Depth-Dependent Contributions of Various Vascular Zones to Cerebral Autoregulation and Functional Hyperemia: An In-Silico Analysis.

Autoregulation and neurogliavascular coupling are key mechanisms that modulate myogenic tone (MT) in vessels to regulate cerebral blood flow (CBF) during resting state and periods of increased neural activity, respectively. To determine relative contributions of distinct vascular zones across different cortical depths in CBF regulation, we developed a simplified yet detailed and computationally efficient model of the mouse cerebrovasculature. The model integrates multiple simplifications and generalizations regarding vascular morphology, the hierarchical organization of mural cells, and potentiation/inhibition of MT in vessels.

Illumination pattern optimization in tomography based on the Kalman estimation filter and optimal experiment design.

Tomography is widely used in medical imaging or industrial non-destructive testing applications. One costly and time consuming operation in any form of tomography is the process of data acquisition where a large number of measurements are made and collected data is used for image reconstruction. Data acquisition can slow down tomography to the point that the scanner cannot catch up with the speed of changes in the medium under test.

Optimal data acquisition in tomography.

In tomography, three-dimensional images of a medium are reconstructed from a set of two-dimensional projections. Each projection is the result of a measurement made by the scanner via radiating some form of energy and collecting the scattered field after interacting with the medium. The information content of these measurements is not equal, and one projection can be more informative than others.

Optimal Scanning Protocol for Optical Tomography.

Tomography is a two step process in which the sample under test is first scanned by the hardware of the system to acquire data and then the operating software reconstruct images from the gathered information. The main objective of this work is to optimize the scanning process to acquire maximum amount of information in each measurement when the system is scanning the sample. By exploiting our prior information about the sample and using estimation theory, we developed a systematic approach to implement the optimal scanning protocol.

Optimization of data acquisition operation in optical tomography based on estimation theory.

The data acquisition process is occasionally the most time consuming and costly operation in tomography. Currently, raster scanning is still the common practice in making sequential measurements in most tomography scanners. Raster scanning is known to be slow and such scanners usually cannot catch up with the speed of changes when imaging dynamically evolving objects.

Optical Coherence Tomography Angiography in the Thirteen-Lined Ground Squirrel.

Purpose: To assess the performance of two spectral-domain optical coherence tomography-angiography systems in a natural model of hypoperfusion: the hibernating thirteen-lined ground squirrel (13-LGS).

Methods: Using a high-speed (130 kHz) OCT-A system (HS-OCT-A) and a commercial OCT (36 kHz; Bioptigen Envisu; BE-OCT-A), we imaged the 13-LGS retina throughout its hibernation cycle. Custom software was used to extract the superior, middle, and deep capillary plexus (SCP, MCP, and DCP, respectively).

A system identification analysis of optogenetically evoked electrocorticography and cerebral blood flow responses.

Objective: The main objective of this research was to study the coupling between neural circuits and the vascular network in the cortex of small rodents from system engineering point of view and generate a mathematical model for the dynamics of neurovascular coupling. The model was adopted to implement closed-loop blood flow control algorithms.

Approach: We used a combination of advanced technologies including optogenetics, electrocorticography, and optical coherence tomography to stimulate selected populations of neurons and simultaneously record induced electrocorticography and hemodynamic signals.

Wheel running for 26 weeks is associated with sustained vascular plasticity in the rat motor cortex.

Vascular pathologies represent the leading causes of mortality worldwide. The nervous system has evolved mechanisms to compensate for the cerebral hypoxia caused by many of these conditions. Vessel dilation and growth of new vessels are two prominent responses to hypoxia, both of which play a critical role in maintaining cerebral homeostasis.

Optogenetic interrogation of neurovascular coupling in the cerebral cortex of transgenic mice.

Objective: We introduce an engineering approach to study spatiotemporal correlations between vasodynamics and the nearby neural activity in open-loop and closed-loop paradigms.

Approach: We integrated optogenetic technology with optical coherence tomography to apply spatiotemporal patterns of optical neurostimulation to the cortex of transgenic optogenetic mice and measure blood flow-rate, velocity, and diameter changes of selected middle cerebral artery branches.

Main Results: The spatiotemporal characteristics of blood flow-rate, velocity, and vessel diameter responses to localized neurostimulation light pulses were measured.

