High-density microfibers as a deep brain bidirectional optical interface

Optical interrogation and manipulation of neural dynamics is a cornerstone of systems neuroscience. Genetic targeting enable delivering fluorescent indicators and opsins to specific neural subpopulations. Optic probes can fluorescently sense and convey calcium, voltage, and neurotransmitter dynamics. This optical toolkit enables recording and perturbing cellular-resolution activity in thousands of neurons across a field of view. Yet these techniques are limited by the light scattering properties of tissues. The cutting edge of microscopy, three-photon imaging, can record from intact tissues at depths up to 1 mm, but requires head-fixed experimental paradigms. To access deeper layers and non-cortical structures, researchers rely on optical implants, such as GRIN lenses or prisms, or the removal of superficial tissue. In this thesis, we introduce a novel implant for interfacing with deep brain regions constructed from bundles of hundreds or thousands of dissociated, small diameter (<8 µm) optical fibers. During insertion into the tissue, the fibers move independently, splaying through the target region. Each fiber achieves near total internal reflection, acting as a bidirectional optical interface with a small region of tissue near the fiber aperture. The small diameter and flexibility of the fibers minimize tissue response, preserving local connectivity and circuit dynamics. Histology and immunohistochemistry from implants into zebra finch basal ganglia (depth 2.9 mm) show the splaying of the fibers and the presence of NeuN-stained cells in close proximity to the fiber tips. By modeling the optical properties of the fibers and tissue, we simulate the interface properties of a bundle of fibers. Overlap in the sensitivity between nearby fibers allows application of blind source separation to extract individual neural traces. We describe a nonnegative independent component analysis algorithm especially suited to the interface. Finally, experimental data from implants in transgenic mice yield proof of principle recordings during both cortical spreading depolarization and forepaw stimulation. Collectively, the data presented here paint a compelling picture of splaying microfibers as a deep brain interface capable of sampling or perturbing neural activity at hundreds or thousands of points throughout a 3D volume of tissue while eliciting less response than existing optical implants

Improved physiological noise regression in fNIRS: a multimodal extension of the General Linear Model using temporally embedded Canonical Correlation Analysis

For the robust estimation of evoked brain activity from functional Near-Infrared Spectroscopy (fNIRS) signals, it is crucial to reduce nuisance signals from systemic physiology and motion. The current best practice incorporates short-separation (SS) fNIRS measurements as regressors in a General Linear Model (GLM). However, several challenging signal characteristics such as non-instantaneous and non-constant coupling are not yet addressed by this approach and additional auxiliary signals are not optimally exploited. We have recently introduced a new methodological framework for the unsupervised multivariate analysis of fNIRS signals using Blind Source Separation (BSS) methods. Building onto the framework, in this manuscript we show how to incorporate the advantages of regularized temporally embedded Canonical Correlation Analysis (tCCA) into the supervised GLM. This approach allows flexible integration of any number of auxiliary modalities and signals. We provide guidance for the selection of optimal parameters and auxiliary signals for the proposed GLM extension. Its performance in the recovery of evoked HRFs is then evaluated using both simulated ground truth data and real experimental data and compared with the GLM with short-separation regression. Our results show that the GLM with tCCA significantly improves upon the current best practice, yielding significantly better results across all applied metrics: Correlation (HbO max. +45%), Root Mean Squared Error (HbO max. -55%), F-Score (HbO up to 3.25-fold) and p-value as well as power spectral density of the noise floor. The proposed method can be incorporated into the GLM in an easily applicable way that flexibly combines any available auxiliary signals into optimal nuisance regressors. This work has potential significance both for conventional neuroscientific fNIRS experiments as well as for emerging applications of fNIRS in everyday environments, medicine and BCI, where high Contrast to Noise Ratio is of importance for single trial analysis.Published versio

Extracellular electrophysiology with close-packed recording sites: spike sorting and characterization

