Publications – 2019

Jake Rabinowitz, Charishma Cohen, and K. L. Shepard, An Electrically Actuated, Carbon-Nanotube-Based Biomimetic Ion Pump, Nano Letters, DOI: 10.1021/acs.nanolett.9b04552

Single-walled carbon nanotubes (SWCNTs) are well-established transporters of electronic current, electrolyte, and ions. Inthis work, we demonstrate an electrically actuated biomimetic ionpump by combining these electronic and nanofluidic transportcapabilities within an individual SWCNT device. Ion pumping isdriven by a solid-state electronic input, as Coulomb drag couplingtransduces electrical energy from solid-state charge along the SWCNTshell to electrolyte inside the SWCNT core. Short-circuit ioniccurrents, measured without an electrolyte potential difference, exceed 1 nA and scale larger with increasing ion concentrationsthrough 1 M, demonstrating applicability under physiological (∼140 mM) and saltwater (∼600 mM) conditions. The interlayercoupling allows ionic currents to be tuned with the source−drain potential difference and electronic currents to be tuned withthe electrolyte potential difference. This combined electronic−nanofluidic SWCNT device presents intriguing applications as abiomimetic ion pump or component of an artificial membrane.

Jaebin Choi, Adriaan J. Taal, Eric H. Pollmann, William Meng, Sajjad Moazeni, Laurent C. Moreaux, Michael L. Roukes, Kenneth L. Shepard. Fully Integrated Time-Gated 3D Fluorescence Imager for Deep Neural Imaging. IEEE Biomedical Circuits and Systems Conference, October 18, 2019.

This paper reports an implantable 3D imager for time-gated fluorescence imaging in the deep brain. Fluorescence excitation is provided by dual ns-pulsed blue micro-light-emitting diodes (μLED), and fluorescence emission is collected by an 8-by-64 single-photon avalanche diode (SPAD) array, together packaged to a width of 420 μm to allow deep insertion through a cannula. Each SPAD is masked by a repeating pattern of Talbot gratings that give each pixel a different angular sensitivity, allowing three-dimensional image reconstruction to a resolution of ~20μm. The integrated imager is able to monitor fluorescent targets across a field of view of 1000 μm by 600 μm by 500 μm at arbitrary tissue depths.

Jaebin Choi, Adriaan J. Taal, Eric H. Pollmann, Changhyuk Lee, Kukjoo Kim, Laurent C. Moreaux, Michael L. Roukes, Kenneth L. Shepard. A 512-Pixel, 51-kHz-Frame-Rate, Dual-Shank, Lens-Less, Filter-Less Single-Photon Avalanche Diode CMOS Neural Imaging Probe. IEEE Journal of Solid-State Circuits, volume 54, pages 2957-2968, November, 2019 DOI:10.1109/JSSC.2019.2941529

We present an implantable single-photon shank-based imager, monolithically integrated onto a single CMOSIC. The imager comprises of 512 single-photon avalanchediodes distributed along two shanks, with a 6-bit depth in-pixelmemory and an on-chip digital-to-time converter. To scale downthe system to a minimally invasive form factor, we substituteoptical filtering and focusing elements with a time-gated,angle-sensitive detection system. The imager computationallyreconstructs the position of fluorescent sources within a 3-Dvolume of 3.4 mm×600μm×400μm.

David Kleinfeld, Lan Luan, Partha P.Mitra, Jacob T.Robinson, Rahul Sarpeshkar Kenneth Shepard, ChongXie, Timothy D.Harris. Can One Concurrently Record Electrical Spikes from Every Neuron in a Mammalian Brain?. Neuron, 5 September 2019, DOI: 10.1016/j.neuron.2019.08.011

Physical limits do not preclude simultaneous recordings of all spikes in neocortex
Future electrodes need nontraditional materials and fabrication procedures
Challenges for dense recording include heat dissipation from interface electronics

Chen-Chi Chien, Siddharth Shekar, David J. Niedzwiecki, Kenneth L. Shepard and Marija Drndić.
Single-Stranded DNA Translocation Recordings through Solid-State Nanopores on Glass Chips at 10 MHz Measurement Bandwidth“. ACS Nano, 26 August, 2019, DOI: 10.1021/acsnano.9b04626

Jacob T. Robinson, Eric Pohlmeyer, Malte C. Gather, Caleb Kemere, John E. Kitching,George G. Malliaras, Adam Marblestone, Kenneth L. Shepard, Thomas Stieglitz, Chong Xie “Developing Next-generation Brain Sensing Technologies – A Review“, IEEE Sensors Journal, 25 July 2019, DOI:10.1109/JSEN.2019.2931159

Advances in sensing technology raise the possibility of creating neural interfaces that can more effectively restore or repair neural function and reveal fundamental properties of neural information processing. To realize the potential of these bioelectronic devices, it is necessary to understand the capabilities of emerging technologies and identify the best strategies to translate these technologies into products and therapies that will improve the lives of patients with neurological and other disorders. Here we discuss emerging technologies for sensing brain activity, anticipated challenges for translation, and perspectives for how to best transition these technologies from academic research labs to useful products for neuroscience researchers and human patients.