Electrical Neural Stimulation and Simultaneous in Vivo Monitoring with Transparent Graphene Electrode Arrays Implanted in GCaMP6f Mice.

Electrical stimulation using implantable electrodes is widely used to treat various neuronal disorders such as Parkinson's disease and epilepsy and is a widely used research tool in neuroscience studies. However, to date, devices that help better understand the mechanisms of electrical stimulation in neural tissues have been limited to opaque neural electrodes. Imaging spatiotemporal neural responses to electrical stimulation with minimal artifact could allow for various studies that are impossible with existing opaque electrodes.

Fluorescence laminar optical tomography for brain imaging: system implementation and performance evaluation.

We present our effort in implementing a fluorescence laminar optical tomography scanner which is specifically designed for noninvasive three-dimensional imaging of fluorescence proteins in the brains of small rodents. A laser beam, after passing through a cylindrical lens, scans the brain tissue from the surface while the emission signal is captured by the epi-fluorescence optics and is recorded using an electron multiplication CCD sensor. Image reconstruction algorithms are developed based on Monte Carlo simulation to model light–tissue interaction and generate the sensitivity matrices.

Fabrication and utility of a transparent graphene neural electrode array for electrophysiology, in vivo imaging, and optogenetics.

Transparent graphene-based neural electrode arrays provide unique opportunities for simultaneous investigation of electrophysiology, various neural imaging modalities, and optogenetics. Graphene electrodes have previously demonstrated greater broad-wavelength transmittance (∼90%) than other transparent materials such as indium tin oxide (∼80%) and ultrathin metals (∼60%). This protocol describes how to fabricate and implant a graphene-based microelectrocorticography (μECoG) electrode array and subsequently use this alongside electrophysiology, fluorescence microscopy, optical coherence tomography (OCT), and optogenetics.

Calibration of digital optical phase conjugation setups based on orthonormal rectangular polynomials.

Digital optical phase conjugation (DOPC) has proven to be a promising technique in deep tissue fluorescence imaging. Nonetheless, DOPC optical setups require precise alignment of all optical components to accurately read the wavefront of scattered light in a turbid medium and playback the conjugated beam toward the sample. Minor misalignments and possible imperfections in the arrangement or the structure of the optical components significantly reduce the performance of the method.

Intracranial Injection of an Optogenetics Viral Vector Followed by Optical Cannula Implantation for Neural Stimulation in Rat Brain Cortex.

Optogenetics is rapidly gaining acceptance as a preferred method to study specific neuronal cell types using light. Optogenetic neuromodulation requires the introduction of a cell-specific viral vector encoding for a light activating ion channel or ion pump and the utilization of a system to deliver light stimulation to brain. Here, we describe a two-part methodology starting with a procedure to inject an optogenetic AAV virus into rat cortex followed by a second procedure to surgically implant an optical cannula for light delivery to the deeper cortical layers.

Analysis of intermediary scan-lens and tube-lens mechanisms for optical coherence tomography.

Combining an optical coherence tomography (OCT) scanner with other techniques such as optogenetic neurostimulation or fluorescence imaging requires integrating auxiliary components into the optical path of the setup. Due to the short scanning distance of most OCT objectives, adding scan and tube lenses in the device is essential to open space between the back-focal-plane of the objective and center of mass of the mirrors in the galvanometer. The effect of the scan and tube lenses on the focal spot size of the scanner using off-the-shelf components are theoretically explored for three different designs in this paper.

OptogenSIM: a 3D Monte Carlo simulation platform for light delivery design in optogenetics.

Optimizing light delivery for optogenetics is critical in order to accurately stimulate the neurons of interest while reducing nonspecific effects such as tissue heating or photodamage. Light distribution is typically predicted using the assumption of tissue homogeneity, which oversimplifies light transport in heterogeneous brain. Here, we present an open-source 3D simulation platform, OptogenSIM, which eliminates this assumption.

Effect of blood vessels on light distribution in optogenetic stimulation of cortex.

In this Letter, the impact of blood vessels on light distribution during photostimulation of cortical tissue in small rodents is investigated. Brain optical properties were extracted using a double-integrating sphere setup, and optical coherence tomography was used to image cortical vessels and capillaries to generate a three-dimensional angiogram of the cortex. By combining these two datasets, a complete volumetric structure of the cortical tissue was developed and linked to a Monte Carlo code which simulates light propagation in this inhomogeneous structure and illustrates the effect of blood vessels on the penetration depth and pattern preservation in optogenetic stimulation.

