High-resolution mapping of infraslow cortical brain activity enabled by graphene microtransistors.

Recording infraslow brain signals (<0.1 Hz) with microelectrodes is severely hampered by current microelectrode materials, primarily due to limitations resulting from voltage drift and high electrode impedance. Hence, most recording systems include high-pass filters that solve saturation issues but come hand in hand with loss of physiological and pathological information. In this work, we use flexible epicortical and intracortical arrays of graphene solution-gated field-effect transistors (gSGFETs) to map cortical spreading depression in rats and demonstrate that gSGFETs are able to record, with high fidelity, infraslow signals together with signals in the typical local field potential bandwidth. The wide recording bandwidth results from the direct field-effect coupling of the active transistor, in contrast to standard passive electrodes, as well as from the electrochemical inertness of graphene. Taking advantage of such functionality, we envision broad applications of gSGFET technology for monitoring infraslow brain activity both in research and in the clinic.

High-density speckle contrast optical tomography (SCOT) for three dimensional tomographic imaging of the small animal brain.

High-density speckle contrast optical tomography (SCOT) utilizing tens of thousands of source-detector pairs, was developed for in vivo imaging of blood flow in small animals. The reduction in cerebral blood flow (CBF) due to local ischemic stroke in a mouse brain was transcanially imaged and reconstructed in three dimensions. The reconstructed volume was then compared with corresponding magnetic resonance images demonstrating that the volume of reduced CBF agrees with the infarct zone at twenty-four hours.

Time resolved speckle contrast optical spectroscopy at quasi-null source-detector separation for non-invasive measurement of microvascular blood flow.

Time (or path length) resolved speckle contrast optical spectroscopy (TD-SCOS) at quasi-null (2.85 mm) source-detector separation was developed and demonstrated. The method was illustrated by in vivo studies on the forearm muscle of an adult subject. The results have shown that selecting longer photon path lengths results in higher hyperemic blood flow change and a faster return to baseline by a factor of two after arterial cuff occlusion when compared to SCOS without time resolution. This indicates higher sensitivity to the deeper muscle tissue. In the long run, this approach may allow the use of simpler and cheaper detector arrays compared to time resolved diffuse correlation spectroscopy that are based on readily available technologies. Hence, TD-SCOS may increase the performance and decrease cost of devices for continuous non-invasive, deep tissue blood flow monitoring.

High-density speckle contrast optical tomography of cerebral blood flow response to functional stimuli in the rodent brain.

Noninvasive, three-dimensional, and longitudinal imaging of cerebral blood flow (CBF) in small animal models and ultimately in humans has implications for fundamental research and clinical applications. It enables the study of phenomena such as brain development and learning and the effects of pathologies, with a clear vision for translation to humans. Speckle contrast optical tomography (SCOT) is an emerging optical method that aims to achieve this goal by directly measuring three-dimensional blood flow maps in deep tissue with a relatively inexpensive and simple system. High-density SCOT is developed to follow CBF changes in response to somatosensory cortex stimulation. Measurements are carried out through the intact skull on the rat brain. SCOT is able to follow individual trials in each brain hemisphere, where signal averaging resulted in comparable, cortical images to those of functional magnetic resonance images in spatial extent, location, and depth. Sham stimuli are utilized to demonstrate that the observed response is indeed due to local changes in the brain induced by forepaw stimulation. In developing and demonstrating the method, algorithms and analysis methods are developed. The results pave the way for longitudinal, nondestructive imaging in preclinical rodent models that can readily be translated to the human brain.

Compact, multi-exposure speckle contrast optical spectroscopy (SCOS) device for measuring deep tissue blood flow.

Speckle contrast optical spectroscopy (SCOS) measures absolute blood flow in deep tissue, by taking advantage of multi-distance (previously reported in the literature) or multi-exposure (reported here) approach. This method promises to use inexpensive detectors to obtain good signal-to-noise ratio, but it has not yet been implemented in a suitable manner for a mass production. Here we present a new, compact, low power consumption, 32 by 2 single photon avalanche diode (SPAD) array that has no readout noise, low dead time and has high sensitivity in low light conditions, such as in vivo measurements. To demonstrate the capability to measure blood flow in deep tissue, healthy volunteers were measured, showing no significant differences from the diffuse correlation spectroscopy. In the future, this array can be miniaturized to a low-cost, robust, battery operated wireless device paving the way for measuring blood flow in a wide-range of applications from sport injury recovery and training to, on-field concussion detection to wearables.

Longitudinal, transcranial measurement of functional activation in the rat brain by diffuse correlation spectroscopy.

Neural activity is an important biomarker for the presence of neurodegenerative diseases, cerebrovascular alterations, and brain trauma; furthermore, it is a surrogate marker for treatment effects. These pathologies may occur and evolve in a long time-period, thus, noninvasive, transcutaneous techniques are necessary to allow a longitudinal follow-up. In the present work, we have customized noninvasive, transcutaneous, diffuse correlation spectroscopy (DCS) to localize changes in cerebral blood flow (CBF) induced by neural activity. We were able to detect changes in CBF in the somatosensory cortex by using a model of electrical forepaw stimulation in rats. The suitability of DCS measurements for longitudinal monitoring was demonstrated by performing multiple sessions with the same animals at different ages (from 6 to 18 months). In addition, functional DCS has been cross-validated by comparison with functional magnetic resonance imaging (fMRI) in the same animals in a subset of the time-points. The overall results obtained with transcutaneous DCS demonstrates that it can be utilized in longitudinal studies safely and reproducibly to locate changes in CBF induced by neural activity in the small animal brain.

High-speed multi-exposure laser speckle contrast imaging with a single-photon counting camera.

Laser speckle contrast imaging (LSCI) has emerged as a valuable tool for cerebral blood flow (CBF) imaging. We present a multi-exposure laser speckle imaging (MESI) method which uses a high-frame rate acquisition with a negligible inter-frame dead time to mimic multiple exposures in a single-shot acquisition series. Our approach takes advantage of the noise-free readout and high-sensitivity of a complementary metal-oxide-semiconductor (CMOS) single-photon avalanche diode (SPAD) array to provide real-time speckle contrast measurement with high temporal resolution and accuracy. To demonstrate its feasibility, we provide comparisons between in vivo measurements with both the standard and the new approach performed on a mouse brain, in identical conditions.

Speckle contrast optical spectroscopy, a non-invasive, diffuse optical method for measuring microvascular blood flow in tissue.

We introduce a new, non-invasive, diffuse optical technique, speckle contrast optical spectroscopy (SCOS), for probing deep tissue blood flow using the statistical properties of laser speckle contrast and the photon diffusion model for a point source. The feasibility of the method is tested using liquid phantoms which demonstrate that SCOS is capable of measuring the dynamic properties of turbid media non-invasively. We further present an in vivo measurement in a human forearm muscle using SCOS in two modalities: one with the dependence of the speckle contrast on the source-detector separation and another on the exposure time. In doing so, we also introduce crucial corrections to the speckle contrast that account for the variance of the shot and sensor dark noises.