Neuronal cell signal analysis: spike detection algorithm development for microelectrode array recordings

Neural signal acquisition and processing techniques are rising trends among wide scientific and commercial areas. Microelectrode array (MEA) technology makes it possible to access and record the electrical activity of neural cells. In this work, human pluripotent stem cell (hPSC) -derived neuronal populations were grown on MEA plates. The activity of the cells was recorded and the research about modern signal processing methods for the neural spike detection was performed. A list of approaches was selected for detailed investigation and the most efficient one was chosen as the new technique for permanent use in the research group. The performed laboratory activities involved cell culture plating, regular medium changes, spontaneous activity recordings and pharmacological manipulations. The data acquired from pharmacological experiments were used for the comparison between the old and new spike detection algorithms in terms of the numbers of the detected events. The Stationary Wavelet Transform-based Teager Energy Operator (SWTTEO) shows prominent performance in the tests with synthetic data. The use of the proposed algorithm in conjunction with the common amplitude-based thresholding enables to lower the threshold and to detect more spikes without an excessive number of false positives. This mode is applicable for real cell data. The detection method was considered superior and was further distributed for the processing of all neural data of the research group which include signals acquired from neuronal populations derived from human embryonic and induced pluripotent stem cells (hESCs and iPSCs) as well as rat cells

Analog VLSI Circuits for Biosensors, Neural Signal Processing and Prosthetics

Stroke, spinal cord injury and neurodegenerative diseases such as ALS and Parkinson's debilitate their victims by suffocating, cleaving communication between, and/or poisoning entire populations of geographically correlated neurons. Although the damage associated with such injury or disease is typically irreversible, recent advances in implantable neural prosthetic devices offer hope for the restoration of lost sensory, cognitive and motor functions by remapping those functions onto healthy cortical regions. The research presented in this thesis is directed toward developing enabling technology for totally implantable neural prosthetics that could one day restore lost sensory, cognitive and motor function to the victims of debilitating neural injury or disease. There are three principal components to this work. First, novel integrated biosensors have been designed and implemented to transduce weak extra-cellular electrical potentials and optical signals from cells cultured directly on the surface of the sensor chips, as well as to manipulate cells on the surface of these chips. Second, a method of detecting and identifying stereotyped neural signals, or action potentials, has been mapped into silicon circuits which operate at very low power levels suitable for implantation. Third, as one small step towards the development of cognitive neural implants, a learning silicon synapse has been implemented and a neural network application demonstrated. The original contributions of this dissertation include: * A contact image sensor that adapts to background light intensity and can asynchronously detect statistically significant optical events in real-time; * Programmable electrode arrays for enhanced electrophysiological recording, for directing cellular growth, for site-specific in situ bio-functionalization, and for analyte and particulate collection; * Ultra-low power, programmable floating gate template matching circuits for the detection and classification of neural action potentials; * A two transistor synapse that exhibits spike timing dependent plasticity and can implement adaptive pattern classification and silicon learning