Closed-Loop Optogenetic Brain Interface.

This paper presents a new approach for implementation of closed-loop brain-machine interface algorithms by combining optogenetic neural stimulation with electrocorticography and fluorescence microscopy. We used a new generation of microfabricated electrocorticography (micro-ECoG) devices in which electrode arrays are embedded within an optically transparent biocompatible substrate that provides optical access to the brain tissue during electrophysiology recording. An optical setup was designed capable of projecting arbitrary patterns of light for optogenetic stimulation and performing fluorescence microscopy through the implant.

Patterned optogenetic modulation of neurovascular and metabolic signals.

The hemodynamic and metabolic response of the cortex depends spatially and temporally on the activity of multiple cell types. Optogenetics enables specific cell types to be modulated with high temporal precision and is therefore an emerging method for studying neurovascular and neurometabolic coupling. Going beyond temporal investigations, we developed a microprojection system to apply spatial photostimulus patterns in vivo.

Monitoring cerebral hemodynamics following optogenetic stimulation via optical coherence tomography.

In this article, spectral domain optical coherence tomography is used to measure the hemodynamic response induced by optogenetic stimulation in the somatosensory cortex of transgenic mice. By analyzing the 3-D angiograms and Doppler measurements produced by coherence tomography, we observed significant increase in blood flow as a result of increased vessel diameter and blood velocity following optical stimulation of cortical neurons. Such distinct responses were not observed in control experiments where the brain of wild-type mice were exposed to the same light pulses.

Graphene-based carbon-layered electrode array technology for neural imaging and optogenetic applications.

Neural micro-electrode arrays that are transparent over a broad wavelength spectrum from ultraviolet to infrared could allow for simultaneous electrophysiology and optical imaging, as well as optogenetic modulation of the underlying brain tissue. The long-term biocompatibility and reliability of neural micro-electrodes also require their mechanical flexibility and compliance with soft tissues. Here we present a graphene-based, carbon-layered electrode array (CLEAR) device, which can be implanted on the brain surface in rodents for high-resolution neurophysiological recording.

Extraction of optical properties and prediction of light distribution in rat brain tissue.

Predicting the distribution of light inside any turbid media, such as biological tissue, requires detailed information about the optical properties of the medium, including the absorption and scattering coefficients and the anisotropy factor. Particularly, in biophotonic applications where photons directly interact with the tissue, this information translates to system design optimization, precision in light delivery, and minimization of unintended consequences, such as phototoxicity or photobleaching. In recent years, optogenetics has opened up a new area in deep brain stimulation with light and the method is widely adapted by researchers for the study of the brain circuitries and the dynamics of neurological disorders.

The effect of micro-ECoG substrate footprint on the meningeal tissue response.

Objective: There is great interest in designing implantable neural electrode arrays that maximize function while minimizing tissue effects and damage. Although it has been shown that substrate geometry plays a key role in the tissue response to intracortically implanted, penetrating neural interfaces, there has been minimal investigation into the effect of substrate footprint on the tissue response to surface electrode arrays. This study investigates the effect of micro-electrocorticography (micro-ECoG) device geometry on the longitudinal tissue response.

Optogenetic brain interfaces.

The brain is a large network of interconnected neurons where each cell functions as a nonlinear processing element. Unraveling the mysteries of information processing in the complex networks of the brain requires versatile neurostimulation and imaging techniques. Optogenetics is a new stimulation method which allows the activity of neurons to be modulated by light.

Optogenetic micro-electrocorticography for modulating and localizing cerebral cortex activity.

Objective: Spatial localization of neural activity from within the brain with electrocorticography (ECoG) and electroencephalography remains a challenge in clinical and research settings, and while microfabricated ECoG (micro-ECoG) array technology continues to improve, complementary methods to simultaneously modulate cortical activity while recording are needed.

Approach: We developed a neural interface utilizing optogenetics, cranial windowing, and micro-ECoG arrays fabricated on a transparent polymer. This approach enabled us to directly modulate neural activity at known locations around micro-ECoG arrays in mice expressing Channelrhodopsin-2.