Neural prosthesis has helped many patients to restore their physiological
functions. To achieve high resolution neural recording/
stimulation, high density microelectrode array (MEA) is necessary
for the development of advanced neural prosthesis. As the electrode
size shrinking, the impedance of the electrodes which are
made of gold, platinum, and silver chloride will increase, thus degrades
the signal-to-noise ratio (SNR) of neural recording. Carbon
nanotube (CNT) possesses good electrical conductance and material
stability. Using CNT-coupled MEA to interface with neurons
has been proposed in literatures, and the electrode impedance is
greatly improved after CNT coating on the electrode. In this thesis,
at first, the high temperature synthesis CNT bundles are employed
to fabricate the two types of CNT probes (i-CNT and g-
CNT probes). The two types of CNT probes have been proved
that can record the neural activity faithfully. Besides, to test the
endurance of the CNT probes, the CNT probes are forced to conduct
a 500 nA direct current for two hours. The experimental results
indicate that this direct current does not degrade the CNT
probes’ performance, instead, improves the recording capability of
the CNT probes. This improvement is attributed to the permanent
(chemical) and non-permanent (physical) mechanisms. Besides,
using low temperature (400C) chemical vapor deposition (CVD)
method to synthesize the CNTs on the flexible substrate directly
has been proposed in this thesis. By combining the designed neural
amplifier array, an active, flexible CNT-coupled microelectrode
array (cMEA) is formed. The experimental results prove that the
proposed active, flexible cMEA can not only reduce the electrode
impedance, but also record the neural activities (neural spike of
crayfish nerves and ECoG of rat brain) faithfully.
In the last part of this thesis, an integrated system for both intracellular
and extracellular neural recording is proposed. This
chip (6.25 mm2) provides four intracellular and four extracellular
neural recording channels. For the designed extracellular neural
recording amplifier, the calculated noise efficiency factor (NEF) is
5.04, which is comparable with the state-of-the-art designs. The
results of the biological experiments further indicate that the designed
extracellular neural amplifier can record the neural activity
faithfully. For the intracellular neural recording channel, both the
size (0.3 mm2) and power consumption (0.304 mW) are lower than
those proposed in literatures. The designed intracellular recording
channel is proved that can record the resting potential and the
action potential of the LG neurons of crayfish. Besides, the designed
current injection circuitry can further inject current pulses
into the LG neurons to evoke the action potentials. The experimental
results demonstrate that the designed circuitry can achieve
intracellular current clamp recording.

[1] G. G. Matthews. Neurobiology. [Online]. Available: http://www.
blackwellpublishing.com/matthews/channel.html
[2] N. R. Carlson, Foundations of Physiological Psychology. Allyn and Bacon,
1992.
[3] Wikipedia. The patch-clamp technique. [Online]. Available: http://en.
wikipedia.org/wiki/Electrophysiology#The_patch-clamp_technique
[4] R. R. Harrison, “A versatile integrated circuit for the acquisition of biopotentials,”
Custom Integrated Circuits Conference, 2007. CICC ’07. IEEE, pp.
115 –122, 2007.
[5] A. Lambacher, M. Jenkner, M. Merz, B. Eversmann, R. Kaul, F. Hofmann,
R. Thewes, and P. Fromherz, “Electrical imaging of neuronal activity by
multi-transistor-array (MTA) recording at 7.8 mu m resolution,” Appl.
Phys. A, vol. 79, no. 7, pp. 1607–1611, 2004.
[6] D. H. Kim, J. Viventi, J. J. Amsden, J. Xiao, L. Vigeland, Y. S. Kim, J. A.
Blanco, B. Panilaitis, E. S. Frechette, D. Contreras, D. L. Kaplan, F. G.
Omenetto, Y. Huang, K. C. Hwang, M. R. Zakin, B. Litt, and J. A. Rogers,“Dissolvable films of silk fibroin for ultrathin conformal bio-integrated
electronics,” Nature Materials, vol. 9, no. 6, pp. 511–517, 2010.