Coupled Correlates of Attention and Consciousness

Introduction: Brain Computer Interfaces (BCIs) have been shown to restore lost motor function that occurs in stroke using electrophysiological signals. However, little evidence exists for the use of BCIs to restore non-motor stroke deficits, such as the attention deficits seen in hemineglect. Attention is a cognitive function that selects objects or ideas for further neural processing, presumably to facilitate optimal behavior. Developing BCIs for attention is different from developing motor BCIs because attention networks in the brain are more distributed and associative than motor networks. For example, hemineglect patients have reduced levels of arousal, which exacerbates their attentional deficits. More generally, attention is a state of high arousal and salient conscious experience. Current models of consciousness suggest that both slow wave sleep and Propofol-induced unconsciousness lie at one end of the consciousness spectrum, while attentive states lie at the other end. Accordingly, investigating the electrophysiology underlying attention and the extremes of consciousness will further the development of attentional BCIs. Phase amplitude coupling (PAC) of neural oscillations has been suggested as a mechanism for organizing local and global brain activity across regions. While evidence suggests that delta-high-gamma PAC, which includes very low frequencies (i.e. delta, 1-3 Hz) coupled with very high frequencies (i.e. gamma 70-150 Hz), is implicated in attention, less evidence exists for the involvement of coupled mid-range frequencies (i.e. theta, 4-7Hz, alpha: 8-15 Hz, beta: 15-30 Hz and low-gamma: 30-50 Hz, aka TABL PAC). We found that TABL PAC correlates with reaction time in an attention task. These mid-range frequencies are important because they can be used in non-invasive electroencephalography (EEG) BCI’s. Therefore, we investigated the origins of these mid-frequency interactions in both attention and consciousness. In this work, we evaluate the relationship between PAC to attention and arousal, with emphasis on developing control signals for an attentional BCI. Objective: To understand how PAC facilitates attention and arousal for building BCI’s that restore lost attentional function. More generally, our objective was to discover and understand potential control features for BCIs that enhance attention and conscious experience. Methods: We used four electrophysiological datasets in human subjects. The first dataset included six subjects with invasive ECoG recordings while subjects engaged in a Posner cued spatial attention task. The second dataset included five subjects with ECoG recordings during sleep and awake states. The third dataset included 6 subjects with invasively monitored ECoG during induction and emergence from Propofol anesthesia. We validated findings from the second dataset with an EEG dataset that included 39 subjects with EEG and sleep scoring. We developed custom, wavelet-based, signal processing algorithms designed to optimally calculate differences in mid-frequency-range (i.e. TABL) PAC and compare them to DH PAC across different attentional and conscious states. We developed non-parametric cluster-based permutation tests to infer statistical significance while minimizing the false-positive rate. In the attention experiment, we used the location of cued spatial stimuli and reaction time (RT) as markers of attention. We defined stimulus-related and behaviorally-related cortical sites and compared their relative PAC magnitudes. In the sleep dataset, we compared PAC across sleep states (e.g. Wake vs Slow Wave Sleep). In the anesthesia dataset, we compared the beginning and ending of induction and emergence (e.g. Wake vs Propofol Induced Loss of Consciousness) Results: We found different patterns of activity represented by TABL PAC and DH PAC in both attention and sleep datasets. First, during a spatial attention task TABL PAC robustly predicted whether a subject would respond quickly or slowly. TABL PAC maintained a consistent phase-preference across all cortical sites and was strongest in behaviorally-relevant cortical sites. In contrast, DH PAC represented the location of attention in spatially-relevant cortical sites. Furthermore, we discovered that sharp waves caused TABL PAC. These sharp waves appeared to be transient beta (50ms) waves that occurred at ~140 ms intervals, corresponding to a theta oscillation. In the arousal dataset DH PAC increased in both slow wave sleep (SWS) and Propofol-induced loss of consciousness (PILOC) states. However, TABL PAC increased only during PILOC and decreased during SWS, when compared to waking states. We provide evidence that TABL PAC represents “gating by inhibition” in the human brain. Conclusions: Our goal was to develop electrophysiological signals representing attention and to understand how these features explain the relationship between attention and low-arousal states. We found a novel biomarker, TABL PAC, that predicted non-spatial aspects of attention and discriminated between two states of unconsciousness. The evidence suggested that TABL PAC represents inhibitory activity that filters out irrelevant information in attention tasks. This inhibitory mechanism of was confirmed by significant increases in TABL PAC during Propofol anesthesia, when compared to SWS or waking brain activity. We conclude that TABL PAC informs the development of electrophysiological control signals for attention and the discrimination of unconscious states

Analysis of the structure of time-frequency information in electromagnetic brain signals

