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Description
Interictal spikes have been used to diagnose idiopathic seizure disorder and localize the seizure onset zone. Interictal spikes are thought to arise primarily from large excitatory postsynaptic potentials, and the role of interictal spikes in idiopathic seizure disorder and epileptogenesis remains unclear. We evaluated how local voltage changes due to interictal spikes impact action potential generation and firing using intracellular recordings from human tissue and the Hodgkin-Huxley model. During interictal spikes, bursts of action potentials underwent variable degrees of depolarization-induced inactivation in the intracellular data. Intracellular recordings in neocortical slices of human brain tissue confirmed that bursts of inactivated action potentials occurred during spontaneous paroxysmal depolarization shifts. These ex vitro findings were predicted using the Hodgkin-Huxley model and showed inactivated action potentials being generated by large depolarizations. As the amplitude of the interictal spike increased, there was a progression from low firing rate normal action potentials to higher firing rate normal action potentials to inactivated action potentials. The results show that the Hodgkin-Huxley model confirmed the effect of large interictal spike depolarizations on action potential firing and inactivation. This supports a key element in the hypothesis that interictal spikes, and the associated action potential firing, may alter the electrical environment of the brain and contribute to idiopathic seizure disorder.
ContributorsLossner, Lauren Nicole (Author) / Greger, Bradley (Thesis director) / Foldes, Stephen (Committee member) / Harrington Bioengineering Program (Contributor) / Barrett, The Honors College (Contributor)
Created2020-12
Description
Deep Brain Stimulation (DBS) is a stimulating therapy currently used to treat the motor disabilities that occur as a result of Parkinson’s disease (PD). Previous literature has proven the DBS to be an effective treatment in the effects of PD but the mechanism to validating this phenomenon is poorly understood. In this study, an evaluation of the DBS mechanism was analyzed in patients who received both contralateral and ipsilateral stimulation by the DBS electrode in relation to the recording microelectrode. I hypothesize that the data recorded from the neural tissue of the Parkinson’s patients will exhibit increased electromagnetic field (EMF) fall-off as spatial distance increases among the DBS lead and the microelectrode within the subthalamic nucleus (STN) as a result of the interaction between the EMF exuded by DBS and the neural tissue. Results depicted that EMF fall-off values increased with distance, observable upon comparing ipsilateral and contralateral patient data. The resulting analysis supported this phenomenon evidenced by the production of greater peak voltage amplitudes in ipsilateral patient stimulation with respect to time when compared to contralateral patient stimulation. The understanding of EMF strength and the associated trends among this data are vital to the progression and continued development of the DBS field relative to future research.
ContributorsKiraly, Alexis B (Author) / Greger, Bradley (Thesis director) / Muthuswamy, Jitendran (Committee member) / Harrington Bioengineering Program (Contributor) / Dean, W.P. Carey School of Business (Contributor) / Barrett, The Honors College (Contributor)
Created2020-12
Description
Functional electrical stimulation (FES) is a technology utilized to attempt to restore motor control in patients affected with paralysis, usually through techniques like intraspinal microstimulation (ISMS). FES uses a surface electrode to delivery extremely small to the target muscles that stimulate their movement and improve signaling within the neighboring nerves. This project sought to measure the impedance of an electrode used for FES in order to characterize other neural structures involved in the electrical impulse transmission process, either through the use of components added to the electrode or through the combination of multiple impedance readings. The electrode used in the present study was composed of 15 microelectrodes, which were fully characterized through electrochemical impedance spectroscopy to analyze the impedance profile with change in frequency. The data points obtained from the microelectrodes were then averaged in order to obtain a larger picture of the impedance of the general electrode. As expected, the impedance of the microelectrodes decreased as frequency increased. The average impedance of a microelectrode at a frequency of 1 kHz was found to be 50 k, although high variance in the data requires further testing to be done to verify the validity of the values that were found.
