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PERIPHERAL SPINAL REFLEX MODEL OF RLS MODELS Mauro Manconi Center of Sleep Medicine, Scientific Institute of Research San Raffaele, Milan, Italy PATHOGENETIC HYPOTHESIS DOPAMINERGIC SYSTEM SPINAL HYPEREXCITABILITY SENSITIVE RLS SYMPTOMS / PLM DOPAMINERGIC HYPOTHESIS Efficacy of dopaminergic treatment Symptomatic form secondary to antidopaminergic drugs (neuroleptics) Association with Parkinson Disease Symptomatic form to iron deficiency (iron is the coenzyme of tyrosin-hidroxilase) Evidences of transcranial magnetic stimulation Circadian trend of dopamine production Low dose of pmx (0.25 mg) is effective in RLS from the first night of administration. These results support a direct involvement of the dopaminergic system in RLS pathogenesis. Spinal Cord involvement in RLS RLS is may be associated with spinal cord injury Hartmann M, Pfister R, Pfadenhauer K. Restless legs syndrome associated with spinal cord lesions. J Neurol Neurosurg Psychiatry 1999;66:688–689. RLS is often associated with spinal anesthesia Lee MS, Lyoo CH, Kim WC, Kang HJ. Periodic bursts of rhythmic dyskinesia associated with spinal anesthesia. Mov Disord 1997;12:816-817. RLS is associated with an increasing in spinal reflex excitability Bara-Jimenez W, Aksu M, Graham B, Sato S, Hallett M. Periodic limb movements in sleep: state-dependent excitability of the spinal flexor reflex. Neurology 2000;54:1609–1616. Abnormal hyperexcitability along the entire spinal cord, especially its lumbosacral and cervical segments • Provini F, Vetrugno R, Meletti S, Plazzi G, Solieri L, Lugaresi E, Coccagna G, Montagna P. Motor pattern of periodic limb movements during sleep. Neurology. 2001 Jul 24;57(2):300-4. Prospective clinical and c/s MRI study in 82 consecutive MS pts 30 subjects (36.5%) had RLS; and they showed a higher EDSS. No difference in whole brain, cerebellar and brainstem T2-LLs. MD and FA histograms derived metrics of the normal appearing brain tissues; basal ganglia MD; number of cervical cord lesions. Cervical cord average FA was significantly reduced in MS patients with RLS. PYRAMIDAL SENSITIVE SYSTEMS NEUROPHISIOLOGY Spinal Reflex Latency FR1 and FR2 normal Amplitude FR1 and FR2 normal ↓ threshold FR1-2 ↑ muscles recruitment Abnormal FR3 response Spinal Iperexcitability FR PLM Bara-Jimenez, W., et al., Periodic limb movements in sleep: state-dependent excitability of the spinal flexor reflex. Neurology, 2000. 54(8): p. 1609-16. Suprachiasmatic nucleus (SCN) HYPOTHALAMUS VIP VP Circadian control A11 dopaminergic neurons DOPAMINE D3 Dorsal horn SPINAL CORD D3 Intermediolateral nucleus (IML) The diencephalic A11 DA neurons possessed long axons extending over several segments and possibly traversing the entire length of the spinal cord. It is the first time to report A10 and A11 DA neuron projections into the spinal cord in mice Highest densities of D3 binding were observed in the superfcial layers of the dorsal horn at cervical and lumbar levels. DOPAMINE / 5HT2 CPG LOCOMOTOR PATTERN ALMA RATIONAL FOR AN ANIMAL MODEL OF RLS/PLM LESIONAL MODELS Methods of previous attempts PHARMACOLOGICAL MODELS GENETIC MODELS The current tendency in achieving an RLS model is generally represented by simulation of a symptomatic condition of RLS, or by a direct interference on the dopaminergic system. • 10 young and 10 old (16-20 months) rats • I.P. dayly injection of Haloperidol 0.1-0.2 mg/kg • 5 days observation of: • EEG + neck EMG • Hindlimbs movements (HLM) by magnetic inductive device located subcutaneusly • PHLM: 4 consecutive movements with inter-movement interval ranged from 5 to 60 sec. (No duration criteria) • 8 sham rats + 11 lesioned rats (wistar) • steretaxical lesion of spinal cord at T9 level • 7 days of recording of the following parameters: • EEG, neck EMG, both gastrocnemious muscles EMG • movements ranged from 3 to 9 sec. were considered in the analysis