<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

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24286号 / 医博第4902号 / 新制||医||1061(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 森本 尚樹, 教授 辻川 明孝, 教授 渡邉 大 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

The ability to perceive speech is related to the listener's ability to differentiate among frequencies (i.e. spectral resolution). Cochlear implant users exhibit variable speech perception and spectral resolution abilities, which can be attributed at least in part to electrode interactions at the periphery (i.e. spatial resolution). However, electrophysiological measures of peripheral spatial resolution have not been found to correlate with speech perception. The purpose of this study was to systematically evaluate auditory processing from the periphery to the cortex using both simple and spectrally complex stimuli in order to better understanding the underlying processes affecting spatial and spectral resolution and speech perception. Eleven adult cochlear implant users participated in this study. Peripheral spatial resolution was assessed using the electrically evoked compound action potential (ECAP) to measure channel interaction functions for thirteen probe electrodes. We evaluated central processing using the auditory change complex (ACC), a cortical response, elicited with both spatial (electrode pairs) and spectral (rippled noise) stimulus changes. Speech perception included a vowel-discrimination task and the BKB-SIN test of keyword recognition in noise. We varied the likelihood of electrode interactions within each participant by creating three experimental programs, or MAPs, using a subset of seven electrodes and varying the spacing between activated electrodes. Linear mixed model analysis was used to account for repeated measures within an individual, allowing for a within-subject interpretation. We also performed regression analysis to evaluate the relationships across participants. Both peripheral and central processing abilities contributed to the variability in performance observed across CI users. The spectral ACC was the strongest predictor of speech perception abilities across participants. When spatial resolution was varied within a person, all electrophysiological measures were significantly correlated with each other and with speech perception. However, the ECAP measures were the best single predictor of speech perception for the within-subject analysis, followed by the spectral ACC. Our results indicate that electrophysiological measures of spatial and spectral resolution can provide valuable information about perception. All three of the electrophysiological measures used in this study, including the ECAP channel interaction functions, demonstrated potential for clinical utility.

Current cochlear implant systems use fast pulsatile stimulation to deliver the temporal modulations of speech and to, potentially, improve the neural representation of such modulations by restoring the independence of neural firing. The realization of these benefits may vary with other pulse rate-dependent temporal interactions that occur at the neural membrane, e.g., per(i)stimulatory adaptation and its post-stimulatory or forward masking effects. This study attempted to characterize adaptation and recovery of the electrically evoked compound action potential (ECAP) using probe pulses delivered within and following brief (100 ms) high-rate masker (1800 pps) pulse trains at various current levels in adults and children. With this stimulus paradigm, the ECAP amplitude typically achieved a steady state during the course of pulse train stimulation. The ECAP amplitude at steady state was, on average, a similar proportion (50-70%) of the amplitude at onset for various stimulus levels and in both age groups. However, long-term adaptation effects, evidenced by the decrease in onset ECAP amplitude, were greater in adults particularly at lower levels in the ECAP dynamic range. Instances of alternation in ECAP amplitude were seen at stimulus levels that were higher in the ECAP dynamic range. The forward masking effects of pulse train stimulation were quantified by the ECAP amplitude in response to a subsequent probe pulse normalized by the response to the same pulse presented alone. Pulse train forward masking increased with the level of the masker pulse train and decreased with the level of the probe stimulus. The recovery of the ECAP for probes that were lower in level than the masker pulse train was incomplete at 600 ms after masker offset, consistent with long-term cumulative effects observed in the response to the probe alone. Masker pulse trains that are lower in level than the probe pulse produced proportionally small decrements in the ECAP amplitude with complete recovery within 250 ms of pulse train offset particularly in adults. ECAP recovery of a probe preceded by a masker pulse train of equal level followed a monotonic or non-monotonic pattern consistent with a hypothesis of both adaptation and facilitation occurring with pulse train stimulation. The various patterns of recovery may attest to the occurrence of more than a single process in the same subset of nerve fibers or in different fibers. We hypothesize that the variations in the recovery patterns may be attributable to individual differences in the status of the auditory nerve and possibly, the variations in temporal interactions across the spatial domain at different stimulus levels. Finally, the probe-evoked ECAP amplitude at steady state in children and briefly, e.g., 20 ms, after pulse train offset in both age groups could be predicted by the ECAP amplitude in response to the same probe pulse when preceded at a brief interval (1.2 or 2 ms) by a single masker pulse of the same level as the masker pulse train. Further investigation may reveal if the observed differences in neural responsiveness to pulsatile stimulation, among individuals account for differences in psychophysical measures, including speech perception and whether there may be an "optimal" neural output that could be evoked by an individually "optimized" signal.

