Spinal root avulsion leads to paralysis and loss of sensory function. Surgical methods can improve motor function and ameliorate pain but sensory recovery in adults is poor. Previous studies have shown that cell transplantation or treatment with trophic factors can improve functional outcome in rodents after dorsal root transection or crush. Here, a dorsal root injury model, more similar to human avulsion injuries, was used. The aims of this thesis were to investigate the behaviour of different stem cells following transplantation to avulsed dorsal roots and asses their potential to serve as possible regenerative therapy. In paper I, different murine stem cell types were transplanted to avulsed dorsal roots in rats. Murine embryonic stem cells remained outside the spinal cord and were surrounded by glutamatergic terminals. Boundary cap neural crest stem cells (bNCSC) formed elongated bands outside the spinal cord and migrated to the spinal cord as single cells. In paper II, transplanted bNCSC were further characterized. bNCSC remaining outside the spinal cord expressed glial markers and were associated with different types of sensory fibres. bNCSC that migrated into the injured spinal cord expressed different neuronal markers. In paper III, effects of bNCSC transplantation on local vasculature and glial scar formation were studied. bNCSC increase angiogenesis in a non dose response manner and participate in boundary glial scar formation. In paper IV, bNCSC spinal migration was analysed using two different injury models - dorsal root transection and dorsal root avulsion. In addition, bNCSC capacity to support sensory regeneration was assessed and the results suggest that bNCSC do not support robust regeneration of avulsed afferents. In paper V, an in vitro stem cell model system was used to assess the possibility of using artificial nanomaterials to deliver differentiation factors. Cells treated with either soluble factors or particle-delivered factors showed similar differentiation patterns. Stem cell transplantation offers several opportunities following dorsal root avulsion, including cell replacement and regenerative support. By elucidating the mechanisms by which stem cells can assist regeneration of avulsed afferents will allow for more targeted or combinatorial approaches, including growth factor treatment.

Introduktion: Vid perifera nervundersökningar med elektroneurografi spelar temperaturen i vävnaden som undersöks stor roll. Kall vävnad leder till försämrad funktion i nervernas jonkanaler, vilket leder till att aktionspotentialer utlöses långsammare och nervledningshastigheten minskar vilket därmed kan ge falskt patologiska undersökningsresultat. För att minska den risken mäts och korrigeras alltid hudtemperaturen. Vid registrering från övre extremiteter mäts hudtemperaturen standardmässigt på handryggen. Trots att stimulering sker från handflatan och från fingrar så mäts inte temperaturen där. Syftet med studien är därför att undersöka om kalla fingrar på en i övrigt varm hand påverkar conduction velocity och peaklatenstiden, jämfört med när hand och fingrar har samma varma temperatur. Metod: 30 unga, friska personer deltog i studien. Ortodrom elektroneurografiundersökning utfördes på nervus medianus sensoriska del. Handryggstemperaturen var konstant 32° Celsius (C) och fingertoppstemperaturerna var 32° C, 27° C respektive 22° C. Vid varje fingertoppstemperatur registrerades conduction velocity och peaklatenstiden vid stimuleringar från handflatan, fingerbasen och fingertoppen på digitorum III. Resultat: En statistiskt signifikant skillnad fanns i både nervledningshastigheten och peaklatenstiden vid registrering från fingerbasen vid fingertoppstemperaturen 32° C jämfört med såväl 27° C som 22° C. Slutsats: Kalla fingrar på en varm hand ger en statistiskt signifikant påverkan på både nervledningshastigheten och peaklatenstiden. / Background: In peripheral nerve examinations with electroneurography, temperatures in the tissue that is being examined is important. Cold tissue leads to impaired function of the ion channels of the nerves, which causes action potentials to be triggered more slowly and the nerve conduction velocity to decrease, which can cause false pathological examination results. To reduce this risk, the skin temperature is always measured and corrected. When registering from the upper extremities, the skin temperature is measured by default on the back of the hand. Despite stimulating in the palm and on the fingers, the temperature is not measured there. The purpose of the study is to investigate whether cold fingers on a warm hand affects the conduction velocity and peak latency time, compared with the hand and the fingers having the same warm temperature. Methods: 30 young, healthy persons participated in the study. An orthodrome electroneurography examination was performed on the sensory part of the median nerve. The backhand temperature was constant 32° Celsius (C) and the fingertip temperatures were 32 ° C, 27 ° C and 22 ° C. Results: A statistically significant difference was found in both nerve conduction velocity and peak latency time when registering from the finger base with fingertip temperature 32 ° C compared with both 27 ° C and 22 ° C Conclusions: Cold fingers on a warm hand give a statistically significant effect on both the nerve conduction velocity and the peak latency time.

