In both n-back tasks activation was most prominent at the border of lobules VI and Crus I, within lobule VII, and within the more caudal parts of the dentate nucleus bilaterally. In Sternberg tasks the most prominent activations were found in lobule VI extending into Crus I on the right. In the verbal Sternberg task activation was significantly larger within right lobule VI compared to the abstract Sternberg task and compared to the verbal n-back task. Activations of rostral parts of the dentate were most prominent in the verbal Sternberg task, whereas activation of caudal parts predominated in the abstract Sternberg task. On the one hand, the lack of difference between abstract and verbal n-back tasks and the lack of significant lateralization suggest a more general contribution of the cerebellum to working memory regardless of the modality. On the other hand, the focus of activation in right lobule VI in the verbal Sternberg task suggests specific cerebellar contributions to verbal working memory. The verbal Sternberg task emphasizes maintenance of stimuli via phonological rehearsal, whereas central executive demands prevail in n-back tasks. Based on the model of working memory by Baddeley and Hitch (1974), the present results show that different regions of the cerebellum support functions of the central executive system and one of the subsidiary systems, the phonological loop.

Evidence for a Motor Somatotopy in the Cerebellar Dentate Nucleus—an FMRI Study in Humans

Previous anatomical studies in monkeys have shown that forelimb motor representation is located caudal to hindlimb representation within the dorso‐rostral dentate nucleus. Here we investigate human dentate nucleus motor somatotopy by means of ultra‐highfield (7 T) functional magnetic brain imaging (fMRI). Twenty five young healthy males participated in the study. Simple finger and foot movement tasks were performed to identify dentate nucleus motor areas. Recently developed normalization procedures for group analyses were used for the cerebellar cortex and the cerebellar dentate nucleus. Cortical activations were in good accordance with the known somatotopy of the human cerebellar cortex. Dentate nucleus activations following motor tasks were found in particular in the ipsilateral dorso‐rostral nucleus. Activations were also present in other parts of the nucleus including the contralateral side, and there was some overlap between the body part representations. Within the ipsilateral dorso‐rostral dentate, finger activations were located caudally compared to foot movement‐related activations in fMRI group analysis. Likewise, the centre of gravity (COG) for the finger activation was more caudal than the COG of the foot activation across participants. A multivariate analysis of variance (MANOVA) on the x, y, and z coordinates of the COG indicated that this difference was significant (P = 0.043). These results indicate that in humans, the lower and upper limbs are arranged rostro‐caudally in the dorsal aspect of the dentate nucleus, which is consistent with studies in non‐human primates. Hum Brain Mapp, 2012.

Activation of the dentate nucleus in a verb generation task: A 7T MRI study.

There is increasing evidence of a topographic organization within the human cerebellar cortex for motor and non-motor functions. Likewise, a subdivision of the dentate nucleus in a more dorsal and rostral motor domain and a more ventral and caudal non-motor domain has been proposed by Dum and Strick (2003) based on anatomical studies in monkey. In humans, however, very little is known about topographic organization within the dentate nucleus. Activation of the dentate nucleus in a verb generation task was examined in young and healthy subjects using ultra-highfield 7T functional magnetic resonance imaging (fMRI) with its increase in signal-to-noise ratio. Data of 17 subjects were included in statistical analysis. Subjects were asked to (i) read words (nouns) aloud presented on a screen, (ii) silently read the same nouns, (iii) silently generate the appropriate verbs to the same nouns and (iv) to silently repeat the names of the months. A block design was used. For image processing, a recently developed region of interest (ROI) driven normalization method of the dentate nuclei was applied. Activation related to motor speech (contrast aloud reading minus silent reading) was strongest in the rostral parts of the dentate nucleus. Dorsorostral activations were present bilaterally. Activation related to verb generation (contrast verb generation minus silent reading) was found in the ventrocaudal parts of the dentate nucleus on the right. The present findings are in good accordance with the anatomical data in monkeys and suggest that the human dentate nucleus can be subdivided into a rostral and more dorsal motor domain and a ventrocaudal non-motor domain.

Activation of the cerebellar cortex and the dentate nucleus in a prism adaptation fMRI study

During prism adaptation two types of learning processes can be distinguished. First, fast strategic motor control responses are predominant in the early course of prism adaptation to achieve rapid error correction within few trials. Second, slower spatial realignment occurs among the misaligned visual and proprioceptive sensorimotor coordinate system. The aim of the present ultra‐highfield (7T) functional magnetic resonance imaging (fMRI) study was to explore cerebellar cortical and dentate nucleus activation during the course of prism adaptation in relation to a similar visuomotor task without prism exposure. Nineteen young healthy participants were included into the study. Recently developed normalization procedures were applied for the cerebellar cortex and the dentate nucleus. By means of subtraction analysis (early prism adaptation > visuomotor, early prism adaptation > late prism adaptation) we identified ipsilateral activation associated with strategic motor control responses within the posterior cerebellar cortex (lobules VIII and IX) and the ventro‐caudal dentate nucleus. During the late phase of adaptation we observed pronounced activation of posterior parts of lobule VI, although subtraction analyses (late prism adaptation > visuomotor) remained negative. These results are in good accordance with the concept of a representation of non‐motor functions, here strategic control, within the ventro‐caudal dentate nucleus. Hum Brain Mapp 35:1574–1586, 2014.