The purpose of this study was to investigate how design changes in Cochlear Nucleus cochlear implants (CIs) (CI24M, CI24R, CI24RE and CI422) affected electrode impedance and ECAP measures, and to determine if these design changes affected post-lingually deafened adults and children with congenital hearing loss in a similar way. Results of this study showed that electrode impedance was inversely related to the area of the electrode contacts in the array: lowest for the full-banded CI24M CI and highest for adults who used the CI422 device which has the smallest electrode contacts of all four devices. The noise floor of the NRT system likely plays a significant role in the finding that CI users with older devices (the CI24M, and CI24R CIs) had higher ECAP thresholds than individuals with the CI24RE electrode array. The position of the electrode array in the cochlea was also found to have a significant effect on ECAP measures. CI users with modiolar hugging (the CI24R and CI24RE CIs) electrode arrays were found to have lower ECAP thresholds than CI users whose electrode arrays were seated more laterally in the cochlear duct (e.g. the CI24M and CI422 implants). The position of the electrode contacts relative to the modiolus of the cochlea was found to be related to slope of the ECAP growth functions. The lowest slopes were found in CI24RE users. It also had a significant impact on the width of the channel interaction function. Electrode arrays seated further from the modiolus have significantly more channel interaction than electrode arrays that hug the modiolus of the cochlea. Differences between results recorded from post-lingually deafened adults and children with congenital hearing loss were minimal. The difference only reflected on the ECAP slopes. Slopes in children with congenital hearing loss were significantly steeper than those recorded from adults. This may indicate that children with congenital hearing loss may have better neural survival than adults with acquired hearing loss. In conclusion, the results of the current study show evidence of the effects of variations in design and function of the implanted components of the Nucleus CI. Perhaps the most significant finding from the current data set is that electrode arrays located closer to the modiolus of the cochlea have lower thresholds and exhibit less channel interaction than electrode arrays that are positioned more laterally. An argument could be made that lower stimulation levels and less channel interaction may result in better outcomes and/or longer battery life. For CI candidates who do not have significant residual acoustic hearing, the CI24RE implant might be a better choice than the more recently introduced CI422 electrode array.

[Truncated abstract] The present study investigated whether any of the characteristics of the compound action potential (CAP) waveform or the spectrum of the neural noise (SNN) recorded from the cochlea, could be used to examine abnormal spike generation in the type I primary afferent neurones, possibly due to pathologies leading to abnormal hearing such as tinnitus or tone decay. It was initially hypothesised that the CAP waveform and SNN contained components produced by the local action currents generated at the peripheral ends of the type I primary afferent neurones, and that changes in these local action currents occurred due to changes in the membrane potential of these neurones. It was further hypothesised that the lateral olivo-cochlear system (LOCS) efferent neurones regulate the membrane potential of the primary afferent dendrites to maintain normal action potential generation, where instability in the membrane potential might lead to abnormal primary afferent firing, and possibly one form of tinnitus. We had hoped that the activity of the LOCS efferent neurones could be observed through secondary changes in the CAP waveform and SNN, resulting from changes in the membrane potential of the primary afferent neurones. The origins of the neural activity generating the CAP waveform and SNN peaks, and the effects of the LOCS on the CAP and SNN were experimentally investigated in guinea pigs using lesions in the auditory system, transient ischemia and asphyxia, focal and systemic temperature changes, and pharmacological manipulations of different regions along the auditory pathway. ... Therefore, the CAP and SNN are altered by changes in the propagation of the action potential along the primary afferent neurones, by changes in the morphology of the tissues surrounding the cochlear nerve, and by changes in the time course of the action currents. If the CAP waveform is not altered, the amplitude of the 1kHz speak in the spontaneous SNN can be used as an objective measure of the spontaneous firing rate of the cochlear neurones. However, because the SNN contains a complex mixture of neural activity from all cochlear neurones, and the amplitude of the spontaneous SNN is variable, it would be difficult to use the spontaneous SNN alone as a differential diagnostic test of cochlear nerve pathologies. To record extratympanic electrocochleography (ET ECochG) from humans, a custom-designed, inexpensive, low-noise, optically isolated biological amplifier was built. Furthermore, a custom-designed extratympanic active electrode and ear canal indifferent electrode were designed, which increased the signal-to-noise ratio of the ECochG recording by a factor of 2, decreasing the overall recording time by 75%. The human and guinea pig CAP waveforms recorded in the present study appeared similar, suggesting that the origins of the human and guinea pig CAP waveforms were the same, and that experimental manipulations of the guinea pig CAP waveform can be used to diagnose the cause of abnormal human ECochG waveforms in cases of cochlear nerve pathologies.