<p>Neurography is the most objective and reliable measure of the peripheral nerve function, and it is used to diagnose both local and generalized neuropathies. Neurography can measure both motor and sensory nerve functions. The principle for sensory neurgraphy is to stimulate over the nerve and record proximal or distal from the stimulated electrode.</p><p>At the Department of Clinical Neurophysiology, University Hospital Uppsala, a problem has been identified, in that young adult patients tend to show unexpected abnormal neurography values in relation to the expected, indicated by the reference limits, without clinical correlates. This concerns foremost the sensory amplitudes in median and ulnar nerves. The hypothesis is that the requirement of young adults’ amplitudes is too high. A reference material better including more subjects in this age group may solve the problem.</p><p>Sensory nerve conduction studies were performed in 33 subjects, aged 15-30. The nerve functions were tested on median, ulnar and radial nerves. Surface electrodes were used for both recording and stimulation.</p><p>The result shows that the presently used reference material for some nerves indeed has too high requirement for young adults. After increasing the reference material for younger age groups, the new reference limits has been changed and this should cause fewer false positive findings.</p>

Neurography is the most objective and reliable measure of the peripheral nerve function, and it is used to diagnose both local and generalized neuropathies. Neurography can measure both motor and sensory nerve functions. The principle for sensory neurgraphy is to stimulate over the nerve and record proximal or distal from the stimulated electrode. At the Department of Clinical Neurophysiology, University Hospital Uppsala, a problem has been identified, in that young adult patients tend to show unexpected abnormal neurography values in relation to the expected, indicated by the reference limits, without clinical correlates. This concerns foremost the sensory amplitudes in median and ulnar nerves. The hypothesis is that the requirement of young adults’ amplitudes is too high. A reference material better including more subjects in this age group may solve the problem. Sensory nerve conduction studies were performed in 33 subjects, aged 15-30. The nerve functions were tested on median, ulnar and radial nerves. Surface electrodes were used for both recording and stimulation. The result shows that the presently used reference material for some nerves indeed has too high requirement for young adults. After increasing the reference material for younger age groups, the new reference limits has been changed and this should cause fewer false positive findings.

No description available.

