A Narrative Analysis of Resilience and Coping in Persons Diagnosed with Multiple Sclerosis by Mildred C. Alford Ph.D., Ed., Berne International Graduate University, 1998 M.S. Ed., Texas A & M University, Commerce, 1989 B.S., Psychology, University of Houston, 1976 Dissertation Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy Health Psychology Walden University June 2017

Demyelination in the CNS is known to involve several immune effector mechanisms, including complement proteins. For this dissertation project the central hypothesis that C3 and downstream effector complement proteins exacerbate demyelination through activation of glial cells was tested. To investigate the role of C3 and downstream complement proteins in demyelination and remyelination pathology in vivo we utilized the cuprizone model. We used C3 knockout mice (C3-/-), which are lacking the central C3 protein and subsequently all downstream complement effector proteins, and transgenic mice expressing C3a or C5a under the control of the glial GFAP promoter. Interestingly, we found no changes in demyelination or remyelination pathology between C3-/- and control mice. However, C3a and C5a transgenic mice had exacerbated demyelination and slightly delayed remyelination in the corpus callosum compared to WT mice. Transgenic mice had increased cellularity in the corpus callosum due to increased activation and/or migration of microglia. There was also evidence of T cells in the corpus callosum during demyelination in C5a transgenic mice, suggesting C5a may modulate BBB permeability. During early remyelination oligodendrocytes migrated to the corpus callosum in higher numbers in C3a and C5a transgenic mice, thus enabling these mice to remyelinate as effectively as WT mice by the end of the ten week study. To determine the effects of anaphylatoxins on individual glial subsets, we created murine recombinant C3a and C5a proteins. We found that the MAPK pathway proteins JNK1 and ERK1/2 were activated in glia upon stimulation with recombinant anaphylatoxin proteins. When microglia and mixed glial cultures were stimulated with C3a and/or C5a, we observed an increase in the production of proinflammatory cytokines and chemokines. In contrast, anaphylatoxin-treated primary astrocytes had suppressed cytokine and chemokine production compared to untreated astrocytes. In vitro, primary microglia and astrocytes did not significantly migrate in response to stimulation with C3a or C5a proteins, suggesting migration may not be a primary anaphylatoxin-mediated function in the CNS. Overall, our findings show that anaphylatoxin production in the brain plays a negative proinflammatory role during demyelination and that anaphylatoxin proteins can activate individual subsets of glia, initiating the production of inflammatory mediators.

Die Multiple Sklerose ist eine chronische neurologische Erkrankung, welche in der industrialisierten Welt einen der häufigsten Gründe für eine bleibende Behinderung bei jungen Erwachsenen darstellt. Obwohl die ZNS-Schädigung, charakterisiert durch Demyelinisierung und axonale Schädigung im Rahmen entzündlicher Vorgänge, durch verschiedene Reparaturmechanismen reduziert wird, akkumuliert die Läsionslast im zentralen Nervensystem mit der Zeit. T2-gewichtete MRT-Studien zeigen, dass die dargestellten Pathologien nur mäßig mit den motorischen Defiziten korrelieren. Diese Diskrepanz wird unter anderem auf Vorgänge der Neuroplastizität zurückgeführt, als deren Basismechanismen Langzeitpotenzierung (LTP) und -depression (LTD) gelten. In verschiedenen fMRT-Studien haben sich Hinweise ergeben, dass diese adaptiven Veränderungen zur Reorganisation kortikaler Repräsentationmuster führen können, so dass bei MS-Patienten eine ausgedehntere Aktivierung ipsilateraler sensomotorischer Areale bei motorischen Aufgaben zu beobachten ist. Die transkranielle Magnetstimulation (TMS) bietet die Möglichkeit, mittels virtueller Läsionstechniken eine direkte Aussage über die kausale Beziehung zwischen Struktur und Funktion zu liefern. Die funktionelle Rolle ipsilateraler Motorareale wurde an 26 MS-Patienten, in Relation zu ihrer motorischen Beeinträchtigung und ZNS-Schädigung, und an nach Alter, Geschlecht und Händigkeit zugeordneten Kontrollprobanden, untersucht. Die motorische Leistungsfähigkeit wurde durch verschiedene Tests zur Handfunktion erhoben. Die ZNS-Schädigung wurde mittels MR-Spektroskopie als NAA/Cr Quotient sowie durch die CML erhoben. Die Aufgabe zur einfachen Reaktionszeit (SRT) bestand aus einer isometrischen Abduktionsbewegung des rechten Daumens gegen einen Kraftaufnehmer auf ein akustisches Go-Signal. Mit TMS-Einzelreizen wurde mit Hilfe einer Neuronavigation eine reversible virtuelle Läsion über bestimmten Gehirnarealen, kontralateraler M1, ipsilateraler M1 und ipsilateraler PMd, erzeugt. Es wurde eine Kontrollstimulation über MO durchgeführt. Die TMS-Einzelreize wurden 100ms nach dem Go-Signal appliziert. Als SRT wurde der Zeitraum zwischen dem Go-Signal und EMG-Beginn im APB definiert. Die signifikanten SRT-Verlängerungen bei TMS über dem ipsilateralen M1 und dem ipsilateralen