Submitted by Leonardo Cavalcante (leo.ocavalcante@gmail.com) on 2018-07-17T18:53:07Z No. of bitstreams: 1 Arquivototal.pdf: 3232624 bytes, checksum: 559aa25bbe9205467b3fdd737354219e (MD5) / Made available in DSpace on 2018-07-17T18:53:07Z (GMT). No. of bitstreams: 1 Arquivototal.pdf: 3232624 bytes, checksum: 559aa25bbe9205467b3fdd737354219e (MD5) Previous issue date: 2016-02-29 / The high incidence of pain in the general population has encouraged research about this theme. Products derived from plant species have been widely used in the pharmacological treatment of pain relief. Recent studies have reported the important role of monoterpenes, active compounds found in the essential oils of aromatic plants, having relevant analgesic and anti-inflammatory potential. The geraniol (GER) is a monoterpenic alcohol, found in >160 essential oil of plant species, especially Cymbopogon gender. In the literature consulted, several biochemical and pharmacological properties are shown of GER: antitumor, antimicrobial, antiinflammatory, antioxidant, gastric and intestinal protector, neuroprotective and antiarrhythmic. In this study was evaluated the antinociceptive activity of GER, not yet reported, by animal behavioral and electrophysiological in vitro models. Male and female adult Swiss mice were used. Initially the acute toxicity of GER was investigated by calculating the lethal dose 50 (LD50) by intraperitoneal (i.p.) (= 199.9 mg/kg) and oral (p.o.) (> 1 g/kg). In psychopharmacological screening, after the administration of single doses of GER (i.p. and p.o.), behavioral changes were observed indicating a depressant profile on the central nervous system (CNS) and/or peripheral nervous system (SNP), and relevant antinociceptive effect of geraniol. Therefore, more specific antinociceptive property evaluation tests were performed. The GER (12.5, 25 or 50 mg/kg i.p. and 50 or 200 mg/kg p.o.) decreased (p<0.001) the number of abdominal contractions induced by i.p. injection of acetic acid, when compared with the control. The opioid antagonist naloxone (5 mg/kg) administered subcutaneously (s.c.) in mice, subsequently treated with GER (25 mg/kg i.p.), did not reverse its antinociceptive activity. The GER (12.5, 25 and 50 mg/kg i.p.) reduced (p<0.001) paw licking time in the second phase (15-30 min, inflammatory phase) of the formalin test. Also, in the glutamate test was reduced (p<0.01) paw licking time when GER 50 mg/kg i.p. administered. In a subsequent step, it was investigated the effect of GER on the excitability of peripheral nerve fibers through extracellular recording in the sciatic nerve in mice. The GER presented depressant effect of the compound action potential (CAP), which was reversed after washing and recovery period. The GER blocked components of the CAP concentration-dependent manner and exposure time to the drug: 1 mM after 120 min for the first component (Aγ and Aβ fibers) and 0.6 mM after 90 min for the second (Aγ and Aδ fibers). The concentration, which induces 50% inhibition of the peak-to-peak amplitude of the PAC (IC50) for the GER was calculated, being equal to 0.48±0.04 mM. The conduction velocity was also reduced by exposure to GER from the 0.3 mM concentration, for the 1st component [46.18±2.60 m/s to 36.04±1.60 m/s; p<0.05 (n=7)] and the 2nd component [18.37±1.31 m/s to 12.71±0.56 m/s; p<0.001 (n=7)]. In conclusion, the results obtained show that GER has antinociceptive activity, mainly in pain related to inflammation. Participation of the opioid pathway in its mechanism of action is unlikely, but the modulation of glutamatergic neurotransmission in a dose-dependent manner is a possible mechanism. Its antinociceptive activity is also related to the reduction in