After injury, dorsal root (DR) axons regenerate in the peripheral nervous system (PNS), but turn around or stop at the dorsal root entry zone (DREZ), the entrance into the central nervous system (CNS). Examination of the dynamic axon regeneration that occurs following injury to the DR provides the opportunity to advance our understanding of what happens to sensory axons as they approach and arrive at the DREZ and expands our knowledge of sensory axon regeneration failure at the entrance to the spinal cord. Additionally, findings from these studies may offer potential avenues to provide insight into regeneration failure elsewhere in the central nervous system. Nevertheless, our understanding of the cellular and molecular processes underlying the failure of DR axons to regenerate through the DREZ is incomplete. The goal of my thesis work was to determine whether application of the time lapse-in vivo imaging technique is feasible and useful in studying dorsal root regeneration. I have also applied recently developed post-mortem analyses to the axons monitored in vivo, which provided additional insights into the mechanisms that prevent axon regeneration at the DREZ. Results in Chapters 2 and 3 demonstrate that wide-field microscopy is indeed feasible and useful for monitoring regenerating sensory axons immediately before, during, and in the days to weeks after lumbar (L5) DR crush. I was surprised to find that most axons were immobilized abruptly and chronically at the CNS portion of the DREZ, with their axon tips and shafts exhibiting features of differentiated nerve terminals. This observation raises the possibility, which has not been appreciated previously, that DR axons stop at the DREZ because their regeneration is terminated prematurely by forming synaptic contacts with unidentified postsynaptic cells. To confirm the immobilization of DR axons at the DREZ, I applied two-photon microscopy to examine the axon behavior at the DREZ at high resolution. Results described in Chapter 4 confirm those obtained with the time-lapse imaging performed with wide-field microscopy: axons arrested soon after their arrival at the DREZ did not exhibit even subtle movements. Light microscopic analyses of the failed axon tips monitored in vivo demonstrated that almost all axons stopped at the CNS territory of the DREZ, and that axon tips and adjacent shafts intensely immunolabeled with synapse markers. Ultrastructural analyses revealed that numerous axonal profiles had the characteristic features of pre- but not postsynaptic endings. Findings from these studies lead us to speculate that most, if not all, dorsal root axons become arrested as they enter the CNS territory of the DREZ by forming presynaptic terminals on non-neuronal cellular elements that differ from the dystrophic-like endings formed by a few axons. In the chapter 5, I discuss what I have found to be the key factors for successful monitoring of regenerating dorsal root axons in living animals; the feasibility, usefulness and limitations of the available techniques and future directions for studying spinal root injury and regeneration. My thesis work represents the first to employ in vivo imaging to study DR regeneration directly in living animals. This approach was more challenging to develop than we had anticipated but provided unexpected insights into the mechanisms preventing sensory nerve regeneration. Continuous application of the powerful in vivo imaging technique in combination with conventional analyses will elucidate critically important issues that previous static analyses could not decipher. / Cell Biology

Thesis (M.Sc.)--Memorial University of Newfoundland, Memorial University of Newfoundland, 1998. / Typescript. Bibliography: leaves 118-132.

