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There is now robust evidence that the cerebellum—apart from its well-established role in motor control—is crucially involved in a wide spectrum of cognitive and affective functions. Clinical and neuropsychological studies together with evidence from anatomical studies and advanced neuroimaging have yielded significant insights into the specific features and clinical relevance of cerebellar involvement in normal cognition and mood.

The role of the cerebellum in pathologies of the trigeminal nervous system is still unknown although recently gathered evidence point to a modulatory rather than a passive role. Here we provide evidence for the activation of specific cerebellar areas during nociceptive trigeminal input in the left nostril in a large number of volunteers (54 subjects) and an additional independent group (18 subjects) as measured by functional magnetic resonance imaging (fMRI). Peak voxel activity ipsilateral to the stimulated side can be seen in cerebellar lobules VI, VIIIa and Crus I, and vermal lobule VIIIa, although some activations are also seen in the contralateral side. The individuals’ intensity and unpleasantness ratings are mostly processed in the hemispheric lobules VI stretching to V, representing the face areas of the cerebellar's fractured homunculus. We found a robust functional connectivity during nociception between the cerebellum and the rostral part of the pons as well as the periaqueductal grey and the thalamus, involving the descending antinociceptive network as well as areas known to form close loops with the cerebellum in the motor domain. Cerebellar connectivity with higher cortical areas include most of the known hubs in pain processing which are the insular cortex, operculum and putamen, and the face areas in the precentral gyrus. The current data provide a solid basis for further research of the cerebellar's activity and connectivity in primary headache and facial pain syndromes. •The cerebellum is highly active during nociceptive, trigeminal processing.•The cerebellar's activity is modulated by perceived intensity of pain.•Its functional connectivity to brainstem and cortex is altered by nociception.

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.

•The cerebellum is activated during context-related recall of learned fear.•Part of original memory likely remains within the cerebellum following extinction.•The cerebellum shows activations related to the CS+ and CS-. The cerebellum is involved in the acquisition and consolidation of learned fear responses. Knowledge about its contribution to extinction learning, however, is sparse. Extinction processes likely involve erasure of memories, but there is ample evidence that at least part of the original memory remains. We asked the question whether memory persists within the cerebellum following extinction training. The renewal effect, that is the reoccurrence of the extinguished fear memory during recall in a context different from the extinction context, constitutes one of the phenomena indicating that memory of extinguished learned fear responses is not fully erased during extinction training. We performed a differential AB-A/B fear conditioning paradigm in a 7-Tesla (7T) MRI system in 31 young and healthy men. On day 1, fear acquisition training was performed in context A and extinction training in context B. On day 2, recall was tested in contexts A and B. As expected, participants learned to predict that the CS+ was followed by an aversive electric shock during fear acquisition training. Skin conductance responses (SCRs) were significantly higher to the CS+ compared to the CS- at the end of acquisition. Differences in SCRs vanished in extinction and reoccurred in the acquisition context during recall indicating renewal. Fitting SCR data, a deep neural network model was trained to predict the correct shock value for a given stimulus and context. Event-related fMRI analysis with model-derived prediction values as parametric modulations showed significant effects on activation of the posterolateral cerebellum (lobules VI and Crus I) during recall. Since the prediction values differ based on stimulus (CS+ and CS-) and context during recall, data provide support that the cerebellum is involved in context-related recall of learned fear associations. Likewise, mean β values were highest in lobules VI and Crus I bilaterally related to the CS+ in the acquisition context during early recall. A similar pattern was seen in the vermis, but only on a trend level. Thus, part of the original memory likely remains within the cerebellum following extinction training. We found cerebellar activations related to the CS+ and CS- during fear acquisition training which likely reflect associative and non-associative aspects of the task. Cerebellar activations, however, were not significantly different for CS+ and CS-. Since the CS- was never followed by an electric shock, the cerebellum may contribute to associative learning related to the CS, for example as a safety cue.

BackgroundFunctional movement disorders (FMDs) are commonly classified along canonical non-ataxic movement disorder patterns, creating a potential blind spot for frequently observed ataxia-like presentations. At the same time, normal diagnostic findings and episodic symptom variability in some cerebellar ataxias predispose to an incorrect FMD diagnosis.CasesWe present three cases that illustrate pitfalls in the differential diagnosis of ataxia. First, a patient treated for presumed immune-mediated cerebellar ataxia was diagnosed with FMD based on clinical signs. Next, a patient with intermittent and inconsistent symptoms was diagnosed with FMD after extensive exclusionary workup, but was then found to have a novel type of spinocerebellar ataxia. The third patient had a genetically confirmed spinocerebellar ataxia but developed additional functional motor symptoms.ConclusionDifferentiating cerebellar ataxias from FMDs and recognising mixed presentations is essential. Enhanced clinical awareness and systematic diagnostic evaluation are crucial to avoid misdiagnosis and ensure optimal treatment.

