Summary Autosomal dominant cerebellar ataxias are hereditary neurodegenerative disorders that are known as spinocerebellar ataxias (SCA) in genetic nomenclature. In the pregenomic era, ataxias were some of the most poorly understood neurological disorders; the unravelling of their molecular basis enabled precise diagnosis in vivo and explained many clinical phenomena such as anticipation and variable phenotypes even within one family. However, the discovery of many ataxia genes and loci in the past decade threatens to cause more confusion than optimism among clinicians. Therefore, the provision of guidance for genetic testing according to clinical findings and frequencies of SCA subtypes in different ethnic groups is a major challenge. The identification of ataxia genes raises hope that essential pathogenetic mechanisms causing SCA will become more and more apparent. Elucidation of the pathogenesis of SCA hopefully will enable the development of rational therapies for this group of disorders, which currently can only be treated symptomatically.

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474442204007379.pdf

Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis.

The cerebellum is an essential part of the neural network involved in adapting goal-directed arm movements. This adaptation might rely on two distinct signals: a sensory prediction error or a motor correction. Sensory prediction errors occur when an initial motor command is generated but the predicted sensory consequences do not match the observed values. In some tasks, these sensory errors are monitored and result in on-line corrective motor output as the movement progresses. Here we asked whether cerebellum-dependent adaptation of reaching relies on sensory or on-line motor corrections. Healthy controls and people with hereditary cerebellar ataxia reached during a visuomotor perturbation in two conditions: "shooting" movements without on-line corrections and "pointing" movements that allowed for on-line corrections. Sensory (i.e., visual) errors were available in both conditions. Results showed that the addition of motor corrections did not influence adaptation in control subjects, suggesting that only sensory errors were needed for learning. Cerebellar subjects were comparably impaired in both adaptation conditions relative to controls, despite abnormal and inconsistent on-line motor correction. Specifically, poor on-line motor corrections were unrelated to cerebellar subjects' adaptation deficit (i.e., adaptation did not worsen), further suggesting that only sensory prediction errors influence this process. Therefore adaptation to visuomotor perturbations depends on the cerebellum and is driven by the mismatch between predicted and actual sensory outcome of motor commands.

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Sensory Prediction Errors Drive Cerebellum-Dependent Adaptation of Reaching

Ordinary differential equations of the first order linear differential equations complex numbers and linear algebra simultaneous linear differential equations numerical methods the descriptive theory of nonlinear differential equations mechanical systems and electric circuits Fourier series Fourier integrals and Fourier transforms the Laplace transformation partial differential equations Bessel functions and Legendre polynomials applications and further properties of matrices vector analysis the calculus of variations analytic functions of a complex variable infinite series in the complex plane the theory of residues conformal mapping.

Advanced Engineering Mathematics. By C. R. Wylie. Pp. xiv, 813. 1966. (McGraw-Hill.)

Mechanisms of recovery following unilateral labyrinthectomy: a review

Neurodegenerative disorders, which are chronic and progressive, are characterized by selective and symmetric loss of neurons in motor, sensory, or cognitive systems. Delineation of the patterns of cell loss and the identification of disease-specific cellular markers have aided in nosologic classification: senile plaques, neurofibrillary tangles, neuronal loss, and acetylcholine deficiency define Alzheimer's disease1,2; Lewy bodies and depletion of dopamine characterize Parkinson's disease3; cellular inclusions and swollen motor axons are found in amyotrophic lateral sclerosis4; and γ-aminobutyric acid–containing neurons of the neostriatum are lost in Huntington's disease.5 Mendelian inheritance can be demonstrated in many of these disorders . . .

Molecular basis of the neurodegenerative disorders.

Spinocerebellar ataxia type 6 (SCA6) was recently identified as a form of autosomal dominant cerebellar ataxia associated with small expansions of the trinucleotide repeat (CAG)n in the gene CACNL1A4 on chromosome 19p13, which encodes the α1 subunit of a P/Q-type voltage-gated calcium channel. We describe clinical, genetic, neuroimaging, neuropathological, and quantitative oculomotor studies in four kindreds with SCA6. We found strong genetic linkage of the disease to the CACNL1A4 locus and strong association with the expanded (CAG)n alleles in two large ataxia kindreds. The expanded alleles were all of a single size (repeat number) within the two large kindreds, numbering 22 and 23 repeat units. It is noteworthy that the age of onset of ataxia ranged from 24 to 63 years among all affected individuals, despite the uniform repeat number. Radiographically and pathologically, there was selective atrophy of the cerebellum and extensive loss of Purkinje cells in the cerebellar cortex. In addition, clinical and quantitative measurement of extraocular movements demonstrated a characteristic pattern of ocular motor and vestibular abnormalities, including horizontal and vertical nystagmus and an abnormal vestibulo-ocular reflex. These studies identify a distinct phenotype associated with this newly recognized form of dominant SCA.

