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An Electrophysiological Study Of Voluntary Movement and Spinal Cord Injury
Get PDFVoluntary movement is generated from the interaction between neurons in our brain and the neurons in our spinal cord that engage our muscles. A spinal cord injury destroys the connection between these two regions, but parts of their underlying neural circuits survive. A new class of treatment (the brain-machine interface) takes advantage of this fact by either a) recording neural activity from the brain and predicting the intended movement (neural prosthetics) or b) stimulating neural activity in the spinal cord to facilitate muscle activity (spinal stimulation). This thesis covers new research studying the brain-machine interface and its application for spinal injury.
First, the electrical properties of the microelectrode (the main tool of the brain-machine interface) are studied during deep brain recording and stimulation. This work shows that the insulation coating the electrode forms a capacitor with the surrounding neural tissue. This capacitance causes large spikes of voltage in the surrounding tissue during deep brain stimulation, which will cause electrical artifacts in neural recordings and may damage the surrounding neurons. This work also shows that a coaxially shielded electrode will block this effect.
Second, the activity of neurons in the parietal cortex is studied during hand movements, which has applications for neural prosthetics. Prior work suggests that the parietal cortex encodes a state-estimator [1], which combines sensory feedback with the internal efference copy to predict the state of the hand. To test this idea, we used a visual lag to misalign sensory feedback from the efference copy. The expectation was that a state-estimator would unknowingly combine the delayed visual feedback with the current efference information, resulting in incorrect predictions of the hand. Our results show a drop in correlation between neural activity in the parietal cortex and hand movement during a visual lag, supporting the idea that the parietal cortex encodes a state-estimator. This correlation gradually recovers over time, showing that parietal cortex is adaptive to sensory delays.
Third, while the intention of spinal stimulation was to interact locally with neural circuits in the spinal cord, results from the clinic show that electrical stimulation of the lumbosacral enlargement enables paraplegic patients to regain voluntary movement of their legs [2]. This means that spinal stimulation facilitates communication across an injury site. To further study this effect, we developed a new behavioral task in the rodent. Rats were trained to kick their right hindlimb in response to an auditory cue. The animals then received a spinal injury that caused paraplegia. After injury, the animals recovered the behavior (they could kick in response to the cue), but only during spinal stimulation. Their recovered behavior was slower and more stereotyped than their pre-injury response. Administering quipazine to these rodents disrupted their ability to respond to the cue, suggesting that serotonin plays an important role in the recovered pathway. This work proves that the new behavioral task is a successful tool for studying the recovery of voluntary movement.
Future work will combine cortical recordings with this behavioral task in the rodent to study plasticity in the nervous system and improve treatment of spinal cord injuries.
[1] Mulliken, Grant H., Sam Musallam, and Richard A. Andersen. "Forward estimation of movement state in posterior parietal cortex." Proceedings of the National Academy of Sciences105.24 (2008): 8170-8177.
[2] Harkema, Susan, et al. "Effect of epidural stimulation of the lumbosacral spinal cord on voluntary movement, standing, and assisted stepping after motor complete paraplegia: a case study." The Lancet 377.9781 (2011): 1938-1947.</p
Human Duration Perception Mechanisms in the Subsecond Range: Psychophysics and Electroencephalography Investigations
Get PDFIn a world full of fleeting events, how do humans perceive time intervals as short as half a second? Unlike primary senses, there are no time receptors. Is sub-second time perception reconstructed from memory traces in the primary senses, or based on the output of a modality-independent internal clock? In analogy to bugs in computer programs or mutations in genetics studies, I studied two types of subjective time warp illusions in order to understand how time perception normally works. One illusion that I examined is called oddball chronostasis, which is a duration distortion effect that happens to an unusual item. The other illusion is called debut chronostasis, which is a time warp effect that occurs to the first item among other identical ones.
Regarding oddball chronostasis, we solved a theoretical dispute over its underlying mechanisms and dissociated three causes. The necessary component is top-down attention to the target item. The other two components are contingent factors. This suggests that a pure sensory modality-dependent view of time perception mechanisms is less likely.