PMd zeigen, dass diese Regionen eine Rolle bei der motorischen Funktion bei MS spielen. Die fehlenden Korrelationen zwischen motorischen Funktionstest und NAA/Cr-Verhältnis sowie die inverse Korrelation zur kortikomuskulären Latenz sind durch strukturell von der krankheitsbedingten Pathologie betroffenen kompensierenden Gehirnregionen erklärbar. Bei dem Theta Burst Experiments (TBS) wurde ein virtueller Läsionseffekt durch eine repetitive TMS-Intervention über dem ipsilateralen M1 induziert. Die Ergebnisse zeigen ähnliche Veränderungen der Exzitabilität bei MS-Patienten und gesunden Kontrollprobanden, was schließen lässt, dass die LTD bei mild bis moderat betroffenen MS-Patienten weitestgehend unbeeinträchtigt ist. MS-Patienten zeigen im Vergleich zu den Kontrollen eine ähnliche Minderung der Verhaltensleistung, Trefferquote in ein Kraftfenster, der MS-Patienten im Kontrollvergleich. Die Ergebnisse zeigen, dass ipsilaterale motorische Areale in der Lage sind den primär motorischen Kortex soweit zu kompensieren, jedoch die Fähigkeit zur Kompensation in fortgeschrittenen Krankheitsstadien eingeschränkt ist. Abschließend kann man zusammenfassen, dass die funktionelle Rekrutierung von ipsilateralen Motorarealen eine adaptive Antwort auf chronische Gehirnschädigung bei MS-Patienten sein kann, allerdings mit Einschränkung der Kapazität in fortgeschrittenen Krankheitsstadien. Nachdem die synaptische Plastizität weitestgehend intakt scheint, sollte man besonders Mechanismen der späten Phase der Plastizität fördern, welche auf eine langfristige kortikale Plastizität abzielen. Weitere Studien in diesem Forschungszweig könnten einen Beitrag zur Entwicklung therapeutischer Konzepte der Neurorehabilitation bei Multipler Sklerose leisten. / Multiple Sclerosis is a chronic neurological disease, which is one of the common reasons in the industrial world causing a lasting disablement at young adults. Despite of reduction by several mechanisms the cns injury characterized by demyelinizing and axonal injury in order of inflammatory processes the lesion load of the cns accumulates over the years. T2-weighted MRI studies only show moderate correlations between the represented pathologies and the motoric deficits. This discrepancy is attributed i.a. to procedures of neuroplasticity whose basic mechanisms are considered as Long-term potentiation (LTP) and -depression (LTD). Several fMRI studies suggest a reogranization of cortical representative pattern due to these adaptive changes. Therefore an extended activation of ipilaterale sensomotoric areas is observed in MS patients performing motoric tasks. Transcranial Magnetic Stimulation (TMS) provides via lesional techniques the possibility of a direct conclusion causal link to structure and function. The functional role of ipsilateral motor areas has been examined in 26 MS patients in relation to their motor impairment and cns injury. Healthy controls were matched for age, sex and handedness. The motor performance was assessed by a test battery of hand function. The cns injury was evaluated using magnetic resonance spectroscopy (NAA/Cr Quotient) and TMS (CML). The Simple Reaction Time task (SRT) consisted of a brisk isometric abduction of the right thumb against a force transducer as a respond to an auditorily Go-Signal. With the help of a neuronavigational device a reversible virtual lesion, delivered by TMS single pulses, were applied to specific brain areas, contralateral M1, ipsilateral M1 and ipsilateral PMD. A control stimulation were assessed to MO??. TMS Single pulses were applied 100ms after Go-Signal. SRT were defined as the time between Go-Signal and EMG onset. Significant extention of SRT after TMS to ipsilateral M1 and ipsilateral PMd evidence the role of these regions in motoric function in MS. The missing correlation between motor performance and NAA/Cr Quotient as well as the inverse correlation to CML are explainable by compensation brain regions which are themselves structurally affected by disease pathologies. In the Thetaburs experiments (TBS) a virtual lesion was induced by a repetitive TMS intervention to ipsilateral M1. The results show a similar change of excitability in MS patients and healthy controls which concludes that LTD is not compromised in mild to moderate affected MS patients. MS patients presented in comparison to controlls a similiar discrease of behavioral performance, hit rate in a force range. The results evidence that ipsilateral motor areas have the ability to compensate the primary motor cortex. But the ability for compensation is limited in advanced stages of illness. The concluding summary is that functional recruitment of ipsilateral motor areas are adaptive response to chronic brain injury in MS patients but with limited capacity in advanced stages of illness. As the synaptic plasticity seem intact to the greatest possible extent mechanism of the late stadium of plasticity should be supported which aim at long term cortical plasticity. Further studies in this branch of research could contribute the development of therapeutic concepts of neurorehabilitation in MS.