Quantifying the volume of the cerebellum and its lobes is of profound interest in various neurodegenerative and acquired diseases. Especially for the most common spinocerebellar ataxias (SCA), for which the first antisense oligonculeotide-base gene silencing trial has recently started, there is an urgent need for quantitative, sensitive imaging markers at pre-symptomatic stages for stratification and treatment assessment. This work introduces CerebNet, a fully automated, extensively validated, deep learning method for the lobular segmentation of the cerebellum, including the separation of gray and white matter. For training, validation, and testing, T1-weighted images from 30 participants were manually annotated into cerebellar lobules and vermal sub-segments, as well as cerebellar white matter. CerebNet combines FastSurferCNN, a UNet-based 2.5D segmentation network, with extensive data augmentation, e.g. realistic non-linear deformations to increase the anatomical variety, eliminating additional preprocessing steps, such as spatial normalization or bias field correction. CerebNet demonstrates a high accuracy (on average 0.87 Dice and 1.742mm Robust Hausdorff Distance across all structures) outperforming state-of-the-art approaches. Furthermore, it shows high test-retest reliability (average ICC >0.97 on OASIS and Kirby) as well as high sensitivity to disease effects, including the pre-ataxic stage of spinocerebellar ataxia type 3 (SCA3). CerebNet is compatible with FreeSurfer and FastSurfer and can analyze a 3D volume within seconds on a consumer GPU in an end-to-end fashion, thus providing an efficient and validated solution for assessing cerebellum sub-structure volumes. We make CerebNet available as source-code (https://github.com/Deep-MI/FastSurfer).

Prediction errors are thought to drive associative fear learning. Surprisingly little is known about the possible contribution of the cerebellum. To address this question, healthy participants underwent a differential fear conditioning paradigm during 7T magnetic resonance imaging. An event-related design allowed us to separate cerebellar fMRI signals related to the visual conditioned stimulus (CS) from signals related to the subsequent unconditioned stimulus (US; an aversive electric shock). We found significant activation of cerebellar lobules Crus I and VI bilaterally related to the CS+ compared to the CS-. Most importantly, significant activation of lobules Crus I and VI was also present during the unexpected omission of the US in unreinforced CS+ acquisition trials. This activation disappeared during extinction when US omission became expected. These findings provide evidence that the cerebellum has to be added to the neural network processing predictions and prediction errors in the emotional domain.

Transcranial direct current stimulation (tDCS) of the cerebellum is of increasing interest as a non-invasive technique to modulate motor performance and learning in health and disease. Previous studies have shown that cerebellar tDCS facilitates reach adaptation and associative motor learning in healthy subjects. In the present study it was tested whether cerebellar tDCS improves learning of a complex whole body motor skill. Because this task involves learning of posture and balance likely including learning of a new motor sequence and cognitive strategies, cerebellar tDCS was applied over midline cerebellar structures and the posterolateral cerebellar hemispheres. 30 young and healthy subjects performed two days of balance training on a Lafayette Instrument 16030 stability platform®. Participants received either anodal, cathodal or sham cerebellar tDCS during training on day 1. The cerebellar electrode (7 cm width by 5 cm height) was centered 2 cm below the inion. Mean platform angle deviation and mean balance time were assessed. All subjects showed significant effects of learning. Learning rate was not different between the three modes of stimulation neither on day 1 nor on day 2. Cerebellar tDCS did not facilitate learning of a complex whole body dynamic balance task in young and healthy subjects. tDCS effects, however, may have been missed because of the small group size. Furthermore, it cannot be excluded that young and healthy subjects learned and performed already at a near optimal level with little room for further improvement. Future work has to evaluate potential benefits of cerebellar tDCS in elderly subjects and subjects with cerebellar deficits, whose motor control and motor learning network is not optimally tuned.

Repeat expansions in FGF14 cause autosomal dominant late-onset cerebellar ataxia (SCA27B) with estimated pathogenic thresholds of 250 (incomplete penetrance) and 300 AAG repeats (full penetrance), but the sequence of pathogenic and non-pathogenic expansions remains unexplored. Here, we demonstrate that STRling and ExpansionHunter accurately detect FGF14 expansions from short-read genome data using outlier approaches. By combining long-range PCR and nanopore sequencing in 169 patients with cerebellar ataxia and 802 controls, we compare FGF14 expansion alleles, including interruptions and flanking regions. Uninterrupted AAG expansions are significantly enriched in patients with ataxia from a lower threshold (180–200 repeats) than previously reported based on expansion size alone. Conversely, AAGGAG hexameric expansions are equally frequent in patients and controls. Distinct 5’ flanking regions, interruptions and pre-repeat sequences correlate with repeat size. Furthermore, pure AAG (pathogenic) and AAGGAG (non-pathogenic) repeats form different secondary structures. Regardless of expansion size, SCA27B is a recognizable clinical entity characterized by frequent episodic ataxia and downbeat nystagmus, similar to the presentation observed in a family with a previously unreported nonsense variant (SCA27A). Overall, this study suggests that SCA27B is a major overlooked cause of adult-onset ataxia, accounting for 23–31% of unsolved patients. We strongly recommend re-evaluating pathogenic thresholds and integrating expansion sequencing into the molecular diagnostic process. Repeat expansions in the FGF14 gene can cause late-onset cerebellar ataxia (SCA27B), however the defining features of pathogenic expansions remain uncertain. Here, the authors compare the sequence and structure of FGF14 repeat expansions in patients and controls, leading them to suggest a lower pathogenic threshold and emphasizing the importance of sequencing the full expansion for accurate interpretation.

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.