ContributorsMathew, Ethan (Co-author) / Fonseca, Sebastian (Co-author) / Greger, Bradley (Thesis director) / Mirzadeh, Zaman (Committee member) / W.P. Carey School of Business (Contributor) / Harrington Bioengineering Program (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
Epilepsy is a complex neurological disease that affects one in twenty-six people. Despite this prevalence, it is very difficult to diagnose. EpiFinder, Inc. has created an app to better diagnose epilepsy through the use of an epilepsy focused ontology and a heuristic algorithm. Throughout this project, efforts were made to improve the user interface and robustness of the EpiFinder app in order to ease usability and increase diagnostic accuracy. A general workflow of the app was created to aid new users with navigation of the app’s screens. Additionally, numerous diagnostic guidelines provided by the International League Against Epilepsy as well as de-identified case studies were annotated using the Knowtator plug-in in Protégé 3.3.1, where new terms not currently represented in the seizure and epilepsy syndrome ontology (ESSO) were identified for future integration into the ontology. This will help to increase the confidence level of the differential diagnosis reached. A basic evaluation of the user interface was done to provide feedback for the developers for future iterations of the app. Significant efforts were also made for better incorporation of the app into a physician’s typical workflow. For instance, an ontology of a basic review of systems of a medical history was built in Protégé 4.2 for later integration with the ESSO, which will help to increase efficiency and familiarity of the app for physician users. Finally, feedback regarding utility of the app was gathered from an epilepsy support group. These points will be taken into consideration for development of patient-based features in future versions of the EpiFinder app. It is the hope that these various improvements of the app will contribute to a more efficient, more accurate diagnosis of epilepsy patients, resulting in more appropriate treatments and an overall increased quality of life.
ContributorsCsernak, Lidia Maria (Author) / Crook, Sharon (Thesis director) / Greger, Bradley (Committee member) / Yao, Robert (Committee member) / School of Life Sciences (Contributor) / School of International Letters and Cultures (Contributor) / Barrett, The Honors College (Contributor)
Created2016-12
Description
Multisensory integration is the process by which information from different sensory modalities is integrated by the nervous system. This process is important not only from a basic science perspective but also for translational reasons, e.g., for the development of closed-loop neural prosthetic systems. A mixed virtual reality platform was developed to study the neural mechanisms of multisensory integration for the upper limb during motor planning. The platform allows for selection of different arms and manipulation of the locations of physical and virtual target cues in the environment. The system was tested with two non-human primates (NHP) trained to reach to multiple virtual targets. Arm kinematic data as well as neural spiking data from primary motor (M1) and dorsal premotor cortex (PMd) were collected. The task involved manipulating visual information about initial arm position by rendering the virtual avatar arm in either its actual position (veridical (V) condition) or in a different shifted (e.g., small vs large shifts) position (perturbed (P) condition) prior to movement. Tactile feedback was modulated in blocks by placing or removing the physical start cue on the table (tactile (T), and no-tactile (NT) conditions, respectively). Behaviorally, errors in initial movement direction were larger when the physical start cue was absent. Slightly larger directional errors were found in the P condition compared to the V condition for some movement directions. Both effects were consistent with the idea that erroneous or reduced information about initial hand location led to movement direction-dependent reach planning errors. Neural correlates of these behavioral effects were probed using population decoding techniques. For small shifts in the visual position of the arm, no differences in decoding accuracy between the T and NT conditions were observed in either M1 or PMd. However, for larger visual shifts, decoding accuracy decreased in the NT condition, but only in PMd. Thus, activity in PMd, but not M1, may reflect the uncertainty in reach planning that results when sensory cues regarding initial hand position are erroneous or absent.
