Characterization of Evoked Potentials During Deep Brain Stimulation in the Thalamus

<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>Dissertatio

Electrophysiological assessment of temporal envelope processing in cochlear implant users

Abstract: Cochlear-implant (CI) users rely on temporal envelope modulations (TEMs) to understand speech, and clinical outcomes depend on the accuracy with which these TEMs are encoded by the electrically-stimulated neural ensembles. Non-invasive EEG measures of this encoding could help clinicians identify and disable electrodes that evoke poor neural responses so as to improve CI outcomes. However, recording EEG during CI stimulation reveals huge stimulation artifacts that are up to orders of magnitude larger than the neural response. Here we used a custom-built EEG system having an exceptionally high sample rate to accurately measure the artefact, which we then removed using linear interpolation so as to reveal the neural response during continuous electrical stimulation. In ten adult CI users, we measured the 40-Hz electrically evoked auditory steady-state response (eASSR) and electrically evoked auditory change complex (eACC) to amplitude-modulated 900-pulses-per-second pulse trains, stimulated in monopolar mode (i.e. the clinical default), and at different modulation depths. We successfully measured artifact-free 40-Hz eASSRs and eACCs. Moreover, we found that the 40-Hz eASSR, in contrast to the eACC, showed substantial responses even at shallow modulation depths. We argue that the 40-Hz eASSR is a clinically feasible objective measure to assess TEM encoding in CI users

Toward a personalized closed-loop stimulation of the visual cortex: Advances and challenges

Current cortical visual prosthesis approaches are primarily unidirectional and do not consider the feed-back circuits that exist in just about every part of the nervous system. Herein, we provide a brief overview of some recent developments for better controlling brain stimulation and present preliminary human data indicating that closed-loop strategies could considerably enhance the effectiveness, safety, and long-term stability of visual cortex stimulation. We propose that the development of improved closed-loop strategies may help to enhance our capacity to communicate with the brain

Wired, wireless and wearable bioinstrumentation for high-precision recording of bioelectrical signals in bidirectional neural interfaces

It is widely accepted by the scientific community that bioelectrical signals, which can be used for the identification of neurophysiological biomarkers indicative of a diseased or pathological state, could direct patient treatment towards more effective therapeutic strategies. However, the design and realisation of an instrument that can precisely record weak bioelectrical signals in the presence of strong interference stemming from a noisy clinical environment is one of the most difficult challenges associated with the strategy of monitoring bioelectrical signals for diagnostic purposes. Moreover, since patients often have to cope with the problem of limited mobility being connected to bulky and mains-powered instruments, there is a growing demand for small-sized, high-performance and ambulatory biopotential acquisition systems in the Intensive Care Unit (ICU) and in High-dependency wards. Furthermore, electrical stimulation of specific target brain regions has been shown to alleviate symptoms of neurological disorders, such as Parkinson’s disease, essential tremor, dystonia, epilepsy etc. In recent years, the traditional practice of continuously stimulating the brain using static stimulation parameters has shifted to the use of disease biomarkers to determine the intensity and timing of stimulation. The main motivation behind closed-loop stimulation is minimization of treatment side effects by providing only the necessary stimulation required within a certain period of time, as determined from a guiding biomarker. Hence, it is clear that high-quality recording of local field potentials (LFPs) or electrocorticographic (ECoG) signals during deep brain stimulation (DBS) is necessary to investigate the instantaneous brain response to stimulation, minimize time delays for closed-loop neurostimulation and maximise the available neural data. To our knowledge, there are no commercial, small, battery-powered, wearable and wireless recording-only instruments that claim the capability of recording ECoG signals, which are of particular importance in closed-loop DBS and epilepsy DBS. In addition, existing recording systems lack the ability to provide artefact-free high-frequency (> 100 Hz) LFP recordings during DBS in real time primarily because of the contamination of the neural signals of interest by the stimulation artefacts. To address the problem of limited mobility often encountered by patients in the clinic and to provide a wide variety of high-precision sensor data to a closed-loop neurostimulation platform, a low-noise (8 nV/√Hz), eight-channel, battery-powered, wearable and wireless multi-instrument (55 × 80 mm2) was designed and developed. The performance of the realised instrument was assessed by conducting both ex vivo and in vivo experiments. The combination of desirable features and capabilities of this instrument, namely its small size (~one business card), its enhanced recording capabilities, its increased processing capabilities, its manufacturability (since it was designed using discrete off-the-shelf components), the wide bandwidth it offers (0.5 – 500 Hz) and the plurality of bioelectrical signals it can precisely record, render it a versatile tool to be utilized in a wide range of applications and environments. Moreover, in order to offer the capability of sensing and stimulating via the same electrode, novel real-time artefact suppression methods that could be used in bidirectional (recording and stimulation) system architectures are proposed and validated. More specifically, a novel, low-noise and versatile analog front-end (AFE), which uses a high-order (8th) analog Chebyshev notch filter to suppress the artefacts originating from the stimulation frequency, is presented. After defining the system requirements for concurrent LFP recording and DBS artefact suppression, the performance of the realised AFE is assessed by conducting both in vitro and in vivo experiments using unipolar and bipolar DBS (monophasic pulses, amplitude ranging from 3 to 6 V peak-to-peak, frequency 140 Hz and pulse width 100 µs). Under both in vitro and in vivo experimental conditions, the proposed AFE provided real-time, low-noise and artefact-free LFP recordings (in the frequency range 0.5 – 250 Hz) during stimulation. Finally, a family of tunable hardware filter designs and a novel method for real-time artefact suppression that enables wide-bandwidth biosignal recordings during stimulation are also presented. This work paves the way for the development of miniaturized research tools for closed-loop neuromodulation that use a wide variety of bioelectrical signals as control signals.Open Acces

