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Neural representations of limb movement kinematic parameters are common among central nervous system structures involved in motor control, such as the interpositus nucleus of the cerebellum. Much experimental evidence indicates that neurons in the interpositus may encode limb kinematic parameters both during active, voluntary actions and during limb motion imposed passively, which entrains only sensory afferents. With respect to the sensory processing of information related to movement kinematics, we show that interpositus neuronal activity can parse out the directional from the scalar component (i.e., the movement speed) of the velocity vector. Moreover, a differential role for the anterior and posterior portion of interpositus in encoding these parameters emerged from these data, since the activity of the posterior interpositus was specifically associated to changes of movement speed. Limb movement representations in the interpositus nucleus may be instrumental for the control of goal-directed movements such as shaping hand during grasping or precise foot placement during gait. Finally, we discuss the idea that sensory information about the movement kinematics contribute to both feedback and anticipatory processes for limb movement control.

Patients with cerebellar lesions may show horizontal (positive)- or downward (perverted)-corrective saccades during horizontal head impulse test (HIT). However, corrective saccades in the direction of head rotation (reversed corrective saccades) have not been reported during HIT. We present two patients who showed reversed corrective saccades during horizontal HIT as an initial sign of acute cerebellitis. In contrast to the corrective saccades mostly observed in peripheral vestibular paresis, this paradoxical response indicates abnormally increased vestibulo-ocular responses due to cerebellar disinhibition over the vestibulo-ocular reflex. This paradoxical response should be considered an additional bedside cerebellar sign.

Friedreich ataxia (FRDA) is the most frequent inherited ataxia. Neuropsychological studies suggest that FRDA may be associated with specific cognitive impairment. Very little is known about the relation between cognitive performance, demographics and disease-related parameters, such as GAA repeat size, age of onset and disease duration. The present investigation aimed at assessing cognitive functions in a representative sample of FRDA patients and at identifying the most relevant disease-related parameters. Twenty-nine adult FRDA patients underwent neuropsychological tests assessing executive functions, attention, memory and visual perception. Performance was compared with 28 age- and education-matched controls as well as with standardized norms. The relation between neuropsychological outcome, demographical variables and disease-related parameters was assessed. Cognitive impairment affected only a subgroup of patients and mostly concerned attentional and executive functions. Good cognitive performance was associated with a later disease onset, shorter GAA repeat length and lower burden of disease. Age at disease onset has been found to be a good predictor when a cut-off of 14 years was chosen. No correlation was found between cognitive performance and education, age or disease duration. The present study extends earlier findings in FRDA showing that performance in attentional and executive function tasks is best predicted by the age at disease onset. Moreover, executive functions show a clear relationship to disease severity and repeat size of the shorter GAA allele. These findings therefore have important implications for patient counselling regarding education and career choices.

The autosomal dominant spinocerebellar ataxias (SCAs) are a group of progressive neurodegenerative diseases characterised by loss of balance and motor coordination due to the primary dysfunction of the cerebellum. To date, more than 30 genes have been identified triggering the well-described clinical and pathological phenotype, but the underlying cellular and molecular events are still poorly understood. Studies of the functions of the proteins implicated in SCAs and the corresponding altered cellular pathways point to major aetiological roles for defects in transcriptional regulation, protein aggregation and clearance, alterations of calcium homeostasis, and activation of pro-apoptotic routes among others, all leading to synaptic neurotransmission deficits, spinocerebellar dysfunction, and, ultimately, neuronal demise. However, more mechanistic and detailed insights are emerging on these molecular routes. The growing understanding of how dysregulation of these pathways trigger the onset of symptoms and mediate disease progression is leading to the identification of conserved molecular targets influencing the critical pathways in pathogenesis that will serve as effective therapeutic strategies in vivo, which may prove beneficial in the treatment of SCAs. Herein, we review the latest evidence for the proposed cellular and molecular processes to the pathogenesis of dominantly inherited spinocerebellar ataxias and the ongoing therapeutic strategies.

Friedreich ataxia (FRDA) is the most common hereditary ataxia. Since the discovery of the genetic cause of this disease, the phenotypic spectrum seems to be wider, including late-onset forms such as late-onset Friedreich ataxia—LOFA (25–39 years at onset). The neuropathological and clinical patterns in patients with LOFA are similar to those in patients with typical FRDA, but LOFA patients tend to have an overall milder, slowly evolving disease. Given the lack of data about cognitive performance of LOFA, we aimed to investigate whether differences in age at disease onset may be related also to differences at a cognitive level. Twenty-nine typical FRDA and seven LOFA patients were administered a comprehensive neuropsychological battery measuring multiple domains: processing speed, attention, working memory, executive functions, verbal and visual memory, visuoperceptive and visuospatial skills, visuoconstructive functions, and language. There were no significant differences in disease duration between the two groups of patients. Every patient group was matched in gender, age, years of education, and estimated IQ with a healthy-participant control group. Results indicate that both patient groups shared slowed motor processing speed and impaired conceptual thinking and verbal fluency. However, only typical FRDA patients showed a diminished cognitive processing speed and impaired visuoperceptive and visuoconstructive abilities. This pattern indicates that a later disease onset is associated to a milder cognitive impairment. Thus, our findings are in concordance with those related to clinical differences between typical FRDA and LOFA.

Understanding how cells from different neuronal and glial lineages contribute to functional circuits has been complicated by the difficulty in tracking cells as they integrate into brain circuits. Sudarov et al. (J Neurosci 31(30):11055–11069, 2011) used a powerful genetics-based lineage marking approach to birth date ventricular zone-derived cells in the mouse cerebellum. The authors use their novel tools to elucidate the spatial and temporal dynamics of how distinct ventricular zone lineages are generated and assemble into the cerebellar microcircuitry. In this journal club, we discuss and evaluate the author's major findings.

Morgagni’s 1761 publication of De sedibus et causis morborum (i.e., of the Seats and Causes of Diseases) represented a paradigmatic moment in the history of medicine. The book ushered in a new way of conceptualizing human disease, shattering old dogma, and linking constellations of symptoms and signs (i.e., clinical disease) with anatomic pathology in specific organs (i.e., organ disease). This was the anatomical-clinical method, and it attempted to unveil “the seat” of each disease in a specific organ. Essential tremor (ET) is among the most common neurological diseases. There is little debate that the origin of ET lies in the brain, but if one tries to delve more deeply than this, things become murky. The dogma for the past 40 years has been that the seat of ET is the inferior olivary nucleus. Closer scrutiny of this model, however, has revealed its many flaws, and the model, based on little if any empiric evidence, has increasingly lost favor. Arising from a wealth of research in recent years is a growing body of knowledge that links ET to a disarrangement of the cerebellum. Data from a variety of sources reviewed in this issue (clinical, neuroimaging, neurochemical, animal model, physiological, and pathological) link ET to the cerebellum. That the cerebellum is involved in an abnormal brain loop that is responsible for ET is not debated. The tantalizing question is whether an abnormality in the cerebellum is the prime mover, and whether the cerebellum is the seat of this particular disease.