ContributorsPhataraphruk, Preyaporn Kris (Author) / Buneo, Christopher A (Thesis advisor) / Zhou, Yi (Committee member) / Helms Tillery, Steve (Committee member) / Greger, Bradley (Committee member) / Santello, Marco (Committee member) / Arizona State University (Publisher)
Created2023
Description
Safety and efficacy of neuromodulation are influenced by abiotic factors like failure of implants, biotic factors like tissue damage, and molecular and cellular mechanisms of neuromodulation. Accelerated lifetime test (ALT) predict lifetime of implants by accelerating failure modes in controlled bench-top conditions. Current ALT models do not capture failure modes involving biological mechanisms. First part of this dissertation is focused on developing ALTs for predicting failure of chronically implanted tungsten stimulation electrodes. Three factors used in ALT are temperature, H2O2 concentration, and amount of charge delivered through electrode to develop a predictive model of lifetime for stimulation electrodes. Second part of this dissertation is focused on developing a novel method for evaluating tissue response to implants and electrical stimulation. Current methods to evaluate tissue damage in the brain require invasive and terminal procedures that have poor clinical translation. I report a novel non-invasive method that sampled peripheral blood monocytes (PBMCs) and used enzyme-linked immunoassay (ELISA) to assess level of glial fibrillary acidic protein (GFAP) expression and fluorescence-activated cell sorting (FACS) to quantify number of GFAP expressing PBMCs. Using this method, I was able to detect and quantify GFAP expression in PBMCs. However, there was no statistically significant difference in GFAP expression between stimulatory and non-stimulatory implants. Final part of this dissertation assessed molecular and cellular mechanisms of non-invasive ultrasound neuromodulation approach. Unlike electrical stimulation, cellular mechanisms of ultrasound-based neuromodulation are not fully known. Final part of this dissertation assessed role of mechanosensitive ion channels and neuronal nitric oxide production in cell cultures under ultrasound excitation. I used fluorescent imaging to quantify expression of nitric oxide in neuronal cell cultures in response to ultrasound stimulation. Results from these experiments indicate that neuronal nitric oxide production increased in response to ultrasound stimulation compared to control and decreased when mechanosensitive ion channels were suppressed. Two novel methods developed in this dissertation enable assessment of lifetime and safety of neuromodulation techniques that use electrical stimulation through implants. The final part of this dissertation concludes that non-invasive ultrasound neuromodulation may be mediated through neuronal nitric oxide even in absence of activation of mechanosensitive ion channels.
ContributorsVoziyanov, Vladislav (Author) / Muthuswamy, Jitendran (Thesis advisor) / Smith, Barbara (Committee member) / Greger, Bradley (Committee member) / Abbas, James (Committee member) / Okandan, Murat (Committee member) / Arizona State University (Publisher)
Created2022
Description
Information processing in the brain is mediated by network interactions between anatomically distant (centimeters apart) regions of cortex and network action is fundamental to human behavior. Disruptive activity of these networks may allow a variety of diseases to develop. Degradation or loss of network function in the brain can affect many aspects of the human experience; motor disorder, language difficulties, memory loss, mood swings, and more. The cortico-basal ganglia loop is a system of networks in the brain between the cortex, basal ganglia, the thalamus, and back to the cortex. It is not one singular circuit, but rather a series of parallel circuits that are relevant towards motor output, motor planning, and motivation and reward. Studying the relationship between basal ganglia neurons and cortical local field potentials may lead to insights about neurodegenerative diseases and how these diseases change the cortico-basal ganglia circuit. Speech and language are uniquely human and require the coactivation of several brain regions. The various aspects of language are spread over the temporal lobe and parts of the occipital, parietal, and frontal lobe. However, the core network for speech production involves collaboration between phonologic retrieval (encoding ideas into syllabic representations) from Wernicke’s area, and phonemic encoding (translating syllables into motor articulations) from Broca’s area. Studying the coactivation of these brain regions during a repetitive speech production task may lead to a greater understanding of their electrophysiological functional connectivity. The primary purpose of the work presented in this document is to validate the use of subdural microelectrodes in electrophysiological functional connectivity research as these devices best match the spatial and temporal scales of brain activity. Neuron populations in the cortex are organized into functional units called cortical columns. These cortical columns operate on the sub-millisecond temporal and millimeter spatial scale. The study of brain networks, both in healthy and unwell individuals, may reveal new methodologies of treatment or management for disease and injury, as well as contribute to our scientific understanding of how the brain works.
