미주신경자극 (VNS) 의역사 우울증과관계되는미주신경의해부학적특성 Table 1. The list of human studies in VNS 1988 First Human Implant Dr. Kiffin Penry 1992 First Randomized A

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1 KISEP Special Articles 우울증치료를위한좌측미주신경자극법 김형섭마음사랑병원 ABSTRACT Left Vagus Nerve Stimulation (VNS) for the Treatment of Depression Hyeong-Seob Kim, MD Maeum Sarang Hospital, Wanjoo, Korea Depressive disorder is one of the very serious mental diseases in terms of personal, social, economical losses. It is not clear for the pathogenesis of the depression, however, even though decreased 5-HT and NE may be the biological causing factors in the neuronal synapses. Moreover, there are many depressive patients who are treatment resistant or partial responders. Thus, we have been needed the other therapeutic methods for those cases. Repeated transcranial magnetic stimulation (rtms) & VNS are the newly introduced methods for the treatment of refractory or partial responders with depression, which nature of therapeutic effect is the stimulation of the CNS. VNS has been used to treat the refractory epilepsy patients. Despite of numerous empirical and preclinical data, although VNS may be effective for the treatment of depression, the parameters for the treatment of depression using the VNS device have not been confirmed yet. However, from the several reports clinical effectiveness were described about 40%, thus, it is interested that VNS will be able to use for the treatment of depression in a future. (Korean J Psychopharmacol 2003;14(2):84-89) KEY WORDS:CNS stimulation Refractory depression Vagus nerve stimulation. 서 - 교신저자 84 론

Kiffin Penry 1992 First Randomized Active Control Study 1994 European Community Approval 1996 5 completed

2 미주신경자극 (VNS) 의역사 우울증과관계되는미주신경의해부학적특성 Table 1. The list of human studies in VNS 1988 First Human Implant Dr. Kiffin Penry 1992 First Randomized Active Control Study 1994 European Community Approval completed controlled studies N USA FDA Commercial Approval ,500Implants ever worldwide 1999 Substantial mood improvements 2000 Detailed rationale for depression Figure 1. Application of VNS

3 Insular Cortx Thalamus Amygdala Hippocampus Hypothalamus Pons Parabrachial Nucleus Dorsal Raphe Medulla Medial Reticular Formation Nuclcus of the Solitary Tract Solitary Tract Nodose Ganglion Spinal Cord Arca Postrema DMN Nucleus Cunneatus Figure 2. Afferent Pathway to the Brain, Epilepsia, 31Sup.2S1-S7, VNS 의우울증치료기전 1) 전간환자의 VNS 시행경험 2) 신경생화학적변화및 PET 연구 3) 항경련제의항우울효과 2. 도구장착과치료 Parameters 및부작용 Korean J Psychopharmacol 2003;14(2):84-89

4 Table 2. Research parameters for VNS Range Nominal value Output current 0.0 to 3.50 ma in 0.25 ma steps 0.00 ma OFF Pulse width 130 to 1000 sec 500 sec Frequency 1 to 30 Hz 20 Hz ON time 7 to 90 sec 30 sec OFF time 0.2 to 60 minutes in 5-minute steps, 5 min 60 to 80 minutes in 30-minute steps Magnetcurrent to 3.50 ma in 0.25-mA steps 0.0 ma Magnet pulse width 130 to 100 sec 500sec Magnet on time 7 to 90 sec 30 sec Table 3. Adverse profiles of VNS Potential surgery related risks; 01. adverse reaction to anesthesia 02. incision pain 03. blood clot 04. infection 05. cyst formation 06. inflammation 07. facial numbness 08. localized surgery related pain 09. facial paralysis 10. nausea 11. fluid accumulation 12. paresthesia 13. hematoma 14. scarring 15. histotoxic reaction 16. skin irritation 17. hoarseness 18. tissue reaction 19. nerve damage possible Potential device & sitimualtion related risks % of previous patients reports 01. aspiration pneumonia hypesthesia cardiovascular effects increased coughing device migration laryngismus dyspepsia muscle twitching during stimulation dysphagia nausea & vomiting dyspnea pain ear pain paresthesia facial paresthesis or paralysis pharyngitis hemidiaphragm paralysis Tinnitus Hiccuping Voice alteration 66.3 Potential Adverse Effects possible but not reported to date Duodenal ulcer or gastric ulcer 87

5 Table 4. Improved rates of VNS in each studies Authors Year No. of subject Duration of study Improved rate Rush et al Wks 40% Marangell et al years 11/12 of acute responder, 16/18 of acute cases nonrespond Sackeim et al Wks 30.5% in HDRS, 34.0% in MDRS, 37.3% in CGI-I Sackeim et al Wks Cognitive improvement Ellen et al years 46% in 1 year, 54% in 2 years Martinez et al Mo 3145%, 1527%remission Mahas Wks 30.5%, partial 27%, full 15.3% Armitage Wks Improved sleep quality Marangell Wks 40% 3. 치료효과 4. 시술비용 88 맺음말 중심단어 참고문헌 1) Bailey P, Bremer F. A sensory cortical representation of the vagus nerve. J Neurophysiol 1938;(40): ) Dell P, Olson R. Projections secondaries mesencephaliques, diencephaliques et amygdaliennes des afferences viscerales vagales. C R Soc Biol 1951;145: ) Maclean PD. The tribune in evolution: role in paleocerebral functions. 1990; New York: Plenum press Korean J Psychopharmacol 2003;14(2):84-89