Structural and Functional Magnetic Resonance Imaging of the Human Cerebellar Nuclei

The present review focuses on recent developments in structural and functional magnetic resonance imaging (MRI) of the deep cerebellar nuclei (DCN), the main output structure of the cerebellum. The high iron content in the DCN allows for their visibility in T2*-weighted images. Spatial resolution has improved allowing the identification of DCN in individual cerebellar patients and healthy subjects. Based on findings in larger groups of healthy subjects, probabilistic MRI-based atlases of the deep cerebellar nuclei have been developed, which are important tools in human lesion and functional imaging studies. High iron content in the DCN, on the other hand, decreases the blood oxygenation level dependent-signal making functional imaging a difficult challenge. Compared to the vast amount of studies reporting activation of the cerebellar cortex, the number of studies demonstrating activation of the DCN is much less. Most studies report activation of the dentate nucleus. Dentate activations appear to be more reliable in more complex tasks for reasons currently unknown. As yet, few studies tried to show activations of functional subunits of the dentate nucleus. Increased signal-to-noise ratio and better spatial resolution using higher MR field strength together with recent progress in dentate normalization methods will allow identification of functional subunits and their interactions with the cerebellar cortex in future studies.

Direct visualization of cerebellar nuclei in patients with focal cerebellar lesions and its application for lesion-symptom mapping

As yet, human cerebellar lesion studies have not taken advantage of direct magnetic resonance imaging (MRI) of the cerebellar nuclei in individual patients. In the present study, susceptibility weighted imaging (SWI) was used to visualize lesions of the dentate nuclei in patients with chronic focal lesions. Fifteen patients with cerebellar lesions either due to stroke or tumor surgery underwent SWI imaging using a 1.5T MRI scanner. Dentate nuclei were seen as hypointensities in all patients. Three of the patients underwent additional SWI imaging at 3T and 7T. Compared to 1.5T, corrugation of the dentate wall was seen with greater precision and the dorsal, iron-poorer part was seen more fully. Lesion-symptom mapping was performed based on the 1.5T MR images. Patients were divided into two groups with and without upper limb ataxia. A region-of-interest-(ROI)-driven normalization technique was used which had initially been developed by Diedrichsen et al. (2011) for functional MRI (fMRI) of the dentate nuclei. Compared to conventional normalization of the cerebellum, overlap of dentate lesions improved and lead to increased sensitivity of lesion-symptom maps. Subtraction analysis revealed that the more dorsal and rostral parts of the dentate nuclei were related to upper limb ataxia. Findings were in good accordance with the dentate hand area shown in recent fMRI studies. These data provide evidence that direct identification of dentate lesions together with the ROI-driven normalization technique allows for improved lesion-symptom mapping at the level of the cerebellar nuclei already at conventional 1.5T MRI field strength.

Deficient Use of Visual Information in Estimating Hand Position in Cerebellar Patients

We tested cerebellar degeneration in human patients in a task designed to isolate different aspects of motor planning and found a specific relationship between their ability to do inverse kinematic transformation and sparing of Crus I. Our approach was based on an experimental design introduced by Sober and Sabes (2003, 2005). Their paradigm allows behavioral deficits in planning of movement direction to be dissociated from deficits in generation of motor commands and also allows for the relative role played by visual and proprioceptive information to be quantified. Perturbation of visual information about hand position affected cerebellar degeneration patients (N = 12) and age-matched controls equally in determining movement direction, but had less of an effect in both groups in the transformation of movement direction to motor command. However, when provided with vision of the joints, control participants were more affected in generating the motor command in perturbed trials, and cerebellar degeneration participants were not. Thus, cerebellar patients were less able to use visual information about the joints in generating motor commands. Voxel-based morphometric analysis showed that this inability was primarily correlated with degeneration of Crus I. These results show that the cerebellum plays a role in motor planning, and specifically in the generation of inverse kinematic models for sensorimotor processing. The involvement of Crus I is consistent with an emerging picture in which increasingly posterior lobules of the anterior cerebellar cortex are associated with increasingly complex and abstract aspects of motor behavior.

Impaired prehension is associated with lesions of the superior and inferior hand representation within the human cerebellum

Impairment of patients with cerebellar disease in prehension is well recognized. So far specific localizations within the human cerebellum associated with the impairment have rarely been assessed. To address this question we performed voxel-based lesion symptom mapping (VLSM) in patients with chronic focal cerebellar lesions in relation to specific deficits in prehensile movements. Patients with stroke within the posterior inferior cerebellar artery territory (n = 13) or the superior cerebellar artery (SCA) territory (n = 7) and corresponding control subjects were included in the study. Participants reached out, grasped, and lifted an object with either the left or right hand and with fast or normal movement speed. Both kinematic and grip-force parameters were recorded. Magnetic resonance imaging anatomical scans of the cerebellum were acquired, and lesions were marked as regions of interest. For VLSM analysis, a nonparametric test (Brunner-Munzel) was applied. Cerebellar patients showed clear abnormalities in hand transport (impaired movement speed and straightness) and, to a lesser degree, in hand shaping (increased finger touch latencies) while grip function was preserved. Deficits were most prominent in patients with SCA lesions and for ipsilesional, fast movements. Disorders in hand transport may be more difficult to compensate than deficits in hand shaping and grip-force control in chronic focal lesions of the cerebellum because of higher demands on predictive control of interaction torques. Lesions of the superior cerebellar cortex (lobules IV, V, VI) were associated with slower hand transport, whereas lesions of both superior (lobules VI, V, VI) and inferior cerebellar cortex (lobules VII, VIII) were associated with impaired movement straightness. These findings show that both the superior and inferior hand representations within the cerebellum contribute to hand transport during prehensile movements; however, they may have a different functional role.