請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/64084
完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 郭鐘金 | |
dc.contributor.author | Chun-Hwei Tai | en |
dc.contributor.author | 戴春暉 | zh_TW |
dc.date.accessioned | 2021-06-16T17:29:20Z | - |
dc.date.available | 2012-09-19 | |
dc.date.copyright | 2012-09-19 | |
dc.date.issued | 2012 | |
dc.date.submitted | 2012-08-15 | |
dc.identifier.citation | Afsharpour S (1985a) Light microscopic analysis of Golgi-impregnated rat subthalamic neurons. J Comp Neurol 236:1-13.
Afsharpour S (1985b) Topographical projections of the cerebral cortex to the subthalamic nucleus. J Comp Neurol 236:14-28. Albin RL, Young AB, Penney JB (1989) The functional anatomy of basal ganglia disorders. Trends Neurosci 12:366-375. Alexander GE, Crutcher MD, DeLong MR (1990) Basal ganglia-thalamocortical circuits: parallel substrates for motor, oculomotor, 'prefrontal' and 'limbic' functions. Prog Brain Res 85:119-146. Alvarez L, Macias R, Guridi J, Lopez G, Alvarez E, Maragoto C, Teijeiro J, Torres A, Pavon N, Rodriguez-Oroz MC, Ochoa L, Hetherington H, Juncos J, DeLong MR, Obeso JA (2001) Dorsal subthalamotomy for Parkinson's disease. Mov Disord 16:72-78. Amtage F, Henschel K, Schelter B, Vesper J, Timmer J, Lucking CH, Hellwig B (2008) Tremor-correlated neuronal activity in the subthalamic nucleus of Parkinsonian patients. Neurosci Lett 442:195-199. Awad H, Hubert GW, Smith Y, Levey AI, Conn PJ (2000) Activation of metabotropic glutamate receptor 5 has direct excitatory effects and potentiates NMDA receptor currents in neurons of the subthalamic nucleus. J Neurosci 20:7871-7879. Benabid AL, Chabardes S, Mitrofanis J, Pollak P (2009) Deep brain stimulation of the subthalamic nucleus for the treatment of Parkinson's disease. Lancet Neurol 8:67-81. Benabid AL, Pollak P, Gervason C, Hoffmann D, Gao DM, Hommel M, Perret JE, de Rougemont J (1991) Long-term suppression of tremor by chronic stimulation of the ventral intermediate thalamic nucleus. Lancet 337:403-406. Benabid AL, Koudsie A, Benazzouz A, Fraix V, Ashraf A, Le Bas JF, Chabardes S, Pollak P (2000) Subthalamic stimulation for Parkinson's disease. Arch Med Res 31:282-289. Benazzouz A, Gross C, Feger J, Boraud T, Bioulac B (1993) Reversal of rigidity and improvement in motor performance by subthalamic high-frequency stimulation in MPTP-treated monkeys. Eur J Neurosci 5:382-389. Benazzouz A, Breit S, Koudsie A, Pollak P, Krack P, Benabid AL (2002) Intraoperative microrecordings of the subthalamic nucleus in Parkinson's disease. Mov Disord 17 Suppl 3:S145-149. Benazzouz A, Tai CH, Meissner W, Bioulac B, Bezard E, Gross C (2004) High-frequency stimulation of both zona incerta and subthalamic nucleus induces a similar normalization of basal ganglia metabolic activity in experimental parkinsonism. FASEB J 18:528-530. Bergman H, Wichmann T, DeLong MR (1990) Reversal of experimental parkinsonism by lesions of the subthalamic nucleus. Science 249:1436-1438. Bergman H, Wichmann T, Karmon B, DeLong MR (1994) The primate subthalamic nucleus. II. Neuronal activity in the MPTP model of parkinsonism. J Neurophysiol 72:507-520. Beurrier C, Bioulac B, Hammond C (2000) Slowly inactivating sodium current (I(NaP)) underlies single-spike activity in rat subthalamic neurons. J Neurophysiol 83:1951-1957. Beurrier C, Bezard E, Bioulac B, Gross C (1997) Subthalamic stimulation elicits hemiballismus in normal monkey. Neuroreport 8:1625-1629. Beurrier C, Congar P, Bioulac B, Hammond C (1999) Subthalamic nucleus neurons switch from single-spike activity to burst-firing mode. J Neurosci 19:599-609. Beurrier C, Bioulac B, Audin J, Hammond C (2001) High-frequency stimulation produces a transient blockade of voltage-gated currents in subthalamic neurons. J Neurophysiol 85:1351-1356. Bevan