Psychobiophysics of transcranial magnetic stimulation

Transcranial magnetic stimulation (TMS) is a technique that stimulates the brain using a magnetic coil placed on the scalp. Since it is applicable to humans non-invasively, directly interfering with neural electrical activity, it is potentially a good tool to study the direct relationship between perceptual experience and neural activity. However, it has been difficult to produce a clear perceptible phenomenon with TMS of sensory areas, especially using a single magnetic pulse. Also, the biophysical mechanisms of magnetic stimulation of single neurons have been poorly understood.

In the psychophysical part of this thesis, perceptual phenomena induced by TMS of the human visual cortex are demonstrated as results of the interactions with visual inputs. We first introduce a method to create a hole, or a scotoma, in a flashed, large-field visual pattern using single-pulse TMS. Spatial aspects of the interactions are explored using the distortion effect of the scotoma depending on the visual pattern, which can be luminance-defined or illusory. Its similarity to the distortion of afterimages is also discussed. Temporal interactions are demonstrated in the filling-in of the scotoma with temporally adjacent visual features, as well as in the effective suppression of transient visual features. Also, paired-pulse TMS is shown to lead to different brightness modulations in transient and sustained visual stimuli.

In the biophysical part, we first develop a biophysical theory to simulate the effect of magnetic stimulation on arbitrary neuronal structure. Computer simulations are performed on cortical neuron models with realistic structure and channels, combined with the current injection that simulates magnetic stimulation. The simulation results account for general and basic characteristics of the macroscopic effects of TMS including our psychophysical findings, such as a long inhibitory effect, dependence on the background activity, and dependence on the direction of the induced electric field.

The perceptual effects and the cortical neuron model presented here provide foundations for the study of the relationship between perception and neural activity. Further insights would be obtained from extension of our model to neuronal networks and psychophysical studies based on predictions of the biophysical model.

Spinal cord injury therapy through active learning

Therapy employing epidural electrostimulation holds great potential for improving therapy for patients with spinal cord injury (SCI) (Harkema et al., 2011). Further promising results from combined therapies using electrostimulation have also been recently obtained (e.g., van den Brand et al., 2012). The devices being developed to deliver the stimulation are highly flexible, capable of delivering any individual stimulus among a combinatorially large set of stimuli (Gad et al., 2013). While this extreme flexibility is very useful for ensuring that the device can deliver an appropriate stimulus, the challenge of choosing good stimuli is quite substantial, even for expert human experimenters. To develop a fully implantable, autonomous device which can provide useful therapy, it is necessary to design an algorithmic method for choosing the stimulus parameters. Such a method can be used in a clinical setting, by caregivers who are not experts in the neurostimulator's use, and to allow the system to adapt autonomously between visits to the clinic. To create such an algorithm, this dissertation pursues the general class of active learning algorithms that includes Gaussian Process Upper Confidence Bound (GP-UCB, Srinivas et al., 2010), developing the Gaussian Process Batch Upper Confidence Bound (GP-BUCB, Desautels et al., 2012) and Gaussian Process Adaptive Upper Confidence Bound (GP-AUCB) algorithms. This dissertation develops new theoretical bounds for the performance of these and similar algorithms, empirically assesses these algorithms against a number of competitors in simulation, and applies a variant of the GP-BUCB algorithm in closed-loop to control SCI therapy via epidural electrostimulation in four live rats. The algorithm was tasked with maximizing the amplitude of evoked potentials in the rats' left tibialis anterior muscle. These experiments show that the algorithm is capable of directing these experiments sensibly, finding effective stimuli in all four animals. Further, in direct competition with an expert human experimenter, the algorithm produced superior performance in terms of average reward and comparable or superior performance in terms of maximum reward. These results indicate that variants of GP-BUCB may be suitable for autonomously directing SCI therapy.

Microelectrode Implants for Spinal Cord Stimulation in Rats

Paralysis is a debilitating condition afflicting millions of people across the globe, and is particularly deleterious to quality of life when motor function of the legs is severely impaired or completely absent. Fortunately, spinal cord stimulation has shown great potential for improving motor function after spinal cord injury and other pathological conditions. Many animal studies have shown stimulation of the neural networks in the spinal cord can improve motor ability so dramatically that the animals can even stand and step after a complete spinal cord transaction.

This thesis presents work to successfully provide a chronically implantable device for rats that greatly enhances the ability to control the site of spinal cord stimulation. This is achieved through the use of a parylene-C based microelectrode array, which enables a density of stimulation sites unattainable with conventional wire electrodes. While many microelectrode devices have been proposed in the past, the spinal cord is a particularly challenging environment due to the bending and movement it undergoes in a live animal. The developed microelectrode array is the first to have been implanted in vivo while retaining functionality for over a month. In doing so, different neural pathways can be selectively activated to facilitate standing and stepping in spinalized rats using various electrode combinations, and important differences in responses are observed.

An engineering challenge for the usability of any high density electrode array is connecting the numerous electrodes to a stimulation source. This thesis develops several technologies to address this challenge, beginning with a fully passive implant that uses one wire per electrode to connect to an external stimulation source. The number of wires passing through the body and the skin proved to be a hazard for the health of the animal, so a multiplexed implant was devised in which active electronics reduce the number of wires. Finally, a fully wireless implant was developed. As these implants are tested in vivo, encapsulation is of critical importance to retain functionality in a chronic experiment, especially for the active implants, and it was achieved without the use of costly ceramic or metallic hermetic packaging. Active implants were built that retained functionality 8 weeks after implantation, and achieved stepping in spinalized rats after just 8-10 days, which is far sooner than wire-based electrical stimulation has achieved in prior work.

Effects produced in GaAs by MeV ion bombardment

Presented in the first part of this thesis is work performed on the ionizing energy beam induced adhesion enhancement of thin (~ 500 Angstrom) Au films on GaAs substrates. The ionizing beam, employed in the present thesis, is the MeV ions (i.e., ¹⁶O, ¹⁹F, and ³⁵Cl), with energies between 1 and 20 MeV. Using the "Scratch" test for adhesion measurement, and ESCA for chemical analysis of the film-substrate interface, the native oxide layer at the interface is shown to play an important role in the adhesion enhancement by the ionizing radiation. A model is discussed which explains the experimental data on the the dependence of adhesion enhancement on the energy which was deposited into electronic processes at the interface. The ESCA data indicate that the chemical bonds (or compounds), which are responsible for the increase in the thin film adherence, are hydroxides rather than oxides.

In the second part of the thesis we present a research performed on the radiation damage in GaAs crystals produced by MeV ions. Lattice parameter dilatation in the surface layers of the GaAs crystals becomes saturated after a high dose bombardment at room temperature. The strain produced by nuclear collisions is shown to relax partially due to electronic excitation (with a functional dependence on the nuclear and electronic stopping power of bombarding ions). Data on the GaAs and GaP crystals suggest that low temperature recovery stage defects produce major crystal distortion. The x-ray rocking curve technique with a dynamical diffraction theory analysis provides the depth distribution of the strain and damage in the MeV ion bombarded crystals.