Spinal Cord Stimulation (SCS) is a treatment for lumbar back pain and despitethe proven effcacy of the technology, there is a lack of knowledge in how the treatment outcome varies between different patients groups. Furthermore, since the method is costly, in the sense of material, surgery and follow-up time, a more accurate patient targeting would decrease healthcare costs. Within recent years, Real World Data (RWD) has become a vital source of information to describe the effects of medical treatments. The complexity, however, calls for new, innovative methods using a larger set of useful features to explain the outcome of SCS treatments. This study has employed machine learning algorithms, e.g., Random Forest Classier (RFC) boosting algorithms to finally compare the result with the baseline; Logistic regression (LR). The results retrieved was that RFC tend to classify successful and unsuccessful patients better while logistic regression was unstable regarding unbalanced data. In order to interpret the insights of the models, we also proposed a Soft Accuracy Measurement (SAM) method to explain how RFC and LR differ. Some factors have shown to impact the success of SCS. These factors were age, income, pain experience time and educational level. Many of these variables could also be supported by earlier studies on factors of success from lumbar spine surgery.

A prototype of a one-time implantable spinal cord stimulation (SCS) system is presented in this thesis. A pair of inductive coils is used to achieve wireless power transmission and bidirectional communication. A rechargeable Li-ion battery is used to extend the lifetime of the implanted SCS device. Therefore, the number of the battery replacement surgery could be reduced such that one-time implantation is feasible. Besides, the proposed system on chip (SOC) controller and many discretes are integrated on a printed circuit board (PCB). The size of the proposed SCS device is competitive compared to the currently commercial products. The proposed SOC controller adopts a dual supply voltage scheme to reduce power consumption. The proposed SCS system employs an amplitude-shift keying (ASK) technique to carry out the data modulation and power transmission. One of the critical factors to affect efficiency of ASK-based wireless power transmission is the oscillating frequency accuracy. A ROM-less direct digital frequency synthesizer (DDFS) is presented in this thesis to fulfill such a high accuracy demand. Since the supply voltages of the discretes are diversified on a system PCB, many level converters are needed to translate different signal output voltage levels. To resolve above problem, the chip, then, must be redesigned to meet the various voltage level requirement, or added level convertors among the SOC and the discretes. Obviously, it will cause a lot of cost. A wide-range I/O buffer, thus, is proposed to resolve the compatibility problem caused by different supply voltages of discretes.

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<p>Modulation of neural activity with electrical stimulation is a widespread therapy for treating neurological disorders and diseases. Two notable applications that have had striking clinical success are deep brain stimulation (DBS) for the treatment of movement disorders (e.g., Parkinson's disease) and spinal cord stimulation (SCS) for the treatment of chronic low back and limb pain. In these therapies, the battery life of the stimulators is much less than the required duration of treatment, requiring patients to undergo repeated battery replacement surgeries, which are costly and obligate them to incur repeatedly the risks associated with surgery. Further, deviations in lead position of 2-3 mm can preclude some or all potential clinical benefits, and in some cases, generate side-effects by stimulation of non-target regions. Therefore, despite the success of DBS and SCS, their efficiency and ability to activate target neural elements over non-target elements, termed selectivity, are inadequate and need improvement.</p><p>We combined computational models of volume conduction in the brain and spine with cable models of neurons to design novel electrode configurations for efficient and selective electrical stimulation of nervous tissue. We measured the efficiency and selectivity of prototype electrode designs in vitro and in vivo. Stimulation efficiency was increased by increasing electrode area and/or perimeter, but the effect of increasing perimeter was not as pronounced as increasing area. Cylindrical electrodes with aspect (height to diameter) ratios of > 5 were the most efficient for stimulating neural elements oriented perpendicular to the axis of the electrode, whereas electrodes with aspect ratios of < 2 were the most efficient for stimulating parallel neural elements.