癲癇是一種最常見的神經系統失調疾病之一，全球約有0.6-0.8%的人患有癲癇，其中三分之二的病人可以由藥物治療來有效的控制癲癇，而剩餘的8-10%的病人可以利用手術治療，其中25%的癲癇患者不能經由任何方式成功治療。癲癇是由大腦的不正常放電所引起，因此在臨床評估、癲癇發作偵測、及治療癲癇上，腦電圖已是極為重要的工具。因此，癲癇腦部刺激閉迴控制是近年被提出的創新與有效的替代方案。目前此類閉迴路癲癇控制系統有兩家公司NeuroPace的RNS與Medtronic的the Intercept™ Epilepsy Control System在美國FDA臨床實驗，此外尚無類似系統的實驗報告被發表。
在這篇論文中，我們成功以現有電路與系統晶片技術，結合腦訊號及時運算，開發一套無線可攜式即時癲癇偵測與抑制系統，具有無線可攜，體積重量小與即時判斷、刺激回授的特點與功能。對癲癇偵測正確率在清醒-睡眠狀態可高達92-99%、誤判率可低於2.5%，在癲癇發作0.6秒內完成癲癇偵測並啟動電刺激。無線傳輸功能更提高使用者在臨床檢驗時的行動自由度，不被麻煩的線路羈絆，未來可延伸為各種不同生醫裝置的開發平台 。目前，我們已有著手運用此套系統來實作一套回饋誘導藥物釋放系統。

Epilepsy is one of the most common neurological disorders with a prevalence of 0.6–0.8% of the world’s population. Two-thirds of the patients achieve sufficient seizure control from anticonvulsive medication, and another 8–10% could benefit from respective surgery. For the remaining 25% of patients, no sufficient treatment is currently available. Epilepsy is caused by abnormal discharges in the brain, thus electroencephalogram (EEG) has been an especially valuable clinical tool for the evaluation, seizure detection, and treatment of epilepsy. Brain stimulation with closed-loop seizure control has recently been proposed as an innovative and effective alternative. At present, two closed-loop epilepsy control system developed by NeuroPace called RNS and Medtronic called the Intercept™ Epilepsy Control System are in U.S. FDA clinical trials.
In this study, we have successfully integrated electrical circuit and system-on-a-chip (SOC) technology, brain signal and real-time computing to develop a wireless and portable real-time closed-loop epilepsy detection and control system. It has several aspects of advantages. The seizure detection rate is about 92-99% during wake-sleep states, false detection rate is less than 2.5%. The seizure detection and electrical stimulation latency is less than 0.6 s after seizure onset. A wireless communication improves and can mobility of users, and also provided flexibility for subjects freeing from the hassle of wires. In the future, our system can also be extended for a variety of biomedical device development applications. Currently, we had applying this system to implement response-induced features of drug delivery system on epilepsy.

Adeli, H., Ghosg-Dastidar, S., and Dadmehr, N., “A wavelet-chaos methodology for analysis of EEGs and EEG subbands to detect seizure and epilepsy,” IEEE Transactions on Biomedical Engineering, vol. 54, no. 2, 2007.
Brudzynski, S.M., Cruickshank, J.W., and McLachlan, R.S., “Cholinergic mechanisms in generalized seizures: important of the zona incerta,” Can. J. Neurol. Sci., vol. 22, 116-120, 1995.
Benazzouz, A., Tai, C.H., Meissner, W., Bioulac, B., Bezard, E., and Gross, C., “High-frequency stimulation of both zona incerta and subthalamic nucleus induces a similar normalization of basal ganglia metabolic activity in experimental parkinsonism,” FASEB J., vol. 18, 528-530 , 2004.
Blumenfeld, H., “Consciousness and epilepsy: why are the patients with absence seizures absent?” Progress in brain research, vol.150, pp. 271-86, 2005.
Bosnyakova, D., Gabova, A., Zharikova, A., Gnezditski, V., Kuznetsova, G., and van Luijtelaar, F., “Some peculiarities of time-frequency dynamics of spike-wave discharges in humans and rats,” Clinical Neurophysiology, vol. 118, pp. 1736-1743, 2007.
Crunelli, V. and Leresche, N., “Childhood absence epilepsy: genes, channels, neurons and networks,” Nature Reviews Neuroscience, vol. 3, no.3, pp. 71-82, 2002.