[7] E. Ben-Jacob and Y. Hanein, “Carbon nanotube micro-electrodes for neuronal
interfacing,” J. Mater. Chem., vol. 18, no. 43, pp. 5181–5186, 2008.
[8] F. Heer, S. Hafizovic, T. Ugniwenko, U. Frey, B. Roscic, A. Blau, and
A. Hierlemann, “Using microelectronics technology to communicate
with living cells,” EMBS 07. 29th Annual International Conference of the
IEEE, pp. 6081–6084, 2007.
[9] S. R. Yeh, Y. C. Chen, H. C. Su, T. R. Yew, H. H. Kao, Y. T. Lee, T. A. Liu,
H. Chen, Y. C. Chang, P. Chang, and H. Chen, “Interfacing Neurons both
Extracellularly and Intracellularly Using Carbon - Nanotube Probes with
Long-Term Endurance,” Langmuir, vol. 25, no. 13, pp. 7718–7724, 2009.
[10] L. Wong, S. Hossain, A. Ta, J. Edvinsson, D. Rivas, and H. Naas, “A
very low-power cmos mixed-signal ic for implantable pacemaker applications,”
Solid-State Circuits, IEEE Journal of, vol. 39, no. 12, pp. 2446 –
2456, dec. 2004.
[11] A. Benabid, “Deep brain stimulation for Parkinson’s disease,” Current
Opinion in Neurobiology, vol. 13, no. 6, pp. 696–706, 2003.
[12] M. Jahanshahi, C. Ardouin, R. Brown, J. Rothwell, J. Obeso, A. Albanese,
M. Rodriguez-Oroz, E. Moro, A. Benabid, P. Pollak, and P. Limousin-
Dowsey, “The impact of deep brain stimulation on executive function in
Parkinson’s disease,” Brain, vol. 123, no. Part 6, pp. 1142–1154, 2000.
[13] J. Georgiou and C. Toumazou, “A 126-mw cochlear chip for a totally
implantable system,” Solid-State Circuits, IEEE Journal of, vol. 40, no. 2,
pp. 430 – 443, feb. 2005.
[14] P. Bhatti and K. Wise, “A 32-site 4-channel high-density electrode array
for a cochlear prosthesis,” Solid-State Circuits, IEEE Journal of, vol. 41,
no. 12, pp. 2965 –2973, 2006.
[15] W. Liu, K. Vichienchom, M. Clements, S. DeMarco, C. Hughes,
E. McGucken, M. Humayun, E. De Juan, J. Weiland, and R. Greenberg,
“A neuro-stimulus chip with telemetry unit for retinal prosthetic device,”
Solid-State Circuits, IEEE Journal of, vol. 35, no. 10, pp. 1487 –1497, oct
2000.
[16] M. Sivaprakasam, W. Liu, M. Humayun, and J. Weiland, “A variable
range bi-phasic current stimulus driver circuitry for an implantable retinal
prosthetic device,” Solid-State Circuits, IEEE Journal of, vol. 40, no. 3,
pp. 763 – 771, 2005.
[17] V. Lovat, D. Pantarotto, L. Lagostena, B. Cacciari, M. Grandolfo, M. Righi,
G. Spalluto, M. Prato, and L. Ballerini, “Carbon nanotube substrates
boost neuronal electrical signaling,” Nano Lett., vol. 5, no. 6, pp. 1107–
1110, 2005.
[18] A. Hodgkin and A. Huxley, “A quantitative description of membrane
current and its application to conduction and excitation in nerve,” Journal
of Physiology-London, vol. 117, no. 4, pp. 500–544, 1952.
[19] P. C. Silva, “Intracellular recording with low-power low-noise CMOS
voltage and current clamp circuits,” Master’s thesis, Electrical Engineering,
North Carolina State University, Raleigh, North Carolina, 2007.
