Kartikeya Murari

Micropower CMOS Integrated Low-Noise Amplification, Filtering, and Digitization of Multimodal Neuropotentials

Electrical activity in the brain spans a wide range of spatial and temporal scales, requiring simultaneous recording of multiple modalities of neurophysiological signals in order to capture various aspects of brain state dynamics. Here, we present a 16-channel neural interface integrated circuit fabricated in a 0.5 mum 3M2P CMOS process for selective digital acquisition of biopotentials across the spectrum of neural signal modalities in the brain, ranging from single spike action potentials to local field potentials (LFP), electrocorticograms (ECoG), and electroencephalograms (EEG). Each channel is composed of a tunable bandwidth, fixed gain front-end amplifier and a programmable gain/resolution continuous-time incremental DeltaSigma analog-to-digital converter (ADC). A two-stage topology for the front-end voltage amplifier with capacitive feedback offers independent tuning of the amplifier bandpass frequency corners, and attains a noise efficiency factor (NEF) of 2.9 at 8.2 kHz bandwidth for spike recording, and a NEF of 3.2 at 140 Hz bandwidth for EEG recording. The amplifier has a measured midband gain of 39.6 dB, frequency response from 0.2 Hz to 8.2 kHz, and an input-referred noise of 1.94 muV rms while drawing 12.2 muA of current from a 3.3 V supply. The lower and higher cutoff frequencies of the bandpass filter are adjustable from 0.2 to 94 Hz and 140 Hz to 8.2 kHz, respectively. At 10-bit resolution, the ADC has an SNDR of 56 dB while consuming 76 muW power. Time-modulation feedback in the ADC offers programmable digital gain (1-4096) for auto-ranging, further improving the dynamic range and linearity of the ADC. Experimental recordings with the system show spike signals in rat somatosensory cortex as well as alpha EEG activity in a human subject.

VLSI Potentiostat Array With Oversampling Gain Modulation for Wide-Range Neurotransmitter Sensing

A 16-channel current-measuring very large-scale integration (VLSI) sensor array system for highly sensitive electrochemical detection of electroactive neurotransmiters like dopamine and nitric-oxide is presented. Each channel embeds a current integrating potentiostat within a switched-capacitor first-order single-bit delta-sigma modulator implementing an incremental analog-to-digital converter. The duty-cycle modulation of current feedback in the delta-sigma loop together with variable oversampling ratio provide a programmable digital range selection of the input current spanning over six orders of magnitude from picoamperes to microamperes. The array offers 100-fA input current sensitivity at 3.4-muW power consumption per channel. The operation of the 3 mm times3 mm chip fabricated in 0.5-mum CMOS technology is demonstrated with real-time multichannel acquisition of neurotransmitter concentration

A compact fiber-optic SHG scanning endomicroscope and its application to visualize cervical remodeling during pregnancy

We report the development of an all-fiber-optic scanning endomicroscope capable of high-resolution second harmonic generation (SHG) imaging of biological tissues and demonstrate its utility for monitoring the remodeling of cervical collagen during gestation in mice. The endomicroscope has an overall 2.0 mm diameter and consists of a single customized double-clad fiber, a compact rapid two-dimensional beam scanner, and a miniature compound objective lens for excitation beam delivery, scanning, focusing, and efficient SHG signal collection. Endomicroscopic SHG images of murine cervical tissue sections at different stages of normal pregnancy reveal progressive, quantifiable changes in cervical collagen morphology with resolution similar to that of bench-top SHG microscopy. SHG endomicroscopic imaging of ex vivo murine and human cervical tissues through intact epithelium has also been performed. Our findings demonstrate the feasibility of SHG endomicroscopy technology for staging normal pregnancy, and suggest its potential application as a minimally invasive tool for clinical assessment of abnormal cervical remodeling associated with preterm birth.

Contrast-enhanced imaging of cerebral vasculature with laser speckle

High-resolution cerebral vasculature imaging has applications ranging from intraoperative procedures to basic neuroscience research. Laser speckle, with spatial contrast processing, has recently been used to map cerebral blood flow. We present an application of the technique using temporal contrast processing to image cerebral vascular structures with a field of view a few millimeters across and approximately 20 microm resolution through a thinned skull. We validate the images using fluorescent imaging and demonstrate a factor of 2-4 enhancement in contrast-to-noise ratios over reflectance imaging using white or spectrally filtered green light. The contrast enhancement enables the perception of approximately 10%-30% more vascular structures without the introduction of any contrast agent.

Integrated multimodal endomicroscopy platform for simultaneous en face optical coherence and two-photon fluorescence imaging

We report an all-fiber-optic scanning, multimodal endomicroscope capable of simultaneous optical coherence tomography (OCT) and two-photon fluorescence (TPF) imaging. Both imaging modalities share the same miniature fiber-optic scanning endomicroscope, which consists of a double-clad fiber with a core operating in single mode at both the OCT (1310 nm) and two-photon excitation (1550 nm) wavelengths, a piezoelectric two-dimensional fiber-optic beam scanner, and a miniature aspherical compound lens suitable for simultaneous acquisition of en face OCT and TPF images. A fiber-optic wavelength division multiplexer was employed in the integrated platform to combine the low coherence OCT light source and the femtosecond two-photon excitation laser into the same optical path. Preliminary imaging results of cell cultures and mouse tissue ex vivo demonstrate the feasibility of simultaneous real-time OCT and TPF imaging in a scanning endomicroscopy setting for the first time.

