Stretch is known to result in an electrically less stable ventricular substrate, yet the reported effects of stretch on measured electrophysiological parameters have been inconsistent and even contradictory. The goal of this study was to evaluate the effects of acute mechanical stretch on cardiac electrical features thought to be key in generation of arrhythmia, namely restitution of action potential duration (APD), electrical memory, and onset of alternans. Microelectrodes were used to record intracellular potentials pre, during, and post-stretch from isolated right ventricular tissues from swine. In separate experiments, the effects of two levels of stretch were quantified. Pacing protocols employing explicit diastolic interval (DI) control and cycle length (CL) control were used to obtain measures of restitution of APD, memory, and alternans of APD. Stretching the tissue had varying effects on APD, restitution and memory. Stretch increased APD, restitution slopes and memory by as much as 24, 30 and 53 % in some cases, while it decreased these by up to 18, 37 and 81 % in others. During stretch, alternans of APD were observed in some cases, which occurred at slower rates of activation than before stretch. Histology of tissue samples showed localized changes in orientation of cells relative to the direction of stretch. Our results show that among individual trials, stretch altered the measured electrophysiological properties, sometimes markedly. However, when pooled together, these changes cancelled each other and the averages showed no statistically significant difference after stretch. A potential mechanism that explains this divergent and inconsistent response to stretch is the presence of local, micron level, variation in orientation of myocytes. Upon stretch, these divergent effects likely increase dispersion of repolarization diffusely and might thus be the reason behind the consistently observed increase in arrhythmic substrate after stretch.

It is widely understood that neurons within the brain produce electrical activity, and electroencephalography—a technique used to measure biopotentials with electrodes placed upon the scalp—has been used to observe it. Today, scientists and engineers work to interface these electrical neural signals with computers and machines through the field of Brain-Computer Interfacing (BCI). BCI systems have the potential to greatly improve the quality of life of physically handicapped individuals by replacing or assisting missing or debilitated motor functions. This research thus aims to further improve the efficacy of the BCI based assistive technologies used to aid physically disabled individuals. This study deals with the testing and modification of a BCI system that uses the alpha and beta bands to detect motor intention by weighing online EEG output against a calibrated threshold.

The hippocampus is known to play a critical role in episodic memory function. Understanding the relation between electrophysiological activity in a rat hippocampus and rat behavior may be helpful in studying pathological diseases that corrupt electrical signaling in the hippocampus, such as Parkinson’s and Alzheimer’s. Additionally, having a method to interpret rat behaviors from neural activity may help in understanding the dynamics of rat neural activity that are associated with certain identified behaviors. In this thesis, neural networks are used as a black-box model to map electrophysiological data, representative of an ensemble of neurons in the hippocampus, to a T-maze, wheel running or open exploration behavior. The velocity and spatial coordinates of the identified behavior are then predicted using the same neurological input data that was used for behavior identification. Results show that a nonlinear autoregressive process with exogenous inputs (NARX) neural network can partially identify between different behaviors and can generally determine the velocity and spatial position attributes of the identified behavior inside and outside of the trained interval

The focus of this thesis was to measure the intracellular voltage of a living neural cell using a silicon transistor. The coupling of neurological tissues with silicon devices is of interest to the fields of neurology, neuroscience, electrophysiology and cellular biology. In previous work by Peter Fromherz, single neurons were successfully coupled to transistors [1]. This thesis aims to show proof of concept of the fabrication of a simple neuro-silicon interface using wafer processing methods currently available at Cal Poly. The types of transistors and cells used, the methods for dissecting and preparing the cells, the electrophysiology methods for validating the experiments, and portions of the design of the junction were based on Fromherz’s 1991 work. Other aspects were revised to be compatible with technologies available at Cal Poly. Leech Retzius cells were isolated and cultured from Hirudo Medicinalis and joined to the gate oxide of a P-channel field effect transistor using SU-8 photoresist wells treated with poly-l-lysine. Transistors were operated in strong inversion and source-drain currentfluctuations were observed that correlated with action potentials of the current clamped Retzius cell. Further work is needed to develop better junctions that can reliably couple action potentials. This work lays a foundation for neuro-silicon interface fabrication at Cal Poly.