Processing Submillisecond Timing Differences in a Model Electrosensory System

Perception of sensory cues requires peripheral encoding followed by extraction of behaviorally relevant signal components by central neurons. Some sensory systems can detect temporal information with submillisecond accuracy, despite these signals occurring faster than the approximately 1 ms timescale of neuronal firing. In sound localization, the best studied example of this phenomenon, there are at least two distinct mechanisms for detecting submillisecond timing differences, indicating that multiple solutions to this fundamental problem exist. I investigated mechanisms for processing submillisecond timing differences by studying electrosensory processing in a time coding expert, mormyrid weakly electric fish, which can detect submillisecond differences in the duration of electric signals. First, I measured responses of peripheral receptors to stimuli of different durations. I found that each unit responded preferentially to longer stimuli, but with response thresholds that varied among units within the behaviorally relevant range of durations. This variability establishes a population code operating at near threshold intensities in which the number and identity of responding receptors represents duration. At higher stimulus intensities all units respond independent of duration, rendering the population code obsolete. Importantly, peripheral receptors respond either to the start or end of a signal. Thus, stimulus duration is also represented by a temporal code, as a difference in spike times between receptors. Next, I investigated the central mechanism for detection of submillisecond spike time differences by recording from time comparator neurons (Small Cells) in the midbrain. Recording from Small Cells is challenging because their somas are small and relatively inaccessible. I therefore designed a novel method using retrograde labeling to directly visualize and record from Small Cells in vivo. I showed that patterns of duration tuning vary among Small Cells due to a combination of blanking inhibition corresponding to one edge of a stimulus and variably delayed excitation corresponding to one or both edges of a stimulus. Other circuits that detect submillisecond timing differences rely either on precisely-timed inhibition or delay-line coincidence detection. I demonstrate a novel mechanism by which mormyrids combine delay-line coincidence detection with precisely-timed blanking inhibition to establish diverse patterns of duration tuning among a population of time comparators

Assessing Side-Differences in the Organization of Biceps Brachii Motor Units in Healthy Subjects and Stroke Patients. An Evaluation from Surface EMG and Incremental Electrical Stimulation

Studies have suggested a degeneration of lower motoneurons in muscles affected after stroke, with a possible collateral reinnervation from the surviving motoneurons to the denervated muscle fibers. If this assumption holds, each surviving motoneuron would innervate a greater amount of muscle fibers following stroke, i.e., motor units’ size would increase in muscles affected after stroke. By combining neuromuscular electrical stimulation with surface electromyography, the present PhD thesis aimed at investigating whether muscle reinnervation following stroke leads to greater variations in the amplitude of M waves elicited in muscles of the affected side of stroke patients, with respect to the contralateral, unaffected side. This issue was verified by applying current pulses at progressively greater intensities in the motoneurons that supply the biceps brachii muscle. Then, the size of increases in the amplitude of M waves elicited consecutively, hereafter defined as increments, was considered to evaluate structural adaptations in biceps brachii motor units following stroke. Changes in the amplitude of M waves evoked in a muscle is usually assumed to reflect changes in the number of motoneurons and, consequently, of muscle fibers activated. Hence, we hypothesized that for similar, relative increases in current intensity, greater increments in the M-waves amplitude would be observed in muscles of the affected than unaffected side of stroke patients. Before verifying this hypothesis, however, we investigated whether the size of increments in biceps brachii M waves differ between arms of healthy subjects. This question was motivated by the fact that, usually, humans tend to control more finely the muscle force production in dominant than non-dominant upper limbs. Once it is well established the recruitment of motor units is a key mechanism for which muscle force is controlled, we hypothesized that a relatively smaller number of motor units maybe recruited in muscles of dominant than nondominant limbs, for any given increase in synaptic input. Hence, we expected to observe smaller increments in the amplitude of M waves evoked in biceps brachii of dominant than non-dominant arms. This PhD thesis was, therefore, based on two main researches, entitled: (1) “Does the biceps brachii muscle respond similarly in both limbs during staircase, electrically elicited contractions?” and (2) “Assessing structural adaptation of biceps brachii motor units after stroke”. Both studies were investigated with the same methodological approach mentioned above. Our main findings showed that: (1) increments were significantly smaller in biceps brachii of dominant than non-dominant arms. These results suggest there was a more gradual motor units’ recruitment and, therefore, a broader spectrum of motor units’ recruitment thresholds in muscles of dominant than non-dominant arms, which may contribute for a finer regulation of force production; (2) there was a clear trend towards greater increments in the amplitude of M waves elicited in biceps brachii of the affected than unaffected arms of most of the stroke patients evaluated. Although for few of these patients it was not clear whether side-differences in the increments magnitude were an outcome of dominance or stroke, the results found corroborate with the notion that collateral reinnervation takes place after stroke, increasing the number of muscle fibers per unit and, therefore, the magnitude of the muscle responses. Overall, the findings of this PhD thesis strengthen the idea that the organization of the neuromuscular system may contribute to accounting for upper limb dominance and that stroke may lead to structural adaptations in motor units of affected muscles

