<p>Deep brain stimulation (DBS) is an established surgical therapy for movement disorders. The mechanisms of action of DBS remain unclear, and selection of stimulation parameters is a clinical challenge and can result in sub-optimal outcomes. Closed-loop DBS systems would use a feedback control signal for automatic adjustment of DBS parameters and improved therapeutic effectiveness. We hypothesized that evoked compound action potentials (ECAPs), generated by activated neurons in the vicinity of the stimulating electrode, would reveal the type and spatial extent of neural activation, as well as provide signatures of clinical effectiveness. The objective of this dissertation was to record and characterize the ECAP during DBS to determine its suitability as a feedback signal in closed-loop systems. The ECAP was investigated using computer simulation and <italic>in vivo</italic> experiments, including the first preclinical and clinical ECAP recordings made from the same DBS electrode implanted for stimulation. </p><p>First, we developed DBS-ECAP recording instrumentation to reduce the stimulus artifact and enable high fidelity measurements of the ECAP at short latency. <italic>In vitro</italic> and <italic>in vivo</italic> validation experiments demonstrated the capability of the instrumentation to suppress the stimulus artifact, increase amplifier gain, and reduce distortion of short latency ECAP signals.</p><p>Second, we characterized ECAPs measured during thalamic DBS across stimulation parameters in anesthetized cats, and determined the neural origin of the ECAP using pharmacological interventions and a computer-based biophysical model of a thalamic network. This model simulated the ECAP response generated by a population of thalamic neurons, calculated ECAPs similar to experimental recordings, and indicated the relative contribution from different types of neural elements to the composite ECAP. Signal energy of the ECAP increased with DBS amplitude or pulse width, reflecting an increased extent of activation. Shorter latency, primary ECAP phases were generated by direct excitation of neural elements, whereas longer latency, secondary phases were generated by post-synaptic activation.</p><p>Third, intraoperative studies were conducted in human subjects with thalamic DBS for tremor, and the ECAP and tremor responses were measured across stimulation parameters. ECAP recording was technically challenging due to the presence of a wide range of stimulus artifact magnitudes across subjects, and an electrical circuit equivalent model and finite element method model both suggested that glial encapsulation around the DBS electrode increased the artifact size. Nevertheless, high fidelity ECAPs were recorded from acutely and chronically implanted DBS electrodes, and the energy of ECAP phases was correlated with changes in tremor. </p><p>Fourth, we used a computational model to understand how electrode design parameters influenced neural recording. Reducing the diameter or length of recording contacts increased the magnitude of single-unit responses, led to greater spatial sensitivity, and changed the relative contribution from local cells or passing axons. The effect of diameter or contact length varied across phases of population ECAPs, but ECAP signal energy increased with greater contact spacing, due to changes in the spatial sensitivity of the contacts. In addition, the signal increased with glial encapsulation in the peri-electrode space, decreased with local edema, and was unaffected by the physical presence of the highly conductive recording contacts.</p><p>It is feasible to record ECAP signals during DBS, and the correlation between ECAP characteristics and tremor suggests that this signal could be used in closed-loop DBS. This was demonstrated by implementation in simulation of a closed-loop system, in which a proportional-integral-derivative (PID) controller automatically adjusted DBS parameters to obtain a target ECAP energy value, and modified parameters in response to disturbances. The ECAP also provided insight into neural activation during DBS, with the dominant contribution to clinical ECAPs derived from excited cerebellothalamic fibers, suggesting that activation of these fibers is critical for DBS therapy.</p> / Dissertation
| Identifer | oai:union.ndltd.org:DUKE/oai:dukespace.lib.duke.edu:10161/8195 |
| Date | January 2013 |
| Creators | Kent, Alexander Rafael |
| Contributors | Grill, Warren M |
| Source Sets | Duke University |
| Detected Language | English |
| Type | Dissertation |
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