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GENOTYPE SPECIFIC CEREBELLAR INVOLVEMENT IN DYT1 AND DYT6 DYSTONIA?
  1. Anna Sadnicka,
  2. James Teo,
  3. Maja Kojovic,
  4. Panagiotis Kassavetis,
  5. Tabish Saifee,
  6. Parees Isabel,
  7. Petra Schwingenschuh,
  8. John Rothwell,
  9. Kailash Bhatia,
  10. Mark Edwards
  1. University College London

    Abstract

    Introduction Dystonia has historically been considered a disorder of the basal ganglia, however recent clinical and experimental observations promote the hypothesis that the dystonic neuroanatomical network is wider. In particular there is evidence that the cerebellum is a key structure within this network.1 Eye blink conditioning is a well characterised experimental paradigm that is highly conserved across species and is dependent upon the cerebellum. Previously it has been shown that levels of eye blink conditioning are reduced in cervical and focal hand dystonia, which suggests impaired cerebellar function in these subsets of dystonia.2

    Method In this study we examined eye blink conditioning in 11 patients with genetically confirmed DYT–1 dystonia and five patients with DYT–6 dystonia. 15 healthy age matched controls were also studied. Eye blink conditioning consisted of the pairing of a conditioning stimulus (CS) (salient 2kHz, 400 ms auditory tone via binaural headphones) with a strong unconditioned electrical stimulus (US) (200 µs pulse width, 5×sensory threshold, supraorbital nerve) 400 ms after the conditioning stimulus in order to elicit a blink reflex. After repeated pairings, conditioned responses (consisting of an eye blink starting before the US) are usually seen in healthy subjects. Conditioning consisted of six learning blocks of 11 trials: trials 1–9 were always CS–US pairs, trial 10 was US only and trial 11 was CS only. The main outcome variable was the number of conditioning responses in the final block.

    Results In both patient groups eye blink conditioning was observed, but at the group level there was a trend for patients with DYT–1 dystonia to condition less well (Mann–Whitney test, p=.097) compared to patients with DYT–6 dystonia, who conditioned at a comparable amount to aged matched controls.

    Conclusions There is now compelling evidence from studies in animal models of dystonia that the cerebellum has a critical role in the pathophysiology of some forms of dystonia. However evidence for cerebellar involvement in humans with the primary form of the disease is less well established. Eye blink conditioning is a unique electrophysiological paradigm in its ability to test associative learning within the cerebellar circuitry. Although the current data do not reveal statistically significant differences between patients with DYT1 and the small group of patients with DYT6 dystonia currently studied, there is an interesting trend towards less conditioning in DYT1 compared with DYT6 mutation carriers, and recruitment of further DYT6 positive patients is ongoing. If confirmed, this trend fits with previous functional imaging and behavioural studies suggesting differences in cerebellar activation patterns during movement in DYT1 and DYT6 dystonia. There may well be important differences in pathophysiology between patients currently grouped within primary dystonia.

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