内容简介
本研究论文聚焦柔性高密度脑电极的集成制备与应用。高时空分辨率脑电信号对于高精度癫痫病灶诊断定位至关重要, 关键突破点在于发展高密度脑电极阵列。本研究提出一种柔性脑电极叠层结构设计方法, 使不同引线分布在不同空间位置, 克服了大量引线布置的挑战。引入回火工艺, 消除残余热应力引起的叠层结构开裂问题, 突破了柔性脑电极高密度集成制备的难题。基于此, 制备了一类柔性、超薄、高密度的皮层电图 (ECoG) 电极阵列。该柔性ECoG电极阵列具有800个电极, 电极密度为4444 mm−2, 电极最小间距15微米, 与单个神经元相当。该柔性高密度ECoG电极阵列可与大脑皮层共形贴附, 实现高时间分辨率和高空间分辨率脑电信号采集。此外, 基于该方法制备的柔性高密度ECoG电极阵列, 采集了高时空分辨率癫痫信号, 癫痫病灶定位精度从厘米级提高到亚毫米级。本研究为难治性癫痫病灶高精度定位和脑功能分析的临床应用奠定了基础。
引用本文（点击最下方阅读原文可下载PDF）
Liu Y, Wang Z, Jiao Y, et al., 2024. Flexible, high-density, laminated ECoG electrode array for high spatiotemporal resolution foci diagnostic localization of refractory epilepsy. Bio-des Manuf 7(4):388–398. https://doi.org/10.1007/s42242-024-00278-2
文章导读
图1 (a) 柔性高密度叠层ECoG电极制备示意图；(b) 柔性高密度层压ECoG电极实物图，最小电极间距为15 μm，总通道为800
图2 (a) 有限元方法模拟高密度柔性叠层ECoG电极阵列在不同弯曲半径下的应变；(b) 柔性高密度叠层ECoG电极的厚度(30 μm)；(c) 柔性高密度叠层ECoG电极在初始和弯曲状态的伏安曲线；(d) 柔性高密度叠层ECoG电极阻抗谱；(e) 生物模拟电信号与采集结果对比；(f) 信号频谱分析；(g) 不同ECoG电极之间的电极密度对比
图3 (a) 柔性高密度叠层ECoG电极采集兔子脑电示意图；(b) 兔子大脑皮层；(c) 植入兔子大脑皮层的柔性高密度叠层ECoG电极；(d)柔性高密度叠层ECoG电极空间位置分布图
图4 (a) 兔子癫痫波中的代表性尖峰波；(b) 尖峰波局部放大图；(c) 兔子脑电能量分布图；(d) 兔子脑电能量分布随时间变化情况
参考文献
上下滑动以阅览
1. Branco MP, Freudenburg ZV, Aarnoutse EJ et al (2017) Decoding hand gestures from primary somatosensory cortex using high-density ECoG. Neuroimage 147:130–142. https://doi.org/10.1016/j.neuroimage.2016.12.004
2. Choi H, Lee J, Park J et al (2018) Improved prediction of bimanual movements by a two-staged (effector-then-trajectory) decoder with epidural ECoG in nonhuman primates. J Neur Eng 15(1):016011. https://doi.org/10.1088/1741-2552/aa8a83
3. Ryvlin P, Cross JH, Rheims S (2014) Epilepsy surgery in children and adults. Lancet Neurol 13(11):1114–1126. https://doi.org/10.1016/S1474-4422(14)70156-5
4. Jette N, Reid AY, Wiebe S (2014) Surgical management of epilepsy. CMAJ 186(13):997–1004. https://doi.org/10.1503/cmaj.121291
5. Jiruska P, Alvarado-Rojas C, Schevon CA et al (2017) Update on the mechanisms and roles of high-frequency oscillations in seizures and epileptic disorders. Epilepsia 58(8):1330–1339. https://doi.org/10.1111/epi.13830
6. Schalk G, Leuthardt EC (2011) Brain-computer interfaces using electrocorticographic signals. IEEE Rev Biomed Eng 4:140–154. https://doi.org/10.1109/RBME.2011.2172408
7. Chestek CA, Gilja V, Blabe CH et al (2013) Hand posture classification using electrocorticography signals in the gamma band over human sensorimotor brain areas. J Neur Eng 10(2):026002. https://doi.org/10.1088/1741-2560/10/2/026002
8. Wang PT, King CE, McCrimmon CM et al (2016) Comparison of decoding resolution of standard and high-density electrocorticogram electrodes. J Neur Eng 13(2):026016. https://doi.org/10.1088/1741-2560/13/2/026016
9. Siero JCW, Hermes D, Hoogduin H et al (2014) BOLD matches neuronal activity at the mm scale: a combined 7T fMRI and ECoG study in human sensorimotor cortex. NeuroImage 101:177–184. https://doi.org/10.1016/j.neuroimage.2014.07.002
10. Kaiju T, Doi K, Yokota M et al (2017) High spatiotemporal resolution ECoG recording of somatosensory evoked potentials with flexible micro-electrode arrays. Front Neur Circ 11:00020. https://doi.org/10.3389/fncir.2017.00020