Millionen Menschen weltweit leiden an den verschiedensten Autoimmunerkrankungen. Diese Krankheiten entstehen, wenn das Immunsystem gesundes körpereigenes Gewebe angreift und zerstört. An der Pathogenese sind sowohl Komponenten des angeborenen Immunsystems als auch Bestandteile des adaptiven Immunsystems, wie Lymphozyten und Antikörper, beteiligt. Da die Ursachen und molekularen Mechanismen der Pathogenese dieser Erkrankungen bis heute weitgehend unbekannt sind, wurden in dieser Arbeit autoaggressive Lymphozyten bei den humanen Autoimmunerkrankungen Polymyositis und Multiple Sklerose näher untersucht. Die Polymyositis ist eine chronisch entzündliche Erkrankung der Skelettmuskulatur. Die Muskelfasern werden dabei von zytotoxischen CD8+ gd-T-Lymphozyten infiltriert, attackiert und schließlich zerstört. In einem seltenen Fall der Polymyositis wurden die Muskelzellen hingegen in ähnlicher Weise von CD8- gd-T-Lymphozyten angegriffen. Die gd-T-Lymphozyten waren monoklonal expandiert und ihr Rezeptor, im Folgenden als M88 bezeichnet, wurde als Vg1.3+Vd2+ identifiziert. Frühere Untersuchungen der Antigenspezifität dieser Zellen zeigten, dass M88 mehrere funktionell und strukturell verschiedene Proteine aus unterschiedlichen Spezies erkennt. Die Bindung erfolgt spezifisch durch die Antigenerkennungsregionen beider Rezeptorketten von M88. In dieser Arbeit wurden verschiedene bakterielle und humane Proteine des Translationsapparates als Antigene von M88 identifiziert. Weitere ausführliche Untersuchungen eines paradigmatischen bakteriellen Antigens, dem Translationsinitiationsfaktor EcIF1, zeigten, dass M88 an Oberflächen-exponierte Konformationsepitope von Proteinen bindet. Interessanterweise erkennt M88 mehrere humane Aminoacyl-tRNA-Synthetasen, Antigene, die in anderen Formen der Myositis von Autoantikörpern angegriffen werden. Diese Beobachtung ergibt eine bemerkenswerte Verbindung zwischen T-Zell- und Antikörper-vermittelten B-Zell-Antworten bei der autoimmunen Myositis. Bei der Multiplen Sklerose ist das zentrale Nervensystem betroffen. Autoaggressive Lymphozyten greifen die Myelinschicht der Nervenzellen im Gehirn und Rückenmark an und zerstören sie. Im Liquor cerebrospinalis von Patienten lassen sich klonal expandierte und affinitätsgereifte B-Zellen sowie „oligoklonale Banden“ (OKB) Antikörper nachweisen. Obwohl diese Merkmale auf eine Antigen-induzierte Immunantwort hindeuten, sind die zugrundeliegenden Antigene und die Rolle der OKB bei der Pathogenese bis heute unbekannt. In dieser Arbeit wurde die Antigenspezifität von fünf IgG OKB-Antikörpern aus drei Patienten untersucht. Durch verschiedene proteinbiochemische Methoden konnten intrazelluläre Kandidatenantigene identifiziert werden. Interessanterweise sind darunter mehrere nukleäre Proteine, die an der Transkriptionsregulation oder der RNA-Prozessierung beteiligt sind. Reaktivitäten gegen intrazelluläre Antigene treten auch bei anderen Autoimmunerkrankungen, wie beispielsweise dem systemischen Lupus erythematodes, auf. Diese Ergebnisse könnten auf einen allgemeinen Mechanismus der Entstehung und Funktion von Autoantikörpern bei diesen humanen Autoimmunerkrankungen hindeuten. / Millions of people worldwide suffer from various autoimmune diseases. These disorders occur if the immune system reacts to and destroys healthy body tissue. Pathogenesis is mediated by components of the innate immune system as well as by constituents of the adaptive immune system, like lymphocytes and antibodies. However, the origin and molecular mechanisms of these diseases remain still largely unknown. Therefore we investigated the role of autoaggressive lymphocytes in the human autoimmune diseases polymyositis and multiple sclerosis. Polymyositis is a chronically inflammatory disease of the skeletal muscles. Cytotoxic CD8+ gd-T lymphocytes invade, attack and finally destroy muscle fibers. However, in a rare variant of polymyositis, muscle fibers are similarly attacked by CD8- gd-T lymphocytes. These gd-T lymphocytes were monoclonally expanded and their receptor, termed M88, was identified as Vg1.3+Vd2+. Previous investigations of the antigen specificity of these cells revealed that M88 recognizes several structurally and functionally different proteins from various species. This recognition is specifically mediated by the antigen recognition sites of both receptor chains of M88. In this work we have identified different bacterial and human proteins of the translation apparatus as antigens of M88. Further detailed investigations of one paradigmatic bacterial antigen, the translation initiation factor EcIF1, have shown that M88 binds to surface-exposed conformational protein epitopes. Interestingly, M88 recognizes several human aminoacyl-tRNA-synthetases. These antigens have been described to be also targeted by autoantibodies in other forms of myositis. This observation reveals a remarkable link between T cell and antibody-mediated B cell responses in autoimmune myositis. In multiple sclerosis the central nervous system is affected. Autoaggressive lymphocytes attack and destroy the myelin sheet of nerve cells of the brain and spinal cord. In the cerebrospinal fluid of these patients clonally expanded and affinity-maturated B cells as well as „oligoclonal band“ (OCB) antibodies can be detected. Although these features indicate an antigen-induced immune response, the underlying antigens and the role of the OCB antibodies in the pathogenesis are still unknown. In this work we describe the antigen specificity of five IgG OCB antibodies from three patients. Through various biochemical methods we have identified intracellular candidate antigens. Interestingly, these include several nuclear proteins involved in transcription regulation and RNA processing. Reactivity against intracellular antigens also occurs in other autoimmune diseases such as systemic lupus erythematosus. These findings suggest a general mechanism for the generation and function of autoantibodies in these human autoimmune diseases.