Coenen AML and van Luijtelaar ELJM, “Genetic animal models for absence epilepsy: a review of the WAG/Rij strain of rats,” Behavior genetics, vol. 33, no. 6, pp. 35-53, 2003.
Drinkenburg, W., van Luijtelaar, E., van Schaik, W. J. and Coenen, A., “Aberrant transients in the EEG of epileptic rats: a spectral analytical approach,” Physiology & behavior, vol. 54, no. 7, pp. 79–83, 1993.
Deransart, C., Marescaux, C., and Depaulis, A., ”Involvement of nigra glutamatergic inputs in the control of seizures in a genetic model of absence epilepsy in the rat,” Neuroscience, vol. 71, 721-728, 1996.
Depaulis, A. and van Luijtelaar, G., Genetic model of absence epilepsy in rat. In: Pitkanen, A., Schwartzkroin, P., Moshe, S., editors. Models of seizures and epilepsy. San Diego: Elsevier, vol.3, pp. 33–43, 2006
Engel, J., Seizure and Epilepsy. Philadelphia, PA: Davis, 1989.
Fanselow, E. E., Reid, A. P., and Nicolelis, M. A. L., “Reduction of pentylenetetrazole-induced seizure activity in awake rats by seizure-triggered trigeminal nerve stimulation,” Journal of Neuroscience, vol. 20, pp. 8160-8168, 2000.
Feddersen, B., Vercueil, L., Noachtar, S., David, O., Depaulis, A., and Deransart, C., “Controlling seizures is not controlling epilepsy: A parametric study of deep brain stimulation for epilepsy,“ Neurobiology of Disease, vol. 27, pp. 292-300, 2007.
Golub, G., “Numerical methods for solving linear least squares problems,” Numerische Mathematik, vol. 7, pp. 206-216, 1965.
Gloor, P., Quesney, L.F. and Zumstein, H., “Pathophysiology of generalized penicillin epilepsy in the cats: the role of cortical and subcortical structures. II. Topical application of penicillin to the cerebral cortex and subcortical structures,” Electroencephalography and clinical neurophysiology, vol.43, pp. 79-94, 1977.
Gurbanova, A.A., Aker, R., Berkman, K., Onat, F.Y., van Rijn, C.M., and van Luijtelaar, G., "Effect of systemic and intracortical administration of phenytoin in two genetic models of absence epilepsy," Br. J. Pharmacol., vol. 148, 1076-1082, 2006.
Ghosh-Dastidar, S., Adeli, H., and Dadmehr, N., “Mixed-band wavelet-chaos-neural network methodology for epilepsy and epileptic seizure detection,” IEEE Transactions on Biomedical Engineering, vol. 54, pp. 1545-1551, 2007.
Ghosh-Dastidar, S., Adeli, H., and Dadmehr, N., “Principal component analysis-enhanced cosine radial basis function neural network for robust epilepsy and seizure detection,” IEEE Transactions on Biomedical Engineering, vol. 55, no. 2, 2008.
Guehl, D., Vital, A., Cuny, E., Spampinato, U., Rougier, A., Bioulac, B., and Burbaud, “P. Postmortem proof of effectiveness of zona incerta stimulation in Parkinson disease,” Neurology, vol. 70, 1489-1490, 2008.
Hamani, C., Sakabe, S., Bortolotto, Z.A., Cavalheiro, E.A., and Mello, L.E.A.M., "Inhibitory role of the zona incerta in the pilocarpine model of epilepsy," Epilepsy Res., vol. 49, 73-80, 2002.
Hese, P. V., Martens, J. P., Boon, P., Dedeurwaerdere, S., Lemahie, I., and Van de Walle, R., “Detection of spike and wave discharges in the cortical EEG of genetic absence epilepsy rats from Strasbourg,” Physics in Medicine and Biology, vol. 48, pp. 1685-1700, 2003.
Hese, P. V., Martens, J. P., Waterschoot, L., Boon, P., Lemahieu, I., “Automatic detection of spike and wave discharges in the EEG of genetic absence epilepsy rats from Strasbourg,” IEEE Trans. on Biomedical Engineering, vol. 56, no. 3, pp. 706-717, 2009.