This thesis encompasses methodological developments and experimental work aimed at revealing information contained in time, frequency, and time–frequency representations of electromagnetic, specifically magnetoencephalographic, brain signals. The work can be divided into six endeavors. First, it was shown that sound slopes increasing in intensity from undetectable to audible elicit event-related responses (ERRs) that predict behavioral sound detection. This provides an opportunity to use non-invasive brain measures in hearing assessment. Second, the actively debated generation mechanism of ERRs was examined using novel analysis techniques, which showed that auditory stimulation did not result in phase reorganization of ongoing neural oscillations, and that processes additive to the oscillations accounted for the generation of ERRs. Third, the prerequisites for the use of continuous wavelet transform in the interrogation of event-related brain processes were established. Subsequently, it was found that auditory stimulation resulted in an intermittent dampening of ongoing oscillations. Fourth, information on the time–frequency structure of ERRs was used to reveal that, depending on measurement condition, amplitude differences in averaged ERRs were due to changes in temporal alignment or in amplitudes of the single-trial ERRs. Fifth, a method that exploits mutual information of spectral estimates obtained with several window lengths was introduced. It allows the removal of frequency-dependent noise slopes and the accentuation of spectral peaks. Finally, a two-dimensional statistical data representation was developed, wherein all frequency components of a signal are made directly comparable according to spectral distribution of their envelope modulations by using the fractal property of the wavelet transform. This representation reveals noise buried processes and describes their envelope behavior. These examinations provide for two general conjectures. The stability of structures, or the level of stationarity, in a signal determines the appropriate analysis method and can be used as a measure to reveal processes that may not be observable with other available analysis approaches. The results also indicate that transient neural activity, reflected in ERRs, is a viable means of representing information in the human brain.reviewe

Influence of Auditory Cues on the Neuronal Response to Naturalistic Visual Stimuli in a Virtual Reality Setting

Virtual reality environments offer great opportunities to study the performance of brain-computer interfaces (BCIs) in real-world contexts. As real-world stimuli are typically multimodal, their neuronal integration elicits complex response patterns. To investigate the effect of additional auditory cues on the processing of visual information, we used virtual reality to mimic safety-related events in an industrial environment while we concomitantly recorded electroencephalography (EEG) signals. We simulated a box traveling on a conveyor belt system where two types of stimuli – an exploding and a burning box – interrupt regular operation. The recordings from 16 subjects were divided into two subsets, a visual-only and an audio-visual experiment. In the visual-only experiment, the response patterns for both stimuli elicited a similar pattern – a visual evoked potential (VEP) followed by an event-related potential (ERP) over the occipital-parietal lobe. Moreover, we found the perceived severity of the event to be reflected in the signal amplitude. Interestingly, the additional auditory cues had a twofold effect on the previous findings: The P1 component was significantly suppressed in the case of the exploding box stimulus, whereas the N2c showed an enhancement for the burning box stimulus. This result highlights the impact of multisensory integration on the performance of realistic BCI applications. Indeed, we observed alterations in the offline classification accuracy for a detection task based on a mixed feature extraction (variance, power spectral density, and discrete wavelet transform) and a support vector machine classifier. In the case of the explosion, the accuracy slightly decreased by –1.64% p. in an audio-visual experiment compared to the visual-only. Contrarily, the classification accuracy for the burning box increased by 5.58% p. when additional auditory cues were present. Hence, we conclude, that especially in challenging detection tasks, it is favorable to consider the potential of multisensory integration when BCIs are supposed to operate under (multimodal) real-world conditions

Recent Applications in Graph Theory

Graph theory, being a rigorously investigated field of combinatorial mathematics, is adopted by a wide variety of disciplines addressing a plethora of real-world applications. Advances in graph algorithms and software implementations have made graph theory accessible to a larger community of interest. Ever-increasing interest in machine learning and model deployments for network data demands a coherent selection of topics rewarding a fresh, up-to-date summary of the theory and fruitful applications to probe further. This volume is a small yet unique contribution to graph theory applications and modeling with graphs. The subjects discussed include information hiding using graphs, dynamic graph-based systems to model and control cyber-physical systems, graph reconstruction, average distance neighborhood graphs, and pure and mixed-integer linear programming formulations to cluster networks

A New Signal Processing Approach to Study Action Potential Content in Sympathetic Neural Signals