peripheral neuronal excitability, firstly in thinner fibers Aδ, which are directly connected to the conduction pain. / A elevada incidência da dor na população em geral tem incentivado as pesquisas entorno desse tema. Produtos oriundos de espécies vegetais têm sido amplamente utilizados no tratamento farmacológico de alívio da dor. Estudos recentes têm relatado o importante papel dos monoterpenos, princípios ativos encontrados nos óleos essenciais de plantas aromáticas, tendo relevante potencial analgésico e anti-inflamatório. O geraniol (GER) é um álcool monoterpênico, encontrado no óleo essencial de >160 espécies vegetais, especialmente do gênero Cymbopogon. Na literatura consultada, pesquisas apontam várias propriedades bioquímicas e farmacológicas para o GER: antitumoral, antimicrobiana, anti-inflamatória, antioxidante, de proteção gástrica e intestinal, neuroprotetora e antiarrítmica. Neste estudo foi avaliada a atividade antinociceptiva do GER, ainda não relatada, mediante modelos animais comportamentais e eletrofisiológicos in vitro. Foram utilizados camundongos machos e fêmeas Swiss adultos. Inicialmente, foi investigada a toxicidade aguda do GER mediante cálculo da dose letal 50 (DL50) pela via intraperitoneal (i.p.) (=199,9 mg/kg) e oral (v.o.) (>1 g/kg). Na triagem psicofarmacológica, após a subministração de doses únicas de GER (i.p. e v.o.) foram observadas alterações comportamentais que indicaram perfil depressor do sistema nervoso central (SNC) e/ou periférico (SNP), e relevante efeito antinociceptivo do geraniol. Portanto, foram realizados testes comportamentais de avaliação de propriedade antinociceptiva mais específicos. O GER (12,5; 25 e 50 mg/kg i.p. e 50 ou 200 mg/kg v.o.) reduziu (p<0,001) o número de contorções abdominais induzidas por injeção i.p. de ácido acético, quando comparado com o controle. O antagonista opióide naloxona (5 mg/kg) administrado pela via subcutânea (s.c.) em camundongos, subsequentemente tratados com GER (25 mg/kg i.p.), não reverteu sua atividade antinociceptiva. O GER (12,5; 25 e 50 mg/kg i.p.) reduziu (p<0,001) o tempo de lambida da pata na segunda fase (15-30 min, fase inflamatória) do teste da formalina. Também, no teste do glutamato houve redução (p<0,01) do tempo de lambida da pata quando administrado GER 50 mg/kg i.p. Em uma etapa subsequente, investigou-se o efeito do GER sobre a excitabilidade de fibras nervosas periféricas, mediante registro extracelular em nervo ciático de camundongo. O GER apresentou efeito depressor do potencial de ação composto (PAC), o qual foi parcialmente revertido após lavagem durante o período de recuperação. O GER bloqueou as componentes do PAC, de maneira dependente da concentração e do tempo de exposição à droga: 1 mM aos 120 min para a primeira componente (fibras Aγ e Aβ) e 0,6 mM aos 90 min para a segunda (fibras Aγ e Aδ). Foi calculada para o GER, a concentração que induz 50% de inibição da amplitude pico-a-pico do PAC (CI50), sendo igual a 0,48±0,04 mM. A velocidade de condução também, foi reduzida pela exposição ao GER, a partir da concentração de 0,3 mM para a 1ª componente [46,18±2,60 m/s para 36,04±1,60 m/s; p<0,05 (n=7)] e para a 2ª componente [18,37±1,31 m/s para 12,71±0,56 m/s; p<0,001 (n=7)]. Em conclusão, os resultados obtidos mostram que o GER tem atividade antinociceptiva, principalmente na dor relacionada à inflamação. A participação da via opióide no seu mecanismo de ação é pouco provável, mas a modulação da neurotransmissão glutamatérgica de maneira dependente da dose é um mecanismo possível. Sua atividade antinociceptiva tambèm, está relacionada à redução da excitabilidade neuronal periférica, primeiramente de fibras mais finas como Aδ, ligadas diretamente à condução da dor.