</p><p>Stimulation selectivity was increased by combining two or more electrodes in multipolar configurations. Asymmetric bipolar configurations were optimal for activating parallel axons over perpendicular axons; arrays of cathodes with short interelectrode spacing were optimal for activating perpendicular axons over parallel axons; anodes displaced from the center of the target region were optimal for selectively activating terminating axons over passing axons; and symmetric tripolar configurations were optimal for activating neural elements based on their proximity to the electrode. The performance of the efficient and selective designs was not be explained solely by differences in their electrical properties, suggesting that field-shaping effects from changing electrode geometry and polarity can be as large as or larger than the effects of decreasing electrode impedance.</p><p>Advancing our understanding of the features of electrode geometry that are important for increasing stimulation efficiency and selectivity facilitates the design of the next generation of stimulation electrodes for the brain and spinal cord. Increased stimulation efficiency will increase the battery life of IPGs, increase the recharge interval of rechargeable IPGs, and potentially reduce stimulator volume. Greater selectivity may improve the success rate of DBS and SCS by mitigating the sensitivity of clinical outcomes to malpositioning of the electrode.</p> / Dissertation

<p>Chronic pain is a distressing, prevalent, and expensive condition that is not well understood and difficult to treat. Spinal cord stimulation (SCS) has emerged as a viable means of managing chronic pain when conventional therapies are ineffective, but the efficacy of SCS has improved little since its inception. The mechanisms underlying SCS, in particular the neuronal responses to SCS, are not well understood, and prior efforts to optimize SCS have focused on electrode design and spatial selectivity without considering how the temporal aspects of SCS (stimulation frequency, pattern) may affect neuronal responses to stimulation. The lack of a biophysical basis in prior attempts to optimize therapy may have contributed to the plateau in the clinical efficacy of SCS over time. This dissertation combines computational modeling and in vivo electrophysiological approaches to investigate the effects of SCS on sensory neuron activity in the dorsal horn and uses the insights gained from these experiments to design novel temporal patterns for SCS that may be more effective than conventional therapy.</p><p>To study the mechanisms underlying SCS, we constructed a biophysically-based network model of the dorsal horn circuit consisting of interconnected dorsal horn interneurons and a wide dynamic range (WDR) projection neuron and representations of both local and surround receptive field inhibition. We validated the network model by reproducing cellular and network responses relevant to pain processing including wind-up, A-fiber mediated inhibition, and surround receptive field inhibition. To quantify experimentally the responses of spinal sensory projection neurons to SCS, we recorded the responses of antidromically identified sensory neurons in the lumbar spinal cord during 1-150 Hz SCS in both healthy rats and neuropathic rats following chronic constriction injury (CCI). In a subset of rats, we additionally assessed the impact of GABAergic inhibition on spinal neuron responses to SCS by conducting SCS experiments following the intrathecal administration of bicuculline, a GABAA receptor antagonist, and CGP 35348, a GABAB receptor antagonist. Finally, we used the computational model to design non-regular temporal patterns capable of inhibiting sensory neuron activity more effectively than conventional SCS and at lower equivalent stimulation frequencies than clinical standard 50 Hz SCS, and we experimentally validated model predictions of the improved efficacy of select patterns against conventional SCS.