Siddharth Shekar, Krishna Jayant, M Angeles Rabadan, Raju Tomer, Rafael Yuste and Kenneth L. Shepard “A miniaturized multi-clamp CMOS amplifier for intracellular neural recordingNature Electronics volume 2pages343–350 (2019)

Intracellular electrophysiology is a foundational method in neuroscience and uses electrolyte-filled glass electrodes and bench-top amplifiers to measure and control transmembrane voltages and currents. Commercial amplifiers perform such recordings with high signal-to-noise ratios but are often expensive, bulky and not easily scalable to many channels due to reliance on board-level integration of discrete components. Here, we present a monolithic complementary metal–oxide–semiconductor multi-clamp amplifier integrated circuit capable of recording both voltages and currents with performance exceeding that of commercial benchtop instrumentation. Miniaturization enables high-bandwidth current mirroring, facilitating the synthesis of large-valued active resistors with lower noise than their passive equivalents. This enables the realization of compensation mod-ules that can account for a wide range of electrode impedances. We validate the amplifier’s operation electrically, in primary neuronal cultures, and in acute slices, using both high-impedance sharp and patch electrodes. This work provides a solution for low-cost, high-performance and scalable multi-clamp amplifiers.

Jake Rabinowitz, Martin A. Edwards, Elizabeth Whittier, Krishna Jayant and Kenneth L. Shepard. “Nanoscale Fluid Vortices and Nonlinear Electroosmotic Flow Drive Ion Current Rectification in the Presence of Concentration Gradients“, J. Phys. Chem. A 2019.

Ion current rectification (ICR) is a transport phenomenon inwhich an electrolyte conducts unequal currents at equal and opposite voltages.Here, we show that nanoscalefluid vortices and nonlinear electroosmoticflow(EOF) drive ICR in the presence of concentration gradients. The same EOFcan yield negative differential resistance (NDR), in which current decreaseswith increasing voltage. Afinite element model quantitatively reproducesexperimental ICR and NDR recorded across glass nanopipettes underconcentration gradients. The model demonstrates that spatial variations ofelectrical double layer properties induce the nanoscale vortices and nonlinearEOF. Experiments are performed in conditions directly related to scanningprobe imaging and show that quantitative understanding of nanoscale transport under concentration gradients requiresaccounting for EOF. This characterization of nanopipette transport physics will benefit diverse experimentation, pushing theresolution limits of chemical and biophysical recordings.

Andreas J.W. Hartel, siddharth Shekar, Peijie Ong, Indra Schroeder, Gerhard Thiel, Kenneth L. Shepard. High bandwidth approaches in nanopore and ion channel recordings – A tutorial review. Analytica Chimica Acta. January 5, 2019, DOI: 10.1016/j.aca.201901.034

Transport processes through ion-channel proteins, protein pores, or solid-state nanopores are tradi-tionally recorded with commercial patch-clamp amplifiers. The bandwidth of these systems is typicallylimited to 10 kHz by signal-to-noise-ratio (SNR) considerations associated with these measurementplatforms. At high bandwidth, the input-referred current noise in these systems dominates, determinedby the input-referred voltage noise of the transimpedance amplifier applied across the capacitance at theinput of the amplifier. This capacitance arises from several sources: the parasitic capacitance of theamplifier itself; the capacitance of the lipid bilayer harboring the ion channel protein (or the membraneused to form the solid-state nanopore); and the capacitance from the interconnections between theelectronics and the membrane. Here, we review state-of-the-art applications of high-bandwidthconductance recordings of both ion channels and solid-state nanopores. These approaches involvetightly integrating measurement electronics fabricated in complementary metal-oxide semiconductors(CMOS) technology with lipid bilayer or solid-state membranes. SNR improvements associated with thistight integration push the limits of measurement bandwidths, in some cases in excess of 10 MHz. Recentcase studies demonstrate the utility of these approaches for DNA sequencing and ion-channel recordings.In the latter case, studies with extended bandwidth have shown the potential for providing new insightsinto structure-function relations of these ion-channel proteins as the temporal resolutions of functionalrecordings matches time scales achievable with state-of-the-art molecular dynamics simulations.

A 0.6 mm2 integrated circuit, fabricated in a 180 nm process, is designed to operate within the field of view of an ultrasound B-mode imager, allowing data to be received from ultra-small-form-factor devices that can be localized, powered, and configured as multiple freely moving ingestible or implantable systems. Power is harvested from ultrasound pulses emitted by the imaging transducer array and a bi-directional data link is established that is synchronized to the frame rate of the imager. The chip consumes 57 pW of power and supports data rates of 25 bit/s for uplink and 50 bit/s for downlink for an imager operating at 50 frames per second. Fully packaged within 11 mm3 with a piezoelectric transducer, the chip enables tissue implants as deep as 71 mm. Real-time localizations of devices is possible within the field of view of the imager at 0.8-mm accuracy. An on-chip instruction set allows for software configuration and a smooth transition to a more power-intensive mode of operation using focused ultrasound pulses after localization, with 280 nW power delivery verified using 0.5% duty cycle ultrasound.

