DOI 10.1515/bmt-2012-0094 Biomed Tech 2014; 59(4): 269–271
Editorial Thomas Stieglitz, Herc Neves and Patrick Ruther
Neural probes – microsystems to interface with the brain The human brain has always been the focus of research in the quest for happiness and wisdom. The cutting-edge research in this field and its importance for science as well as for the general public resulted, on July 17, 1990, in Presidential Proclamation 6158 of President George H.W. Bush, who designated the 1990s as the “Decade of the Brain” [12] and launched a dedicated brain research program in the United States. Questions of how the brain works, how nerve cells connect and communicate properly to achieve complex movements and astonishing cognitive and artistic accomplishments, and how small misconnections in circuitry and biochemistry result in vast behavioral changes and fatal neurological diseases are among the many aspects that have been addressed in the last decades. The improved understanding of the function of the brain and the pathophysiology of diseases enables the development of novel therapies and rehabilitation approaches. Some of these neuro-electrical approaches go beyond pharmaceutical possibilities and open opportunities for diseases that have been fatal, thus far. Surprisingly, Europe was about a decade late when leading German neuroscientists re-announced the Decade of the Brain in 2000 [4]. This is even more surprising when we consider that many clinical improvements in neurology and neurosurgery that were introduced after World War II have been driven by groups from the old world. Particularly, Europe in general, and especially Germany, strongly contributed over the centuries to the stable electrical recording of nerve signals, development of electrical diagnosis methods, and major discoveries on how the brain works. Volta and Galvani discovered the electrical nature of nerve and muscle signals in 1791 [11]. Berger developed the electroencephalogram as a diagnostic method for the brain in 1929 [8]. The most stable recordings from freely behaving animals were obtained from European groups with wire electrodes [7], and the contribution of mirror neurons in learning about emotions and empathy was discovered in Italy [14]. Nonetheless, the development of implantable technical systems to interface with the peripheral and central nervous systems was mainly driven by US groups. Precision
mechanics approaches were used first, sometimes derived from the cardiac pacemaker industry, to develop novel therapeutic approaches that eventually led to neuromodulation techniques used to alleviate chronic pain and suppress tremor, rigidity (akinesia), and overshooting movements (dyskinesia) in Parkinson’s (Lou Gehrig’s) disease [17]. The invention of the transistor and integrated electronic circuits promoted the microelectronic revolution with its offspring, i.e., microelectromechanical systems, or microsystems engineering. The idea to apply these technologies to observe the function of nerve cells and to develop tools to interface with single cells goes back to the 1960s. Wise et al. published the first micromachined neural probe in 1970 [22]. Others followed and formed a community of microengineers that closely collaborated with neuroscientists. Different approaches eventually divided the “neuromicro” research world into two spheres: those who use the Michigan probes [21] and those who apply the Utah array [2]. In the meantime, various groups [19] have developed different new approaches that rely on the basic principles of these ancestors and incorporate electrodes either in a micromachined bed of nails (out-of-plane, Utah approach) or along a single shaft or multiple comb-like probes (inplane, Michigan approach). Sophisticated tools are needed in experimental neuroscience to investigate the brain and to validate models from computational neuroscience. Scientists and engineers from 10 European countries, decided in 2005, to bridge the existing technological gap with the US groups, in neural probe development and joined forces in the European NeuroProbes project [Sixth Framework Program (FP6) of the European Commission, Project IST-027017]. A modular design of silicon-based neural probes providing a one-dimensional (1D), 2D, and 3D arrangement of electrode arrays was developed, providing electrical, microfluidic, and chemical sensing functionalities. Further applications required additional materials such as glass for alternative fluidic applications or flexible substrates for interconnecting cables and fluid delivery. The integration of recording and stimulation sites [15] combined with the electronic selection of recording electrodes, named