Huang, W. C., Hu, S. H., Liu, K. H., Chen, S. Y.,Liu, D. M., “A flexible drug delivery chip for the magnetically-controlled release of anti-epileptic drugs,” J. Control. Release, 139(3):221-8, 2009.
Iasemidis, L. D., “Epileptic seizure prediction and control,” IEEE Transactions on Biomedical Engineering, vol. 50, no. 5, pp. 549-558, 2003.
Kossoff, E. H., Ritzl, E. K., Politsky, J. M., Murro, A. M., Smith, J. R., Duckrow, R. B., Spencer, D. D., and Bergey, G. K., “Effect of an external responsive neurostimulator on seizures and electrographic discharges during subdural electrode monitoring,” Epilepsia, vol. 45, pp. 1560-1567, 2004.
Kannathal, N., Choo, M. L., Acharya, R. U., and Sadasivan, P. K., “Entropies for detection of epilepsy in EEG,” Computer Method and Programs in Biomedicine, vol. 80, pp. 187-194, 2005.
Leppik, I.E., “Contemporary diagnosis and management of the patient with epilepsy,” Handbooks in health care, Newton, Pennsylvania, USA, fifth edition, 2000.
Litt, B. and Echauz, J., “Prediction of epileptic seizures,” Lancet Neurology, vol. 1, no. 1, pp. 22–30, 2002.
Litt, B., “Evaluating devices for treating epilepsy,” Epilepsia, vol. 44(Suppl. 7), pp. 30-37, 2003.
Lehnertz, K., Mormann, F., Kreuz, T., Andrzejak, R. G., Rieke, C., David, P., and Elger, C. E., “ Seizure prediction by nonlinear EEG analysis,” IEEE Engineering in Medicine and Biology Magazine, vol. 22, pp. 57-63, 2003.
Liao, Y. F., “Role of zona incerta in absence seizure and facial tremor of the rat with spontaneous spike-wave discharge,” Tzu-Chi University, Graduate Institute of Medical Sciences, Master thesis, 2005.
Liu, T. Y., Chen, S. Y., Lin, Y. L., and Liu, D. M., "Synthesis and Characterization of Amphiphatic Carboxymethyl-hexanoyl Chitosan Hydrogel: Water-Retention Ability and Drug Encapsulation," American Chemical Society, 22 (23), pp 9740–9745, 2006.

Li, X., Ouyang, G., and Richards, D. A., “Predictability analysis of absence seizures with permutation entropy,” Epilepsy Research, vol. 77, pp. 70-74, 2007.
Liang, S. F., Chang, W. L., Liao, Y. C., Chen, Y. J., Wang, H. C., Shaw, F. Z., “On-line real-time seizure detection in rats with spontaneous absence or pentylenetetrazol-induced epilepsy,” IEEE Transactions on Biomedical Engineering (2010) in revision.
Marescaux, C., Vergnes, M. and Depaulis, A., “Genetic absence epilepsy in rats from Strasburg,” Journal of neural transmission, vol. 35, pp. 37-69, 1992.
Meeren, H.K.M., Pijn, J.P.M., van Luijtelaar, E.L.J.M., Coenen, A.M.L., and Lopes da Silva, F.H.,"Cortical focus drives widespread corticothalamic networks during spontaneous absence seizures in rats," Journal of Neuroscience, vol. 22, 1480-1495, 2002.
Meeren, H., van Luijtelaar, G., Lopes da Silva, F.,and Coenen, A., "Evolving concepts on the pathophysiology of absence seizures. The cortical focus theory," Arch. Neurol., vol. 62, 371-376, 2005.
Mormann, F., Andrzejak, R. G., Elger, C. E. and Lenhnertz, K.,“Seizure prediction: the long and winding road,” Brain, vol. 130, no. 2, pp. 313–333, 2006.
Niedermayer, E., “Primary (idiopathic) generalized epilepsy and underlying mechanisms,” Clinical EEG electroencephalography, vol.27, pp. 1-21, 1996.
Niedermeyer, E., “Epileptic seizure disorders.” In: Electroencephalography. Basic principles, clinical applications, and related fields, edited by E. Niedermeyer and F. H. Lopes da Silva. Hong Kong: Williams & Wilkins, pp. 476-585, 1999.
Nicolelis, M. A. L., “Actions from thoughts,” Nature, vol. 409, pp. 403-407, 2001.