No description available.

The recovery from prior stimulation of the compound action potential (CAP) was measured using a forward masking stimulus paradigm in four normal-hearing, human subjects. The CAP was recorded using a wick electrode placed on the tympanic membrane. The effects of a 4000-Hz, 97-dB SPL conditioning stimulus on CAP amplitude in response to a 4000-Hz probe were measured as a function of conditioner–probe interval for three probe levels. The normalized probe response amplitude was completely recovered to the control values at an average conditioner–probe interval of 1359 ms, similar to that observed in chinchilla (Relkin, E.M., Doucet, J.R., Sterns, A., 1995. Recovery of the compound action potential following prior stimulation: evidence for a slow component that reflects recovery of low spontaneous-rate auditory neurons, Hear. Res. 83, 183–189). The present results are interpreted as a consequence of the slow recovery of low spontaneous-rate (SR), high threshold neurons from prior stimulation (Relkin, E.M., Doucet, J.R., 1991. Recovery from prior stimulation. I: Relationship to spontaneous firing rates of primary auditory neurons. Hear. Res. 55, 215–222) and may provide indirect physiological evidence for the existence of a class of low-SR auditory neurons in humans.

Effective cochlear implant fitting (or programming) is essential for providing good hearing outcomes, yet it is a subjective and error-prone task. The initial objective of this research was to automate the procedure using the auditory nerve electrically evoked compound action potential (the ECAP) and machine intelligence. The Nucleus?? cochlear implant measures the ECAP via its Neural Response Telemetry (NRT™) system. AutoNRT™, a commercial intelligent system that measures ECAP thresholds with the Nucleus Freedom™ implant, was firstly developed in this research. AutoNRT uses decision tree expert systems that automatically recognise ECAPs. The algorithm approaches threshold from lower stimulus levels, ensuring recipient safety during postoperative measurements. Clinical studies have demonstrated success on approximately 95% of electrodes, measured with the same efficacy as a human expert. NRT features other than ECAP threshold, such as the ECAP recovery function, could not be measured with similar success rates, precluding further automation and loudness prediction from data mining results. Despite this outcome, a better application of the ECAP threshold profile towards fitting was established. Since C-level profiles (the contour of maximum acceptable stimulus levels across the implant array) were observed to be flatter than T-level profiles (the contour of minimum audibility), a flattening of the ECAP threshold profile was adopted when applied as a fitting profile at higher stimulus levels. Clinical benefits of this profile scaling technique were demonstrated in a 42 subject study. Data mining results also provided an insight into the ECAP recovery function and refractoriness. It is argued that the ECAP recovery function is heavily influenced by the size of the recruited neural population, with evidence gathered from a computational model of the cat auditory nerve and NRT measurements with 21 human subjects. Slower ECAP recovery, at equal loudness, is a consequence of greater neural recruitment leading to lower mean spike probabilities. This view can explain the counterintuitive association between slower ECAP recovery and greater temporal responsiveness to increasing stimulation rate. This thesis presents the first attempt at achieving completely automated cochlear implant fitting via machine intelligence; a future generation implant, capable of high fidelity auditory system measurements, may realise the ultimate objective.