Bei der Multiplen Sklerose (MS) handelt es sich um eine Autoimmunerkrankung des zentralen Nervensystems (ZNS). Abhängig von der betroffenen ZNS-Region kann es zu vielfältigen Symptomen kommen. Neben neurologischen Symptomen verursacht durch ZNS-Läsionen leidet ein Großteil der MS-Patienten auch unter gastrointestinalen Funktionsstörungen. Diese gastrointestinalen Symptome wurden bisher eher auf Läsionen im Rückenmark zurückgeführt und nicht direkt in Verbindung mit der autoimmunen Ätiologie der Erkrankung gebracht. In dieser Studie wurde das enterische Nervensystem (ENS) in einem B-Zell- und Antikörper-abhängigen Mausmodell der MS untersucht. Dafür wurde der Autoimmunprozess durch Immunisierung mit MP4, einem Fusionsprotein aus dem Myelin-Basischen-Protein (MBP) und dem Proteolipid-Protein (PLP), ausgelöst. Das ZNS und ENS wurden in den unterschiedlichen Erkrankungsstadien immunhistochemisch und elektronenmikroskopisch analysiert. Neben der Immunpathologie des ZNS konnte dabei eine Degeneration des ENS schon vor dem Einsetzen der ersten neurologischen Defizite nachgewiesen werden. Die ENS-Pathologie war antikörper-mediiert und ging einher mit einer verringerten gastrointestinalen Motilität sowie mit einer Gliose und Neurodegeneration des ENS. Mithilfe von Immunpräzipitation und Massenspektrometrie konnten im ENS vier mögliche Zielstrukturen des Autoimmunprozesses identifiziert werden, was auf sog. epitope spreading hindeutet. Auch im Plasma von MS-Patienten konnten Antikörper gegen drei dieser Antigene nachgewiesen werden. Des Weiteren zeigten sich in Kolon-Resektaten von MS-Patienten erste Ansätze einer Neurodegeneration und Gliose des ENS. In dieser Studie wurde zum ersten Mal ein direkter Zusammenhang zwischen der Autoimmunreaktion gegen das ZNS und einer simultanen Reaktion gegen das ENS gezeigt. Dies kann einen Paradigmenwechsel im Verständnis der Immunpathogenese der MS anstoßen und neue therapeutische und diagnostische Ansätze initiieren. / Multiple sclerosis (MS) is a chronic autoimmune disease, in which the immune system attacks the central nervous system (CNS). Clinical symptoms and the course of the disease can vary among patients, depending on the region of the brain primarily affected. Besides the neurological symptoms caused by CNS lesions, a great amount of MS patients display functional gastrointestinal impairments. Gastrointestinal symptoms were previously explained by the presence of spinal cord lesions rather than being linked to the autoimmune pathomechanisms of the disease. Here, the enteric nervous system (ENS) was studied in a B cell- and antibody-dependent mouse model of MS, in which the myelin basic protein (MBP) - proteolipid protein (PLP) fusion protein MP4 was used to initiate the autoimmune attack. Immunohistochemistry and electron microscopy were performed at different stages of the disease. We noted that in addition to the immune pathology in the CNS itself, the ENS also showed signs of degeneration. ENS degeneration was evident prior to the manifestation of CNS lesions and to the onset of neurological deficits in mice. ENS pathology was antibody-mediated and accompanied by impaired gastrointestinal motility, ENS gliosis and neurodegeneration. Using immunoprecipitation and mass spectrometry, four autoimmune targets expressed by enteric glia and/or neurons could be identified suggesting that epitope spreading to antigens of the ENS had occurred. MS patients displayed plasma antibodies against three of the ENS autoantigens. Studying human colon resectates provided preliminary evidence for gliosis and neurodegeneration of the ENS in MS patients, which was absent in non-MS controls. Overall, this study establishes a pathomechanistic link between the well-established autoimmune attack on the CNS and a simultaneous attack on the ENS that has not been described so far. These findings can initiate a paradigm shift in the current understanding of the pathomechanism of MS with diagnostic and therapeutic implications.