MD, Wilson CJ (1999) Mechanisms underlying spontaneous oscillation and rhythmic firing in rat subthalamic neurons. J Neurosci 19:7617-7628. Bevan MD, Wilson CJ, Bolam JP, Magill PJ (2000) Equilibrium potential of GABA(A) current and implications for rebound burst firing in rat subthalamic neurons in vitro. J Neurophysiol 83:3169-3172. Brown LL, Markman MH, Wolfson LI, Dvorkin B, Warner C, Katzman R (1979) A direct role of dopamine in the rat subthalamic nucleus and an adjacent intrapeduncular area. Science 206:1416-1418. Carlson JD, Cleary DR, Cetas JS, Heinricher MM, Burchiel KJ (2010) Deep brain stimulation does not silence neurons in subthalamic nucleus in Parkinson's patients. Journal of neurophysiology 103:962-967. Carpenter MB, Carleton SC, Keller JT, Conte P (1981) Connections of the subthalamic nucleus in the monkey. Brain Res 224:1-29. Crossman AR (1987) Primate models of dyskinesia: the experimental approach to the study of basal ganglia-related involuntary movement disorders. Neuroscience 21:1-40. Deiber MP, Pollak P, Passingham R, Landais P, Gervason C, Cinotti L, Friston K, Frackowiak R, Mauguiere F, Benabid AL (1993) Thalamic stimulation and suppression of parkinsonian tremor. Evidence of a cerebellar deactivation using positron emission tomography. Brain 116 ( Pt 1):267-279. DeLong M, Wichmann T (2007) Circuits and circuit disorders of the basal ganglia. Archives of neurology 64:20. Delong MR, Georgopoulos AP, Crutcher MD, Mitchell SJ, Richardson RT, Alexander GE (1984) Functional organization of the basal ganglia: contributions of single-cell recording studies. Ciba Found Symp 107:64-82. Dewey RB, Jr., Jankovic J (1989) Hemiballism-hemichorea. Clinical and pharmacologic findings in 21 patients. Arch Neurol 46:862-867. Do MT, Bean BP (2003) Subthreshold sodium currents and pacemaking of subthalamic neurons: modulation by slow inactivation. Neuron 39:109-120. Do MT, Bean BP (2004) Sodium currents in subthalamic nucleus neurons from Nav1.6-null mice. J Neurophysiol 92:726-733. Dostrovsky JO, Lozano AM (2002) Mechanisms of deep brain stimulation. Mov Disord 17 Suppl 3:S63-68. Elble RJ (2000) Origins of tremor. Lancet 355:1113-1114. Feger J, Hammond C, Rouzaire-Dubois B (1979) Pharmacological properties of acetylcholine-induced excitation of subthalamic nucleus neurones. Br J Pharmacol 65:511-515. Feger J, Bevan M, Crossman AR (1994) The projections from the parafascicular thalamic nucleus to the subthalamic nucleus and the striatum arise from separate neuronal populations: a comparison with the corticostriatal and corticosubthalamic efferents in a retrograde fluorescent double-labelling study. Neuroscience 60:125-132. Flores G, Hernandez S, Rosales MG, Sierra A, Martines-Fong D, Flores-Hernandez J, Aceves J (1996) M3 muscarinic receptors mediate cholinergic excitation of the spontaneous activity of subthalamic neurons in the rat. Neurosci Lett 203:203-206. Francois C, Savy C, Jan C, Tande D, Hirsch EC, Yelnik J (2000) Dopaminergic innervation of the subthalamic nucleus in the normal state, in MPTP-treated monkeys, and in Parkinson's disease patients. J Comp Neurol 425:121-129. Garcia L, Audin J, D'Alessandro G, Bioulac B, Hammond C (2003) Dual effect of high-frequency stimulation on subthalamic neuron activity. J Neurosci 23:8743-8751. Georgopoulos AP, DeLong MR, Crutcher MD (1983) Relations between parameters of step-tracking movements and single cell discharge in the globus pallidus and subthalamic nucleus of the behaving monkey. J Neurosci 3:1586-1598. Guridi J, Herrero MT, Luquin R, Guillen J, Obeso JA (1994) Subthalamotomy improves MPTP-induced parkinsonism in monkeys. Stereotact Funct Neurosurg 62:98-102. Hardman CD, Henderson JM, Finkelstein DI, Horne MK, Paxinos G, Halliday GM (2002) Comparison of the basal ganglia in