Advances in recording technologies now allow us to record populations of neurons simultaneously, data necessary to understand the network dynamics of the brain. Extracellular probes are fabricated with ever greater numbers of recording sites to capture the activity of increasing numbers of neurons. However, the utility of this extracellular data is limited by an initial analysis step, spike sorting, that extracts the activity patterns of individual neurons from the extracellular traces. Commonly used spike sorting methods require manual processing that limits their scalability, and errors can bias downstream analyses. Leveraging the replication of the activity from a single neuron on nearby recording sites, we designed a spike sorting method consisting of three primary steps: (1) a blind source separation algorithm to estimate the underlying source components, (2) a spike detection algorithm to find the set of spikes from each component best separated from background activity and (3) a classifier to evaluate if a set of spikes came from one individual neuron. To assess the accuracy of our method, we simulated multi-electrode array data that encompass many of the realistic variations and the sources of noise in in vivo neural data. Our method was able to extract individual simulated neurons in an automated fashion without any errors in spike assignment. Further, the number of neurons extracted increased as we increased recording site count and density. To evaluate our method in vivo, we performed both extracellular recording with our close-packed probes and a co-localized patch clamp recording, directly measuring one neuron’s ground truth set of spikes. Using this in vivo data we found that when our spike sorting method extracted the patched neuron, the spike assignment error rates were at the low end of reported error rates, and that our errors were frequently the result of failed spike detection during bursts where spike amplitude decreased into the noise. We used our in vivo data to characterize the extracellular recordings of burst activity and more generally what an extracellular electrode records. With this knowledge, we updated our spike detector to capture more burst spikes and improved our classifier based on our characterizations

Motion Artifact Processing Techniques for Physiological Signals

The combination of reducing birth rate and increasing life expectancy continues to drive the demographic shift toward an ageing population and this is placing an ever-increasing burden on our healthcare systems. The urgent need to address this so called healthcare \time bomb" has led to a rapid growth in research into ubiquitous, pervasive and distributed healthcare technologies where recent advances in signal acquisition, data storage and communication are helping such systems become a reality. However, similar to recordings performed in the hospital environment, artifacts continue to be a major issue for these systems. The magnitude and frequency of artifacts can vary signicantly depending on the recording environment with one of the major contributions due to the motion of the subject or the recording transducer. As such, this thesis addresses the challenges of the removal of this motion artifact removal from various physiological signals. The preliminary investigations focus on artifact identication and the tagging of physiological signals streams with measures of signal quality. A new method for quantifying signal quality is developed based on the use of inexpensive accelerometers which facilitates the appropriate use of artifact processing methods as needed. These artifact processing methods are thoroughly examined as part of a comprehensive review of the most commonly applicable methods. This review forms the basis for the comparative studies subsequently presented. Then, a simple but novel experimental methodology for the comparison of artifact processing techniques is proposed, designed and tested for algorithm evaluation. The method is demonstrated to be highly eective for the type of artifact challenges common in a connected health setting, particularly those concerned with brain activity monitoring. This research primarily focuses on applying the techniques to functional near infrared spectroscopy (fNIRS) and electroencephalography (EEG) data due to their high susceptibility to contamination by subject motion related artifact. Using the novel experimental methodology, complemented with simulated data, a comprehensive comparison of a range of artifact processing methods is conducted, allowing the identication of the set of the best performing methods. A novel artifact removal technique is also developed, namely ensemble empirical mode decomposition with canonical correlation analysis (EEMD-CCA), which provides the best results when applied on fNIRS data under particular conditions. Four of the best performing techniques were then tested on real ambulatory EEG data contaminated with movement artifacts comparable to those observed during in-home monitoring. It was determined that when analysing EEG data, the Wiener lter is consistently the best performing artifact removal technique. However, when employing the fNIRS data, the best technique depends on a number of factors including: 1) the availability of a reference signal and 2) whether or not the form of the artifact is known. It is envisaged that the use of physiological signal monitoring for patient healthcare will grow signicantly over the next number of decades and it is hoped that this thesis will aid in the progression and development of artifact removal techniques capable of supporting this growth

Precise multimodal optical control of neural ensemble activity.