Στην μελέτη μας - που σκοπό είχε την αναζήτηση των ηλεκτροφυσιολογιών παραμέτρων εκείνων οι οποίες πρωϊμώτερα καθίστανται παθολογικές σε αρχόμενη συμπιεστική βλάβη του μέσου νεύρου στον καρπό - εξετάσαμε συνολικά 72 ασθενείς (42 χέρια δεξιά, 30 αριστερά) από τους οποίους οι 66 ήταν γυναίκες και οι 6 άνδρες. Ο μέσος όρος ηλικίας των ασθενών ήταν 49.6±9.8 έτη. Όρος επιλογής των προς μελέτη ασθενών ήταν να παρουσιάζουν συμπτώματα και σημεία τέτοια ώστε κλινικά να τίθεται βάσιμα η υπόνοια συνδρομής καρπιαίου σωλήνα, ταυτόχρονα όμως, στον ηλεκτρονευρογραφικό έλεγχο η τιμή του τελικού κινητικού χρόνου να μην υπερβαίνει τα 4.2 msec, ώστε να εξασφαλίζεται το αρχόμενο - μη προχωρημένο της συμπιεστικής συνδρομής. Στην μελέτη χρησιμοποιήθηκαν και 43 μάρτυρες (19 χέρια δεξιά, 24 χέρια αριστερά). Οι μάρτυρες επελέγησαν με κριτήρια την παντελή απουσία συμπτωμάτων και σημείων από το περιφερικό νευρικό σύστημα και με τον περιορισμό της ουδέποτε λήψης νευροτοξικών ουσιών. Από αυτούς οι 31 ήταν γυναίκες και οι 12 άνδρες, είχαν δε μέσο όρο ηλικίας 41.3±16.4 έτη. Τόσο στους ασθενείς όσο και στους μάρτυρες μελετήθηκαν οι αισθητικές αγωγιμότητες με την ορθοδρομική μέθοδο. Σε κάθε χέρι η μελέτη έγινε με ερεθισμό ένα προς ένα όλων των δακτύλων (1ου, 2ου, 3ου και 4ου) και καταγραφή με επιφανειακό ηλεκτρόδιο στον καρπό από το μέσο νεύρο επιπλέον ερεθίστηκε και ο 5ος δάκτυλος και κατεγράφη το αισθητικό δυναμικό στον καρπό από το ωλένιο νεύρο. Τα αποτελέσματα αυτών των καταγραφών αφορούσαν όλες τις παραμέτρους του αισθητικού δυναμικού (λανθάνων χρόνος, εύρος, διάρκεια) καθώς και αλλοιώσεις της μορφολογίας του, από όλους τους δακτύλους. Στη συνέχεια προχωρήσαμε σε πολλαπλές συσχετίσεις κάθε μιας παραμέτρου σε διαφορετικούς δακτύλους, διαφορετικών παραμέτρων στον ίδιο δάκτυλο, αλλά και σε διαφορετικούς δακτύλους καθώς και στην απαρίθμηση των ανώμαλων κυματομορφών όπου αυτές εμφανίζονταν. Η στατιστική επεξεργασία όλων αυτών των δεδομένων κατέληξε στην συγκρότηση μιας κλίμακος ευαισθησίας ως προς την εγκαιρότερη αλλοίωση ηλεκτροφυσιολογιών παραμέτρων σε αρχόμενη συνδρομή καρπιαίου σωλήνα. Συμπερασματικά από τη μελέτη μας προκύπτουν τα εξής: 1) Η ανάδειξη δικόρυφου δυναμικού ενεργείας σε ερεθισμό είτε του 4ου είτε του 1ου δακτύλου είναι συχνό και ισχυρό εύρημα ως προς την τεκμηρίωση αρχόμενης συνδρομής καρπιαίου σωλήνα. 2) Σε αρχόμενη συνδρομή καρπιαίου σωλήνα πρώιμα παρατείνεται ο λανθάνων χρόνος από 4ο και από 1ο δάκτυλο, αλλοιώνονται όλες οι παράμετροι από τον 4ο δάκτυλο και παρατείνεται ο λανθάνων χρόνος από 3ο δάκτυλο. Δεν υπήρξε διαφοροποίηση των παραπάνω αποτελεσμάτων που να συσχετίζονται με το φύλο ή την ηλικία. / The purpose of the present work was to investigate cases with early median nerve entrapment neuropathy (carpal tunnel syndrome) and to identify the most sensitive neurophysiological parameter by which an early diagnosis of the syndrome can be established. We examined 72 patients (42 right hands and 30 left hands) 66 women and 6 men. The mean age was 49.6±9.8 years. The inclusion criteria were symptoms and signs compatible with the diagnosis of carpal tunnel syndrome and the distal motor latency to be less than 4.2msec. We also examined 43 control subjects (19 right hands and 24 left hands) 31 women and 12 men with a mean age 41.3±16.4 years The control subjects were free of peripheral neurological problems. In all patients and control subjects we studied the sensory conduction parameters using the orthodrom method. In all hands we stimulated all five fingers and we recorded the sensory potentials from the wrist for both nerves (the median nerve for the 4 first fingers and the ulnar nerve for the 5th finger). In all patients and controls median distal motor latency, amplitude and duration of compound sensory nerve action potentials and sensory nerve conduction velocity of all five fingers were measured. The statistical analysis of the results showed the following conclusions. 1. Double peak potentials after stimulation of the 4th finger was the most sensitive test for detecting early carpal tunnel syndrome. Double peak potentials after stimulation of the 1st finger was a less frequent finding. 2. In early carpal tunnel syndrome there is a prolongation of the latency of the 4th and 1st finger Also there are changes in all parameters of the 4th finger potential and there is a prolongation of the latency of 3rd finger. Finally there were no differences between male and female measurements.