[20] P. Weerakoon, E. Culurciello, Y. Yang, J. Santos-Sacchi, P. J. Kindlmann,
and F. J. Sigworth, “Patch-clamp amplifiers on a chip,” J. Neurosci. Methods,
vol. 192, no. 2, pp. 187–192, 2010.
[21] F. Heer, S. Hafizovic, W. Franks, A. Blau, C. Ziegler, and A. Hierlemann,
“Cmos microelectrode array for bidirectional interaction with neuronal
networks,” Solid-State Circuits, IEEE Journal of, vol. 41, no. 7, pp. 1620
–1629, 2006.
[22] M. A. Lebedev and M. A. L. Nicolelis, “Brain-machine interfaces: past,
present and future,” Trends Neurosci., vol. 29, no. 9, pp. 536–546, 2006.
[23] J. P. Donoghue, “Bridging the Brain to the World: A Perspective on Neural
Interface Systems,” Neuron, vol. 60, no. 3, pp. 511–521, 2008.
[24] C. Nordhausen, E. Maynard, and R. Normann, “Single unit recording
capabilities of a 100 microelectrode array,” Brain Research, vol. 726, no.
1-2, pp. 129–140, 1996.
[25] R. H. Olsson and K. D. Wise, “A three-dimensional neural recording microsystem
with implantable data compression circuitry,” Solid-State Circuits,
IEEE Journal of, vol. 40, no. 12, pp. 2796 – 2804, 2005.
[26] C. W. Lin, Y. T. Lee, C. W. Chang, W. L. Hsu, Y. C. Chang, and W. Fang,
“Novel glass microprobe arrays for neural recording,” Biosens. Bioelectron.,
vol. 25, no. 2, pp. 475–481, 2009.
[27] B. Eversmann, M. Jenkner, F. Hofmann, C. Paulus, R. Brederlow,
B. Holzapfl, P. Fromherz, M. Merz, M. Brenner, M. Schreiter, R. Gabl,
K. Plehnert, M. Steinhauser, G. Eckstein, D. Schmitt-Landsiedel, and
R. Thewes, “A 128 times; 128 cmos biosensor array for extracellular
recording of neural activity,” Solid-State Circuits, IEEE Journal of, vol. 38,
no. 12, pp. 2306 – 2317, 2003.
[28] C. H. Chang, S. R. Chang, J. S. Lin, Y. T. Lee, S. R. Yeh, and H. Chen,
“A CMOS neuroelectronic interface based on two-dimensional transistor
arrays with monolithically-integrated circuitry,” Biosens. Bioelectron.,
vol. 24, no. 6, pp. 1757–1764, 2009.
[29] T. Pistohl, T. Ball, A. Schulze-Bonhage, A. Aertsen, and C. Mehring, “Prediction
of arm movement trajectories from ECoG-recordings in humans,”
J. Neurosci. Methods, vol. 167, no. 1, pp. 105–114, 2008.
[30] K. D. Wise, A. M. Sodagar, Y. Yao, M. N. Gulari, G. E. Perlin, and
K. Najafi, “Microelectrodes, microelectronics, and implantable neural microsystems,”
Proceedings of the IEEE, vol. 96, no. 7, pp. 1184 –1202, 2008.
[31] G. Loeb, R. Peck, and J. Martyniuk, “Toward the ultimate metal microelectrode,”
J. Neurosci. Methods, vol. 63, no. 1-2, pp. 175–183, 1995.
[32] S. F. Cogan, A. A. Guzelian, W. F. Agnew, T. G. H. Yuen, and D. B.
McCreery, “Over-pulsing degrades activated iridium oxide films used for intracortical neural stimulation,” J. Neurosci. Methods, vol. 137, no. 2,
pp. 141–150, 2004.
[33] T. Gabay, M. Ben-David, I. Kalifa, R. Sorkin, Z. R. Abrams, E. Ben-Jacob,
and Y. Hanein, “Electro-chemical and biological properties of carbon
nanotube based multi-electrode arrays,” Nanotechnology, vol. 18, no. 3,
p. 035201, 2007.