Die Multiple Sklerose ist eine chronisch entzündliche Erkrankung des zentralen Nervensystems. Durch ein komplexes Zusammenspiel von Genetik, Autoimmunvorgängen und proinflammatorischen Prozessen kommt es zur Demyelinisierung sowie zu axonalen Schäden und kortikalen Läsionen (Calabrese et al., 2010; Ciccarelli et al., 2014; International Multiple Sclerosis Genetics et al., 2011; Leray et al., 2015). In den Industrieländern ist diese Erkrankung eine der häufigsten Ursachen für langfristige Behinderung bereits im frühen Lebensalter (Flores-Alvarado, Gabriel- 46 Ortiz, Pacheco-Mois, & Bitzer-Quintero, 2015). Die Diskrepanz allerdings zwischen klinischer Symptomatik und den Befunden der Bildgebung (Barkhof, 2002) gibt Anlass dafür, Adaptionsmöglichkeiten detailliert zu erforschen. Vorgänge der Neuroplastizität mit LTP und LTD als Basismechanismen erscheinen dabei zunehmend Beachtung zu finden (Dayan & Cohen, 2011; Zeller et al., 2011). Welche Rolle diese Prozesse allerdings im akuten Schub, während der häufig stark ausgeprägten Symptomatik, insbesondere aber auch während ihrer Rückbildung spielen, bleibt bisher weitgehend ungeklärt. Eine Untersuchung zu stimulationsinduzierter LTP-artiger Plastizität im Schub deutete auf einen möglichen Zusammenhang zwischen Ausmaß der Symptomrückbildung und PAS25-induziertem LTP-Effekt hin (Mori et al., 2014). In der vorliegenden Arbeit wurde komplementär hierzu die stimulationsinduzierte LTD-artige Plastizität bei 19 MS- bzw. CIS-Patienten während des steroidbehandelten akuten Schubes untersucht. Als Kontrollgruppe wurden alters- und geschlechtsgematchte gesunde Probanden untersucht. Die Messungen wurden mithilfe eines Protokolls der assoziativen Paarstimulation durchgeführt. Paarstimulation wird die Kombination aus der peripher elektrischen und transkraniell magnetischen Stimulation genannt. Das in unserer Studie verwendete Protokoll sieht ein Interstimulusintervall von 10ms vor (PAS10). Der Effekt der Paarstimulation wird durch Messungen der Exzitabilität des motorischen Kortex mittels motorisch evozierter Potenziale (MEP) jeweils vor und nach der Intervention gemessen. Bei den MS-Patienten wurden diese Daten zum Zeitpunkt des Schubes (t1) und 12 Wochen danach (t2) erhoben; die gesunden Kontrollen wurden nur einmal gemessen. Daneben wurde bei den Schubpatienten zur Quantifizierung der klinischen Symptomatik jeweils zum ersten und zum zweiten Zeitpunkt der MSFC erhoben. Die MS-Patienten zeigten im akuten MS-Schub im Gegensatz zu der Kontrollgruppe aus Gesunden keinen LTD-artigen, sondern einen inversen, sprich einen signifikant LTP-artigen Effekt; dieser war zum Zeitpunkt t2 nicht mehr zu erkennen. Der Unterschied zwischen den PAS10-Effekten der MS- und der Kontrollgruppe war ebenfalls signifikant. Der Vergleich der MSFC-Werte der MS-Gruppe zwischen t1 und t2 erbrachte eine signifikante klinische Besserung. Eine signifikante Korrelation zwischen 47 den neurophysiologischen und klinischen Daten bzw. ihren Veränderungen zwischen t1 und t2 zeigte sich nicht. Diese Ergebnisse untermauern und erweitern bereits bestehende Hinweise, dass während der akuten Inflammationsprozesse des MS-Schubes veränderte Voraussetzungen für die Induzierbarkeit von Plastizität gegeben sind. Nicht nur, wie bereits gezeigt, die LTP-artige, sondern offenbar auch die LTD-artige assoziative Plastizität zeigt sich stark von den humoralen Veränderungen im steroidbehandelten Schub beeinflusst. Weitere Studien in stärker vorselektierten Patientengruppen sollten der Frage nachgehen, inwieweit LTD-artige Plastizität sich in verschiedenen Subgruppen mit unterschiedlichen Schubsymptomen unterscheidet. Des Weiteren ist der Frage weiter nachzugehen, ob LTD-artige Plastizität funktional zur Adaption im Rahmen des Schubereignisses notwendig ist und inwieweit deren Unterdrückung bzw. Ersatz durch Langzeitpotenzierung potenziell einer Adaption im Wege steht. Sollten potenzielle Folgestudien bestätigen, dass LTD- und LTP-artige Plastizität im Schub möglicherweise häufig dysfunktional ausgeprägt ist und einer optimalen Regeneration entgegensteht, wären daraus praktische Implikationen zu ziehen. Die Entwicklung neuer Trainingsprogramme oder elektrophysiologischer Konzepte könnte