Osorio, I., Frei, M. G., Manly, B. F. J., Sunderam, S., Bhavaraju, N. C., and Wilkinson, S. B., “An introduction to contingent (closed-loop) brain electrical stimulation for seizure blockage, to ultra-short-term clinical trials, and to multidimensional statistical analysis of therapeutic efficacy,” J. Clin. Neurophysiology, vol. 18, pp. 533–44, 2001.
Osorio, I., Frei, M. G., Giftakis, J., Peters, T., Ingram, J., Turnbull, M., Herzog, M., Rise, M. T., Schaffner, S., Wennberg, R. A., Walczak, T. S., Risinger, M.W. and Ajmone-Marsan, C., “Performance reassessment of a real-time seizure-detection algorithm on long ECoG series,” Epilepsia, vol. 43, no. 12, pp. 1522-1535, 2002.

Osorio, I., Frei, M. G., Sunderam, S., Giftakis, J., Bhavaraju, N. C., Schaffner, S. F., and Wilkinson S. B., “Automated seizure abatement in humans using electrical stimulation,” Annals of Neurology, vol. 57, pp. 258-268, 2005.
Ocak, H., “Automatic detection of epileptic seizures in EEG using discrete wavelet transform and approximate entropy,” Expert System with Applications, vol. 36, pp. 2027-2096, 2009.
Pincus, S. M., “Approximate entropy as a measure of system complexity,” Proceedings of the National Academy of Science of the United State of America, vol. 88, pp. 2297-2301, 1991.
Paul, J. S., Patel, C. B., Al-Nashash, H., Zhang, N., Ziai, W. C., Mirski, M. A., Sherman, D. L., “Prediction of PTZ-induced seizures using wavelet-based residual entropy of cortical and subcortical field potentials,” IEEE Trans. on Biomedical Engineering, vol. 50, no. 5, pp. 640-648, 2003.
Politsky, J. M., Estellar, R., Murro, A. M., Smith, J. R., Ray, P., Park, Y. D., and Morrell, M. J., “Effects of electrical stimulation paradigm on seizure frequency in medically intractable partial seizure patients with a cranially implanted responsive cortical neurostimulator,” Proc. Annual Meeting of American Epilepsy Society (AES) (2005), 2005.
Plaha, P., Ben-Shlomo, Y., Patel, N.K., and Gill, S.S., “Stimulation of the caudal zona incerta is superior to stimulation of the subthalamic nucleus in improving contralateral parkinsonism,” Brain 129, 1732-1747, 2006.
Racin, R. J., “Modification of seizure activity by electrical stimulation, II: motor seizure,” Electroencephalography and Clinical Neurophysiology, vol. 32, pp. 281-294, 1972.
Rosso, O. A., Blanco, S., Yordanova, J., Kolev, V., Figliola, A., Schürmann, M., and Basar, E., “Wavelet entropy: a new tool for analysis of short duration brain electrical signals,” Journal of Neuroscience Methods, vol. 105, pp. 65-75, 2001.
Rosso, O. A., “Entropy changes in brain function,” International Journal of Psychophysiology, vol. 64, pp. 75-80, 2007.
Raghunathan, S., Gupta, S. K., Ward, M. P., Worth, R. M., Roy, K., Irazoqui, P. P., “The design and hardware implementation of a low-power real-time seizure detection algorithm,” Journal of Neural Engineering, vol. 6, no. 5, article number 056005, 2009.
Snead III, O. C., Depaulis, A., Vergnes, M., Marescaux, C., “Absence epilepsy: advances in experimental animal models,” Advances in Neurology, vol. 79, pp. 253-278, 1999.
Shaw, F. Z., “Is spontaneous high-voltage rhythmic spike discharge in Long Evans rats an absence-like seizure activity?” Journal of Neurophysiology, vol. 91, pp. 63-77, 2004.
Shaw, F. Z., Liao, Y. F., “Relation between activities of the cortex and vibrissae muscle during high-voltage rhythmic spike discharges in rats,” J Neurophysiol 93: 2435-2448, 2005.
Srinivasan, V., Eswaran, C., and Sriraam, N., “Artificial neural network based epileptic detection using time-domain and frequency-domain features,” Journal of Medical Systems, vol. 29, no. 6, pp. 647-660, December, 2005.