11. Thomschewski A, Hincapie AS, Frauscher B (2019) Localization of the epileptogenic zone using high frequency oscillations. Front Neurol 10:00094. https://doi.org/10.3389/fneur.2019.00094
12. Burnos S, Fedele T, Schmid O et al (2016) Detectability of the somatosensory evoked high frequency oscillation (HFO) co-recorded by scalp EEG and ECoG under propofol. Neuroimage Clin 10(C):318–325. https://doi.org/10.1016/j.nicl.2015.11.018
13. Annecchino LA, Schultz SR (2018) Progress in automating patch clamp cellular physiology. Brain Neurosci Adv 2:1–16 https://doi.org/10.1177/2398212818776561
14. Polikov VS, Tresco PA, Reichert WM (2005) Response of brain tissue to chronically implanted neural electrodes. J Neurosci Methods 148(1):1–18. https://doi.org/10.1016/j.jneumeth.2005.08.015
15. Kim DH, Lu NS, Ma R et al (2011) Epidermal electronics. Science 333(6044):838–843. https://doi.org/10.1126/science.1206157
16. Rogers JA, Someya T, Huang YG (2010) Materials and mechanics for stretchable electronics. Science 327(5973):1603–1607. https://doi.org/10.1126/science.1182383
17. Ma YJ, Zhang YC, Cai SS et al (2020) Flexible hybrid electronics for digital healthcare. Adv Mater 32(15):e1902062. https://doi.org/10.1002/adma.201902062
18. Liang ZW, Cheng JH, Zhao Q et al (2019) High-performance flexible tactile sensor enabling intelligent haptic perception for a soft prosthetic hand. Adv Mater Technol 4(8):1900317. https://doi.org/10.1002/admt.201900317
19. Cho Y, Park S, Lee J et al (2021) Emerging materials and technologies with applications in flexible Neur implants: a comprehensive review of current issues with neural devices. Adv Mater 33(47):e2005786. https://doi.org/10.1002/adma.202005786
20. Lang RJ, Tolman KA, Crampton EB et al (2018) A review of thickness-accommodation techniques in origami-inspired engineering. Appl Mech Rev 70(1):010805. https://doi.org/10.1115/1.4039314
21. Marsden AL, Esmaily-Moghadam M (2015) Multiscale modeling of cardiovascular flows for clinical decision support. Appl Mech Rev 67(3):030804. https://doi.org/10.1115/1.4029909
22. Yang SY, Sharma P (2023) A tutorial on the stability and bifurcation analysis of the electromechanical behaviour of soft materials. Appl Mech Rev 75(4):044801. https://doi.org/10.1115/1.4056303
23. Tian L, Zimmerman B, Akhtar A et al (2019) Large-area MRI-compatible epidermal electronic interfaces for prosthetic control and cognitive monitoring. Nat Biomed Eng 3(3):194–205. https://doi.org/10.1038/s41551-019-0347-x
24. Liu YF, Liu Q, Long JF et al (2020) Bioinspired color-changeable organogel tactile sensor with excellent overall performance. ACS Appl Mater Interfaces 12(44):49866–49875. https://doi.org/10.1021/acsami.0c12811
25. Chen YH, Lu SY, Zhang SS et al (2017) Skin-like biosensor system via electrochemical channels for noninvasive blood glucose monitoring. Sci Adv 3(12):e1701629. https://doi.org/10.1126/sciadv.1701629
26. Du QF, Liu LL, Tang RT et al (2021) High-performance flexible pressure sensor based on controllable hierarchical microstructures by laser scribing for wearable electronics. Adv Mater Technol 6(9):2100122. https://doi.org/10.1002/admt.202100122
