1. VOXEL BASED TECHNIQUES AND fMRI DURING PRONOUNCED PERIOD OF SYMPTOMS OF EARLY-ONSET RESTLESS LEGS SYNDROME PATIENTS P.N. Margariti, L.Astrakas, S.Konitsiotis, L.C.Tzarouchi, S.Tsouli, M.I.Argyropoulou Medical School, University of Ioannina, Greece

2. Restless Legs Syndrome (RLS)  sensorimotor disorder  circadian pattern of symptoms insomnia insomnia daytime fatigue daytime fatigue sensory periodic limb movement, PLM

4. Pathophysiology Iron Dopamine

5. Conflicting results Functional MRI (fMRI) MRI Normal brain morphology Voxel-based morphometry T2 relaxometry Low iron content of the Substantia Nigra (*) Cerebellar, thalamic, red nucleus, reticular formation activity(*) *Bucher SF, Seelos KC, Oertel WH, Reiser M, Trenkwalder C. Ann Neurol. 1997 May;41(5):639-45

6. low iron in SNc on T2 relaxometry fMRI during active dorsiflexion –plantar flexion of foot: significant activation of the dorsolateral prefrontal cortex Astrakas LG, Konitsiotis S, Margariti P, Tsouli S, Tzarouhi L, Argyropoulou MI. Neurology. 2008 Sep ;71(12):911-6 primary or secondary effects due to iron deficiency

7. Purpose VBM VBR fMRI

8. Materials 11 RLS patients early onset 9 women, 2 men 55.3 +/- 8.4 years 17.5 +/- 14.05 years disease duration International Restless Legs Severity Scale (IRLS) : 18.4 +/- 4.8 (range 12-26)

9. Methods 1.5-Tesla scanner (INTERA, Philips Medical Systems, Best, The Netherlands). T1-weighted high-resolution (0.86 _ 0.86 _ 1 mm) three dimensional spoiled gradient echo sequence TR/TE 25 msec/4.6 msec) multislice spin echo T2-weighted sequence (TR, 2,200 msec; TE, 16 values between 32 and 112 msec; slice thickness, 5 mm; gap, 0.5 mm) single-shot multislice gradient echo planar imaging (EPI) (TR/TE, 3,000 msec/50 msec; flip angle, 40°; matrix, 64 _ 64; slice thickness, 5 mm; gap, 0 mm). Data pre-processing and analysis was implemented using statistical parametric mapping software (SPM5) running in MATLAB 7.6

10. VBMSegmentation Scanner specific template Modulation Smoothing Voxel by voxel Student’s t-test P < 0.05 FDR correction

11. Voxel by voxel Student’s t-test SmoothingNormalisation MNI template P < 0.05 FDR correction VBR T2 maps R2

12. fMRI MNI template P<0.001

13. Results - VBM

14. Results - VBR

15. Results - fMRI

16. Regression Analysis

17. Discussion-VBM Whole brain analysis at night hours VBM : no changes of GM, WM ≠ previous reports -Different populations -Different levels of statistical significance Medication treatment may have modulated controversial findings of previous reports

18. Discussion- VBR Whole brain analysis of the R2 index voxel- to-voxel VBR : normal R2 ≠ previous reports. -Different populations -ROI analysis The time of the exam may have modulated the relaxation rates measurements

19. Discussion Pars Opercularis (R)  Respone inhibition on a Stop-Signal task(*) (*)A componential analysis of task-switching deficits associated with lesions of left and right frontal cortex. Aron AR, Monsell S,Sahakian BJ, Robbins TW. Brain 2004, 27(Pt7):1561-73

20. Discussion-Regression analysis Positive relationship of the activation of the pulvinar with age cortical –basal ganglia- thalamic circuits

21. Conclusions Early-onset RLS is not associated with brain volumetric alterations Low iron content shown in previous imaging or autopsy studies may be a secondary effect Hyperactivity of the pars opercularis possibly shows that brainstem or spinal neurones generate PLM

22. Thank you !