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270 T. Stieglitz et al.: Neural probes electronic depth control, to follow the signal without physically moving a probe in the brain, and the 3D integration of probes into a slender platform were achievements driven by the technological partners of NeuroProbes. A close and trusting collaboration between engineers and neuroscientists was established that paved the way for successful neuroscientific applications and the commercialization of the silicon-based probes through a European spin-off (Atlas Neueroengineering). This special issue of Biomedical Engineering/Biomedizinische Technik gives a comprehensive overview of selected results accomplished in the framework of the NeuroProbes project. Neuronal activity from single cells (single-unit activity) could be reliably recorded from non-human primates with the passive silicon-based neural probes used to discriminate between different grasping patterns [1]. On the other hand electrodes were actively selected by complementary metal-oxide-semiconductor (CMOS)-based electronics integrated in the slender probe shafts [5]. Specific machine learning algorithms were further applied to identify those electrodes out of hundreds of recording sites along each single probe shaft [20] that are most appropriate for dedicated experiments in different brain regions [5]. Neural probes with integrated microfluidic channels providing in-plane and out-of-plane drug delivery close to the electrical recording sites were used to locally inactivate a dedicated brain region by lidocaine administration [16]. These fluidic probes were successfully combined with an innovative drug delivery system designed for use in small, freely behaving animals. The functionality of probes was further increased by integrating chemical microsensors for the detection of the neurotransmitter choline. The amperometric principle of operation was supported by a custom-made CMOS chip used to amplify, digitize, and multiplex the sensor signals, resulting in a detection limit for choline of 1 μm [6]. The biocompatibility of the innovative probe arrays was improved by specific coating protocols functionalizing hyaluronic acid, a major component of the extracellular matrix, onto the probe shafts [3]. Apart from work in fundamental neurosciences in the central nervous system, basic and translational research on peripheral nerve interfaces have been performed [9] and brought into human clinical trials [13]. New tools and devices will be developed by transdisciplinary groups worldwide, in Germany, for example, in the Cluster of Excellence “BrainLinksBrainTools” [10, 18] and in the United States in President Obama’s BRAIN (Brain Research through Advancing Innovative Neurotechnologies) initiative to make the dream of controlling paralyzed limbs with our thoughts come true.
References [1] Bonini L, Maranesi M, Livi A, et al. Application of floating silicon-based linear multielectrode arrays for acute recording of single neuron activity in awake behaving monkeys. Biomed Eng/Biomed Tech 2014; 59: 273–281. [2] Campbell PK, Jones KE, Huber RJ, Horch KW, Normann RA. A silicon-based, three-dimensional neural interface: manufacturing processes for an intracortical electrode array. IEEE Trans Biomed Eng 1991; 38: 758–768. [3] Chow WY, Herwik S, Kisban S, et al. Influence of bio-coatings on the recording performance of neural electrodes. Biomed Eng/Biomed Tech 2014; 59: 315–322. [4] Decade of the human brain [in German]. http://www.meb.unibonn.de/epileptologie/aktion/dekade/dekade.htm. Accessed 8 July, 2014. [5] Dombovári B, Fiáth R, Kerekes BP, et al. In vivo validation of the electronic depth control probes. Biomed Eng/Biomed Tech 2014; 59: 283–289. [6] Frey O, Rothe J, Heer F, van der Wal PD, de Rooij NF, Hierlemann A. Multisite monitoring of choline using biosensor microprobe arrays in combination with CMOS circuitry. Biomed Eng/ Biomed Tech 2014; 59: 305–314. [7] Krüger J, Caruana F, Volta RD, Rizzolatti G. Seven years of recording from monkey cortex with a chronically implanted multiple microelectrode. Front Neuroeng 2010; 3: 6. [8] Kugler J. Electroencephalography 60 years later. Rec Prog Med 1991; 82: 163–165. [9] Navarro X, Krueger TB, Lago N, et al. A critical review of interfaces with the peripheral nervous system for the control of neuroprostheses and hybrid bionic systems. J Periph Nerv Syst 2005; 10: 229–258. [10] Paul O, Ruther P. MEMS and more for the brain: the cluster of excellence BrainLinks-BrainTools at the University of Freiburg, in Solid-State Sensors, Actuators and Microsystems Workshop, Hilton Head, SC, 2014: 1–4. [11] Piccolino M. Animal electricity and the birth of electrophysiology: the legacy of Luigi Galvani. Brain Res Bull 1998; 46: 381–407. [12] Project on the decade of the brain. http://www.loc.gov/loc/ brain/proclaim.html. Accessed 8 July, 2014. [13] Raspopovic S, Capogrosso M, Petrini FM, et al. Restoring natural sensory feedback in real-time bidirectional hand prostheses. Sci Transl Med 2014; 6: 222ra19, 10 pp. [14] Rizzolatti G, Fadiga L, Fogassi L, Gallese V. Resonance behaviors and mirror neurons. Arch Ital Biol 1999; 137: 85–100. [15] Ruther P, Herwik S, Kisban S, Seidl K, Paul O. Recent progress in neural probes using silicon MEMS technology. IEEJ Trans Elec Electron Eng 2010; 5: 505–515. [16] Spieth S, Schumacher A, Trenkle F, et al. Approaches for drug delivery with intracortical probes. Biomed Eng/Biomed Tech 2014; 59: 291–303. [17] Stieglitz T. Neuroprothetik und neuromodulation – forschungsansätze und klinische praxis bei therapie und rehabilitation. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2010; 53: 783–790. [18] Stieglitz T. Miniaturized neural interfaces and implants in neurological rehabilitation. In: Jensen W, Andersen OK, Akay M, editors. Replace, repair, restore, relieve – bridging clinical and engineering solutions in neurorehabilitation. Biosystems & biorobotics volume 7. Berlin: Springer 2014: 9–14.
