科技部新聞稿

生醫聯手半導體精準治療帕金森氏症

-微型前瞻系統單晶片開發

日期：109年8月26日

發稿單位：生命科學研究發展司

聯絡人：李慧欣博士

電話：(02)2737-7461

E-mail：hhlee@nstc.gov.tw

全球人口結構加速邁入高齡化，如何完善老年生活是你我即將面對的問題，科技部配合「5+2產業創新方案」，自108年起推動「台灣腦科技發展及國際躍升計畫(108-109)」，透過跨領域結合臺灣在資通訊、機械控制、臨床醫學及人文社會等領域優質研發能量，提升腦科學研發及腦科技應用，帶動生醫領域、大數據、智慧/精準醫療、健康福祉等產業發展。

帕金森氏症(Parkinson's disease)是僅次於阿茲海默症的神經退化疾病，是老年人中最常見的神經退化疾病之一。帕金森氏病的病程很長，長期服用左多巴藥物易產生肢體不受控制的異動症，或突然出現藥效的開-關現象等副作用，嚴重影響病人的生活品質。中、晚期的帕金森氏症患者目前也可選擇「深腦刺激系統」，透過外科手術在腦部植入電極，藉由高頻率電刺激來治療帕金森氏患者的動作障礙以及改善生活品質，但目前自美國進口的深腦刺激系統只能採用無差別連續性的電刺激，具有過於耗電且容易產生副作用等缺點，因此在療效提升與副作用控制等各方面，仍有很大改善空間。會降低病患日常活動以及失去自主生活的能力，經常加劇病人及家屬在醫療及經濟上的負擔。

在科技部「台灣腦科技發展及國際躍升計畫(108-109)」的支持下，交通大學電子研究所柯明道教授，也是交通大學生醫電子轉譯研究中心(註一)主任，與林口長庚醫院動作障礙科陳瓊珠主治醫師共組跨領域研究團隊，採用台積電(TSMC)半導體製程研製出一款「微型前瞻系統單晶片(System-on-a-Chip)」，應用於開發最新的「智慧型可適性閉迴路深腦刺激系統(adaptive deep brain stimulation)」，可根據個別帕金森氏病患者腦中獨特生理訊號來驅動電刺激，透過回饋控制訊號機制，給予所需要的電刺激治療，達到帕金森氏症的高效率智慧型療法(圖一)。

該項新治療技術的成功關鍵在於長庚醫院研究團隊與英國牛津大學在過去數年內，經由分析帕金森氏症病人深腦訊號，發現與疾病相關的生理標記，只要透過這些特殊的生理標記指引之下，便可根據病人臨床症狀的不同來決定進行電刺激的最佳時機，增強療效、降低副作用，達到帕金森氏症的精準療法。此外，最近亦發現在深腦刺激手術過程當中所記錄到的生理訊號，可以預測該項手術的長期療效以及病人後續的情緒變化，這些結果有助於深腦刺激術的個人化、精準化，並可擴展到其他神經疾病的治療。

利用深腦訊號的生理標記作為回饋控制訊號是新一代深腦刺激術的發展趨勢，但目前國際間的研究仍是透過如桌上型電腦體積大小的裝置在測試，若要能讓病人長時間配戴可適性深腦刺激裝置，勢必要讓相關裝置大幅度地微型化。深腦刺激裝置微型化的實現，可藉由系統單晶片的技術來達成。柯教授團隊所開發的「微型前瞻系統單晶片」整合了類比前端放大器、類比數位轉換器、數位訊號處理器、可調式多通道電刺激器、以及無線傳輸及電源管理等多項電路功能，採用台積電(TSMC)半導體製程所實際製作之系統單晶片，將晶片體積縮減到比米粒還小，並大幅降低耗電量與提升運算效能。目前此系統單晶片(圖二)已製作完成，即將以此系統單晶片為核心組建「智慧型可適性閉迴路深腦刺激系統」，並進行迷你豬的動物實驗以驗證安全性以及功能性，在通過安規檢驗等相關認證後，預計將於今年底申請人體臨床試驗，在病患身上驗證此「智慧型可適性閉迴路深腦刺激系統」的功效。

計畫所開發適用於人體規格之「智慧型可適性閉迴路深腦刺激系統」，將臺灣先進的半導體積體電路技術與優異的醫療專業做完美的結合，充分善用臺灣的優勢，未來科技部也將透過過往奠定的深厚基礎，跨部會推動「臺灣精準健康戰略產業發展方案」，發展全球首創之前瞻技術，提供神經調控精準醫療一盞明燈，也為臺灣生醫電子產業的未來發展種下希望的種子。

註一：交通大學生醫電子轉譯研究中心以「高階植入式電子醫材」為研究主軸，並以「透過跨領域研究人才的共同努力，研發可供多領域共用的生醫電子技術平台，用以治療目前醫學難以醫治的神經損傷與疾病」為中心的使命與願景，匯集各專業領域的專家學者與工程團隊來共同研發創新性的電子醫材技術，借力於臺灣傲視全球的半導體產業技術，結合神經科學與專業醫師合作開發符合臨床應用的醫療電子產品，為臺灣生醫電子產業的未來發展做出貢獻。

註二：NSA-AFE：Neural Signal Acquisition Analog Front-End
      ADC：Analog-to-Digital Converter
      DSP：Digital Signal Processor
      OSC：Ring Oscillator
      WirelessTRX：Wireless Transmitter
      PMU：Power Management Unit

研究成果聯絡人

柯明道 特聘教授

國立交通大學電子研究所

生醫電子轉譯研究中心

神經調控醫療電子系統研究中心

聯絡電話(公)：03-5712121 ext.59450

電子郵件信箱：mdker@mail.nctu.edu.tw

Press Release

August 26, 2020

Biomedicine Combining with Semiconductor to Precisely Treat Parkinson’s Disease - The Development of Prospective Miniature System-on-a-Chip

    The demographic structure of global population is accelerating towards aging society. How to improve the quality of life of the elderly is an important problem that we are going to deal with it. Under the "5+2 Industrial Innovation Plan" policy, the Ministry of Science and Technology (MOST) has promoted the "Taiwan Brain Technology Development and International Rising Program" since 2019. Through cross-field integration of Taiwan’s high-quality R&D energy in the fields of information and communication technology, machine control, clinical medicine, and humanities and social sciences, the program enhances brain technologies and facilitates the development of Taiwan’s biomedical industry in the field of big data, smart health, precision medicine, health and well-being.