[34] M. K. Gheith, T. C. Pappas, A. V. Liopo, V. A. Sinani, B. S. Shim, M. Motamedi,
J. R. Wicksted, and N. A. Kotov, “Stimulation of neural cells by
lateral layer-by-layer films of single-walled currents in conductive carbon
nanotubes,” Adv. Mater., vol. 18, no. 22, pp. 2975–2979, 2006.
[35] E. W. Keefer, B. R. Botterman, M. I. Romero, A. F. Rossi, and G. W.
Gross, “Carbon nanotube coating improves neuronal recordings,” Nature
Nanotech., vol. 3, no. 7, pp. 434–439, 2008.
[36] A. Mazzatenta, M. Giugliano, S. Campidelli, L. Gambazzi, L. Businaro,
H. Markram, M. Prato, and L. Ballerini, “Interfacing neurons with carbon
nanotubes: Electrical signal transfer and synaptic stimulation in cultured
brain circuits,” J. Neurosci., vol. 27, no. 26, pp. 6931–6936, 2007.
[37] T. D. B. Nguyen-Vu, H. Chen, A. M. Cassell, R. Andrews, M. Meyyappan,
and J. Li, “Vertically aligned carbon nanofiber arrays: An advance toward
electrical-neural interfaces,” Small, vol. 2, no. 1, pp. 89–94, 2006.
[38] C. Y.Wang, T. H. Chen, S. C. Chang, T. S. Chin, and S. Y. Cheng, “Flexible
field emitter made of carbon nanotubes microwave welded onto polymer
substrates,” Appl. Phys. Lett., vol. 90, no. 10, p. 103111, 2007.
[39] S. H. Hur, O. O. Park, and J. A. Rogers, “Extreme bendability of singlewalled
carbon nanotube networks transferred from high-temperature
growth substrates to plastic and their use in thin-film transistors,” Appl.
Phys. Lett., vol. 86, no. 24, p. 243502, 2005.
[40] C. M. Lin, Y. T. Lee, S. R. Yeh, andW. L. Fang, “Flexible carbon nanotubes
electrode for neural recording,” Biosens. Bioelectron., vol. 24, no. 9, pp.
2791–2797, 2009.
[41] M. Chen, C. M. Chen, S. C. Shi, and C. F. Chen, “Low-temperature synthesis
multiwalled carbon nanotubes by microwave plasma chemical vapor
deposition using CH4-CO2 gas mixture,” JJAP, vol. 42, no. 2A, pp.
614–619, 2003.
[42] R. Harrison, R. Kier, A. Leonardo, H. Fotowat, R. Chan, and F. Gabbiani,
“A wireless neural/emg telemetry system for freely moving insects,” in
Circuits and Systems (ISCAS), Proceedings of 2010 IEEE International Symposium
on, 2010, pp. 2940 –2943.
[43] T. D. Halbig, W. Tse, P. G. Frisina, B. R. Baker, E. Hollander, H. Shapiro,
M. Tagliati, W. C. Koller, and C. W. Olanow, “Subthalamic deep brain
stimulation and impulse control in Parkinson’s disease,” European Journal
of Neurology, vol. 16, no. 4, pp. 493–497, 2009.
[44] T. Seese, H. Harasaki, G. Saidel, and C. Davies, “Characterization of tissue
morphology, angiogenesis, and temperature in the adaptive response
of muscle tissue to chronic heating,” Laboratory Investigation, vol. 78,
no. 12, pp. 1553–1562, 1998.
[45] K. Sohee, P. Tathireddy, R. Normann, and F. Solzbacher, “Thermal impact
of an active 3-d microelectrode array implanted in the brain,” Neural
Systems and Rehabilitation Engineering, IEEE Transactions on, vol. 15, no. 4,
pp. 493 –501, 2007.
[46] M. K. Yeh, N. H. Tai, and J. H. Liu, “Mechanical behavior of phenolicbased
composites reinforced with multi-walled carbon nanotubes,” Carbon,
vol. 44, no. 1, pp. 1–9, 2006.
