Project

Discipline

Cerebellum; Human; Cerebellar disease; Rebound in cerebellar disease; Eye movements; Ocular motor control; Perception of gravity; 4-Aminopyridine; Functional MR imaging; Internal model theory; Gravity perception; Mechanisms of Rebound

Lead
Lay summary
Ziele des Forschungsprojekts:Das obengenannte Projekt widmet sich der Erforschung von Mechanismen, über welche das Kleinhirn die Kontrolle der Okulomotorik steuert sowie in die Wahrnehmung der Schwerkraft eingreift. Kontext und Bedeutung des Projekts:Patienten mit Kleinhirnerkrankungen leiden oft unter Sehbeschwerden wie Verschwommensehen, verursacht durch Augenbewegungsstörungen, sowie unter erheblicher Stand- und Gangunsicherheit. Mit unserem Projekt verfolgen wir die Absicht, die Mechanismen, über welche das Kleinhirn die Kontrolle der Augenbewegungen sowie die Wahrnehmung der Körperposition im Raum steuert, besser zu erforschen. Wir erhoffen uns davon nicht nur eine bessere Kenntnis der cerebellären Physiologie, sondern insbesondere auch ein besseres Verständnis der Beschwerden von Kleinhirnpatienten, beides wiederum dient der Erarbeitung von neuen therapeutischen Optionen, welche bis anhin bei Kleinhirnerkrankungen leider nur spärlich bestehen. Wissenschaftlicher Rahmen und Methodologie Bei Patienten mit Kleinhirnerkrankungen und bei gesunden Vergleichspersonen werden wir verschiedene Augenbewegungen sowie die Wahrnehmung der Orientierung im Raum testen. Hierfür kommen state-if-the-art-Methoden aus dem Gebiet der Vestibulo-Okulomotorik zur Anwendung. Aus der vergleichenden Analyse der Ergebnisse bei Gesunden und Patienten werden wir Erkenntnise zum Einfluss des Kleinhirns auf eben die Kontrolle der Augenbewegungen und der posturalen Kontrolle gewinnen. Ein weiterer Teil des Projekts widmet sich der Erforschung dieser Mechanismen mittels funktioneller Bildgebung.

Direct link to Lay Summary

Last update: 21.02.2013

Active participation

Background: The cerebellum plays a fundamental role in sensory-motor transformation and adaptive processes, yet the exact mechanisms remain to be determined. A fascinating phenomenon in this context is rebound: when a healthy subject’s arm is pressed against the examiner’s tension, and then tension is suddenly released, the limb travels a short distance in direction of the previous resistance before rebounding. Cerebellar patients show an excessive range of limb movement in direction of the previous resistance, but little or no backward correction, i.e. they fail to maintain the desired position of the limb. A related phenomenon can be observed in the ocular motor system: rebound nystagmus denotes a transient ocular drift in the direction of a previous gaze eccentricity after sudden return to straight-ahead gaze. This drift is excessive in cerebellar patients, and reflects a failure to maintain the desired straight-ahead gaze position following eccentric gaze. The similarities between excessive range of limb rebound and rebound ocular drift prompted us to propose a novel theory on the pathophysiology of rebound in cerebellar disease. Our theory is based on the concept that the nervous system has internalized reference estimates for motor control and sensory processing, and that the cerebellum is critically involved in the mechanisms, which maintain this internal estimates. Working hypotheses: The overriding hypothesis of this proposal is that abnormal rebound in cerebellar disease reflects instability of internal null reference estimates in the presence of asymmetric input signals and that this principle not only applies to motor control, but can be generalized to include sensory processing. We will investigate this hypothesis in privileged motor and sensory systems, which have easily definable null positions from the mechanical point of view and which are under control of the vestibulo-cerebellum: ocular motor control and perception of earth-verticality. We define the ocular motor null as the internal representation of the elastic equilibrium position of the eye, and the graviceptive null as the internal reference estimate of the earth-vertical. We hypothesize that rebound in the ocular motor system reflects a shift of the internal estimate of the ocular motor null, which is induced by an antecedent sustained asymmetric input signal to the ocular motor system. Likewise, for perception of earth-verticality the nervous system must remember a pattern of sensory neural activity as corresponding to earth-vertical, and we hypothesize that rebound in the perception of earth-verticality reflects a shift of this internal reference estimate of the earth-vertical in the presence of an asymmetric stimulation of the gravity sensors. The specific objective of this research is to explore whether or not abnormal ocular motor rebound in cerebellar disease is caused by instability of the ocular motor null, and, analogously, abnormal rebound in the perception of earth-verticality by instability of the internal estimate of the vertical. In healthy subjects and cerebellar patients, we will analyze and compare ocular motor rebound (Aim 1) and rebound in the perception of earth-verticality (Aim 2) with behavioral and psychophysical paradigms. We will also test whether 4-Aminopyridine (4-AP), which was shown to enhance overall excitability of cerebellar Purkinje cells, reduces ocular motor and perceptual rebound in the patients (Aim 1&2). The correlation of behavioral data with functional magnetic resonance activation will further elucidate anatomical and functional aspects of rebound mechanisms (Aim 3). Follow-up studies aim to develop computational models of rebound to obtain mechanistic insights into the underlying circuitries. Aim 1: We systematically assess the three-dimensional kinematics of (1) rebound drift evoked by sustained gaze eccentricities in healthy subjects and cerebellar patients. (2) We explore whether cerebellar patients with Downbeat nystagmus exhibit a rebound of gravity-dependent drift induced by sustained pitch positions. We test (3) whether or not 4-AP, known to restore integrator function and to minimize GD drift modulation in cerebellar patients, reduces rebound drifts evoked by paradigms (1) and (2). Aim 2: In healthy subjects and cerebellar patients, we explore (1) whether exposure to prolonged roll tilts leads to a bias of perceived earth-verticality in direction of the previous tilt upon returning to upright. Self-orientation relative to gravity will be assessed by settings of a visual line along the perceived earth-vertical (subjective visual vertical, SVV). (2) We also test whether or not 4-AP influences perceptual rebound. Aim 3: Using fMRI BOLD signals, we aim to determine in healthy subjects and cerebellar patients the activation patterns during rebound drifts induced by sustained gaze-holding in order to (1) define the underlying anatomical substrate and (2) gain information on the temporal evolution of ocular motor rebound mechanisms. Methods: We use a combination of vestibular testing (multi-axis turntable), eye movement recordings (dual search coil technique, MR eye tracker), psychophysical instruments (visual line settings for SVV), pharmacological testing (4-AP), computational modeling and functional MR imaging techniques. Expected value of the project: This proposal investigates the pathophysiology of abnormal rebound in cerebellar disease, embedded in the context of modern concepts of cerebellar function. State-of-the-art instruments for behavioral and perceptual evaluation are combined with functional imaging techniques. The mechanisms of action and the potential therapeutic benefit of 4-AP for cerebellar disorders are further elucidated. Overall, this research helps to understand the mechanisms by which the cerebellum influences sensory processing and adaptive control of motor performance.