6 4) Zabara J. Peripheral control of hypersynchronous discharge in epilepsy. Electroencephalogr Clin Neurophysiol 1985;61s:162. 5) Foley JO, D.uBois F. Quantative studies of the vagus nerve in the cat. I. The ratio of sensory and motor studies. J Comp Neurol 1937;67: ) Penry JK, Dean JC. Prevention of intractable partial seizures by intermittent vagal stimulation in humans: Preliminary results (abstract). Epilepsy 1990;31(Sup.):S40-S43. 7) Rutecki P. Anatomical, physiological and theological basis for the antiepileptiv effect of vagus nerve stimulation. Epilepsia 1990; 31:S1-S6. 8) Van Bockstaele EJ, Peoples J, Valentino RJ. Anatomic basis for differential regulation of the rostrolateral peri-locus ceruleus region by limbic afferents. Biol Psychiatry 1999;46: ) Ketter TA, George MS, Kimbrell TA, Benson BA, Post RM. Functional brain imaging in mood and anxiety disorders. Curr Rev Mood Anxiety Disorder 1997;1: ) Ben-Menacham E, Manon-Espaillat R, Ristanovis R, Wilder BJ, Stefan H, Mirza W, et al. Vagus stimulation fo treatment of partial seizure: A control study of effect on seizure. Epilepsia 1994;35: ) Handforth A, DeGeorgio CM, Schachter SC, Uthman BM, Naritoku DK, Tecoma ES, et al. Vagus nerve stimulation therapy for partial onset seizures: A randomized active control trial. Neurology 1998;51: ) Harden CL, Pulver MC, Nikolov B, Halper JP, Labar DR. Effect of vagus nerve stimulation on mood in adult epilepsy patients (abstract). Neuroloy 1999;52(Sup. 2):A238-P ) Morris GL, Muller WM. Vagus nerve stimulation study group (E01-E05). Long term treatment with vagus nerve stimulation in patients with refractory epilepsy. Neurology 1999;53: ) Ben-Menacham E, Hamberger A, Hender T, Hammond EJ, Uthman BM, slater J, et al. Effects of vagus nerve stimulation on amino acids and other metabolites in the CSF of patients with partial seizure. Epilepsy Research. 1995;20: ) Krahl SE, Clark KB, Smith DC, Browning RA. Locus Cerulleus lesions supress the seizure attenuating effects of vagus nerve stimulation. Epilepsia 1998;39: ) Walker BR, Easton A, Gale K. Regulation of limbic motor seizures by GABA and glutamate transmission in nucleus tracus solitarius. Epilepsia 1999;40: ) Henry TR, Votaw JR, Pennell PB, Epstein CM, Bakay RAE, Faber TL, et al. Acute blood flow changes and efficacy of vagus nerve stimulation in partial epilepsy. Neurology 1999;52: ) Thomas RH, Roy AEB, John RV, Page BP, Charles ME, Tracy LF, et al. Brain blood flow alterations induced by therapeutic vagus nerve stimulation in partial Epilepsy: I. Acute effects at high and low levels of stimulation. Epilepsia 1998;39(9): ) Naritoku DK, Terry WJ, Helfert RH. Regional induction of Fos immunoreactivity in the brain by anticonvulsant stimulation of the vagus nerve. Epilepsy Res 1995;22: ) Ballenger JC, Post RM. Carbamzepine in manic depressive illness: A new treatment. Am J Psychiatry 1980;137: ) Swann AC, Bowden CL, Morris D, Calabrese JR, Petty F, Small J, et al. Depression during mania. Treatment response to lithium or divalproex. Arch Gen Psychiatry 1997;54: ) Fatemi SH, Rapport DJ, Calabrese JR, Thuras P. Lamotrigine in rapid cycling bipolar disorder. J Clin Psychiatry 1997;58: ) Sacheim HA. The anticonvulsant hypothesis of the mechanisms of action of ECT: Current status. J ECT 1999;15: ) Olfson M, Marcus S, Sackeim HA, Thompson J, Pincus HA. Use of ECT for the inpatient treatment of reccurent major depression. Am J Psychiatry 1998;155: ) Rush AJ, George MS, Sackeim HA, Marangell LB, Husain MM, Giller C, et all. Vagus Nerve Stimulation (VNS) for treatment resistant depression: A multiple study. Biol Psychiatry 2000;47; ) Ramsay RE, Uthman BM, Augustinesson LE, Upton ARM, Natritoku D, Willis J, et al. First interantional Vagus Nerve Stimulation Study Group. Epilepsia 1994;35(3): ) MarangellLauren B. Vagus nerve stimulation (VNS) for major depressive episodes: one year outcomes BIOLOGICAL Psychiatry 2002;51(4): ) SackeimHarold A. Vagus Nerve Stimulation (VNS(TM)) for Treatment-Resistant Depression-Efficacy, Side Effects, and Predictors of Outcome NEUROPSYCHOPHARMACOLOGY, 2001;25(5): ) Marangell, Lauren B. A Review of Vagus Nerve Stimulation for Treatment-Resistant Depression EPILEPSY AND BEHAVIOR 2001;3(2):S6. 89

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee University College of Medicine & Hospital E mail : ycell2@yahoo.co.kr Abstract