[47] K. Wang, H. A. Fishman, H. Dai, and J. S. Harris, “Neural stimulation
with a carbon nanotube microelectrode array,” Nano Lett., vol. 6, no. 9,
pp. 2043–2048, 2006.
[48] C. C. Hu, J. H. Su, and T. C. Wen, “Modification of multi-walled carbon
nanotubes for electric double-layer capacitors: Tube opening and surface
functionalization,” Journal of Physics and Chemistry of Solids, vol. 68, no. 12,
pp. 2353–2362, 2007.
[49] H. L. Hsu, I. J. Teng, Y. C. Chen, W. L. Hsu, Y. T. Lee, S. J. Yen, H. C.
Su, S. R. Yeh, H. Chen, and T. R. Yew, “Flexible UV-Ozone-Modified Carbon
Nanotube Electrodes for Neuronal Recording,” Adv. Mater., vol. 22,
no. 19, pp. 2177 –2181, 2010.
[50] G. E. Perlin, A. M. Sodagar, and K. D. Wise, “Neural recording frontend
designs for fully implantable neuroscience applications and neural
prosthetic microsystems,” EMBS ’06. 28th Annual International Conference
of the IEEE, pp. 2982–2985, 2006.
[51] B. Razavi, Design of Analog CMOS Integrated Circuits. McGraw-Hill, 2001.
[52] J. M. Nugent, K. S. V. Santhanam, A. Rubio, and P. M. Ajayan, “Fast
electron transfer kinetics on multiwalled carbon nanotube microbundle
electrodes,” Nano Lett., vol. 1, no. 2, pp. 87–91, 2001.
[53] A. M. Sodagar, K. D. Wise, and K. Najafi, “A fully integrated mixedsignal
neural processor for implantable multichannel cortical recording,”
IEEE Trans. Biomed. Eng., vol. 54, no. 6, pp. 1075–1088, 2007.
[54] A. Lambacher, M. Jenkner, M. Merz, B. Eversmann, R. A. Kaul, F. Hofmann,
R. Thewes, and P. Fromherz, “Electrical imaging of neuronal activity
by multi-transistor-array (MTA) recording at 7.8 um resolution,”
Appl. Phys. A, vol. 79, no. 7, pp. 1607–1611, 2004.
[55] R. J. Staba, C. L. Wilson, A. Bragin, I. Fried, and J. Engel, “Quantitative
analysis of high-frequency oscillations (80-500 Hz) recorded in human
epileptic hippocampus and entorhinal cortex,” J. Neurophysiol., vol. 88,
no. 4, pp. 1743–1752, 2002.
[56] G. Schalk, K. J. Miller, N. R. Anderson, J. A. Wilson, M. D. Smyth,
J. G. Ojemann, D. W. Moran, J. R. Wolpaw, and E. C. Leuthardt, “Twodimensional
movement control using electrocorticographic signals in humans,”
J. Neural Eng., vol. 5, no. 1, pp. 75–84, 2008.
[57] Y. Y. Chen, H. Y. Lai, S. H. Lin, C. W. Cho, W. H. Chao, C. H. Liao,
S. Tsang, Y. F. Chen, and S. Y. Lin, “Design and fabrication of a polyimidebased
microelectrode array: Application in neural recording and repeatable
electrolytic lesion in rat brain,” J. Neurosci. Methods, vol. 182, no. 1,
pp. 6–16, 2009.
[58] S. Suner, M. Fellows, C. Vargas-Irwin, G. Nakata, and J. Donoghue, “Reliability
of signals from a chronically implanted, silicon-based electrode
array in non-human primate primary motor cortex,” IEEE Transactions on
Neural Systems and Rehabilitation Engineering, vol. 13, no. 4, pp. 524–541,
2005.
[59] R. Fried and C. Enz, “Simple and accurate voltage adder/subtracter,”
Electronics Letters, vol. 33, no. 11, pp. 944–945, 1997.