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T. Stieglitz et al.: Neural probes 271 [19] Stieglitz T, Rubehn B, Henle C, et al. Brain-computer interfaces: an overview of the hardware to record neural signals from the cortex. Progr Brain Res 2009; 175: 297–315. [20] van Dijck G, van Hulle MM. Review of machine learning and signal processing techniques for automated electrode selection in high-density microelectrode arrays. Biomed Eng/Biomed Tech 2014; 59: 323–333. [21] Wise KD, Anderson DJ, Hetke JF, Kipke DR, Najafi K. Wireless implantable microsystems: high-density electronic interfaces to the nervous system. Proc IEEE 2004; 92: 76–97. [22] Wise KD, Angell JB, Starr A. An integrated-circuit approach to extracellular microelectrodes. IEEE Trans Biomed Eng 1970; 17: 238–247.
*Corresponding author: Thomas Stieglitz, BrainLinks-BrainTools, Research Cluster of Excellence (ExC 1086), University of Freiburg, Freiburg, Germany; Bernstein Center Freiburg, University of Freiburg, Freiburg, Germany; and Laboratory for Biomedical Microdevices, Department of Microsystems Engineering (IMTEK), University of Freiburg, Georges-Koehler-Allee 102, 79110, Freiburg, Germany, Phone: +497612037471, Fax:+497612037472, E-mail: [email protected] Herc Neves: Department of Engineering Sciences, University of Uppsala, Uppsala, Sweden Patrick Ruther: BrainLinks-BrainTools, Research Cluster of Excellence (ExC 1086), University of Freiburg, Freiburg, Germany; and Microsystem Materials Laboratory, Department of Microsystems Engineering (IMTEK), University of Freiburg, Freiburg, Germany
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Editorial Thomas Stieglitz, Herc Neves and Patrick Ruther
Neural probes – microsystems to interface with the brain The human brain has always been the focus of research in the quest for happiness and wisdom. The cutting-edge research in this field and its importance for science as well as for the general public resulted, on July 17, 1990, in Presidential Proclamation 6158 of President George H.W. Bush, who designated the 1990s as the “Decade of the Brain” [12] and launched a dedicated brain research program in the United States. Questions of how the brain works, how nerve cells connect and communicate properly to achieve complex movements and astonishing cognitive and artistic accomplishments, and how small misconnections in circuitry and biochemistry result in vast behavioral changes and fatal neurological diseases are among the many aspects that have been addressed in the last decades. The improved understanding of the function of the brain and the pathophysiology of diseases enables the development of novel therapies and rehabilitation approaches. Some of these neuro-electrical approaches go beyond pharmaceutical possibilities and open opportunities for diseases that have been fatal, thus far. Surprisingly, Europe was about a decade late when leading German neuroscientists re-announced the Decade of the Brain in 2000 [4]. This is even more surprising when we consider that many clinical improvements in neurology and neurosurgery that were introduced after World War II have been driven by groups from the old world. Particularly, Europe in general, and especially Germany, strongly contributed over the centuries to the stable electrical recording of nerve signals, development of electrical diagnosis methods, and major discoveries on how the brain works. Volta and Galvani discovered the electrical nature of nerve and muscle signals in 1791 [11]. Berger developed the electroencephalogram as a diagnostic method for the brain in 1929 [8]. The most stable recordings from freely behaving animals were obtained from European groups with wire electrodes [7], and the contribution of mirror neurons in learning about emotions and empathy was discovered in Italy [14]. Nonetheless, the development of implantable technical systems to interface with the peripheral and central nervous systems was mainly driven by US groups. Precision