     Parkinson's disease is a common neurodegenerative disease among the elderly. The course of Parkinson's disease is very long. Long-term use of levodopa drugs is prone to cause dyskinesia, i.e. uncontrolled muscle movements, or motor fluctuation, i.e. sudden changes in movement control, which seriously affect the quality of life of the patients. Patients with advanced Parkinson's disease may choose the deep brain stimulation, which involves implanting electrodes in the brain through surgery, and using high-frequency electrical stimulation to treat Parkinson’s disease and alleviate drug-induced adverse effects, and improve the quality of life of Parkinson’s patients. However, the conventional deep brain stimulation delivers continuously electrical stimulation, which has disadvantages such as excessive power consumption and prone to cause stimulation-related side effects. Therefore, there is still much room for improvement in terms of efficacy and side effects control.

    With the support from "Taiwan Brain Technology Development and International Rising Program" of the MOST, Professor Ming-Dou Ker of the Institute of Electronics, National Chiao Tung University, and also director of the Biomedical Electronics Translational Research Center of National Chiao Tung University, and the attending physician Chiung-Chu Chen of the Department of Neurology, Linkou Chang Gung Memorial Hospital, formed a cross-disciplinary research team. They developed a "prospective miniature system-on-a-chip" using TSMC semiconductor process, which was applied to develop the latest "intelligent adaptive deep brain stimulator". Adaptive deep brain stimulator can deliver electrical stimulation based on the unique pathological signals in the brain of individual Parkinson's patients. Through the feedback control algorithm, it can deliver the required electrical stimulation on the basis of highly efficient and intelligent integrated circuit design to achieve the optimal therapy for Parkinson’s patients.

    The key of this new treatment technology lies in the fact that the research team at Linkou Chang Gung Memorial Hospital and the University of Oxford in the past few years have analyzed the deep brain signals of Parkinson’s patients and found pathological biomarkers related to the disease. Through the guidance of these unique pathological biomarkers, the best timing for electrical stimulation can be determined according to the different clinical symptoms of the patient, to enhance the efficacy, reduce side effects, and achieve precise treatment of Parkinson’s disease. In addition, it has recently been reported that the pathological signals recorded during the deep brain stimulation surgery can predict the long-term effects of the surgery and the subsequent emotional changes of the patients. These results contribute to the personalization and precision of deep brain stimulation.

     The use of pathological biomarker as feedback control signal is the trend of the next generation of deep brain stimulation. So far the international research is using bulky external device to carry out the tests. It is necessary for patients to wear miniature device for testing the adaptive deep brain stimulation chronically. The miniaturization of deep brain stimulator can be achieved by system-on-a-chip technology. The "prospective miniature system-on-a-chip" developed by Professor Ker's team integrates analog front-end amplifiers, analog-to-digital converters, digital signal processors, adjustable multi-channel electrical stimulators, wireless transmission and power management and other circuit functions. This system-on-a-chip is produced by the TSMC semiconductor process which reducing the size of the chip to be smaller than a rice grain, and greatly reduces power consumption and improves computing performance. At present, the production of system-on-a-chip has been completed (Figure 1). The system-on-a-chip will be used as the core to build a "intelligent adaptive deep brain stimulation system", and animal experiments using minipigs will be conducted to verify safety and functionality. After passing relevant certifications such as safety inspections, it is expected that the clinical trials will be applied at the end of this year to verify the efficacy of this new system on patients.

     The "intelligent adaptive deep brain stimulation system" developed by this project is applicable for specifications of human use. It perfectly combines Taiwan's advanced semiconductor integrated circuit technology with excellent medical expertise, and makes full use of Taiwan's advantages. The MOST will use the robust innovative energy to promote the "Taiwan Precision Health Strategy Development Plan" across the ministries, develop the world's first forward-looking technology, and provide a beacon of neurological precision medicine, which is also the future of Taiwan's biomedical electronics industry.

Note:

NSA-AFE: Neural Signal Acquisition Analog Front-End

ADC: Analog-to-Digital Converter

DSP: Digital Signal Processor

OSC: Ring Oscillator

WirelessTRX: Wireless Transmitter

PMU: Power Management Unit

Author Information:

Ming-Dou Ker, Distinguished Professor

    Professor Ming-Dou Ker, a professor in the Institute of Electronics, National Chiao-Tung University, is also the director of the Biomedical Electronics Translational Research Center (BETRC). The mission and vision of BETRC is to "treat intractable neurological disorders by conducting interdisciplinary research to develop multidisciplinary technology platform." This center can hopefully become a research platform for gathering experts and engineering teams in all disciplines to research and develop innovative technology for medical devices.

Media Contact

Prof. Ming-Dou Ker

Institute of Electronics, National Chiao-Tung University

Biomedical Electronics Translational Research Center (BETRC)

TEL: 03-5712121 ext.59450

Email: mdker@mail.nctu.edu.tw

Dr. Hui-Hsin Lee

Department of Life Sciences, Ministry of Science and Technology

TEL: 02-27377461

Email: hhlee@nstc.gov.tw