High spatiotemporal resolution imaging of the neurovascular response to electrical stimulation of rat peripheral trigeminal nerve as revealed by in vivo temporal laser speckle contrast

Previous studies have implicated the abnormal activation of the trigeminal system to be a factor in the pathogenesis of migraine. The relationship between vascular changes and migraine, however, is under considerable debate. In this study, temporal laser speckle contrast imaging is combined with ridge tracking based vessel detection to obtain high resolution (6.7 microm x 6.7 microm), high contrast images of cerebral vascular structure. For the first time, the vasomotor and blood flow responses to electrical stimulation in rat peripheral trigeminal system were obtained simultaneously. The system is capable of picking up individual vessels with diameters down to 30 microm. The spatial spread of the blood velocity response relative to the point of stimulation was studied. Analysis of branching vessels showed a 50+/-5% vs. 30+/-5% change in mean peak magnitude and a 54% per second vs. 17% per second change in mean rate of increase for vessels proximal vs. distal to the stimulation site. The penetration depth of the laser used was proven to be sufficient to image dural as well as cortical vessels through a thinned skull preparation. Different responses were observed from cortical and dural vessels. While the diameter of cortical vessels did not change in response to the stimulation the blood velocity went up by 65+/-5% per second. Dural vessels enlarged by 40+/-8% and the blood velocity increased by 50+/-5%. The method described here could be very useful in understanding and studying disorders in the neurovascular system.

Which Photodiode to Use: A Comparison of CMOS-Compatible Structures

While great advances have been made in optimizing fabrication process technologies for solid state image sensors, the need remains to be able to fabricate high quality photosensors in standard CMOS processes. The quality metrics depend on both the pixel architecture and the photosensitive structure. This paper presents a comparison of three photodiode structures in terms of spectral sensitivity, noise and dark current. The three structures are n+/p-sub, n-well/p-sub and p+/n-well/p-sub. All structures were fabricated in a 0.5 mum 3-metal, 2-poly, n-well process and shared the same pixel and readout architectures. Two pixel structures were fabricated-the standard three transistor active pixel sensor, where the output depends on the photodiode capacitance, and one incorporating an in-pixel capacitive transimpedance amplifier where the output is dependent only on a designed feedback capacitor. The n-well /p-sub diode performed best in terms of sensitivity (an improvement of 3.5 times and 1.6 times over the n+/p-sub and p+/n-well/p-sub diodes, respectively) and signal-to-noise ratio (1. 5times and 1.2 times improvement over the n+/p-sub and p+/n-well/p-sub diodes, respectively) while the p+/n-well/p-sub diode had the minimum (33% compared to other two structures) dark current for a given sensitivity.

Compensation-free, all-fiber-optic, two-photon endomicroscopy at 1.55 μm

We present an all-fiber-optic scanning multiphoton endomicroscope with 1.55 μm excitation without the need for prechirping femtosecond pulses before the endomicroscope. The system consists of a 1.55 μm femtosecond fiber laser, a customized double-clad fiber for light delivery and fluorescence collection, and a piezoelectric scan head. We demonstrate two-photon imaging of cultured cells and mouse tissue, both labeled with indocyanine green. Free-space multiphoton imaging with near-IR emission has previously shown benefits in reduced background fluorescence and lower attenuation for the fluorescence emission. For fiber-optic multiphoton imaging there is the additional advantage of using the soliton effect at the telecommunication wavelengths (1.3-1.6 μm) in fibers, permitting dispersion-compensation-free, small-footprint systems. We expect these advantages will help transition multiphoton endomicroscopy to the clinic.

A CMOS In-Pixel CTIA High-Sensitivity Fluorescence Imager

Traditionally, charge-coupled device (CCD)-based image sensors have held sway over the field of biomedical imaging. Complementary metal-oxide semiconductor (CMOS)-based imagers so far lack sensitivity leading to poor low-light imaging. Certain applications including our work on animal-mountable systems for imaging in awake and unrestrained rodents require the high sensitivity and image quality of CCDs and the low power consumption, flexibility, and compactness of CMOS imagers. We present a 132 × 124 high sensitivity imager array with a 20.1-μ m pixel pitch fabricated in a standard 0.5- μm CMOS process. The chip incorporates n-well/p-sub photodiodes, capacitive transimpedance amplifier (CTIA)-based in-pixel amplification, pixel scanners, and delta differencing circuits. The 5-transistor all-nMOS pixel interfaces with peripheral pMOS transistors for column-parallel CTIA. At 70 frames/s, the array has a minimum detectable signal of 4 nW/cm2 at a wavelength of 450 nm while consuming 718 μA from a 3.3-V supply. The peak signal-to-noise ratio (SNR) was 44 dB at an incident intensity of 1 μW/cm2. Implementing 4 × 4 binning allowed the frame rate to be increased to 675 frames/s. Alternately, sensitivity could be increased to detect about 0.8 nW/cm2 while maintaining 70 frames/s. The chip was used to image single-cell fluorescence at 28 frames/s with an average SNR of 32 dB. For comparison, a cooled CCD camera imaged the same cell at 20 frames/s with an average SNR of 33.2 dB under the same illumination while consuming more than a watt.

Integrated potentiostat for neurotransmitter sensing

We have presented a chemical analysis paradigm for neurochemical studies, as opposed to the traditional electrophysiological regime. We described electrochemical analysis and the instrumentation involved in doing such analysis. The article presents the design and characterization of a 16-channel, high-sensitivity, wide-range VLSI potentiostat. We demonstrate the use of this potentiostat in real-time in vitro monitoring of the neurotransmitter dopamine.