[EN] Chronic pain disease has 35-50% of prevalence worldwide. When drugs stop working, spinal cord stimulation (SCS) therapy is a non-drug alternative treatment for several conditions of chronic pain, such as neuropathic pain. In the last 40 years, SCS computational modeling has been the key tool to analyze and understand the effect of the stimulation parameters on neural response. However, the lack of realistic models limits the model-based predictions accuracy for SCS therapy optimization concerning the stimulation parameters management and the development of clinical applications. This thesis presents three improvements in SCS modeling from cellular to organic levels: · Cellular level: a human A -beta sensory myelinated nerve fiber model is shown. The model simulates the action potential creation and propagation of human sensory fibers produced by electrical stimulation. Moreover, to consider the current losses produced at the internodal compartments, a realistic myelin model is included. · Organic level: two spinal cord volume conductor models are presented. The first one is a generalized SCS model, which is based on in vivo 3T high-resolution magnetic resonance images from the human spinal cord, solving then one of the main limitations of previous SCS models, which is the inclusion of cadaveric measurements. The second one is a 3D patient-specific SCS model, which includes the entire spinal cord geometry variation of three different vertebral levels (T8, T9, and T10) from patients undergoing SCS treatment. This novel approach is validated clinically, showing that patient-specific modeling improves model-based predictions accuracy compared to generalized SCS models. In addition to this, this thesis presents three studies related to SCS therapy by using the three computational models developed previously: - Role of stimulation frequency: it is performed using the human A-beta sensory myelinated nerve fiber model. The outcome of this study showed that frequency could have a significant influence on the reduction or increase of the neuron activity, participating thus in the selection of the targeted neural elements in SCS therapy, in tonic stimulation. - Effect of electrode polarity: using the 3D generalized SCS model, the effect of the most used and known polarities (bipolar, guarded cathode, and dual-guarded cathode) is shown. The results showed that, unlike guarded cathode, dual-guarded cathode maximized the activating area and depth in dorsal columns, also increasing the probability of activating dorsal roots fibers. - Clinical applications: the pre-implantation selection of the electrode polarity was performed with the 3D patient-specific model. The findings showed that this clinical application could determine the electrode configurations that best overlapped paresthesia coverage to the painful dermatomes of the patient before the SCS device implant. On the other hand, the effect of offset electrodes was also investigated. In this case, the results revealed that staggered offset placement canceled the left- or right-activation displacement in the dorsal columns, suggesting that offset electrodes placement should be avoided in tonic stimulation. / [ES] El dolor crónico es una enfermedad que tiene una prevalencia de entre el 35% y el 50% de la población mundial. Cuando los fármacos dejan de hacer efecto, la terapia de estimulación de médula espinal (EME) es una alternativa no farmacológica que se usa para el tratamiento de diversas condiciones de dolor crónico, como el dolor neuropático. En los últimos 40 años, el modelado computacional de la EME ha sido la herramienta clave para analizar y entender el efecto de los parámetros de estimulación eléctrica en la respuesta neuronal. Sin embargo, la falta de modelos realistas limita la precisión de las predicciones de los modelos para la optimización de la terapia de EME, en referencia a la programación de los parámetros de estimulación y el desarrollo de aplicaciones clínicas. Esta tesis presenta tres mejoras en el modelado computacional de la terapia de EME, desde el nivel celular hasta el nivel orgánico: · Nivel celular: se presenta un modelo de fibra mielínica A-beta sensitiva humana. El modelo simula la creación y propagación del potencial de acción de fibras humanas sensitivas que se produce bajo el efecto de un estímulo eléctrico. Además, con el fin de considerar las pérdidas de corriente producidas en los compartimentos internodales, la mielina se modeliza de forma realista. · Nivel orgánico: se presentan dos modelos de conductor volumétrico de médula espinal. El primero se trata