rats, marmosets, macaques, baboons, and humans: volume and neuronal number for the output, internal relay, and striatal modulating nuclei. J Comp Neurol 445:238-255. Hassani OK, Feger J (1999) Effects of intrasubthalamic injection of dopamine receptor agonists on subthalamic neurons in normal and 6-hydroxydopamine-lesioned rats: an electrophysiological and c-Fos study. Neuroscience 92:533-543. Hollerman J, Grace A (1992) Subthalamic nucleus cell firing in the 6-OHDA-treated rat: basal activity and response to haloperidol. Brain research 590:291-299. Hurtado JM, Gray CM, Tamas LB, Sigvardt KA (1999) Dynamics of tremor-related oscillations in the human globus pallidus: a single case study. Proc Natl Acad Sci U S A 96:1674-1679. Hutchison WD, Allan RJ, Opitz H, Levy R, Dostrovsky JO, Lang AE, Lozano AM (1998) Neurophysiological identification of the subthalamic nucleus in surgery for Parkinson's disease. Ann Neurol 44:622-628. Joel D, Weiner I (1997) The connections of the primate subthalamic nucleus: indirect pathways and the open-interconnected scheme of basal ganglia-thalamocortical circuitry. Brain Res Brain Res Rev 23:62-78. Krack P, Pollak P, Limousin P, Benazzouz A, Deuschl G, Benabid AL (1999) From off-period dystonia to peak-dose chorea. The clinical spectrum of varying subthalamic nucleus activity. Brain 122 ( Pt 6):1133-1146. Krack P, Batir A, Van Blercom N, Chabardes S, Fraix V, Ardouin C, Koudsie A, Limousin PD, Benazzouz A, LeBas JF, Benabid AL, Pollak P (2003) Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson's disease. N Engl J Med 349:1925-1934. Kreiss DS, Mastropietro CW, Rawji SS, Walters JR (1997) The response of subthalamic nucleus neurons to dopamine receptor stimulation in a rodent model of Parkinson's disease. J Neurosci 17:6807-6819. Kumar R, Lozano AM, Kim YJ, Hutchison WD, Sime E, Halket E, Lang AE (1998) Double-blind evaluation of subthalamic nucleus deep brain stimulation in advanced Parkinson's disease. Neurology 51:850-855. Kuo CC, Yang S (2001) Recovery from inactivation of t-type ca2+ channels in rat thalamic neurons. J Neurosci 21:1884-1892. Lavoie B, Smith Y, Parent A (1989) Dopaminergic innervation of the basal ganglia in the squirrel monkey as revealed by tyrosine hydroxylase immunohistochemistry. J Comp Neurol 289:36-52. Lee MS, Marsden CD (1994) Movement disorders following lesions of the thalamus or subthalamic region. Mov Disord 9:493-507. Lenz FA, Kwan HC, Martin RL, Tasker RR, Dostrovsky JO, Lenz YE (1994) Single unit analysis of the human ventral thalamic nuclear group. Tremor-related activity in functionally identified cells. Brain 117 ( Pt 3):531-543. Levy R, Dostrovsky JO, Lang AE, Sime E, Hutchison WD, Lozano AM (2001) Effects of apomorphine on subthalamic nucleus and globus pallidus internus neurons in patients with Parkinson's disease. J Neurophysiol 86:249-260. Limousin P, Krack P, Pollak P, Benazzouz A, Ardouin C, Hoffmann D, Benabid AL (1998) Electrical stimulation of the subthalamic nucleus in advanced Parkinson's disease. N Engl J Med 339:1105-1111. Limousin P, Pollak P, Benazzouz A, Hoffmann D, Le Bas JF, Broussolle E, Perret JE, Benabid AL (1995) Effect of parkinsonian signs and symptoms of bilateral subthalamic nucleus stimulation. Lancet 345:91-95. Lozano AM, Dostrovsky J, Chen R, Ashby P (2002) Deep brain stimulation for Parkinson's disease: disrupting the disruption. Lancet Neurol 1:225-231. Marchand R (1987) Histogenesis of the subthalamic nucleus. Neuroscience 21:183-195. McIntyre C, Savasta M, Kerkerian-Le Goff L, Vitek J (2004) Uncovering the mechanism (s) of action of deep brain stimulation: activation, inhibition, or both. Clinical Neurophysiology 115:1239-1248. Mehta A, Menalled L, Chesselet MF (2005) Behavioral responses to injections of muscimol into the subthalamic