ein nächstes Ziel dieses Forschungszweiges sein, um potenziell dysfunktionale Plastizität zu vermeiden und physiologische Prozesse bereits im Schub zu fördern. / In relapsing-remitting MS (RRMS), the symptoms of a clinical relapse subside over time. Neuroplasticity is believed to play an important compensatory role. In this study, we assessed excitability-decreasing plasticity during an acute relapse of MS and 12 weeks afterwards. Motor plasticity was examined in 19 patients with clinically isolated syndrome or RRMS during a steroidtreated relapse (t1) and 12 weeks afterwards (t2) using paired-associative stimulation (PAS10). This method combines repetitive electric nerve stimulation with transcranial magnetic stimulation of the contralateral motor cortex to model long-term synaptic depression in the human cortex. Additionally, 19 age-matched healthy controls were assessed. Motor-evoked potentials of the abductor pollicis brevis muscle were recorded before and after intervention. Clinical disability was assessed by the multiple sclerosis functional composite and the subscore of the nine-hole peg test taken as a measure of hand function. The effect of PAS10 was significantly different between controls and patients; at t1, but not at t2, baseline-normalized postinterventional amplitudes were significantly higher in patients compared to controls. Additional exploratory analysis indicated a significant excitability-enhancing effect of PAS10 in patients as opposed to controls. Significant clinical improvement between t1 and t2 was not correlated with PAS10 effects. Our results indicate an alteration of PAS10-induced synaptic plasticity during relapse, presumably reflecting a polarity shift due to metaplastic processes within the motor cortex. Further studies will need to elucidate the functional significance of such changes for the clinical course of MS. Furthermore in following studies should be explored, if subgroups with different relapse symptoms show different PAS10-stimulation induced plasticity. In future studies training programs or stimulation concepts could be developed to avoid dysfunctional plasticity and promote physiological adaptive processes.

This study offers a new approach to raising mathematics achievement through the synthesis of Multiple Intelligences theory and Self-Efficacy theory. It proposes that the opportunity to learn through intellectual strengths will raise mathematics achievement both directly from students' increased understanding and indirectly through raising students' self-efficacy for mathematics. A mathematics learning program was developed for year eight students in a rural secondary school based on tasks resonating with their intellectual strengths. Both quantitative and qualitative indicators were used to compare the effects of the Multiple Intelligences learning program with the standard delivery of the mathematics curriculum to year eight students over their first term of study. After nine weeks participation in the Multiple Intelligences learning program, students demonstrated improved engagement and more positive attitudes in mathematics classes relative to their peers receiving standard instruction. The expected gains in mathematics achievement and self-efficacy were not demonstrated within the one-term span of the study. Assessment of the fidelity of implementation of the principles of Multiple Intelligences theory was confirmed through assessment of the classroom learning environment. Analysis of the reasons for the lack of differentiation revealed limitations in the traditional measures used for assessing the mathematics learning outcomes gained within the Multiple Intelligences program. / The loss of available year eight classroom instruction time from institutional assessment requirements and school policy decisions were found to be higher for the class receiving the Multiple Intelligences program than for the comparison class, and this is a significant confounding variable. It is concluded that significant changes to school organisational structures and assessment procedures are required before the cognitive and affective advantages of Multiple Intelligences learning may be realised optimally in the mathematics classroom.

