1. Chairpersons: Byron Jones and Shawn Hochman (Director involved: Dr. Earley) From the Bed to the Bench: what features should any model of RLS have? Paul Christian Baier Section V. Animal Models of RLS

2. Baier 2008 Animal Models – general considerations What is it we want to be represented in animal models?  underlying (neuro)biology  the entire syndrome  specific symptoms of a syndrome/disorder  prediction of treatment efficacy with the aims:  to improved diagnosis and treatment of patients  to advance in understanding biological systems and/or

3. Baier 2008 Animal Models – general considerations Understanding of Pathophysiology (involved structures, molecular mechanisms, genetics,…) Disorder phenotype (behaviour, morphology, physiology, biochemistry,…) manipulation lesioning, reverse genetics analysis Environmental/ risk factor

4. Baier 2008 Restless Legs Syndrom is a clinical diagnosis. What clinical features can we observe and measure?  „ urge to move“  motor activity/actigraphy  worsened by rest  relieved by movement  tied to the circadian system and (supportive/associated features)  sleep disturbance  „polysomnography“  PLM  „polysomnography“ Animal Models – specific considerations

5. Baier 2008 What else can we observe and measure? changes in brain iron status (Earley 2000) changes in spinal chord excitability (Bara-Jimez 2000) changes in pain sensitiviy (Stiasny-Kolster 2004) hyperexcitability of the motor cortex (Scalise 2004) Animal Models – specific considerations

6. Proposed minimal essential criteria for a behavioural animal (murine) phenotype of RLS  Urge to move (indicated by increased locomotor activity, abnormal findings in the murine version of the suggested immobilization test)  Underlies circadian changes Facultativ, but sound and usefull  Is responsive to dopaminergic treatment (?)  Sleep disturbance  Periodic limb movements

8. A model is a simple representation of a complex system. An animal model of a disorder is an attempt to capture the essence of the condition, but it does not necessarily reproduce the human condtion in an animal. Fundamentally, a powerful and useful model has to lead to further understanding of the original clinical problem. Depending on the purpose of the model, the requirements of „what features it should have“ may differ. Animal Models – general considerations

9. Useful animal models have to be valid and reliable. Validity  Face validity (phenotypes and endophenotypes)  Predictive validity  Construct validity Reliability  inter-laboratory reproducibility  test-retest reliability Animal Models – general considerations

10. Example for the construction of a psychiatric animal model 1. Manipulation X produces psychiatric symptoms when given to humans 2. Manipulation X produces similar behavioural effects (  indicator) in animals, allowing for species dependent differences 3. Manipulation X produces specific biochemical effects in animals 4.The biochemical effects produced in animals provide data relevant to the behavioural effect of drug X in humans Animal Models – general considerations

11. Van der Staay, 2006 indicator

12. Baier 2008 Animal Models – specific considerations The problem of RLS animal modelling to date:  no manipulation, risk-factor, genetic mutation leading to RLS in humans with a 100% penetrance  no specific indicator (biomarker, phenotype)