[60] T. Delbruck and P. Lichtsteiner, “Fully programmable bias current generator
with 24 bit resolution per bias,” in Circuits and Systems, 2006. ISCAS
2006. Proceedings. 2006 IEEE International Symposium on, 2006, p. 2852.
[61] Y. C. Chen, H. L. Hsu, Y. T. Lee, H. C. Su, S. J. Yen, C. H. Chen, W. L.
Hsu, T. R. Yew, S. R. Yeh, D. J. Yao, Y. C. Chang, and H. Chen, “An
active, flexible carbon nanotube microelectrode array for recording electrocorticograms,”
Journal of Neural Eng., vol. 8, no. 3, 2011.
[62] M. Steyaert, W. Sansen, and Z. Chang, “A Micropower low-noise monolithic
instrumentation amplifier for medical purposes,” Solid-State Circuits,
IEEE Journal of, vol. 22, no. 6, pp. 1163–1168, 1987.
[63] V. Majidzadeh, A. Schmid, and Y. Leblebici, “Energy efficient low-noise
neural recording amplifier with enhanced noise efficiency factor,” IEEE
Transactions on Biomedical Circuits and Systems, vol. 5, no. 3, pp. 262–271,
2011.
[64] X. Zou, X. Xu, L. Yao, and Y. Lian, “A 1-V 450-nW Fully Integrated Programmable
Biomedical Sensor Interface Chip,” Solid-State Circuits, IEEE
Journal of, vol. 44, no. 4, pp. 1067 –1077, 2009.
[65] T. Denison, K. Consoer, W. Santa, A. T. Avestruz, J. Cooley, and A. Kelly,
“A 2 mW 100 nV/rtHz Chopper-Stabilized Instrumentation Amplifier for
Chronic Measurement of Neural Field Potentials,” Solid-State Circuits,
IEEE Journal of, vol. 42, no. 12, pp. 2934 –2945, 2007.
[66] M. Gruhn and W. Rathmayer, “An implantable electrode design for both
chronic in vivo nerve recording and axon stimulation in freely behaving
crayfish,” Journal of Neurosci. Methods, vol. 118, no. 1, pp. 33–40, 2002.
[67] R. Metherate, C. Cox, and J. Ashe, “Cellular bases of neocortical activation
- modulation of neural oscillations by the nucleus basalis and
endogenous acetylcholine,” Journal of Neuroscience, vol. 12, no. 12, pp.
4701–4711, 1992.
[68] H. Pape and D. Mccormick, “Noradrenaline and serotonin selectively
modulate thalamic burst firing by enhancing a hyperpolarizationactivated
cation current,” Nature, vol. 340, no. 6236, pp. 715–718, 1989.
[69] P. Magill, A. Sharott, J. Bolam, and P. Brown, “Brain state-dependency of
coherent oscillatory activity in the cerebral cortex and basal ganglia of
the rat,” Journal of Neurophysiology, vol. 92, no. 4, pp. 2122–2136, 2004.
[70] M. Sekerli, C. Del Negro, R. Lee, and R. Butera, “Estimating action potential
thresholds from neuronal time-series: new metrics and evaluation of methodologies,” Biomedical Engineering, IEEE Transactions on, vol. 51,
no. 9, pp. 1665 –1672, 2004.
[71] P. Weerakoon, F. Sigworth, and E. Culurciello, “Integrated patch-clamp
biosensor for high-density screening of cell conductance,” Electronics Letters,
vol. 44, no. 2, pp. 81–82, 2008.
[72] H. C. Su, C. M. Lin, S. J. Yen, Y. C. Chen, C. H. Chen, S. R. Yeh, W. Fang,
H. Chen, D. J. Yao, Y. C. Chang, and T. R. Yew, “A cone-shaped 3d carbon
nanotube probe for neural recording,” Biosnesors & Bioelectronics, vol. 26,
no. 1, pp. 220–227, 2010.