de un modelo de EME generalizado, el cual está basado en imágenes de resonancia magnética de 3T de alta resolución de médula espinal humana obtenidas in vivo. Esta propuesta resuelve una de las principales limitaciones presente en modelos de EME anteriores, que es la inclusión de medidas geométricas obtenidas de cadáveres. El segundo modelo es un modelo tridimensional personalizado al paciente, el cual incluye la variación de la geometría de la médula espinal en tres niveles vertebrales diferentes (T8, T9 y T10) a partir de pacientes sometidos al tratamiento de EME. Esta novedosa propuesta es validada clínicamente, mostrando además que el modelado computacional personalizado mejora la precisión de las predicciones del modelo en comparación a un modelo generalizado. Además, esta tesis presenta tres estudios relacionados con la terapia de EME usando los tres modelos desarrollados previamente: - El papel de la frecuencia de estimulación: se realiza mediante el uso del modelo de fibra mielínica A -beta sensitiva humana. Los resultados de este estudio muestran que la frecuencia podría tener una influencia significante en la reducción o aumento de la actividad de la neurona, participando de este modo en la selección de los elementos neurales objetivo en la terapia de EME, en estimulación tónica. - Efecto de la polaridad del electrodo: usando el modelo 3D generalizado de EME, se muestra el efecto de las polaridades más conocidas y usadas: bipolar, cátodo guardado y doble-cátodo guardado. Los resultados muestran que, a diferencia del cátodo guardado, la polaridad de doble-cátodo guardado maximiza el área y profundidad de activación en los cordones posteriores, aumentando también la probabilidad de activar las fibras de las raíces dorsales. - Aplicaciones clínicas: usando el modelo 3D personalizado al paciente, se ha realizado la selección pre-implante de la polaridad del electrodo. Los resultados muestran que esta aplicación clínica podría determinar las configuraciones de electrodos que mejor solapan la cobertura de parestesia con los dermatomas dolorosos del paciente antes del implante del dispositivo de EME. Por otro lado, también se ha estudiado el efecto de la posición escalonada de los electrodos en el paciente. En este caso, los resultados revelan que el posicionamiento escalonado cancela el desplazamiento izquierdo o derecho de la activación neuronal en los cordones posteriores, sugiriendo así que el posicionamiento escalonado debería evitarse cuando se aplica la estimu / [CAT] El dolor crònic es una enfermetat amb una prevalència d'entre el 35% i el 50% de la població mundial. Quan els fàrmacs deixen de fer efecte, la teràpia d'estimulació de mèdul·la espinal (EME) és una alternativa no farmacològica que s'usa per al tractament de diverses condicions de dolor crònic, com el dolor neuropàtic. En els últims 40 anys, el modelatge computacional de l'EME ha sigut la ferramenta clau per a analitzar i entendre l'efecte dels paràmetres d'estimulació elèctrica en la resposta neuronal. No obstant això, la falta de models realistes limita la precisió de les prediccions dels models per a l'optimizació de la teràpia d'EME, en referència a la programació dels paràmetres d'estimulació i el desenvolupament d'aplicacions clíniques. Esta tesi presenta tres millores en el modelatge computacional de la teràpia d'EME, des del nivell cel·lular fins al nivell orgànic: · Nivell cel·lular: es presenta un model de fibra mielínica A-beta sensitiva humana. El model simula la creació i propagació del potencial d'acció de fibres humanes sensitives que es produeix baix l'efecte d'un estímul elèctric. A més a més, amb la finalitat de considerar les pèrdues de corrent produïdes als compartiments internodals, la mielina es modela de forma realista. · Nivell orgànic: es presenten dos models de conductor volumètric de mèdul·la espinal. El primer es tracta d'un model d'EME generalitzat, el qual es basa en imatges de ressonància magnètica de 3T d'alta resolució de mèdul·la espinal humana obtingudes in vivo. Esta proposta resol una de les principals limitacions present en models d'EME anteriors, que és la inclusió de mesures geomètriques obtingudes de cadàvers. El segon model és un model tridimensional personalitzat al pacient, el qual inclou la variació de la geometria de la mèdul·la espinal en tres nivells vertebrals diferentes (T8, T9 i T10) a partir de pacients sotmesos al tractament d'EME. Aquesta innovadora proposta és validada clínicament, demostrant també que el modelatge computacional personalitzat millora la precisió de les prediccions del model en comparació a un