mechanics approaches were used first, sometimes derived from the cardiac pacemaker industry, to develop novel therapeutic approaches that eventually led to neuromodulation techniques used to alleviate chronic pain and suppress tremor, rigidity (akinesia), and overshooting movements (dyskinesia) in Parkinson’s (Lou Gehrig’s) disease [17]. The invention of the transistor and integrated electronic circuits promoted the microelectronic revolution with its offspring, i.e., microelectromechanical systems, or microsystems engineering. The idea to apply these technologies to observe the function of nerve cells and to develop tools to interface with single cells goes back to the 1960s. Wise et al. published the first micromachined neural probe in 1970 [22]. Others followed and formed a community of microengineers that closely collaborated with neuroscientists. Different approaches eventually divided the “neuromicro” research world into two spheres: those who use the Michigan probes [21] and those who apply the Utah array [2]. In the meantime, various groups [19] have developed different new approaches that rely on the basic principles of these ancestors and incorporate electrodes either in a micromachined bed of nails (out-of-plane, Utah approach) or along a single shaft or multiple comb-like probes (inplane, Michigan approach). Sophisticated tools are needed in experimental neuroscience to investigate the brain and to validate models from computational neuroscience. Scientists and engineers from 10 European countries, decided in 2005, to bridge the existing technological gap with the US groups, in neural probe development and joined forces in the European NeuroProbes project [Sixth Framework Program (FP6) of the European Commission, Project IST-027017]. A modular design of silicon-based neural probes providing a one-dimensional (1D), 2D, and 3D arrangement of electrode arrays was developed, providing electrical, microfluidic, and chemical sensing functionalities. Further applications required additional materials such as glass for alternative fluidic applications or flexible substrates for interconnecting cables and fluid delivery. The integration of recording and stimulation sites [15] combined with the electronic selection of recording electrodes, named
Brought to you by | Western University Authenticated Download Date | 6/9/15 6:51 PM
270 T. Stieglitz et al.: Neural probes electronic depth control, to follow the signal without physically moving a probe in the brain, and the 3D integration of probes into a slender platform were achievements driven by the technological partners of NeuroProbes. A close and trusting collaboration between engineers and neuroscientists was established that paved the way for successful neuroscientific applications and the commercialization of the silicon-based probes through a European spin-off (Atlas Neueroengineering). This special issue of Biomedical Engineering/Biomedizinische Technik gives a comprehensive overview of selected results accomplished in the framework of the NeuroProbes project. Neuronal activity from single cells (single-unit activity) could be reliably recorded from non-human primates with the passive silicon-based neural probes used to discriminate between different grasping patterns [1]. On the other hand electrodes were actively selected by complementary metal-oxide-semiconductor (CMOS)-based electronics integrated in the slender probe shafts [5]. Specific machine learning algorithms were further applied to identify those electrodes out of hundreds of recording sites along each single probe shaft [20] that are most appropriate for dedicated experiments in different brain regions [5]. Neural probes with integrated microfluidic channels providing in-plane and out-of-plane drug delivery close to the electrical recording sites were used to locally inactivate a dedicated brain region by lidocaine administration [16]. These fluidic probes were successfully combined with an innovative drug delivery system designed for use in small, freely behaving animals. The functionality of probes was further increased by integrating chemical microsensors for the detection of the neurotransmitter choline. The amperometric principle of operation was supported by a custom-made CMOS chip used to amplify, digitize, and multiplex the sensor signals, resulting in a detection limit for choline of 1 μm [6]. The biocompatibility of the innovative probe arrays was improved by specific coating protocols functionalizing hyaluronic acid, a major component of the extracellular matrix, onto the probe shafts [3]. Apart from work in fundamental neurosciences in the central nervous system, basic and translational research on peripheral nerve interfaces have been performed [9] and brought into human clinical trials [13]. New tools and devices will be developed by transdisciplinary groups worldwide, in Germany, for example, in the Cluster of Excellence “BrainLinksBrainTools” [10, 18] and in the United States in President Obama’s BRAIN (Brain Research through Advancing Innovative Neurotechnologies) initiative to make the dream of controlling paralyzed limbs with our thoughts come true.