nucleus: temporal changes after nigrostriatal lesions. Neuroscience 131:769-778. Miller WC, DeLong MR (1988) Parkinsonian symptomatology. An anatomical and physiological analysis. Ann N Y Acad Sci 515:287-302. Mink J (1996) The basal ganglia: focused selection and inhibition of competing motor programs. Progress in Neurobiology 50:381-425. Mink JW (2003) The Basal Ganglia and involuntary movements: impaired inhibition of competing motor patterns. Arch Neurol 60:1365-1368. Mink JW, Thach WT (1993) Basal ganglia intrinsic circuits and their role in behavior. Curr Opin Neurobiol 3:950-957. Miocinovic S, Parent M, Butson CR, Hahn PJ, Russo GS, Vitek JL, McIntyre CC (2006) Computational analysis of subthalamic nucleus and lenticular fasciculus activation during therapeutic deep brain stimulation. J Neurophysiol 96:1569-1580. Nakanishi H, Kita H, Kitai ST (1987) Electrical membrane properties of rat subthalamic neurons in an in vitro slice preparation. Brain Res 437:35-44. Nambu A (2005) A new approach to understand the pathophysiology of Parkinson's disease. J Neurol 252 Suppl 4:IV1-IV4. Nambu A, Tokuno H, Takada M (2002a) Functional significance of the cortico-subthalamo-pallidal 'hyperdirect' pathway. Neurosci Res 43:111-117. Nambu A, Takada M, Inase M, Tokuno H (1996) Dual somatotopical representations in the primate subthalamic nucleus: evidence for ordered but reversed body-map transformations from the primary motor cortex and the supplementary motor area. Journal of Neuroscience 16:2671. Nambu A, Tokuno H, Inase M, Takada M (1997) Corticosubthalamic input zones from forelimb representations of the dorsal and ventral divisions of the premotor cortex in the macaque monkey: comparison with the input zones from the primary motor cortex and the supplementary motor area. Neurosci Lett 239:13-16. Nambu A, Kaneda K, Tokuno H, Takada M (2002b) Organization of corticostriatal motor inputs in monkey putamen. J Neurophysiol 88:1830-1842. Nambu A, Tokuno H, Hamada I, Kita H, Imanishi M, Akazawa T, Ikeuchi Y, Hasegawa N (2000) Excitatory cortical inputs to pallidal neurons via the subthalamic nucleus in the monkey. Journal of Neurophysiology 84:289-300. Ni Z, Bouali-Benazzouz R, Gao D, Benabid AL, Benazzouz A (2001a) Intrasubthalamic injection of 6-hydroxydopamine induces changes in the firing rate and pattern of subthalamic nucleus neurons in the rat. Synapse 40:145-153. Ni ZG, Bouali-Benazzouz R, Gao DM, Benabid AL, Benazzouz A (2001b) Time-course of changes in firing rates and firing patterns of subthalamic nucleus neuronal activity after 6-OHDA-induced dopamine depletion in rats. Brain Res 899:142-147. Parent A, Hazrati LN (1995a) Functional anatomy of the basal ganglia. II. The place of subthalamic nucleus and external pallidum in basal ganglia circuitry. Brain Res Brain Res Rev 20:128-154. Parent A, Hazrati LN (1995b) Functional anatomy of the basal ganglia. I. The cortico-basal ganglia-thalamo-cortical loop. Brain Res Brain Res Rev 20:91-127. Perez-Reyes E, Cribbs LL, Daud A, Lacerda AE, Barclay J, Williamson MP, Fox M, Rees M, Lee JH (1998) Molecular characterization of a neuronal low-voltage-activated T-type calcium channel. Nature 391:896-900. Reck C, Florin E, Wojtecki L, Krause H, Groiss S, Voges J, Maarouf M, Sturm V, Schnitzler A, Timmermann L (2009) Characterisation of tremor-associated local field potentials in the subthalamic nucleus in Parkinson's disease. Eur J Neurosci 29:599-612. Romansky KV, Usunoff KG (1985) The fine structure of the subthalamic nucleus in the cat. I. Neuronal perikarya. J Hirnforsch 26:259-273. Sadikot AF, Parent A, Francois C (1992) Efferent connections of the centromedian and parafascicular thalamic nuclei in the squirrel monkey: a PHA-L study of subcortical projections. J Comp Neurol 315:137-159. Sato F, Parent