model generalitzat. A més, esta tesi presenta tres estudis relacionats amb la teràpia d'EME utilitzant els tres models desenvolupats prèviament: - El paper de la freqüència d'estimulació: es realitza mitjançant l'ús del model de fibra mielínica A-beta sensitiva humana. Els resultats d'este estudi mostren que la freqüència podria tindre una influència significant en la reducció o augment de l'activitat de la neurona, participant així en la selecció dels elements neurals objectiu en la teràpia d'EME, en estimulació tònica. - Efecte de la polaritat de l'elèctrode: usant el model 3D generalitzat d'EME, es mostra l'efecte de les polaritats més conegudes i utilitzades: bipolar, càtode guardat i doble-càtode guardat. Els resultats mostren que, a diferència del càtode guardat, la polaritat de doble-càtode guardat maximitza l'àrea i profunditat d'activació en els cordons posteriors, augmentant també la probabilitat d'activar les fibres de les arrels dorsals. - Aplicacions clíniques: usant el model 3D personalitzat al pacient, s'ha realitzat la selecció pre-implant de la polaritat de l'elèctrode. Els resultats mostren que esta aplicació clínica podria determinar les configuracions d'elèctrodes que millor solapen la cobertura de parestèsia amb els dermatomes dolorosos del pacient abans de l'implant del dispositiu d'EME. D'altra banda, també s'ha estudiat l'efecte de la posició esglaonada dels elèctrodes en el pacient. En este cas, els resultats revelen que el posicionament esglaonat cancel·la el desplaçament esquerre o dret de l'activació neuronal en els cordons posteriors, sugerint així que el posicionament esglaonat deuria evitar-se quan s'aplica l'estimulació tònica. / Solanes Galbis, C. (2021). Patient-specific computational modeling for spinal cord stimulation therapy optimization [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/176007

This study determined whether the Hodgkin-Huxley model for unmyelinated nerve fibres could be more comprehensively modified to predict excitation behaviour at Ranvier nodes of a human sensory nerve fibre, as specifically applied to the prediction of temporal characteristics of the human auditory system. The model was developed in three phases. Firstly, the Hodgkin-Huxley model was modified to describe action potential dynamics at Ranvier nodes using recorded ionic membrane current data from single human myelinated peripheral nerve fibres. A nerve fibre cable model, based on a combination of two existing models, was subsequently developed using human sensory nerve fibre morphometric data. Lastly the morphological parameters of the nerve fibre model were changed to resemble a Type I peripheral auditory nerve fibre and coupled to a volume-conduction model of the cochlea. This study is the first to show that the Hodgkin-Huxley model equations can be modified successfully to predict excitation behaviour of a generalised human peripheral sensory nerve fibre without using the Goldman-Hodgkin-Katz equations. The model includes a more comprehensive establishment of temperature dependence of the physiological and electrical parameters compared to existing models. Two versions of the human Type I auditory nerve fibre model were developed, one simulating an undamaged (non-degenerate) fibre and another a damaged (degenerate) fibre. Comparison between predicted and measured results indicated similar transient and persistent sodium, as well as slow potassium ionic membrane currents to those found in generalised sensory nerve fibres. Results confirm that chronaxie, rheobase current, mean latency, threshold and relative refractive periods depend on the amount of degeneracy of fibres. The model could account for threshold differences observed between different asymmetric waveforms. The combination of persistent sodium and slow potassium ionic membrane currents could in part predict non-monotonic excitation behaviour observed experimentally. A simplified method was developed to calculate electrically evoked compound action potential responses following neural excitation. It provided a computationally effective way to obtain an estimate of profile widths from the output of models that calculate neural excitation profiles, and an indirect way to estimate stimulus attenuation by calculating the value of the parameter that produces the best fit to experimental data. Results also confirmed that electrode arrays located closer to the modiolus produce more focussed neural excitation spread than more laterally located arrays. / Thesis (PhD)--University of Pretoria, 2010. / Electrical, Electronic and Computer Engineering / unrestricted