</p><p>Computational modeling revealed that the response of spinal sensory neurons to SCS depends on the SCS frequency; SCS frequencies of 30-100 Hz maximally inhibited the model WDR neuron consistent with clinical reports, while frequencies under 30 Hz and over 100 Hz excited the model WDR neuron. SCS-mediated inhibition was also dependent on GABAergic inhibition in the spinal cord: reducing the influence GABAergic interneurons by weakening their inputs or their connections to the model WDR neuron reduced the range of optimal SCS frequencies and changed the frequency at which SCS had a maximal effect. Experimentally, we observed that the relationship between SCS frequency and projection neuron activity predicted by the Gate Control circuit described a subset of observed SCS-frequency dependent responses but was insufficient to account for the heterogeneous responses measured experimentally. In addition, intrathecal administration of bicuculline, a GABAA receptor antagonist, increased spontaneous and evoked activity in projection neurons, enhanced excitatory responses to SCS, and reduced inhibitory responses to SCS, consistent with model predictions. Finally, computational modeling of dual frequency SCS, implemented by delivering two distinct frequencies simultaneously to distinct fiber populations, revealed frequency pairs that were more effective at inhibiting sensory neuron activity than equivalent conventional SCS and at lower average frequencies than clinically employed 50 Hz SCS. Experimental assessments of the effect of dual frequency SCS on spinal sensory neurons confirmed model predictions of greater efficacy at lower equivalent stimulation frequencies and suggest the use of non-regular temporal patterns as a novel approach to optimizing SCS. The outcomes of this dissertation are an improved understanding of the mechanisms underlying SCS, computational and experimental tools with which to continue the development and improvement of SCS. The insights and knowledge gained from the work described in this dissertation may result in translational applications that significantly improve the therapeutic outcomes of SCS and the quality of life of individuals affected by chronic pain.</p> / Dissertation

<p>Mainstream electrical stimulation therapies, e.g., spinal cord stimulation (SCS) and deep brain stimulation, use pulse trains that are delivered at rates no higher than 200 Hz. In recent years, stimulation of nerve fibers using kilohertz-frequency (KHF) signals has received increased attention due to the potential to penetrate deeper in the tissue and to the ability to block conduction of action potentials. As well, there are a growing number of clinical applications that use KHF waveforms, including transcutaneous electrical stimulation (TES) for overactive bladder and SCS for chronic pain. However, there is a lack of fundamental understanding of the mechanisms of action of KHF stimulation. The goal of this research was to analyze quantitatively KHF neurostimulation. </p><p>We implemented a multilayer volume conductor model of TES including dispersion and capacitive effects, and we validated the model with in vitro measurements in a phantom constructed from dispersive materials. We quantified the effects of frequency on the distribution of potentials and fiber excitation. We also quantified the effects of a novel transdermal amplitude modulated signal (TAMS) consisting of a non-zero offset sinusoidal carrier modulated by a square-pulse train. The model revealed that high-frequency signals generated larger potentials at depth than did low frequencies, but this did not translate into lower stimulation thresholds. Both TAMS and conventional rectangular pulses activated more superficial fibers in addition to the deeper, target fibers, and at no frequency did we observe an inversion of the strength-distance relationship. In addition, we performed in vivo experiments and applied direct stimulation to the sciatic nerve of cats and rats. We measured electromyogram and compound action potential activity evoked by pulses, TAMS and modified versions of TAMS in which we varied the amplitude of the carrier. Nerve fiber activation using TAMS showed no difference with respect to activation with conventional pulse for carrier frequencies of 20 kHz and higher, regardless the size of the carrier. Therefore, TAMS with carrier frequencies >20 kHz does not offer any advantage over conventional pulses, even with larger amplitudes of the carrier, and this has implications for design of waveforms for efficient and effective TES. </p><p>We developed a double cable model of a dorsal column (DC) fiber to quantify the responses of DC fibers to a novel KHF-SCS signal. We validated the model using in vivo recordings of the strength-duration relationship and the recovery cycle of single DC fibers. We coupled the fiber model to a model of SCS in human and applied the KHF-SCS signal to quantify thresholds for activation and conduction block for different fiber diameters at different locations in the DCs. Activation and block thresholds increased sharply as the fibers were placed deeper in the DCs, and decreased for larger diameter fibers. Activation thresholds were > 5 mA in all cases and up to five times higher than for conventional (~ 50 Hz) SCS. For fibers exhibiting persistent activation, the degree of synchronization of the firing activity to the KHF-SCS signal, as