M, Levesque M, Parent A (2000) Axonal branching pattern of neurons of the subthalamic nucleus in primates. J Comp Neurol 424:142-152. Shen KZ, Johnson SW (2000) Presynaptic dopamine D2 and muscarine M3 receptors inhibit excitatory and inhibitory transmission to rat subthalamic neurones in vitro. J Physiol 525 Pt 2:331-341. Shen KZ, Johnson SW (2001) Presynaptic GABA(B) receptors inhibit synaptic inputs to rat subthalamic neurons. Neuroscience 108:431-436. Song WJ, Baba Y, Otsuka T, Murakami F (2000) Characterization of Ca(2+) channels in rat subthalamic nucleus neurons. J Neurophysiol 84:2630-2637. Svenningsson P, Le Moine C (2002) Dopamine D1/5 receptor stimulation induces c-fos expression in the subthalamic nucleus: possible involvement of local D5 receptors. Eur J Neurosci 15:133-142. Tai CH, Kuo CC (2006) [Electrophysiology of subthalamic nucleus in normal and Parkinson's disease]. Acta Neurol Taiwan 15:206-216. Tai CH, Boraud T, Bezard E, Bioulac B, Gross C, Benazzouz A (2003) Electrophysiological and metabolic evidence that high-frequency stimulation of the subthalamic nucleus bridles neuronal activity in the subthalamic nucleus and the substantia nigra reticulata. FASEB J 17:1820-1830. Takada M, Tokuno H, Hamada I, Inase M, Ito Y, Imanishi M, Hasegawa N, Akazawa T, Hatanaka N, Nambu A (2001) Organization of inputs from cingulate motor areas to basal ganglia in macaque monkey. Eur J Neurosci 14:1633-1650. Timmermann L, Gross J, Dirks M, Volkmann J, Freund HJ, Schnitzler A (2003) The cerebral oscillatory network of parkinsonian resting tremor. Brain 126:199-212. Tseng HM, Su PC, Liu HM, Liou HH, Yen RF (2007) Bilateral subthalamotomy for advanced Parkinson disease. Surg Neurol 68 Suppl 1:S43-50; discussion S50-41. Urbain N, Rentero N, Gervasoni D, Renaud B, Chouvet G (2002) The switch of subthalamic neurons from an irregular to a bursting pattern does not solely depend on their GABAergic inputs in the anesthetic-free rat. J Neurosci 22:8665-8675. Vila M, Perier C, Feger J, Yelnik J, Faucheux B, Ruberg M, Raisman-Vozari R, Agid Y, Hirsch EC (2000) Evolution of changes in neuronal activity in the subthalamic nucleus of rats with unilateral lesion of the substantia nigra assessed by metabolic and electrophysiological measurements. Eur J Neurosci 12:337-344. Volkmann J, Joliot M, Mogilner A, Ioannides AA, Lado F, Fazzini E, Ribary U, Llinas R (1996) Central motor loop oscillations in parkinsonian resting tremor revealed by magnetoencephalography. Neurology 46:1359-1370. White OB, Saint-Cyr JA, Tomlinson RD, Sharpe JA (1983) Ocular motor deficits in Parkinson's disease. II. Control of the saccadic and smooth pursuit systems. Brain 106 (Pt 3):571-587. Wichmann T, Bergman H, DeLong MR (1994) The primate subthalamic nucleus. I. Functional properties in intact animals. J Neurophysiol 72:494-506. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/64084 | - |
dc.description.abstract | 巴金森症是中老年人主要的神經退化性疾病,常引起病患嚴重的運動症狀及日常生活障礙。巴金森症的病態生理尚未完全明瞭,但藉助巴金森症的動物模型的發展,目前已進行有相當廣泛的研究。巴金森症運動症狀的可能病態生理機制,可以用大腦基底核迴路模型在多巴胺缺乏狀態下的變化來的解釋,而視丘下核在此一病態狀況下的迴路中扮演病態生理形成的重要角色。在巴金森症病人或巴金森症模型動物給予視丘下核高頻率電流刺激或甚至破壞此一結構,可以有效地改善實驗動物及病人的巴金森運動症狀,亦說明了視丘下核在巴金森病態生理的重要性。在實驗動物研究中,視丘下核神經元叢集式放電的明顯增加,是目前公認巴金森症的病態電氣生理特徵。但是,視丘下核叢集式放電及巴金森運動症狀之間的因果關係目前尚未建立,而造成此一叢集式放電的離子通道機制目前亦尚未明瞭。本研究藉由活體動物的胞外電生理記錄及動物運動行為測試等實驗,針對實驗動物視丘下核直接注射不同的離子通道阻斷劑或各種方式的電流刺激,並記錄給藥/刺激前、中及後的變化,詳細探討視丘下核叢集式放電行為的形成機制,及視丘下核叢集式放電對巴金森症大鼠運動障礙的影響。我們首先發現可以有效抑制T型鈣離子通道的Ni2+, Mibefradil, NNC55-396 及 Efonidipine能夠有效地降低活體動物視丘下核的叢集式放電數量,但主要抑制L型或其他型鈣離子通道的Cd2+或 Nifedipine則無法降低叢集式放電的現象。直接給予視丘下核上述的T型鈣離子通道抑制劑,可以有效地改善巴金森症大鼠的運動障礙;而Cd2+及 Nifedipine則對動物的行為沒有效果。至此,我們首先作出視丘下核叢集式放電與巴金森症大鼠運動礙症狀有直接關聯的結論,並且發現到視丘下核的神經元細胞膜的性質,尤其是T型鈣離子通道,在視丘下核叢集式放電的生成,以及巴金森運動症狀的出現扮演關鍵的角色。這些發現,更進一步促使我們去探討深腦刺激治療巴金森症的原理,是否與電流改變T型鈣離子通道的作用有關。