Regarding debut chronostasis, we discovered auditory debut chronostasis and found that its illusion strength is about the same as the visual case. At first glance, this seems to suggest that time perception is independent of the primary sensory modalities. However, when visual and auditory events were compared against each other (inter-modal comparison), debut chronostasis disappeared. Therefore, modality-dependent mechanisms of time perception do exist. Further, we found a special factor that could counteract debut chronostasis and thus re-interpreted the main cause of debut chronostasis as internal duration template uncertainty. By examining both intra- and inter-modal comparisons, this uncertainty effect turned out to be a modality-independent effect. Therefore, modality-independent mechanisms of time perception also exist.
In conclusion, this dissertation work contributed to novel theoretical understanding of two types of time perception illusions. Unlike many simplified theories in the literature either holding a modality-dependent or independent view, our findings altogether indicate that time perception involves both intra- and supra-modal stages. Future experimental work could thus target on separating intra- and supra-modal time perception mechanisms.</p
Analyzing Stress Change and Energy Budget of Earthquakes Through Physics-Based Modeling
Get PDFResearchers use concepts such as stress drop, breakdown energy, and available energy to describe earthquakes sources and study earthquake physics. These quantities represent the spatially and temporally varying dynamic events by single, event-averaged values. They are inferred indirectly from observations, often based on simplified models. Thus, their relationship to fault constitutive properties, which are local on the fault, is not straightforward.
Here, we use simulations of earthquake sequences in fault models with friction laws motivated by laboratory experiments to examine how the event-averaged observables arise from spatially and temporally varying earthquake rupture. In particular, we consider whether several typically used fault mechanisms, such as rate-and-state friction, thermal pressurization of pore fluids, and flash heating, are consistent with common observations such as magnitude-invariant stress drop, increasing breakdown energy with the event size, and radiation efficiencies of ~0.5.
Stress drops, observed to be magnitude invariant, are a key characteristic used to describe natural earthquakes. Theoretical studies and lab experiments indicate that dynamic weakening, such as thermal pressurization of pore fluids, may be present on natural faults. At first glance, these two observations seem incompatible, since larger events may experience greater weakening and should thus have lower final stresses. We hypothesize that dynamic weakening can be reconciled with magnitude-invariant stress drops due to larger events having lower average prestress when compared to smaller events. The additional weakening would allow the final stresses to also be lower, but the stress drops may be similar.
To explore this hypothesis, we study long-term earthquake sequences on a rate-and-state fault segment with enhanced dynamic weakening due to thermal pressurization using a fully dynamic simulation approach with a seismogenic segment that has uniform friction properties. Our results show, for a range of event sizes, that such models can explain both observationally inferred stress drop invariance and breakdown energy increase with event magnitude. Smaller events indeed have larger average initial stresses than medium-sized events, and we get nearly constant stress drops for events spanning up to five orders of magnitude in seismic moment. Segment-spanning events have more complex behavior, which is dependent on the properties of the velocity-strengthening (VS) region at the edges of the fault. Models with large values of velocity strengthening in their boundary regions do not allow ruptures to propagate much into the velocity-strengthening region, thus containing the rupture area and leading to higher stress drops for a larger amount of slip. Decreasing the velocity strengthening of the boundaries leads to farther rupture propagation into the velocity-strengthening region and thus lower stress drops.
In all models with the thermal pressurization of pore fluids that we have examined, both the smaller and segment-spanning events exhibit increases in breakdown energy consistent with observations. The breakdown energy is the portion of the dissipated energy that governs the event dynamics, analogous to the fracture energy concept of fracture mechanics. The increase in the breakdown energy is due to continuous weakening of the fault with slip, as hypothesized in previous analytical studies.