Gochlear implants from model to patients

Cochlear implants (CI) are by now an accepted form of rehabilitation for profoundly deaf patients. CI users regain part of their hearing by direct electrical stimulation of the auditory nerve. With modern cochlear implants most users are able to achieve open-set speech understanding and are able to use the telephone. There are, however, still a lot of unanswered questions regarding the optimal design, stimulation paradigms, fitting methods and objective measurements. With the development of a realistic computer model of the implanted cochlea, as described in this thesis, these questions are analyzed from a fundamental perspective. This realistic model enables the analysis of clinical devices and gives insight in discrepancies between human and animal results. Insights gained from the model are used to improve clinical practice. Based on the model outcomes presented the characteristics of an improved electrode design were defined, and finally tested in a temporal bone study.UBL - phd migration 201

Can the Voluntary Drive to a Paretic Muscle be Estimated from the Myoelectric Signal during Stimulation?

Patients with SCI sometimes recover lost function after using FES. This phenomenon, known as the carry-over effect, is not fully understood. One theory used to explain this mechanism is that electrical stimulation of the peripheral nerve causes antidromic action potentials to reach the anterior horn cells in time with the patient’s voluntary effort. This may reinforce the motor pathways and consequently restore voluntary control. However, the theory has never been properly tested and testing requires a method of measuring the voluntary drive. This project aims to find out whether it is possible to estimate the voluntary drive from measured myoelectric signals. The project is based on an FES cycling system with the ability to adjust the stimulation intensity relating to the corresponding voluntary drive. In paretic muscles, the weak voluntary contraction produces an EMG response. The EMG signal cannot be used directly as an indication of the voluntary drive because of the presence of stimulus artefact and reflexes. Two methods were investigated to estimate the voluntary drive. A time domain method was tested using RMS EMG extracted from a range of time windows following the stimulation pulse. This approach was unsatisfactory because the large variations seen in the RMS EMG amplitudes for the same power output as well as the low sensitivity of it to the change of power output. A frequency domain approach was then tested using coherence between co-contracting muscles. It was encouraging to see that the area under the coherence curve in the β band reflected changes in the power output level. However, further tests showed that this area was also greatly influenced by exercise time, becoming unpredictable after 3 minutes. In conclusion, neither of the two methods of using the myoelectric signal from muscles under stimulation is practical for the estimation of voluntary drive

Knee extension with less hip flexion: biomechanical and evoked EMG analysis during selective surface stimulation of the quadriceps

During FES cycling when the Quadriceps muscles are activated both knee extension and hip flexion moments occur simultaneously, decreasing the total power output. Of the three superficial muscles, Rectus femoris is a biarticular muscle that produces both a knee extension and a hip flexion, while Vastus lateralis and Vastus medialis are only knee extensors. This thesis is an investigation whether, using surface stimulation, selective stimulation of the Vastii can produce knee extension moment with less hip flexion. A system was developed for measurement of the joint moments and evoked myoelectric response in these three muscles, while seated subjects were stimulated. The dynamometer measures the magnitude and position of two forces that restrain the leg, from which joint moments are calculated. The design and construction of the hardware, electronics and software is presented. Validation of the dynamometer against known moments produced with a spring-loaded dummy leg showed good correlation. The influence of random and systematic errors on the estimated joint moments indicate that the dynamometer should be used for comparing the responses for different electrode configurations within single sessions. The close proximity of the EMG recording electrodes to the stimulating electrodes causes artefact that obscures the M-wave. This was partly overcome by amplifying with a current conveyor circuit, and by a novel biphasic stimulator with pulse width ratio adjustment. The design and construction of both stimulator and amplifier are discussed, also the mechanisms causing the artefact (voltage gradient, skin-electrode interface and common mode voltage). A study with ten able-bodied subjects was performed. EMG analysis showed that it is possible to selectively stimulate the Vastii and this does reduce hip flexion moment, however beside the inevitable reduction of knee extension moment, the reduction of the hip flexion is less than expected, perhaps due to stimulation of other muscles of the anterior thigh