接著我們將各種不同形態的電流刺激直接注入視丘下核,包括不同頻率,各種波寬或甚至相反極性的持續性電流,來研究電流刺激對正常及巴金森症大鼠的電生理和行為所產生的改變。我們發現給予視丘下核負極性的持續性電流可以有效地改善巴金森大鼠的運動障礙症狀,而進一步的電生理記錄發現,此電流亦能有效降低的視丘下核神經元叢集式放電的出現,其效果類似T型鈣離子通道抑制劑。相反地,給予視丘下核正極性的持續性電流可以引起正常大鼠出現類似巴金森運動障礙的症狀。更令我們感到興趣的是,注射相反極性的持續性電流,在電生理記錄時可以發現對視丘下核叢集式放電產生完全相反的作用。依照前面所述的原理,我們認為T型鈣離子通道的可利用率與巴金森症運動症狀的產生,有著極為密切的關係,我們因此考慮利用先前認為無效的低頻率深腦刺激(頻率<85Hz)來驗證。我們給予低頻率刺激時,將電刺激的波寬大幅延長,原先無效的低頻率電刺激在巴金森實驗動物身上也可以轉變為有效。我們並將此發現進一步應用在臨床上接受深腦刺激治療的病患上。我們蒐集原本裝置深腦刺激治療但卻沒有理想效果的三位病患,將其治療的波寬由傳統的60微秒增加至240微秒,並將刺激的頻率降低至先前認為無效的60Hz以增加病患的耐受度,結果三位病患皆獲得良好的巴金森運動症狀改善的效果。我們總結對於視丘下核的叢集式放電,與造成此一放電形態的T型鈣離子通道進行調控,可以為未來的巴金森症提供發展全新且更有效治療方式的契機。視丘下核叢集式放電的增加,與動物的巴金森症狀有直接的關聯,此一作用甚至與多巴胺是否正常存在無關。有效的深腦刺激治療巴金森症的機制,很可能與視丘下核神經元是否能夠適當地去極化、調控其離子通道特性、或改變其相關的放電形態有關。本計劃的發現,證明了視丘下核叢集式放電行為與巴金森運動症狀的高度關聯,也為視丘下核深腦刺激治療巴金森症的機制,提出了清楚的說明。 | zh_TW |
dc.description.abstract | Parkinson’s disease (PD) is a major neurodegenerative disease in the middle-aged and elderly population, causing severe motor symptoms and marked disability in these patients. The pathophysiology of PD is not yet clearly understood and has been studied extensively by animal models of PD. The cortico-basal ganglia loop model in a dopamine deficiency state has been used to explain the possible pathophysiological mechanism underlying these motor symptoms. According to this model, the subthalamic nucleus (STN) exerts great influences on the basal ganglia output nuclei and plays an important role during the PD pathophysiological state. Giving high frequency electrical stimulation to STN or even lesioning this structure, can effectively ameliorate contralateral parkinsonian motor symptoms in both experimental animals and human PD patients, and these evidences further illustrate the importance of STN in PD pathophysiology. In experimental animal studies, an increase of neuronal burst activities in the STN is a well-documented electrophysiological feature in PD. However, the causal relation between subthalamic burst discharges and PD symptoms remains to be established. The ionic basis underlying the pathological bursts is also obscure. In this project, we studied the in vivo single-units extracellular electrophysiology and open field behavior test, before, during and after direct administration of various channel blockers and different protocols of electrical current stimulation into STN, in normal rats and in the 6-hydroxydopamine (6-OHDA)-induced parkinsonian rat model. We first showed that Ni2+, mibefradil, NNC55-0396, and efonidipine which can evidently inhibit T-type Ca2+ currents, but not Cd2+ or nifedipine that preferentially inhibits L-type or the other Ca2+ currents, effectively diminish STN burst activities in single-units extracellular recordings in vivo. More interestingly, topical administration of T channel inhibitors also dramatically remedies the locomotor deficits in 6-OHDA-lesioned parkinsonian rats. Cd2+ and nifedipine show no such behavioral effects. We first concluded that STN burst discharges is directly correlated with locomotor deficit in 6-OHDA-lesioned parkinsonian rats. The knowledge that intrinsic membrane properties, especially T-type Ca2+ channels, play a key role in the genesis of burst discharges in STN and parkinsonian locomotor symptoms, promoted us to further explore whether DBS exerts its clinical benefits on PD with changes in T-currents or other conductances. We applied different stimulation protocols, including different frequencies, various pulse widths and even constant currents of opposite polarity, to STN in vivo and documented the electrophysiological and behavioral effects of the stimulation in normal and parkinsonian rodents. We found that delivery of negative constant current into STN dramatically ameliorated locomotor deficits in parkinsonian rats. It also decreased burst discharges effectively in STN neurons, similar to T