Spinocerebellar ataxia type 6: Gaze‐evoked and vertical nystagmus, Purkinje cell degeneration, and variable age of onset

1.

The activity of cat semicircular canal and otolith afferents was studied during yaw and roll rotations, respectively, to examine their dynamic behavior.




2.

A sinusoidal analysis of the canal afferent activities showed that their dynamic characteristics are similar to those of second order vestibular neurons, except for a two to three-fold lower absolute gain. This agrees with earlier studies using angular acceleration steps.




3.

Both divisions of the eighth nerve were sampled so as to examine afferents from both the utriculus and sacculus. Within the range of inputs used (± 25 degrees lateral tilt), the presumed saccular afferents (inferior division) showed either a γ- or β-response. However, the gain of their response was generally much less than for the afferents of the superior division (mostly utricular). This behavior is to be expected on the basis of receptor orientations and the components of gravity acting upon the macular receptors.




4.

In response to ramp changes in angular position, some otolith units showed a phasic-tonic response pattern, i.e., an overshoot followed by an adaptation to a new steady state level of activity. The majority of units showed predominantly tonic responses proportional to displacement.




5.

During sinusoidal rotations the predominantly tonic units showed small phase leads of 0 to 15 degrees at 0.025 Hz which remained constant or decreased to 0 to −15 degrees at 1.0 Hz. The gains were flat or increased by up to 2 fold. The phasic-tonic units showed greater phase leads, 10 to 50 degrees, and gains which increased from 2 to 8 fold.




6.

This behavior of otolith afferents suggests that they can provide information about both the magnitude and the rate of change of linear acceleration stimuli.

Response characteristics of semicircular canal and otolith systems in cat. I. Dynamic responses of primary vestibular fibers.

Sensory organization of balance responses in children 3-6 years of age: a normative study with diagnostic implications.

Vestibular impairments have not been routinely identified in patients with multiple sclerosis (MS), because of the confounding effects of deficits in other neural systems. In this study, 35 patients with MS were evaluated by means of a systematic alteration of the sensory environment (dynamic posturography) in order to identify those patients who became unstable when vestibular inputs were needed to maintain stance. Subjects were assigned to either a high-function (HF) or a low-function (LF) group on the basis of a functional status assessment score obtained prior to the posturography test. For the HF group, 30% (7/23) had abnormal posturography scores. Of those subjects, 3 had a vestibular dysfunction pattern or a somatosensory-vestibular impairment. In contrast, 58% of the LF group (7/ 12) had abnormal posturography scores. Nearly all of these LF patients (677) had a vestibular dysfunction pattern or a combined visual-vestibular or somatosensory-vestibular impairment. Posturography might serve as one me...

Vestibular and Sensory Interaction Deficits Assessed by Dynamic Platform Posturography in Patients with Multiple Sclerosis

Detection of Fos protein expression with a polyclonal antibody was used to identify brainstem neurons responding to acute (24 h) effects of a unilateral sodium arsanilate chemical labyrinthectomy in Long-Evans rats. Asymmetrical expression was apparent in the medial and inferior vestibular nuclei, the prepositus hypoglossi, the dorsolateral central gray, and the inferior olivary beta subnucleus. These data suggest different distributions of neural activation compared with previous electrophysiological and 2-deoxyglucose results. In addition, there was some Fos expression bilaterally in the olivary dorsomedial cell column, interstitial nucleus of Cajal and the Darkschewitsch nucleus. These results support the concept of multiple systems participating in vestibular compensation and further define some specific nuclei involved in the acute stage.

John H. Anderson

Papers

Spinocerebellar ataxia type 6: Gaze‐evoked and vertical nystagmus, Purkinje cell degeneration, and variable age of onset

Response characteristics of semicircular canal and otolith systems in cat. I. Dynamic responses of primary vestibular fibers.

Sensory organization of balance responses in children 3-6 years of age: a normative study with diagnostic implications.

Vestibular and Sensory Interaction Deficits Assessed by Dynamic Platform Posturography in Patients with Multiple Sclerosis

Brainstem fos Expression Following Acute Unilateral Labyrinthectomy in The Rat