Shaw, F. Z., Lee, S. Y., and Chiu, T. H., “Modulation of somatosensory evoked potentials during wake-sleep states and spike-wave discharges in the rat,” Sleep, vol, 29, pp. 285-293, 2006.
Shaw, F. Z., “7-12 Hz high-voltage rhythmic spike discharges in rats evaluated by antiepileptic drugs and flicker stimulation,” Journal of Neurophysiology, vol. 97, 238-247, 2007.
Schuyler, R., White, A., Staley, K., and Cios, K. J., “Epileptic seizure detection,” IEEE Engineering in Medicine and Biology Magazine, vol. 26, pp. 74-81, 2007.
Srinivasan, V., Eswaran, C., and Sriraam, N., “Approximate entropy-based epileptic EEG detection using artificial neural networks,” IEEE Transactions on Information Technology in Biomedicine, vol. 11, pp. 288-295, 2007.
Shaw, F. Z. and Liao, Y. F., “Incertal control of high-voltage cortical oscillation and whisker tremor in rats with spontaneous absence epileptic discharges,” Forum of European Neuroscience Society, Geneva, Switzerland, 2008.
Stacey, W. C. and Litt, B., “Technology insight: neuroengineering and epilepsy – designing devices for seizure control,” Nature Clinical Practice Neurology, vol. 4, pp. 190-201, 2008.
Sun, F. T., Morell, M. J. and Wharen, R. E., “Responsive cortical stimulation for the treatment of epilepsy,” Neurotherapeutics, vol. 5, pp. 68-74, 2008.
Theodore, W. H. and Fisher, R. S., “Brain stimulation for epilepsy,” The Lancet Neurology, vol. 3, pp. 111-118, 2004.
Talathi, S. S., Hwang, D. U., Spano, M. L., Simonotto, J., Furman, M. D., Myers, S. M., Winters, J. T., Ditto, W. L., and Carney, P. R., “Non-parametric early seizure detection in an animal model of temporal lobe epilepsy,” Journal of Neural Engineering, vol. 5, no. 1, pp. 85-98, 2008.
Texas Instruments, “A true system-on-chip solution for 2.4 GHz IEEE 802.15.4/ZigBee,” [Online] Available: http://www.ti.com/lit/gpn/cc2430, 2009.
Texas Instruments, “CC2430 software examples user’s guide,” [Online] Available: http://focus.ti.com/lit/ug/swru178b/swru178b.pdf, 2009.
Vergnes, M., Marescaux, C., Micheletti, G., Reis, J., Depaulis, A. and Rumbach, L., “Spontaneous paroxysmal electroclinical pattern in rat: a model　of generalized non-convulsive epilepsy,” Neuroscience, vol. 33, pp. 97-101, 1982.
van Luijtelaar ELJM, and Coenen AML. “Two types of electrocortical paroxysms in an inbred strain of rats,” Neuroscience letters, vol. 70, no. 39 pp. 3-7, 1986.
Voges, J., Volkmann, J., Allert, N., Lehrke, R., Koulousakis, A., Freund, H. J., and Sturm, V., “Bilateral high-frequency stimulation in the subthalamic nucleus for the treatment of Parkinson disease: correlation of therapeutic effect with anaton mical electrode position,” J. Neurosurg. 96, 269-279 ,2002.
Whitchurch, A. K., Ashok, B. H., Kumaar, R. V., Saurkesi, K., and Varadan, V. K., “Wireless system for long-term EEG monitoring of absence epilepsy,” Proceeding of SPIE, vol. 4937, pp. 343-349, 2002.
White, A. M., Williams, P. A., Ferraro, D. J., Clark, S., Kadam, S. D., Dudek, F. E. and Staley, K. J., “Efficient unsupervised algorithms for the detection of seizures in continuous EEG recordings from rats after brain injury,” Journal of Neuroscience Methods, vol. 152, pp. 255-266, 2006.
Wilson, S. B., “Algorithm architectures for patient dependent seizure detection,” Clinical Neurophysiology, vol. 117, pp. 1204-1215, 2006.
Young, C. P., Liang, S. F., Chang, D. W., Liao, Y. C., Shaw, F. Z., and Hsieh, C. H., “A portable wireless online closed-loop seizure controller in freely moving rats,” IEEE Trans. on Instrumentation & Measurement, in press.