Brain Advance Access originally published online on April 27, 2007
Brain 2007 130(6):1538-1551; doi:10.1093/brain/awm081
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Eyeblink conditioning is impaired in subjects with essential tremor
1Department of Neurology, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany, 2Department of Neurology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45147 Essen, Germany and 3Department of Neurology, HELIOS Kliniken Schwerin, Wismarsche Strasse 393-397, 19055 Schwerin, Germany
Corresponding to: Correspondence to: Dagmar Timmann, MD, Department of Neurology, University of Duisburg-Essen, Hufelandstrasse 55, 45147 Essen, Germany E-mail: dagmar.timmann{at}uni-essen.de
Several lines of evidence point to an involvement of the olivo-cerebellar system in the pathogenesis of essential tremor (ET), with clinical signs of cerebellar dysfunction being present in some subjects in the advanced stage. Besides motor coordination, the cerebellum is critically involved in motor learning. Evidence of motor learning deficits would strengthen the hypothesis of olivo-cerebellar involvement in ET. Conditioning of the eyeblink reflex is a well-established paradigm to assess motor learning. Twenty-three ET subjects (13 males, 10 females; mean age 44.3 ± 22.3 years, mean disease duration 17.4 ± 17.3 years) and 23 age-matched healthy controls were studied on two consecutive days using a standard delay eyeblink conditioning protocol. Six ET subjects exhibited accompanying clinical signs of cerebellar dysfunction. Care was taken to examine subjects without medication affecting central nervous functioning. Seven ET subjects and three controls on low-dose beta-blocker treatments, which had no effect on eyeblink conditioning in animal studies, were allowed into the study. The ability to acquire conditioned eyeblink responses was significantly reduced in ET subjects compared with controls. Impairment of eyeblink conditioning was not due to low-dose beta-blocker medication. Additionally, acquisition of conditioned eyeblink response was reduced in ET subjects regardless of the presence of cerebellar signs in clinical examination. There were no differences in timing or extinction of conditioned responses between groups and conditioning deficits did not correlate with the degree of tremor or ataxia as rated by clinical scores. The findings of disordered eyeblink conditioning support the hypothesis that ET is caused by a functional disturbance of olivo-cerebellar circuits which may cause cerebellar dysfunction. In particular, results point to an involvement of the olivo-cerebellar system in early stages of ET.
Key Words: cerebellum; action tremor; ataxia; olivo-cerebellar pathways; motor learning
Abbreviations: CS, conditioned stimulus; ET, essential tremor; US, unconditioned stimulus; MRI, Magnetic Resonance Imaging; CR, conditioned response; SPL, sound pressure level; bmp, blinks per minute; EMG, electromyography; CRST, Clinical Rating Scale for Tremor; ICARS, International Cooperative Ataxia Rating Scale; SPT, symptomatic palatal tremor
Received August 2, 2006. Revised January 10, 2007. Accepted March 16, 2007.