quantified using the vector strength, was low for a broad amplitude range, and the dissimilarity between the activities in pairs of fibers, as quantified using the spike time distance, was high and decreased for more closely positioned fibers. Conduction block thresholds were higher than 30 mA for all fiber diameters at any depth and well above the amplitudes used clinically (0.5 – 5 mA). KHF-SCS appears to activate few, large, superficial fibers, and the activated fibers fire asynchronously to the stimulation signal and to other activated fibers. </p><p>The outcomes of this work contribute to the understanding of KHF neurostimulation by establishing the importance of the tissue filtering properties on the distribution of potentials, assessing quantitatively the impact of KHF stimulation on nerve fiber excitation, and developing and validating a detailed model of a DC fiber to characterize the effects of KHF stimulation on DC axons. The results have implications for design of waveforms for efficient and effective nerve fiber stimulation in the peripheral and central nervous system.</p> / Dissertation

We sought to determine whether spinal cord stimulation (SCS) therapy, when applied chronically to canines, imparts long-lasting cardio-protective effects on neurogenic atrial tachyarrhythmia induction and, if so, whether its effects can be attributable to i) changes in intrinsic cardiac (IC) neuronal transmembrane properties vs ii) modification of their interneuronal stochastic interactivity that initiates such pathology. Data derived from canines subjected to long-term SCS [(group 1: studied after 3-4 weeks SCS; n = 5) (group 2: studied after 5 weeks SCS; n = 11)] were compared to data derived from 10 control animals (including 4 sham SCS electrode implantations). During terminal studies conducted under anesthesia, chronotropic and inotropic responses to vagal nerve or stellate ganglion stimulation were similar in all 3 groups. Chronic SCS suppressed atrial tachyarrhythmia induction evoked by mediastinal nerve stimulation. When induced, arrhythmia durations were shortened (controls: median of 27 s; SCS 3-4 weeks: median of 16 s; SCS 5 weeks: median of 7 s). Phasic and accommodating right atrial neuronal somata displayed similar passive and active membrane properties in vitro, whether derived from sham or either chronic SCS group. Synaptic efficacy was differentially enhanced in accommodating (not phasic) IC neurons by chronic SCS. Taken together these data indicate that chronic SCS therapy modifies IC neuronal stochastic inter-connectivity in atrial fibrillation suppression by altering synaptic function without directly targeting the transmembrane properties of individual IC neuronal somata. •Spinal cord stimulation (SCS) suppresses neurally induced atrial fibrillation (AF).•Effectiveness of SCS in AF suppression increases with time.•SCS minimally impacts active and passive properties of individual intrinsic cardiac neurons.•SCS modifies synaptic efficacy of the IC network.•SCS differentially impacts the neurotransmission to the accommodating sub-population of IC neurons.

Spinal cord stimulation (SCS) inhibits substance P (SP) release and decreases the expression of the transient receptor potential vanilloid 1 (TRPV1) in the spinal cord at thoracic 4 (T4) during cardiac ischemia in rat models (. Ding et al., 2007). We hypothesized that activation of TRPV1 in the T4 spinal cord segment by intermittent occlusion of the left anterior descending coronary artery (CoAO) mediates spinal cord SP release. Experiments were conducted in urethane-anesthetized Sprague-Dawley male rats using SP antibody-coated microprobes to measure SP release at the central terminal endings of cardiac ischemic-sensitive afferent neurons (CISAN) in the spinal T4 dorsal horns. Vehicle, capsaicin (CAP; TRPV1 agonist) and capsazepine (CZP; TRPV1 antagonist) were injected into the left T4 prior to stimulation of CISAN by intermittent CoAO (with or without upper cervical SCS). CAP induced endogenous SP release from laminae I and II in the T4 spinal cord above baseline. Conversely, CZP injections significantly inhibited SP release from laminae I-VII in the T4 spinal cord segment below baseline. CZP also attenuated CoAO-induced SP release, while T4 injections of CZP with SCS completely restored SP release to basal levels during CoAO activation. CAP increased the number of c-Fos (a marker for CISAN activation) positive T4 dorsal horn neurons compared to sham-operated animals, while CZP (alone or during CoAO and SCS. +. CoAO) significantly reduced the number of c-Fos positive neurons. These results suggest that spinal release of the putative nociceptive transmitter SP occurs, at least in part, via a TRPV1 mechanism.