We also examine the accuracy of seismically estimated breakdown energies GSE for a range of models, by comparing the values computed directly from our fault models and indirectly from seismically available observations. Observationally, GSE is typically obtained as the difference between the seismically estimated available energy ΔW0 per unit area and radiated energy ER. This defines the available energy ΔWA as the sum of the breakdown energy and radiated energy. However, the seismically estimated available energy ΔW0 is obtained as one-half of the product of the (average) stress drop and (average) final slip, based on a simplified model. As such, we examine the relation between the actual available energy ΔWA and its seismic estimate ΔW0 in our models. We find that, as rupture mode changes from crack-like to pulse-like, the actual available energy ΔWA, becomes increasingly larger that the seismically estimated available energy ΔW0, due to significant and increasing stress undershoot characteristic of pulse-like ruptures. The extra available energy for more pulse-like ruptures either makes the breakdown energy much larger than its seismically estimated value, or makes the radiated energy much larger than the seismically estimated available energy ΔW0, or both. In the two latter cases, the radiation ratio η (sometimes called radiation efficiency) between the radiated energy and seismically estimated available energy increases beyond 1, consistent with some observations that were previously thought to be aphysical.
Overall, we find that models with rate-and-state friction and thermal pressurization of pore fluids, when resulting in continuous weakening of fault with slip and crack-like ruptures, produce events with magnitude-invariant stress drops, increases in breakdown energies with the event sizes consistent with observations, radiation ratios consistent with observations, and available energies similar to the ones inferred seismically. More pulse-like ruptures, which result occasionally in such models and reliably in models that incorporate more severe enhanced weakening motivated by flash heating, have increasingly more significant undershoot and hence extra energy available for breakdown and radiation compared with the seismically estimated available energy. Therefore, current seismic estimates of their breakdown energy and radiation ratio are not reliable. More work is needed to understand the energy budget of pulse-like events obtained in realistic fault models, especially since one of the common paradigms in earthquake physics is that many large events occur as pulse-like ruptures.</p
Thermalization in Periodically-Driven Interacting Quantum Systems
Get PDFPeriodically-driven (Floquet) quantum systems are ubiquitous in science and technology. For example, when a laser illuminates a material or an AC voltage is applied to a device, the system is well-described by a time-periodic Hamiltonian. In recent years, periodic driving has been proposed, not just as a tool to excite and probe devices, but actually as a mechanism of engineering new phases of matter, some of which have no equilibrium analog. However, with this promise comes a serious problem. Intuitively, if energy is injected into and distributed throughout a system, it is no surprise that it tends to heat up indefinitely to infinite temperature.
In this thesis, we study the mechanisms of heating, i.e. the process of thermalization, in Floquet systems and propose methods to control them. Specifically, for non-interacting Floquet systems that are coupled to external bosonic and fermionic baths (e.g. laser-driven electrons in a semiconductor that interact with phonons and an external lead), we classify the relevant scattering processes that contribute to cooling/heating in the Floquet bands and suggest methods to suppress heating via bandwidth-restrictions on the baths. We find that is possible, with appropriate dissipative engineering, to stabilize a controlled incompressible nonequilibrium steady-state resembling a ground state - a state we term the "Floquet insulator." We extend this analysis to include short-range interactions that contribute additional heating processes and show, under the same framework, that heating can be controlled with dissipation. In the process, we develop a simple effective model for the Floquet band densities that captures the essence of all the Floquet scattering processes and that is useful for ballparking experimentally-relevant estimates of heating. Next, we turn our attention to strongly-interacting closed Floquet systems and study how heating emerges through a proliferation of resonances. We find a novel integrable point governing the strong-interaction limit of the Floquet system and examine the breakdown of integrability via the proliferation of resonances. We observe two distinct scaling regimes, attributed to non-thermal and thermal behavior, and discover a power-law scaling of the crossover between them as a function of system size. The lingering ergodicity-breaking effects of the conserved quantities in the vicinity (in parameter space) of the integrable point at finite size is a phenomena we term "near-integrability." These results suggest that small quantum systems, which are accessible currently in many platforms (e.g. trapped ions, cold atoms, superconducting devices), intrinsically host non-thermal states that one may be able to utilize to avoid heating. Furthermore, our results suggest a "dual" interpretation, in the thermodynamic limit, that a periodically-driven system exhibits prethermalization as a power-law in interaction strength.</p
Transcriptional Enhancer Activity of Biochemically Marked Genomic Elements