channel inhibitors. In contrast, delivery of positive constant currents to STN induced PD-like locomotor deficits in normal rats. Interestingly, injection of constant currents of opposite polarity altered STN burst discharges in exactly opposite ways. According to the rationale that the availability of T-type Ca2+ currents is critically involved in the genesis of parkinsonian locomotor deficits, we showed that low-frequency (frequency <85 Hz) deep brain stimulation (DBS) which has been considered ineffective in PD can be readily turned into an effective treatment if only the depolarizing pulse is lengthened. The effect of correlatively adjusted DBS protocols was also explored clinically. The therapeutic effect of DBS was greatly improved in three PD patients simply by increasing the pulse width from 60 to 240 μs, even at a lower stimulation frequency of 60 Hz which was considered in non-effective stimulation range. We concluded that modulation of subthalamic T-type Ca2+ currents and consequently burst discharges may provide novel and promising strategies for the treatment of Parkinson’s disease. The increased tendency of STN burst discharges may by itself serve as a direct cause of parkinsonian locomotor deficits, even in the absence of deranged dopaminergic innervation. Effective DBS therapy in PD very likely relies on adequate depolarization, and consequent modification of the relevant ionic currents and discharge patterns, of STN neurons. The findings of this study well illustrate the role of subthalamic discharges in the pathophysiology of PD motor symptoms and further demonstrate the underlying mechanism of STN DBS in Parkinson’s disease. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T17:29:20Z (GMT). No. of bitstreams: 1 ntu-101-D93441005-1.pdf: 31800220 bytes, checksum: 544b6ae8db936bc1c6a90f4f111a4428 (MD5) Previous issue date: 2012 | en |
dc.description.tableofcontents | 口試委員會審定書……………………………………………………………… i
誌謝………………………………………………………………………………. ii 中文摘要………………………………………………………………………… iii 英文摘要…………………………………………………………………………. v 第一章 Introduction…………………………………………………………….. 1 1.1 The anatomy of the basal ganglia…………………................................. 4 1.2 The classic and dynamic models of the cortico-basal ganglia circuit….. 6 1.3 The cortico-basal ganglia circuit in parkinsonism and targeting subthalamic nucleus for the treatment of Parkinson’s disease……………………............ 10 1.4 Parkinson’s disease as a circuit disorder of brain…………………….... 13 1.5 The anatomy of the subthalamic nucleus…………………………........ 14 1.6 The effect of neurotransmitters in the subthalamic nucleus………….... 17 1.7 The electrophysiology of the subthalamic nucleus……………………. 19 1.8 Ablation of the subthalamic nucleus and its influence on movement…. 25 1.9 Electrical stimulation of the subthalamic nucleus…………………....... 26 1.10 The aim of this study………………………………………………..... 30 第二章 Materials and Methods ……………………………………………….. 31 1 Six-hydroxydopamine injection and animal model of parkinsonism….. 32 2.2 Tyrosine hydroxylase immunohistochemistry……………………......... 33 2.3 Implantation of the stimulation electrode and the microinjection cannula for chronic use……………………………………………….............................. 33 2.4 Microinjection of different pharmacological agents into STN during in vivo electrophysiology………………………………………………................... 34 2.5 Electrical stimulation of STN during in vivo electrophysiology……… 34 2.6 In vivo single-unit extracellular recording…………….......................... 34 2.7 Histological verification of the location of STN and the implanted cannula.......................................................................................................... 35 2.8 In vivo electrophysiological data analysis…………............................. 