Understanding brain function requires technologies that can control the activity of large populations of neurons with high fidelity in space and time. We developed a multiphoton holographic approach to activate or suppress the activity of ensembles of cortical neurons with cellular resolution and sub-millisecond precision. Since existing opsins were inadequate, we engineered new soma-targeted (ST) optogenetic tools, ST-ChroME and IRES-ST-eGtACR1, optimized for multiphoton activation and suppression. Employing a three-dimensional all-optical read-write interface, we demonstrate the ability to simultaneously photostimulate up to 50 neurons distributed in three dimensions in a 550 × 550 × 100-µm3 volume of brain tissue. This approach allows the synthesis and editing of complex neural activity patterns needed to gain insight into the principles of neural codes

Technology applications

A summary of NASA Technology Utilization programs for the period of 1 December 1971 through 31 May 1972 is presented. An abbreviated description of the overall Technology Utilization Applications Program is provided as a background for the specific applications examples. Subjects discussed are in the broad headings of: (1) cancer, (2) cardiovascular disease, (2) medical instrumentation, (4) urinary system disorders, (5) rehabilitation medicine, (6) air and water pollution, (7) housing and urban construction, (8) fire safety, (9) law enforcement and criminalistics, (10) transportation, and (11) mine safety

Southwest Research Institute assistance to NASA in biomedical areas of the technology utilization program

The activities are reported of the NASA Biomedical Applications Team at Southwest Research Institute between 25 August, 1972 and 15 November, 1973. The program background and methodology are discussed along with the technology applications, and biomedical community impacts

Applications of aerospace technology in the public sector

Current activities of the program to accelerate specific applications of space related technology in major public sector problem areas are summarized for the period 1 June 1971 through 30 November 1971. An overview of NASA technology, technology applications, and supporting activities are presented. Specific technology applications in biomedicine are reported including cancer detection, treatment and research; cardiovascular diseases, diagnosis, and treatment; medical instrumentation; kidney function disorders, treatment, and research; and rehabilitation medicine

Study of the Term Neonatal Brain Injury with combined Diffuse Optical Tomography and Electroencephalography

This thesis describes the application of combined diffuse optical tomography (DOT) and electroencephalography (EEG) in the investigation of neonatal term brain injury. With hypoxic ischaemic encephalopathy (HIE) and perinatal stroke being the most frequent contributors to brain injury in the term neonatal population, the first part of the thesis focuses on the description and ongoing requirement for their further investigation. In continuation to that, the characteristics and unique properties of both DOT and EEG are described and explored. The combination of these two modalities was utilised in elucidating the relationship between neuronal activity and cerebral haemodynamics both in physiological processes as well as in disease, by the infant’s cot side. This work differs to previous studies using near-infrared technologies and EEG, as a denser whole head array was used, offering the potential of 3-dimensional image reconstruction of the cortical haemodynamic events in relation to electro-cortical activity. These methods were applied in the study of critically ill infants presenting with seizures in the first few days of life. The relevant results are presented in three separate chapters of the thesis. Distinct neurophysiological phenomena such as seizures and burst suppression were detected and studied in association to underlying HIE. On the grounds of a pre-existing pilot study of our research group, distinct prolonged de-oxygenated cortical areas were identified following electrical seizure activity. Further exploration of infants with seizures provided limited supporting evidence. The investigation of burst suppression in HIE led to the first ever identification of repeated, waveform, cortical haemodynamic events in response to bursts of electrical activity with some spatial correlation to regions of brain injury. Further analysis of the low frequencies within the diffuse optical signal in cases of perinatal stroke, showed a consistent interhemispheric difference between the healthy and stroke-affected brain regions. The limitations, prospects and conclusions are presented in the final chapter. The use of simultaneous DOT and EEG offers a unique neuro-monitoring and neuro-investigating tool in the neonatal intensive care environment, which is safe, portable, and cost-effective, Ongoing research is required for the exploration and development of the methodology and its potential diagnostic properties