Get PDFFunctional genomics aspires to explain how a transcription factor (TF) and its measured biochemical occupancy relates to the enhancer activity of the underlying sequence elements. Tissue-specific TFs exhibit remarkable selectivity and reproducibility in the available genome-wide sequence motifs accessed. A consistent central conclusion is that, irrespective of the element selection criteria used, ~50% of candidate Enhancers score as transcriptionally active in both mouse and human cell types, while the remaining 50% of similarly biochemically marked regions are unable to activate transcription on their own. This finding is based on an integrated comparison of a group of functionally assayed elements containing TF-occupied elements, evolutionarily conserved elements, and TF agnostic elements with hallmark biochemical signatures of known enhancers. Quantitatively, the level of TF occupancy signal was the best predictor of the proportion of active enhancers detected, but overall (and contrary to expectation) it is a weak predictor of the magnitude of enhancer activity readout. In specific cell types, elements can display all of the hallmark signatures of enhancers, but can remain inactively poised prior to a stimulus that either activates them or releases a repressive factor. Against previous expectations these poised occupancy sites, once released, behave comparatively in magnitude of enhancer activity as their counterparts that are only directly accessed upon stimulation. Based on our findings, the vast majority of active enhancers in the genome, including some of the most individually powerful ones, are expected to display relatively modest biochemical signatures. Finally, the combined set of over a hundred genomic regions that lacked biochemical marks, even while containing the motifs known to be necessary to bind the relevant TFs, did not support significant enhancer function. We also found evidence that both enhancer orientation and combinations of relatively closely spaced candidate Enhancers, can yield additive functions, with possible fine tuning of the enhancer activity controlled by the type and the distance between individually accessed motifs. In special cases, these elements might cooperate to recruit stable complexes resulting in a synergistic transcriptional activation, suggesting that both local "super-enhancers" and recruited multi-element combinatorics are likely to play an important role in vivo. These findings provide an expectation for enhancer function in the comprehensive annotations provided by the new ENCODE encyclopedia and may help guide future efforts to define the mechanisms by which enhancer activity is achieved and conferred selectively to target genes. Surprisingly, elements that deeply sample the biochemical occupancy of complex loci, match a random population of selected elements remarkably well. Our findings also indicate that carefully designed and lower throughput approaches, rather than high numerical assays that focus on the outstanding features, will bring widely applicable answers to the remaining questions of how relative enhancers are tuned and how seemingly identical regions at a biochemical and motif level are selected for or against function
The Gun Wa Trials: Chinese Doctors, Narrative Advertisement, and Consumer Fraud in the Late Nineteenth Century American West
Get PDFIn the late nineteenth century, the United States experienced a surge of anti-Chinese sentiment that targeted both Chinese laborers and skilled Chinese professionals. Chinese doctors were thus caught between two disadvantageous developments as, during the same decades, the regular or allopathic school of medicine asserted increasing control over the medical profession and successfully lobbied for restrictive licensing laws. This thesis examines the relationship between TCM newspaper advertisements and the way Americans viewed Chinese doctors and culture in Denver, Colorado and Milwaukee, Wisconsin from 1888 to 1897. In particular, it focuses on the case of Gun Wa, a fake Chinese doctor created by a handful of white men to sell their medicines, and discusses the ways in which the company exploited TCM as it faced attacks from two fronts. To understand the unique interpretation of TCM and Chinese culture the white men brought, Gun Wa’s advertisements are compared to those of real Denver Chinese doctors. By combining elements of Chinese and western culture, the company was able to create a convincing persona with convincing remedies in the newspapers to attract customers. The use of narrative testimonials was particularly important to capture ethos and respectability, revealing the relative social status Chinese doctors held in their adoptive communities. The subsequent Gun Wa trials exposed the fraud and damaged relations between Chinese doctors and their non-Chinese communities. Although Chinese doctors could repair their relations with the Denver community, they would ultimately fail to obtain the approval of professional medical societies, pointing to the limitations of Denver acceptance of Chinese culture
Neutrino Radiation Transport and Other Topics in High Energy Density Astrophysics
Get PDFNeutron star mergers and the collapse of massive stars result in some of the universe’s most violet explosions. However, the detailed mechanisms behind all of these astrophysical explosions remain elusive. Their strongly nonlinear and complicated nature makes them difficult and expensive to simulate, and the properties of matter in these extreme conditions are poorly constrained. I use a variety of computational tools to understand the detailed mechanisms behind both types of events.