References [1] Bonini L, Maranesi M, Livi A, et al. Application of floating silicon-based linear multielectrode arrays for acute recording of single neuron activity in awake behaving monkeys. Biomed Eng/Biomed Tech 2014; 59: 273–281. [2] Campbell PK, Jones KE, Huber RJ, Horch KW, Normann RA. A silicon-based, three-dimensional neural interface: manufacturing processes for an intracortical electrode array. IEEE Trans Biomed Eng 1991; 38: 758–768. [3] Chow WY, Herwik S, Kisban S, et al. Influence of bio-coatings on the recording performance of neural electrodes. Biomed Eng/Biomed Tech 2014; 59: 315–322. [4] Decade of the human brain [in German]. http://www.meb.unibonn.de/epileptologie/aktion/dekade/dekade.htm. Accessed 8 July, 2014. [5] Dombovári B, Fiáth R, Kerekes BP, et al. In vivo validation of the electronic depth control probes. Biomed Eng/Biomed Tech 2014; 59: 283–289. [6] Frey O, Rothe J, Heer F, van der Wal PD, de Rooij NF, Hierlemann A. Multisite monitoring of choline using biosensor microprobe arrays in combination with CMOS circuitry. Biomed Eng/ Biomed Tech 2014; 59: 305–314. [7] Krüger J, Caruana F, Volta RD, Rizzolatti G. Seven years of recording from monkey cortex with a chronically implanted multiple microelectrode. Front Neuroeng 2010; 3: 6. [8] Kugler J. Electroencephalography 60 years later. Rec Prog Med 1991; 82: 163–165. [9] Navarro X, Krueger TB, Lago N, et al. A critical review of interfaces with the peripheral nervous system for the control of neuroprostheses and hybrid bionic systems. J Periph Nerv Syst 2005; 10: 229–258. [10] Paul O, Ruther P. MEMS and more for the brain: the cluster of excellence BrainLinks-BrainTools at the University of Freiburg, in Solid-State Sensors, Actuators and Microsystems Workshop, Hilton Head, SC, 2014: 1–4. [11] Piccolino M. Animal electricity and the birth of electrophysiology: the legacy of Luigi Galvani. Brain Res Bull 1998; 46: 381–407. [12] Project on the decade of the brain. http://www.loc.gov/loc/ brain/proclaim.html. Accessed 8 July, 2014. [13] Raspopovic S, Capogrosso M, Petrini FM, et al. Restoring natural sensory feedback in real-time bidirectional hand prostheses. Sci Transl Med 2014; 6: 222ra19, 10 pp. [14] Rizzolatti G, Fadiga L, Fogassi L, Gallese V. Resonance behaviors and mirror neurons. Arch Ital Biol 1999; 137: 85–100. [15] Ruther P, Herwik S, Kisban S, Seidl K, Paul O. Recent progress in neural probes using silicon MEMS technology. IEEJ Trans Elec Electron Eng 2010; 5: 505–515. [16] Spieth S, Schumacher A, Trenkle F, et al. Approaches for drug delivery with intracortical probes. Biomed Eng/Biomed Tech 2014; 59: 291–303. [17] Stieglitz T. Neuroprothetik und neuromodulation – forschungsansätze und klinische praxis bei therapie und rehabilitation. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2010; 53: 783–790. [18] Stieglitz T. Miniaturized neural interfaces and implants in neurological rehabilitation. In: Jensen W, Andersen OK, Akay M, editors. Replace, repair, restore, relieve – bridging clinical and engineering solutions in neurorehabilitation. Biosystems & biorobotics volume 7. Berlin: Springer 2014: 9–14.
Brought to you by | Western University Authenticated Download Date | 6/9/15 6:51 PM
T. Stieglitz et al.: Neural probes 271 [19] Stieglitz T, Rubehn B, Henle C, et al. Brain-computer interfaces: an overview of the hardware to record neural signals from the cortex. Progr Brain Res 2009; 175: 297–315. [20] van Dijck G, van Hulle MM. Review of machine learning and signal processing techniques for automated electrode selection in high-density microelectrode arrays. Biomed Eng/Biomed Tech 2014; 59: 323–333. [21] Wise KD, Anderson DJ, Hetke JF, Kipke DR, Najafi K. Wireless implantable microsystems: high-density electronic interfaces to the nervous system. Proc IEEE 2004; 92: 76–97. [22] Wise KD, Angell JB, Starr A. An integrated-circuit approach to extracellular microelectrodes. IEEE Trans Biomed Eng 1970; 17: 238–247.
*Corresponding author: Thomas Stieglitz, BrainLinks-BrainTools, Research Cluster of Excellence (ExC 1086), University of Freiburg, Freiburg, Germany; Bernstein Center Freiburg, University of Freiburg, Freiburg, Germany; and Laboratory for Biomedical Microdevices, Department of Microsystems Engineering (IMTEK), University of Freiburg, Georges-Koehler-Allee 102, 79110, Freiburg, Germany, Phone: +497612037471, Fax:+497612037472, E-mail: [email protected] Herc Neves: Department of Engineering Sciences, University of Uppsala, Uppsala, Sweden Patrick Ruther: BrainLinks-BrainTools, Research Cluster of Excellence (ExC 1086), University of Freiburg, Freiburg, Germany; and Microsystem Materials Laboratory, Department of Microsystems Engineering (IMTEK), University of Freiburg, Freiburg, Germany
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