Sympathetic nerve activity plays an essential role in the normal regulation of blood pressure in humans and in the etiology and progression of many chronic diseases. Sympathetic nerve recordings associated with blood pressure regulation can be recorded directly using microneurography. A general characteristic of this signal is spontaneous burst activity of spikes (action potentials) separated by silent periods against a background of considerable gaussian noise. During measurement with electrodes, the raw muscle sympathetic nerve activity (MSNA) signal is amplified, band-pass filtered, rectified and integrated. This integration process removes important information regarding action potential content and their discharge properties. The first objective of this thesis was to propose a new method for detecting action potentials from the raw MSNA signal to enable investigation of post-ganglionic neural discharge properties. The new method is based on the design of a mother wavelet that is matched to an actual mean action potential template extracted from a raw MSNA signal and applying it to the raw MSNA signal using a continues wavelet transform (CWT) for spike detection. The performance of the proposed method versus two previous wavelet-based approaches was evaluated using 1) MSNA recorded from seven healthy participants and, 2) simulated MSNA. The results show that the new matched wavelet performs better than the previous wavelet-based methods that use a non-matched wavelet in detecting action potentials in the MSNA signal. The second objective of this thesis was to employ the proposed action potential detection and classification technique to study the relationship between the recruitment of sympathetic action potentials (i.e., neurons) and the size of integrated sympathetic bursts in human MSNA signal. While in other neural systems (e.g. the skeletal motor system) there is a well understood pattern of neural recruitment during activation, our understanding of how sympathetic neurons are coordinated during baseline and baroreceptor unloading are very limited. We demonstrate that there exists a hierarchical pattern of recruitment of additional faster conducting neurons of larger amplitude as the sympathetic bursts become stronger. This information has important implications for how blood pressure is controlled, and the malleability of sympathetic activation in health and disease

Brain-Computer Interface

Brain-computer interfacing (BCI) with the use of advanced artificial intelligence identification is a rapidly growing new technology that allows a silently commanding brain to manipulate devices ranging from smartphones to advanced articulated robotic arms when physical control is not possible. BCI can be viewed as a collaboration between the brain and a device via the direct passage of electrical signals from neurons to an external system. The book provides a comprehensive summary of conventional and novel methods for processing brain signals. The chapters cover a range of topics including noninvasive and invasive signal acquisition, signal processing methods, deep learning approaches, and implementation of BCI in experimental problems

Residual Deficits Observed In Athletes Following Concussion: Combined Eeg And Cognitive Study

The neurocognitive sequelae of a sport-related concussion and its management are poorly defined. Emerging evidence suggests that the residual deficits can persist one year or more following a brain injury. Detecting and quantifying the residual deficits are vital in making a decision about the treatment plan and may prevent further damage. For example, improper return to play (RTP) decisions in sports such as football have proven to be associated with the further chance of recurring injury, long-term neurophysiological impairments, and worsening of brain functional activity. The reliability of traditional cognitive assessment tools is debatable, and thus attention has turned to assessments based on electroencephalogram (EEG) to evaluate subtle post-concussive alterations. In this study, we calculated neurocognitive deficits in two different datasets. One dataset contains a combination of EEG analysis with three standard post-concussive assessment tools. The data for this dataset were collected for all testing modalities from 21 adolescent athletes (seven concussive and fourteen healthy) in three different trials. Another dataset contains post-concussion eyes closed EEG signal for twenty concussed and twenty age-matched controls. For EEG assessment, along with linear frequency-based features, we introduced a set of time-frequency and nonlinear features for the first time to explore post-concussive deficits. In conjunction with traditional frequency band analysis, we also presented a new individual frequency based approach for EEG assessment. A set of linear, time-frequency and nonlinear EEG markers were found to be significantly different in the concussed group compared to their matched peers in the healthy group. Although EEG analysis exhibited discrepancies, none of the cognitive assessment resulted in significant deficits. Therefore, the evidence from the study highlight that our proposed EEG analysis and markers are more efficient at deciphering post-concussion residual neurocognitive deficits and thus has a potential clinical utility of proper concussion assessment and management. Moreover, a number of studies have clearly demonstrated the feasibility of supervised and unsupervised pattern recognition algorithms to classify patients with various health-related issues. Inspired by these studies, we hypothesized that a set of robust features would accurately differentiate concussed athletes from control athletes. To verify it, features such as power spectral, statistical, wavelet, and other nonlinear features were extracted from the EEG signal and were used as an input to various classification algorithms to classify the concussed individuals. Various techniques were applied to classify control and concussed athletes and the performance of the classifiers was compared to ensure the best accuracy. Finally, an automated approach based on meaningful feature detection and efficient classification algorithm were presented to systematically identify concussed athletes from healthy controls with a reasonable accuracy. Thus, the study provides sufficient evidence that the proposed analysis is useful in evaluating the post-concussion deficits and may be incorporated into clinical assessments for a standard evaluation of athletes after a concussion