The introduction of cellular wireless systems in the 1980s has resulted in a huge demand for personal communication services. This demand has made larger capacity systems necessary. This has been partially satisfied by the introduction of second generation digital systems. New third generation systems are now under going standardisation and will require even more efficient utilisation of the spectrum if the high bandwidth features and larger capacity are to become a reality. Motivated by these growing requirements we discuss methods of achieving large improvements in spectral efficiency and performance. Multiple-user communications over a channel can only be achieved with some form of diversity. In this work we point out that the efficient utilisation of the dimensions of space, time, and frequency will ultimately maximise the system capacity of a multiple-user system. We apply our receiver techniques solely to the base-station design where capacity limitations are currently present. We note however, that some of these techniques could also be applied at the mobile terminal receiver. We primarily focus our attention on the direct-sequence code-division multiple-access (DS/CDMA) channel, since this channel is inherently interference limited by other users in the cell of interest. We exploit a new powerful channel coding technique named " turbo coding" for its iterative decoding approach. We show how we can substitute the inner convolutional code of a turbo code encoder with the CDMA channel. By " iterative detection/decoding" or " turbo equalisation" at the receiver we achieve performance results which show the interference from other users to approach complete removal. We develop and analyse a new, low complexity, iterative interference canceller/decoder. This receiver has complexity per user linear with the memory of the channel and independent of the number of users in the system. We extend this receiver to more realistic channels that are asynchronous and include multi-path, and include spatial diversity by using an antenna array at the receiver. The CDMA channel we study exclusively uses randomly generated spreading codes. With this channel model we still achieve single user performance (no interference from other users) with a 10logL gain from L antenna elements and a gain of up to 10logP from P multi-path components. With any new receiver design, sensitivity to channel parameter errors is of paramount interest. We find that the sensitivity of our receiver is low with respect to the parameter errors induced. This is as we desire for a realisable receiver design. Finally we investigate the application of this new iterative interference canceller/decoder receiver to a number of other interference channels. These include the intersymbol interference (ISI) channel, partial response signalling (PRS), and continuous phase modulation (CPM). For these channels excellent performance improvement is generally achieved by the utilisation of the iterative interference canceller/decoder solution. / Thesis (PhD)--University of South Australia, 1999

There are many problems in mathematical finance which require the evaluation of a multivariate integral. Since these problems typically involve the discretisation of a continuous random variable, the dimension of the integrand can be in the thousands, tens of thousands or even more. For such problems the Monte Carlo method has been a powerful and popular technique. This is largely related to the fact that the performance of the method is independent of the number of dimensions. Traditional quasi-Monte Carlo techniques are typically not independent of the dimension and as such have not been suitable for high-dimensional problems. However, recent work has developed new types of quasi-Monte Carlo point sets which can be used in practically limitless dimension. Among these types of point sets are Sobol' sequences, Faure sequences, Niederreiter-Xing sequences, digital nets and lattice rules. In this thesis, we will concentrate on results concerning lattice rules. The typical setting for analysis of these new quasi-Monte Carlo point sets is the worst-case error in a weighted function space. There has been much work on constructing point sets with small worst-case errors in the weighted Korobov and Sobolev spaces. However, many of the integrands which arise in the area of mathematical finance do not lie in either of these spaces. One common problem is that the integrands are unbounded on the boundaries of the unit cube. In this thesis we construct function spaces which admit such integrands and present algorithms to construct lattice rules where the worst-case error in this new function space is small. Lattice rules differ from other quasi-Monte Carlo techniques in that the points can not be used sequentially. That is, the entire lattice is needed to keep the worst-case error small. It has been shown that there exist generating vectors for lattice rules which are good for many different numbers of points. This is a desirable property for a practitioner, as it allows them to keep increasing the number of points until some error criterion is met. In this thesis, we will develop fast algorithms to construct such generating vectors. Finally, we apply a similar technique to show how a particular type of generating vector known as the Korobov form can be made extensible in dimension.

Franchising performs an important role in the production and distribution of goods and services. Current research suggests that much of the future growth in franchising in many world economies will be attributable to the growth in multiple unit franchising arrangements. Multiple unit franchising refers to an organisational arrangement in which franchisees are permitted to own more than one unit in the same franchise system. Although the Australian franchising sector has reached an early stage of maturity, the limited acceptance of multiple unit practices contrasts with overseas experiences. This remains a curious anomaly, as significantly higher levels of multiple unit ownership are observable in comparably mature markets in other countries. Multiple unit franchising appears a conceptually unsound alternative to traditional dyadic revenue sharing franchising relationships as it does not benefit from the structural and operational synergies commensurate with ownership attention at the unit level. Therefore, from the franchisor's perspective, multiple unit franchising appears a suboptimal alternative to traditional franchising. From the franchisee's perspective, alternative investment opportunities may present superior choices to multiple unit arrangements. Franchisees have only limited control of their organisation, pay substantial percentages of their gross revenues in the form of fees and royalties, and forgo the ability to capitalise on the growth in the value of their intangible assets. While these apparent disadvantages may be overcome by an individual's desire to 'buy a job', the reasons explaining a franchisee's desire to own multiple units is less clear. Recent research has attempted to explain the ubiquity and increasing popularity of this organisational form, given these operational disadvantages, albeit mostly from the perspective of the franchisor. Previous empirical research in the United States views multiple unit franchising as a driver of system growth, promoting system-wide adaptation to competition. However, this conventional wisdom fails to consider additional franchisor motivational incentives. Moreover, anecdotal evidence in the Australian franchising sector contrasts markedly with the relationships exposed in multiple unit analyses overseas. Thus, existing franchising research