Ataxia telangiectasia : a “ disease model ” to understand 1 cerebellar control of vestibular reflexes 2 3

47 Experimental animal models suggest that modulation of the amplitude and 48 direction of vestibular reflexes are important functions of the vestibulo-cerebellum and 49 contribute to the control of gaze and balance. These critical vestibular functions have 50 been infrequently quantified in human cerebellar disease. In 13 subjects with ataxia 51 telangiectasia (A-T), a disease associated with profound cerebellar cortical 52 degeneration, we found abnormalities of several key vestibular reflexes. The vestibulo53 ocular reflex (VOR) was measured by eye-movement responses to changes in head 54 rotation. The vestibulo-collic reflex (VCR) was assessed with cervical vestibular-evoked 55 myogenic potentials (cVEMPs), in which auditory clicks lead to EMG activity of the of 56 the sternocleidomastoid muscle. The VOR gain (eye velocity/head velocity) was 57 increased in all subjects with A-T. An increase of the VCR, paralleling that of the VOR, 58 was indirectly suggested by an increase in cVEMP amplitude. 59 In A-T subjects, alignment of the axis of eye rotation was not with that of head 60 rotation. Subjects with A-T thus manifested VOR cross-coupling; abnormal eye 61 movements directed along axes orthogonal to that of head rotation. Degeneration of the 62 Purkinje neurons in the vestibulo-cerebellum probably underlies these deficits. This 63 study offers insights into how the vestibulo-cerebellum functions in healthy humans. It 64 may also be of value to the design of treatment trials as a surrogate biomarker of 65 cerebellar function that does not require controlling for motivation or occult changes in 66 motor strategy on the part of experimental subjects. 67