ContributorsO'Neill, Kevin John (Author) / Greger, Bradley (Thesis advisor) / Santello, Marco (Committee member) / Helms Tillery, Stephen (Committee member) / Papandreou-Suppapola, Antonia (Committee member) / Kleim, Jeffery (Committee member) / Arizona State University (Publisher)
Created2021
Description
Intrauterine devices, or IUDs, are long-lasting forms of birth control that have effectiveness comparable to sterilization, while they can be removed at any time. However, the insertion process can be very painful, especially for individuals who have never given vaginal birth. The most common form of pain management for this procedure is having the patient take an ibuprofen an hour or so before the procedure, but this only helps with cramping afterwards, not the acute pain caused by insertion. Pain, and anxiety and fear regarding potential pain, serve as a barrier between users and this highly effective form of birth control. This report uses COMSOL to model lidocaine diffusion from 4% topical hydrogel into the cervix (the main site of acute pain during IUD insertion) over 180 minutes. The cervix was modeled axisymmetrically, using average experimental values for cervix size. Concentration at four specific probe points were measured over time and compared at different concentrations. A sensitivity analysis was performed by adjusting the diffusion coefficient of the epithelial layer. This model was developed to serve as a predictor for future drug applications across the cervix, to determine in advance whether a novel formulation of drug would be effective to significantly reduce pain. This model may be refined further with experimental values for the constants, and with further testing of different lidocaine concentrations.
ContributorsRuby, Sarah (Author) / Arquiza, J.M.R. Apollo (Thesis director) / Greger, Bradley (Committee member) / Barrett, The Honors College (Contributor) / Harrington Bioengineering Program (Contributor)
Created2022-05
Description
A reliable method for real-time blood flow monitoring in vivo is critical for several medical applications, including monitoring cardiovascular diseases, evaluating interventional procedures and surgeries, and increasing the safety and efficacy of neuromodulation procedures. High-speed methods are particularly necessary for neural monitoring, due to the brain's
heightened sensitivity to hypoxic and ischemic conditions. High-speed CBF monitoring methods may also provide a useful biomarker for the development of a closed-loop deep brain stimulation (DBS) system. Current methods such as laser Doppler, bold fMRI, and positron emission tomography (PET) often involve cumbersome instrumentation and are therefore not well-
suited for chronic microvasculature monitoring. The purpose of this study is to develop a method for real-time measurement of blood flow changes using electrochemical impedance spectra (EIS). Utilizing EIS to measure CBF has the potential to be included in a chronic, closed-loop DBS system that is modulated by fluctuations in CBF, using minimal additional instrumentation. Five experiments in rodents were conducted, with the objective of 1) determining whether electrochemical impedance spectra showed impedance changes correlated with changes in blood flow, assessing the sensitivity, specificity, and limitations of detection of this method, and 2) determining whether cyclic voltammetry-based method could be used to produce EIS more rapidly than current methods. The experimental set-up included electrodes in the femoral artery with the administration of endothelin (ET-1) to induce blood flow changes (N=1), electrodes in the motor cortex using isoflurane variation to induce blood flow changes (N=3), and electrodes in the femoral artery with the administration of nitroglycerin (NTG) to induce blood flow changes (N=1). Preliminary results suggest that impedance changes in the higher frequencies (over 160 Hz) demonstrated higher sensitivity to blood flow changes in the femoral artery model compared to <100 Hz frequencies, with inconclusive results in the motor cortex model. Future in vivo experiments will be conducted using endothelin-1 to further establish the relationship between impedance and cerebral blood flow in the brain.
ContributorsJitendran, Elizabeth (Author) / Greger, Bradley (Thesis director) / Kodibagkar, Vikram (Committee member) / Muthuswamy, Jitendran (Committee member) / Barrett, The Honors College (Contributor) / Harrington Bioengineering Program (Contributor)
Created2024-05
Description
With millions of people living with a disease as restraining as migraines, there are no ways to diagnose them before they occur. In this study, a migraine model using nitroglycerin is used in rats to study the awake brain activity during the migraine state. In an attempt to search for a biomarker for the migraine state, we found multiple deviations in EEG brain activity across different bands. Firstly, there was a clear decrease in power in the delta, beta, alpha, and theta bands. A slight increase in power in the gamma and high frequency bands was also found, which is consistent with other pain-related studies12. Additionally, we searched for a decreased pain threshold in this deviation, in which we concluded that more data analysis is needed to eliminate the multiple potential noise influxes throughout each dataset. However, with this study we did find a clear change in brain activity, but a more detailed analysis will narrow down what this change could mean and how it impacts the migraine state.
ContributorsStrambi, McKenna (Author) / Muthuswamy, Jitendran (Thesis director) / Greger, Bradley (Committee member) / Barrett, The Honors College (Contributor) / Harrington Bioengineering Program (Contributor)
Created2023-05