does not adequately capture the range of incentives motivating an entrepreneur's decision to elect the franchising channel of distribution. In addition, at this time no theoretical framework exists espousing the reasons that lead to a franchisee's adoption of these hybridised organisational forms. This has led some researchers to conclude that multiple unit franchising is in an embryonic stage. Further complicating our understanding of the choice of this organisational form is the absence of multiple unit incentives analysis in Australia. In addition to gaining valuable insights into current managerial practice, the first purpose of this research is to support informed decision-making in the future through an investigation of the fundamental and under-researched question of why franchisors choose to grow and expand through multiple unit arrangements. This research focuses upon theory development by integrating known concepts with newly identified motivational incentives that caveat the adoption of this organisational arrangement. These incentives are incorporated in a model of multiple unit franchising from the perspective of the franchisor. The model describes multiple unit franchising as a function of the context of franchise system context (age, system corporatisation, plurality of distribution, geographic dispersion of available units and level of existing intra-firm conflict), and strategic (ownership redirection, perceived future agency cost minimisation, and system rewards) factors. In an attempt to extend the cross cultural boundaries of previous franchising research, a given level of multiple unit expansion is described through the predicted outcome of franchise system growth. Secondly, this research investigates the reasons why franchisees become multiple unit holders. This process involved the integration of existing theories drawn from different disciplines and presents an integrated theoretical model explaining why individuals are driven to create their own subsystems within a franchisor-owned network. The multi-perspective approach is critical to advancing our understanding of the genesis of this organisational arrangement, and specifically the issues of who should engage in multiple unit franchising arrangements, and when franchisors and franchisees should sanction and adopt mini-chains within a single franchising system. Thus, this proposal addresses gaps in the literature by investigating the research question: What are the motivational incentives that influence franchisors and franchisees to adopt multiple unit franchising? That is, this thesis aims to identify the reasons that justify the existence of multiple unit franchising forms from the franchisor and franchisee perspectives. A three-stage methodological approach is used in this research. Franchisor motivations are examined within stages one and two. Franchisee motivations are detailed in section three. An examination of the parent disciplines of resource scarcity theory, agency theory, and the immediate discipline of multiple unit franchising resulted in the development of a preliminary conceptual model and general set of propositions explaining why franchisors choose to engage in multiple unit franchising arrangements. In stage one an exploratory survey of seven franchisors from a range of industries of different type, size and age was conducted using a convergent interviewing technique, to gather insights and reasons into multiple unit practices. The stage one findings were used to clarify and confirm the appropriateness of the conceptual model of multiple unit franchising. Permission was granted by the Franchise Council of Australia to include a limited number of questions in the Franchising Australia 2002 survey. In the (second) stage of this research, a sample of the population of franchisors in Australia was surveyed by an electronic questionnaire administered on the World Wide Web in June and July 2002. The resultant data was analysed to test a revised theoretical model of franchisor motivations to adopt multiple unit franchising arrangements. Inferential statistical tests were used to test the relationships hypothesised in the model of multiple unit franchising from the franchisor's perspective. The results built upon the inductive stage of the research, providing a descriptive snapshot of multiple unit franchising in Australia. The third stage of this research explored the factors influencing a franchisee's decision to become a multiple unit owner. Following a review of the predominantly single unit literature, a model and series of general propositions explaining multiple unit franchising was developed explaining multiple unit ownership in terms of subsystem size (expected decision making power and anticipated subsystem economies of scale), franchisee context (franchisee liquidity, entrepreneurial orientation), and strategic (pre-empt future intra-system competition) factors. The appropriateness of the conceptual model and propositions were tested through convergent interviews with ten multiple unit and nine single unit franchisees within a prominent fast-food system. This resulted in a revised conceptual model and general set of propositions that contribute to the development of existing theory and will form the basis of future empirical assessment. This research makes an original contribution to the body of knowledge about multiple unit practice through inductive analysis that not only recognises the reach of this franchising phenomenon, but also develops our theoretical understanding of why franchisors and franchisees engage in intra-firm mini-chain development. So, apart from gaining valuable insight into current managerial motivations and practice in Australia, a concomitant aim of this research is to enhance the generalisability of prior franchising theory developed in the United States through examination of the under-researched areas of why franchisors allow, and franchisees choose, to own more than one unit within the same franchising system. This research has contributed to the body of knowledge on franchising. Based upon the extant literature and exploratory analyses, models of multiple unit franchising from the franchisor and franchisee perspective were developed. It is the first empirical analysis of multiple unit franchising in Australia and provides a starting point for future research. This research has made a valuable contribution in being the first to: investigate multiple unit franchising in an Australian setting using primary data sources; utilise an inductive convergent interviewing technique to clarify and confirm the appropriateness of theories derived from the extant literatures; survey a large representative sample of Australian franchisors about multiple unit franchising; survey a sample of franchisees about multiple unit franchising; incorporate aspects of agency theory, resource constraints theory and multiple unit franchising to develop a model of multiple unit franchising; use a three-stage methodology involving qualitative and quantitative analyses; investigate motivations and factors influencing multiple unit franchising choice; introduce new constructs and reposition existing constructs into multiple unit franchising theory. In conclusion, this original and comprehensive research has found that more experienced Australian franchisors appear to adopt multiple unit franchising, possibly as a method of sustaining growth in units and system-wide sales. Furthermore, entrepreneurial franchisees appear to source private sources of equity in order to grow their holdings sequentially as they anticipate savings accruing from economies of scale while limiting competition within their franchise system.