27. Nguyen JK, Park DJ, Skousen JL et al (2014) Mechanically-compliant intracortical implants reduce the neuroinflammatory response. J Neur Eng 11(5):056014. https://doi.org/10.1088/1741-2560/11/5/056014
28. Subbaroyan J, Martin DC, Kipke DR (2005) A finite-element model of the mechanical effects of implantable microelectrodes in the cerebral cortex. J Neur Eng 2(4):103–113. https://doi.org/10.1088/1741-2560/2/4/006
29. Xu KD, Li SJ, Dong SR et al (2019) Bioresorbable electrode array for electrophysiological and pressure signal recording in the brain. Adv Healthc Mater 8(15):e1801649. https://doi.org/10.1002/adhm.201801649
30. Park AH, Lee SH, Lee CJ et al (2016) Optogenetic mapping of functional connectivity in freely moving mice via insertable wrapping electrode array beneath the skull. ACS Nano 10(2):2791–2802. https://doi.org/10.1021/acsnano.5b07889
31. Zhang YC, Zheng N, Cao Y et al (2019) Climbing-inspired twining electrodes using shape memory for peripheral nerve stimulation and recording. Sci Adv 5(4):eaaw1066. https://doi.org/10.1126/sciadv.aaw1066
32. Yang LT, Liu Q, Zhang ZL et al (2022) Materials for dry electrodes for the electroencephalography: advances, challenges, perspectives. Adv Mater Technol 7(3):00041. https://doi.org/10.1002/admt.202100612
33. Kellis S, Sorensen L, Darvas F et al (2016) Multi-scale analysis of neural activity in humans: implications for micro-scale electrocorticography. Clin Neurophysiol 127(1):591–601. https://doi.org/10.1016/j.clinph.2015.06.002
34. Viventi J, Kim DH, Vigeland L et al (2011) Flexible, foldable, actively multiplexed, high-density electrode array for mapping brain activity in vivo. Nat Neurosci 14(12):1599–1605. https://doi.org/10.1038/nn.2973
35. Khodagholy D, Gelinas JN, Thesen T et al (2015) NeuroGrid: recording action potentials from the surface of the brain. Nat Neurosci 18(2):310–315. https://doi.org/10.1038/nn.3905
36. Hotson G, McMullen DP, Fifer MS et al (2016) Individual finger control of a modular prosthetic limb using high-density electrocorticography in a human subject. J Neur Eng 13(2):026017. https://doi.org/10.1088/1741-2560/13/2/026017
37. Tchoe Y, Bourhis AM, Cleary DR et al (2022) Human brain mapping with multithousand-channel PtNRGrids resolves spatiotemporal dynamics. Sci Transl Med 14(628):eabj1441. https://doi.org/10.1126/scitranslmed.abj1441
38. Zijlmans M, Worrell GA, Dumpelmann M et al (2017) How to record high-frequency oscillations in epilepsy: a practical guideline. Epilepsia 58(8):1305–1315. https://doi.org/10.1111/epi.13814
39. Freeman WJ, Rogers LJ, Holmes MD et al (2000) Spatial spectral analysis of human electrocorticograms including the alpha and gamma bands. J Neurosci Meth 95(2):111–121. https://doi.org/10.1016/S0165-0270(99)00160-0
40. Muller L, Hamilton LS, Edwards E et al (2016) Spatial resolution dependence on spectral frequency in human speech cortex electrocorticography. J Neur Eng 13(5):056013. https://doi.org/10.1088/1741-2560/13/5/056013
41. Wodlinger B, Degenhart AD, Collinger JL et al (2011) The impact of electrode characteristics on electrocorticography. In: Proceedings of the 33rd Annual International Conference of the IEEE EMBS, p.3083–3086. https://doi.org/10.1109/IEMBS.2011.6090842