I describe my relativistic time-independent multidimensional Monte Carlo neutrino radiation transport code Sedonu that provides an accurate account of the neutrino radiation fields and the interaction with neutrinos and background fluid. Though Sedonu calculations are time-independent, I demonstrate their utility in dynamical general relativistic variable Eddington tensor radiation hydrodynamics simulations.
I apply Sedonu to simulations of accretion disks following neutron star mergers to demonstrate that more realistic disk cooling and neutrino-driven mass ejection rates are larger than is predicted using approximate transport methods. I also reinforce that neutrino pair annihilation from these disk configurations is unlikely to be able to energize a gamma-ray burst jet.
I subject Sedonu to the first thorough comparison of Boltzmann neutrino radiation transport methods in multiple spatial dimensions in the context of core-collapse supernovae. The comparisons with the other highly accurate discrete ordinates-based transport scheme show remarkably similar results, verifying the accuracy of both methods and underscoring the importance of numerical fidelity.
I perform the first broad parameter study on how different descriptions of dense nuclear matter and star rotation rates influence the dynamics of, and hence gravitational waves from, the bounce and early post-bounce phase of rapidly rotating core collapse supernovae. Using the results of 1824 two-dimensional general relativistic core-collapse simulations, I demonstrate that the equation of state is unlikely to be constrained by LIGO observations. I show that the effect of the equation of state on the gravitational wave frequency can be described by a single universal relation.
Finally, I use results of three-dimensional general relativistic magnetohydrodynamics simulations of rapidly rotating core collapse to demonstrate that the polar magnetic structures that form are destroyed by a magnetohydrodynamic kink instability.</p
Why the Turing Test Revised is Still the Turing Test
No full textCan machines think? So Alan Turing begins his paper "Computing Machinery and Intelligence", discussing how one might assess whether an electronic computer can truly "think" (Turing, 1950, p. 29). It is here that Turing explains his famous Turing Test: can a computer win in an "imitation game" with a human? That is, can an electronic computer provide written answers to an interrogator which would fool the interrogator into believing that device is human? To answer yes, Turing argues, is to acknowledge the reality of a thinking machine (Turing, 1950, p. 30). Since 1950, technology has advanced impressively. There has been a computer that “passed” the Turing Test, fooling testers with a clever ability to redirect conversation when questions became too challenging (Marcus, 2014). Yet this strategy feels more like a cheap trick than the mark of an authentic thinker, casting doubt on the test’s validity. What could be a more reliable test for machine understanding? I argue for two simple additions to the Turing Test that would eliminate loopholes but leave the spirit of the test unchanged. That Turing's original imagination of the Turing Test involved a game of deception is distracting to its fundamental principle: we will say a machine “thinks” when its logical outputs are in no way noticeably inferior to that of a human
Ultrasound Speckle Image Velocimetry: Studies on System Performance and Application to Cardiovascular Fluid Dynamics
Get PDFKnowledge of detailed blood flow characteristics can be extremely valuable in a variety of settings. Examples range from studying disease processes such as
atherosclerosis to aiding in the design of medical devices such as prosthetic cardiac valves. For in vivo and optically inaccessible in vitro flows, accurate measurements of velocity fields and shear stresses can be difficult to obtain. Doppler ultrasound and magnetic resonance imaging are the most commonly used techniques, but have important limitations. Recently, there has been increased interest in the application of particle image velocimetry principles towards tracking of ultrasound speckle patterns to determine multidimensional flow velocities with increased temporal resolution. We refer to our implementation as ultrasound speckle image velocimetry (USIV). In this research project, our first objective was to obtain a detailed characterization of the factors unique to ultrasound imaging that can influence the accuracy of velocity measurements. By conducting in vitro experiments with uniform speckle phantom translation as well as steady tube flow, we have shown that characteristics such as transducer focal depth and beam sweep speed as well as particle motion direction and velocity can all influence USIV results. Our second objective was to demonstrate the utility of USIV for analyzing in vivo blood flows. After administering ultrasound contrast agent to anesthetized