36 2.9 Open field locomoter activity test………………….............................. 36 2.10 Statistics………………………………………………....................... 37 第三章 Results………………………………………………........................... 38 3.1 Dopamine depletion in six-hydroxydopamine-lesioned parkinsonian rats and the location of implanting cannula/electrode in the STN are documented by immunohistochemistry and histological study………………………......... 39 3.2 Dopamine depletion causes increased in-vivo burst discharges of STN in parkinsonian rats…………........................................................................... 42 3.3 Open field locomotor activity test shows a reliable quantified data on rat locomotor behavior………………............................................................... 45 3.4 T-type Ca2+ channel blockers remedy locomotor deficits in parkinsonian rats..……........................................................……....................................... 49 3.5 Local administration of Ni2+ and mibefradil, but not nifedipine and Cd2+, decreases in-vivo burst activity of STN in parkinsonian rats…………....... 55 3.6 Tetrodotoxin and other channel blockers also modulate STN burst discharges………………............................................................................. 58 3.7 Thirty hertz stimulation with longer depolarizing pulse also remedies locomotor deficits in parkinsonian rats………………................................ 62 3.8 Constant negative current stimulation readily remedies locomotor deficits of parkinsonian rats……………….................................................................. 66 3.9 Constant positive current stimulation of STN causes PD-like locomotor deficits in normal rats……………….......................................................... 69 3.10 Increase of pulse width turns ineffective DBS therapy into effective in PD patients………………................................................................................ 72 第四章 Discussion……........................................................…....................... 75 4.1 The causal relation between increased STN burst discharges and the genesis of locomotor deficits in PD………………................................................. 76 4.2 The critical role of T-type Ca2+ channels in the genesis of STN burst discharges…………..................................................................................... 78 4.3 Possible origin of the differential effects between high- and low-frequency stimulation of STN in the treatment of PD………….................................. 79 4.4 Electrical stimulation of STN by itself could be either a causal or a remedying maneuver of parkinsonian locomotor deficits…………........... 81 4.5 Inactivation of T-type Ca2+ channel and/or Na+ channel may be the principal mechanism underlying DBS therapy against PD…………........................ 82 4.6 Physiological and clinical implications…………............................... 84 參考文獻…………………………………………………………………….. 90 附錄 發表文獻………………………………………………………........... 101 | |
dc.language.iso | en | |
dc.title | 視丘下核放電行為在巴金森症之病態生理角色 | zh_TW |
dc.title | The Pathophysiological Role of Subthalamic Discharges in Parkinson’s Disease | en |
dc.type | Thesis | |
dc.date.schoolyear | 100-2 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 蔡明正,劉天申,黃榮棋,曾勝弘,葉炳強 | |
dc.subject.keyword | 巴金森症,視丘下核,動物模型,電氣生理,行為測試,離子通道,電流刺激, | zh_TW |
dc.subject.keyword | Parkinson’s disease,Subthalamic nucleus,Animal model,Electrophysiology,Behavior test,Ion channel,Electrical stimulation, | en |
dc.relation.page | 100 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2012-08-16 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 生理學研究所 | zh_TW |
顯示於系所單位: | 生理學科所 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-101-1.pdf 目前未授權公開取用 | 31.05 MB | Adobe PDF |
系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。