In 1882, Sydney Ringer, a professor of medicine at University College in London, experimented with the frog ventricle to better understand how each constituent of blood influences contraction. The ultimate goal was to create an artificial circulating fluid to use for the perfusion of isolated organs, in this case, a frog heart. Today, Ringer’s solution is still used in research for physiological studies requiring the survival and maintenance of specimens outside of their host bodies. One such example is the use of medicinal leech ganglia for electrophysiological measurements. In this thesis, I am comparing two Ringer’s solutions, original versus added glucose, and their impact on the longevity of the ganglia. By stimulating cells in the dissected ganglia submerged in Ringer’s solution with a micropipette, action potential responses can be recorded and used to compare longevity of the cells in each solution. By providing the dissected ganglia with an additional source of fuel, I hypothesized that cells in the glucose-enriched Ringer’s solution would live longer, and thus provide action potentials longer, than cells in regular Ringer’s solution with a minimum increase in longevity of thirty minutes. Data analysis showed that glucose Ringer’s solution did not keep the cells alive longer than regular Ringer’s solution when the difference of means was set to 30 minutes. However, data did show a significant difference in the average longevity of the Retzius cell in glucose Ringer’s solution versus regular Ringer’s solution when the difference of means was set to zero.

Heart failure is a common condition during which the pumping action of the heart is affected because the heart does not contract or relax properly. Heart failure affects about 5 million Americans, with 550,000 new cases diagnosed each year. Cardiac resynchronization therapy (CRT) is used to treat symptoms and other complications associated with a heart failure. While performing CRT, Implantation of a pacing lead in the left ventricle of the heart is a very challenging surgical procedure performed with fluoroscopy. The target location is often difficult to reach through the tortuous coronary venous anatomy, which varies greatly among individuals. Placement of the pacing lead is an important research topic because the ideal pacing location for some patients with heart disease may be the site of latest contraction in the left ventricle. The purpose of this project is to develop an algorithm to locate and track points on a lead in a sequence of images. The algorithm will track the motion of the points over time and generate displacement plots over time.

There have been many different studies performed in order to examine various properties of neurons. One of the most important properties of neurons is an ability to originate and propagate action potential. The action potential is a source of communication between different neural structures located in different anatomical regions. Many different studies use modeling to describe the action potential and its properties. These models mathematically describe physical properties of neurons and analyze and explain biological and electrochemical processes such as action potential initiation and propagation. Therefore, one of the most important functions of neurons is an ability to provide communication between different neural structures located in different anatomical regions. This is achieved by transmitting electrical signals from one part of the body to another. For example, neurons transmit signals from the brain to the motor neurons (efferent neurons) and from body tissues back to the brain (afferent neurons). This communication process is extremely important for a being to function properly. One of the most valuable studies in neuroscience was conducted by Alan Hodgkin and Andrew Huxley. In their work, Alan Hodgkin and Andrew Huxley used a giant squid axon to create a mathematical model which analyzes and explains the ionic mechanisms underlying the initiation and propagation of action potentials. They received the 1963 Nobel Prize in Physiology/Medicine for their valuable contribution to medical science. The Hodgkin and Huxley model is a mathematical model that describes how the action potential is initiated and how it propagates in a neuron. It is a set of nonlinear ordinary differential equations that approximates the electrical characteristics of excitable cells such as neurons and cardiomyocytes. This work focuses on modeling the Hodgkin and Huxley model using MATLAB extension - Simulink. This tool provides a graphical editor, customizable block libraries, and solvers for modeling and simulating dynamic systems. Simulink model is used to describe the mechanisms and underlying processes involved in action potential initiation and propagation.

In this thesis, the perturbation-based decomposition technique developed by Szlavik [1] was used in an attempt to solve the inverse problem in EEG source localization. A set of dipole locations were forward modeled using a 4-layer sphere model of the head at uniformly distributed lead locations to form the vector basis necessary for the method. Both a two-dimensional and a pseudo-three-dimensional versions of the model were assessed with the two-dimensional model yielding decompositions with minimal error and the pseudo-three-dimensional version having unacceptable levels of error. The utility of interpolation as a method to reduce the number of data points to become overdefined was assessed as well. The approach was effective as long as the number of component functions did not exceed the number of data points and stayed relatively small (less than 77 component functions). This application of the method to a spatially variate system indicates its potential for other systems and with some tweaking to the least squares algorithm used, could be applied to multivariate systems.