pigs, we were able to obtain detailed images of both left ventricular flow and
abdominal aortic flow. Velocity profiles were measured during both left ventricular filling and ejection. Our most interesting finding was the presence in certain cases of highly asymmetric retrograde flow in the infrarenal aorta. The factors that lead to such flows may have relevance to the development of atherosclerosis and abdominal aneurysms. USIV is likely to be very useful for further studies both in vivo and with in vitro elastic aorta models
Computational Studies of Noncovalent Interactions in Ligand-Gated Ion Channels – and - Synthesis and Characterization of Red and Near Infrared Cyanine Dyes
Get PDFThis thesis is presented in two parts. The first part, Chapter 2, 3, and 4, offers a series of studies on noncovalent interactions in Ligand Gation Ion Channels (LGICs). The second part describes a series of studies involving the synthesis and characterization of cyanine dyes. The common thread in this work is the use of Density Functional Theory (DFT) to study chemical-scale phenomenon. Chapter 1 offers a brief introduction to DFT and a comparison with other traditional computational chemistry methodology; Hartree-Fock (HF). Summaries of the use of DFT to study both noncovalent interations and electronically excited states are also presented. In addition, the author comments on the correct application of DFT.
Chapter 2 details a computational study of the cation-π interaction of complex cations to substituted benzenes and indoles. The cation-π interaction is the electrostatic interaction between a cation and the negative electrostatic potential on an aromatic ring originating from its large permanent quadrupole moment. This chapter, in addition to establishing the correct computational parameters, establishes a large set of substituent effects with which to study cation-π interactions in vivo. These binding energy values are compared to previous applications of cation-π binding energies from our lab, and it was found that the derived binding energies are sufficiently accurate.
Chapter 3 applies the foundational knowledge from the previous chapter to study cation-π interactions of cationic ligands to multiple aromatics. This is a common motif in vivo known as the aromatic box. Using this methodology, it is established that cation binding in this form is cooperative. Further, many aromatic boxes from crystal structures were evaluated energetically.
Chapter 4 describes work to develop a new amino acid to study hydrogen bonds in Xenopus laevis oocytes. These fluorinated aliphatic amino acids inductively attenuate the hydrogen bond accepting ability of the carbonyl. This new strategy was used to probe for a hydrogen bond between the indole NH α4 TrpB and a backbone carbonyl associated with L119 on the β2 subunit of the α4β2 nicotinic acetylcholine receptor (nAChR). The fluorinated amino acids were validated computationally and with NMR studies. This new strategy showed that the α4-β2 interfacial hydrogen prediction was false.
Chapter 5 describes the synthesis and characterization of a series of meso-aromatic-acetylene cyanine dyes which feature a very large Stokes shift. Synthesis of the dyes features a key Sonagashira reaction. These dyes are investigated photophysically and computationally using time dependent DFT (TDDFT). The mechanism for this Stokes shift is an excitation to the S2 state, relaxation to the S1 state, and normal cyanine fluorescence.
Chapter 6 describes three separate strategies to construct a cyanine-based photocage to release drugs in vivo using an ortho-quinone methide strategy. One strategy utilized an acetylene-aromatic cyanine dye much like those described in Chapter 5, the second utilized an ethynyl-trimethylphenyl cation dye, and the third a photoinduced electron transfer cyanine dye. None of these strategies produced a usable photocage. The failure of these strategies are ascribed to both the short excited state lifetime of cyanine dyes and the direction of the transition dipole moment.
Finally, three appendices are presented. Appendix A describes early work to synthesize and characterize a meso-hydroxy substituted Cy5 dye. Appendix B offers many of the same computations as Chapters 2 and 3 using HF instead of DFT. Appendix C describes orbital mixing of cyanine dyes from Chapter 5 using HF instead of DFT.</p