Our objective was to determine whether atrial fibrillation (AF) results from excessive activation of intrinsic cardiac neurons (ICNs) and, if so, whether select subpopulations of neurons therein represent therapeutic targets for suppression of this arrhythmogenic potential. Trains of five electrical stimuli (0.3-1.2 mA, 1 ms) were delivered during the atrial refractory period to mediastinal nerves (MSN) on the superior vena cava to evoke AF. Neuroanatomical studies were performed by injecting the neuronal tracer DiI into MSN sites that induced AF. Functional studies involved recording of neuronal activity in situ from the right atrial ganglionated plexus (RAGP) in response to MSN stimulation (MSNS) prior to and following neuromodulation involving either preemptive spinal cord stimulation (SCS; T 1-T 3, 50 Hz, 200-ms duration) or ganglionic blockade (hexamethonium, 5 mg/kg). The tetramethylindocarbocyanine perchlorate (DiI) neuronal tracer labeled a subset (13.2%) of RAGP neurons, which also colocalized with cholinergic or adrenergic markers. A subset of DiI-labeled RAGP neurons were noncholinergic/nonadrenergic. MSNS evoked an ~4-fold increase in RAGP neuronal activity from baseline, which SCS reduced by 43%. Hexamethonium blocked MSNS-evoked increases in neuronal activity. MSNS evoked AF in 78% of right-sided MSN sites, which SCS reduced to 33% and hexamethonium reduced to 7%. MSNS-induced bradycardia was maintained with SCS but was mitigated by hexamethonium. We conclude that MSNS activates subpopulations of intrinsic cardiac neurons, thereby resulting in the formation of atrial arrhythmias leading to atrial fibrillation. Stabilization of ICN local circuit neurons by SCS or the local circuit and autonomic efferent neurons with hexamethonium reduces the arrhythmogenic potential.

Aberrant afferent signaling drives adverse remodeling of the cardiac nervous system in ischemic heart disease. The study objective was to determine whether thoracic spinal dorsal column stimulation (SCS) modulates cardiac afferent sensory transduction of the ischemic ventricle. In anesthetized canines (n = 16), extracellular activity generated by 62 dorsal root ganglia (DRG) soma (T1-T3), with verified myocardial ischemic (MI) sensitivity, were evaluated with and without 20-min preemptive SCS (T1-T3 spinal level; 50 Hz, 90% motor threshold). Transient MI was induced by 1-min coronary artery occlusion (CAO) of the left anterior descending (LAD) or circumflex (LCX) artery, randomized as to sequence. LAD and LCX CAO activated cardiac-related DRG neurons (LAD: 0.15 ± 0.04-1.05 ± 0.20 Hz, P < 0.00002; LCX: 0.08 ± 0.02-1.90 ± 0.45 Hz, P < 0.0003). SCS decreased basal neuronal activity of neurons that responded to LAD (0.15 ± 0.04 to 0.02 ± 0.01 Hz, P < 0.006) and LCX (0.08 ± 0.02 to 0.02 ± 0.01 Hz, P < 0.003). SCS suppressed responsiveness to transient MI (LAD: 1.05 ± 0.20-0.03 ± 0.01 Hz; P < 0.0001; LCX: 1.90 ± 0.45-0.03 ± 0.01 Hz; P < 0.001). Suprathreshold SCS (1 Hz) did not activate DRG neurons antidromically (n = 10 animals). Ventricular fibrillation (VF) was associated with a rapid increase in DRG activity to a maximum of 4.39 ± 1.07 Hz at 20 s after VF induction and a return to 90% of baseline within 10 s thereafter. SCS obtunds the capacity of DRG ventricular neurites to transduce the ischemic myocardium to second-order spinal neurons, a mechanism that would blunt reflex sympathoexcitation to myocardial ischemic stress, thereby contributing to its capacity to cardioprotect.NEW & NOTEWORTHY Aberrant afferent signaling drives adverse remodeling of the cardiac nervous system in ischemic heart disease. This study determined that thoracic spinal column stimulation (SCS) obtunds the capacity of dorsal root ganglia ventricular afferent neurons to transduce the ischemic myocardium to second-order spinal neurons, a mechanism that would blunt reflex sympathoexcitation to myocardial ischemic stress. This modulation does not reflect antidromic actions of SCS but likely reflects efferent-mediated changes at the myocyte-sensory neurite interface.