Functional recovery following peripheral nerve injuries is poor due to muscle atrophy and fibrosis being major contributing factors. Electrical muscle stimulation has been used for decades in some capacity to treat denervation related muscular changes. The research presented in this thesis explores a new stimulation paradigm and its effects on short and long term muscle denervation. The first part of this work describes the new stimulation paradigm and the design and development of the stimulator used to deliver this paradigm. The paradigm involved daily 1-hour stimulation sessions featuring 600 contractions at high stimulus frequencies (100 Hz) and low pulse durations (200 μs). To test the device and paradigm, a pilot study involving muscle stimulation throughout a one month period of denervation in rat lower limb muscles was carried out. The results showed that this short but intense stimulus session significantly reduced the rate of muscle atrophy compared to animals that did not receive stimulation. Furthermore, muscle weight and consequently muscle force were also significantly greater. The stimulus paradigm was then used to investigate muscle that was denervated and immediately repaired. Ideally, immediate nerve repair following nerve injuries produces the best outcome. One month of electrical muscle stimulation following nerve repair enhanced this outcome through significant increases in muscle weight and force. Additionally, contrary to many previous studies, the stimulus paradigm had no negative effects on reinnervation. Taken together, electrical muscle stimulation can provide significant improvements over the best case scenario of immediate nerve repair. The third part of this work investigated the use of chronic electrical muscle stimulation throughout three months of denervation and the impact on reinnervation. Results showed that reinnervation in chronically stimulated animals were no different than animals that were denervated and immediately repaired. The last part of this work combined the use of electrical muscle stimulation with sensory protection in chronically denervated muscle. Sensory protection involves suturing a sensory nerve to protect a muscle during denervation and was shown in previous studies to reduce muscle atrophy, preserve muscle spindles and the structure of the distal nerve stump. The results showed significantly greater muscle weights and force in the combined treatment compared to the individual treatments alone. Reinnervation in these animals was as good as those that were immediately repaired. This suggests that contractile support combined with sensory protection may provide superior functional outcomes in chronically denervated muscle. The findings presented in this thesis provide new evidence for the use of short duration daily electrical muscle stimulation immediately following nerve repair or throughout long term denervation. Evidence for a new therapy, muscle stimulation with sensory protection, is also presented and shown to provide superior functional outcomes compared to either therapy alone. The contributions made in this body of work may provide clinicians with evidence to pursue clinical use of the outlined strategies and ultimately help patients optimally recover from peripheral nerve injuries. / Doctor of Philosophy (PhD)

Peripheral nerve stimulation (PNS) is commonly used to promote use-dependent cortical plasticity for rehabilitation of motor function in spinal cord injury. Pairing transcranial magnetic stimulation (TMS) with PNS has been shown to increase motor evoked potentials most when the two stimuli are timed to arrive in the cortex simultaneously. This suggests that a mechanism of timing-dependent plasticity (TDP) may be a more effective method of promoting motor rehabilitation. The following thesis is the result of applying a brain-computer interface to apply PNS in closed-loop simultaneously to movement intention onset as measured by EEG of the sensorimotor cortex to test whether TDP can be induced in incomplete spinal cord injured individuals with upper limb motor impairment. 4 motor incomplete SCI subjects have completed 12 sessions of closed-loop PNS delivered over 4-6 weeks. Benefit was observed for every subject although not consistently across metrics. 3 out of 4 subjects exhibited increased maximum voluntary contraction force (MVCF) between first and last interventions for one or both hands. TMS-measured motor map volume increased for both hemispheres in one subject, and TMS center of gravity shifted in 3 subjects consistent with studies in which motor function improved or was restored. These observations suggest that rehabilitation using similar designs for responsive stimulation could improve motor impairment in SCI.