Tiago Costa, Chen Shi, Kevin Tien, and K. L. Shepard, “A CMOS 2D transmit beamformer with integrated PZT ultrasound transducers for neuromodulation,” Custom Integrated Circuits Conference, 2019

While the mechanisms are not yet completely understood, ultrasound-based neuromodulation has been emerging as a noninvasive modality for interfacing to both the central and peripheral nervous systems, due to its high penetration depth and good spatial resolution. Commercially available ultrasound transducers for neuromodulation applications are typically single-element focused transducers with a bulky form factor and off-the-shelf electronics for drive. Changing the focal position requires mechanical movement of the transducer itself. High-density ultrasound phased arrays allow for electronic focusing. Here, we present a CMOS 2D beamformer with integrated lead zirconate titanate (PZT) ultrasound transducers for neuromodulation of the peripheral nerves. The proposed prototype can achieve a maximum focal pressure of approximately 100 kPa with a 5 V supply at 0.5 cm depth without including an acoustic matching layer.

Changhyuk Lee, Adriaan J. Taal, Jaebin Choi, Kukjoo Kim, Kevin Tien, Laurent Moreaux, Michael L. Roukes, Kenneth L. Shepard. A 512-Pixel 3kHz-Frame-Rate Dual-Shank Lensless Filterless Single-Photon-Avalanche-Diode CMOS Neural Imaging Probe. IEEE International Solid-State Circuits Conference February 19, 2019.

Siddharth Shekar, Chen-Chi Chien, Andreas Hartel, Peijie Ong, Oliver B Clarke, Andrew Marks, Marija Drndic, and Kenneth L Shepard. Wavelet Denoising of High-Bandwidth Nanopore and Ion-Channel Signals. Nano Letters January 2, 2019, DOI: 10.1021/acs.nanolett8b04388.

Recent work has pushed the noise-limitedbandwidths of solid-state nanopore conductance recordings tomore than 5 MHz and of ion channel conductance recordingsto more than 500 kHz through the use of integratedcomplementary metal-oxide-semiconductor (CMOS) inte-grated circuits. Despite the spectral spread of the pulse-likesignals that characterize these recordings when a sinusoidalbasis is employed, Besselfilters are commonly used to denoisethese signals to acceptable signal-to-noise ratios (SNRs) at thecost of losing many of the faster temporal features. Here, wereport improvements to the SNR that can be achieved usingwavelet denoising instead of Besselfiltering. When combinedwith state-of-the-art high-bandwidth CMOS recording in-strumentation, we can reduce baseline noise levels by over a factor of 4 compared to a 2.5 MHz Besselfilter while retainingtransient properties in the signal comparable to thisfilter bandwidth. Similarly, for ion-channel recordings, we achieve atemporal response better than a 100 kHz Besselfilter with a noise level comparable to that achievable with a 25 kHz Besselfilter. Improvements in SNR can be used to achieve robust statistical analyses of these recordings, which may provide importantinsights into nanopore translocation dynamics and mechanisms of ion-channel function.

Krishna Jayant, Michael Wenzel, Yuki Bando, Jorndan P Hamm, Nicola Mandriota, Jake H Rabinowitz, Ilan Jen-La Plante, Jonathan S Owen, Ozgur Sahin, Kenneth L Shepard, and Rafael Yuste. Flexible Nanopipettes for Minimally Invasive Intracellular Electrophysiology In Vivo. Cell Reports January 2, 2019, DOI:

Intracellular recordingsin vivoremains the best tech-nique to link single-neuron electrical properties tonetwork function. Yet existing methods are limitedin accuracy, throughput, and duration, primarily viawashout, membrane damage, and movement-induced failure. Here, we introduce flexible quartznanopipettes (inner diameters of 10–25 nm andspring constant of ~0.08 N/m) as nanoscale analogsof traditional glass microelectrodes. Nanopipettesenable stable intracellular recordings (seal resis-tances of 500 to ~800 MΩ,5 to ~10 cells/nanopip-ette, and duration of ~1 hr) in anaesthetized andawake head-restrained mice, exhibit minimal diffu-sional flux, and facilitate precise recording and stim-ulation. When combined with quantum-dot labelsand microprisms, nanopipettes enable two-photontargeted electrophysiology from both somata anddendrites, and even paired recordings from neigh-boring neurons, while permitting simultaneous popu-lation imaging across cortical layers. We demon-strate the versatility of this method by recordingfrom parvalbumin-positive (Pv) interneurons whileimaging seizure propagation, and we find that Pv de-polarization block coincides with epileptic spread.Flexible nanopipettes present a simple method toprocure stable intracellular recordingsin vivo.