42. Cotter D, Mackay D, Landau S et al (2001) Reduced glial cell density and neuronal size in the anterior cingulate cortex in major depressive disorder. Arch Gen Psychiat 58(6):545–553. https://doi.org/10.1001/archpsyc.58.6.545
43. Roeske MJ, Konradi C, Heckers S (2021) Hippocampal volume and hippocampal neuron density, number and size in schizophrenia: a systematic review and meta-analysis of postmortem studies. Mol Psychiat 26(7):3524–3535. https://doi.org/10.1038/s41380-020-0853-y
44. Slutzky MW, Jordan LR, Krieg T et al (2010) Optimal spacing of surface electrode arrays for brain-machine interface applications. J Neur Eng 7(2):26004. https://doi.org/10.1088/1741-2560/7/2/026004
45. Ashoori E, Yin HY, Parsnejad S et al (2018) ECoG electrode array with embedded coupling capacitors for area efficient neural recording. In: Proceeding of IEEE Biomedical Circuits and Systems Conference, p.18328093. https://doi.org/10.1109/BIOCAS.2018.8584815
46. Harrison RR, Charles C (2003) A low-power low-noise CMOS for amplifier neural recording applications. IEEE J Solid-S Circ 38(6):958–965. https://doi.org/10.1109/JSSC.2003.811979
47. Yin HY, Ashoori E, Parsnejad S et al (2019) Microfabricated capacitive electrodes for high channel count ECoG recording. In: Proceeding of 9th International IEEE EMBS Conference on Neural Engineering, p.839–842. https://doi.org/10.1109/NER.2019.8717074
48. Wang C, Wei YC, Sung HK et al (2021) Wafer-scale fabrication and assembly method of multichannel microelectrode arrays for ECoG application. Electronics 10(3):316. https://doi.org/10.3390/electronics10030316
49. Wang X, Gkogkidis CA, Iljina O et al (2017) Mapping the fine structure of cortical activity with different micro-ECoG electrode array geometries. J Neur Eng 14(5):056004. https://doi.org/10.1088/1741-2552/aa785e
50. Fischl B, Dale AM (2000) Measuring the thickness of the human cerebral cortex from magnetic resonance images. Proc Natl Acad Sci USA 97(20):11050–11055. https://doi.org/10.1073/pnas.200033797
51. Guz N, Dokukin M, Kalaparthi V et al (2014) If cell mechanics can be described by elastic modulus: study of different models and probes used in indentation experiments. Biophys J 107(3):564–575. https://doi.org/10.1016/j.bpj.2014.06.033
52. Brückner BR, Janshoff A (2015) Elastic properties of epithelial cells probed by atomic force microscopy. BBA-Mol Cell Res 11:3075–3082.
关于本刊
Bio-Design and Manufacturing（中文名《生物设计与制造》），简称BDM，是浙江大学主办的专业英文双月刊，主编杨华勇院士、崔占峰院士，2018年新创，2019年被SCI-E等库检索，2023年起改为双月刊，年末升入《2023年中国科学院文献情报中心期刊分区表》医学一区，2024年公布的最新影响因子为8.1，位列JCR的Q1区，13/122。
初审迅速：初审快速退稿，不影响作者投其它期刊。
审稿速度快：过去两年平均录用时间约40天；平均退稿时间约10天。文章录用后及时在线SpringerLink。一般两周左右即被SCI-E检索。
收稿方向 ：先进制造（3D打印及生物处理工程等）、生物墨水与配方、组织与器官工程、医学与诊断装置、生物产品设计、仿生设计与制造等。
文章类型：Research Article, Review, Short Paper (包括Editorial, Perspective, Letter, Technical Note, Case Report, Lab Report, Negative Result等）。
期刊主页：
http://www.springer.com/journal/42242
http://www.jzus.zju.edu.cn/ （国内可下载全文）
在线投稿地址：
http://www.editorialmanager.com/bdmj/default.aspx
入群交流
围绕BDM刊物的投稿方向，本公众号建有“生物设计与制造”学术交流群，加小编微信号icefires212入群交流，或扫以下二维码
