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Submitted by Cássia Santos (cassia.bcufg@gmail.com) on 2015-03-27T15:07:30Z No. of bitstreams: 2 Tese - Kelly Cristina Borges Tacon - 2014.pdf: 4461403 bytes, checksum: e975e7f60e35777b6fce998bd219ce69 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2015-03-27T15:52:37Z (GMT) No. of bitstreams: 2 Tese - Kelly Cristina Borges Tacon - 2014.pdf: 4461403 bytes, checksum: e975e7f60e35777b6fce998bd219ce69 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Made available in DSpace on 2015-03-27T15:52:37Z (GMT). No. of bitstreams: 2 Tese - Kelly Cristina Borges Tacon - 2014.pdf: 4461403 bytes, checksum: e975e7f60e35777b6fce998bd219ce69 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Previous issue date: 2014-07-18 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Introduction: Among the neuropathic pain to trigeminal neuralgia (TN) belongs to the group of chronic painful conditions of the head and neck region, characterized by paroxysmal and recurrent attacks of excruciating and sudden pain, shock-like. Various specialties may be involved in the process of differential diagnosis and treatment, and the lack of integration of this process a major cause of the complexity of diagnosis and lack of treatment effectiveness. There are few specialized services to treat this type of chronic pain and the knowledge about the existing approaches of those is of fundamental importance for stimulating the process of integrating them, the translation of accumulated knowledge to other professionals and creating new ones. Objective: To investigate the medical and dental approaches front of trigeminal neuralgia in two at a public university services. Methodology: An exploratory study, cross-sectional, qualitative. The subjects were 19 professionals working in one of the services studied. The data collection instrument was an interview guide with 13 questions divided into four axes, based on literature: a) pathophysiology and diagnosis of TN; b) knowledge and use of different treatments; c) professionals' perception of the services and d) routing flows and monitoring of patients. The taped interview, open and semi-structured guided the construction of a descriptive analysis that enabled the identification of emerging analytical categories (Bardin, 1995). Results: Of the analyzed statements seven categories. Among the main results are: lack of consensus among professionals about the pathophysiology; the diagnostic process was considered eminently clinical, while further tests are requested for differential diagnosis and exclusion of secondary causes for TN; perceived lack of training for the diagnosis, particularly for dental professionals; the choice of treatment is associated with vocational training, and the reported pharmacotherapy as the most used; integrative and complementary practices are known as part of the TN treatment, reported by some use; the limitations found in the treatment included the professional integration of disabled and knowledge to suit the individual needs of patients and also those found in the Unified Health System (UHS); as the perception of the services, despite reporting poor infrastructure, understand that there are other more significant problems such as those related to human resources; lack of specific nuclei for the treatment of pain; the teaching-learning environment as a facilitator for the care and multiprofessional and multidisciplinary approach; the lack of effectiveness of previous treatment and the limitations of the UHS regulation system as increased demand generators in the investigated services; the lack of understanding on the part of patients, that healing does not occur when pain control achieved by therapeutic dose, makes it difficult to follow. Considerations: The investigation of medical and dental approaches against TN in both investigated services identified aspects that can motivate and closer to them and the enhancement of existing resources, creating more favorable results to affected individuals, vocational training, research and the solvability of UHS actions. / Introdução: Dentre as dores neuropáticas a neuralgia trigeminal (NT) pertence ao grupo das condições álgicas crônicas da região de cabeça e pescoço, caracterizada por ataques paroxísticos e recorrentes de dor lancinante e súbita, tipo choque. Diversas especialidades podem estar envolvidas no seu processo de diagnóstico diferencial e tratamento, sendo a falta de integração desse processo uma das principais causas da complexidade do diagnóstico e falta de efetividade do tratamento. Poucos são os serviços especializados no tratamento desse tipo de dor crônica e o conhecimento a respeito das abordagens daqueles existentes é de fundamental importância para o estímulo ao processo de integração dos mesmos, a tradução do conhecimento acumulado para outros profissionais e criação de novos centros. Objetivo: Investigar as abordagens médica e odontológica frente à neuralgia trigeminal em dois serviços de uma universidade pública. Metodologia: Estudo exploratório, transversal, qualitativo. Os sujeitos foram 19 profissionais que atuam em um dos serviços estudados. O instrumento de coleta de dados foi um roteiro de entrevista com 13 perguntas divididas em 4 eixos, fundamentados na literatura: a) fisiopatologia e diagnóstico da NT; b) conhecimento e utilização de diferentes tratamentos; c) percepção dos profissionais sobre os serviços e d) fluxos de encaminhamento e acompanhamento dos pacientes. A entrevista gravada, aberta e semi-estruturada orientou a construção de uma análise descritiva que possibilitou a identificação de categorias analíticas emergentes (BARDIN,1995). Resultados: Das falas analisadas emergiram sete categorias. Dentre os principais resultados destacam-se: falta de consenso entre os profissionais sobre a fisiopatologia; o processo de diagnóstico foi considerado como eminentemente clínico, sendo os exames complementares solicitados para diagnóstico diferencial e exclusão de causas secundárias para NT; percepção da falta de capacitação para o diagnóstico, principalmente para os profissionais da área odontológica; a escolha do tratamento está associada à formação profissional, sendo a farmacoterapia relatada como o mais utilizado; as práticas integrativas e complementares são conhecidas como parte do tratamento da NT, sendo relatada sua utilização por alguns; as limitações encontradas no tratamento incluíram a deficiência de integração profissional e do conhecimento para adequação às necessidades individuais dos pacientes e, ainda, aquelas encontradas no Sistema Único de Saúde (SUS); quanto à percepção sobre os serviços, apesar de relatarem uma infraestrutura deficiente, entendem que existem outros problemas mais significantes como aqueles relativos a recursos humanos; a falta de núcleos específicos para tratamento da dor; o ambiente de ensino-aprendizagem como facilitador para o atendimento e acompanhamento multiprofissional e multidisciplinar; a falta de efetividade de tratamentos anteriores e as limitações do sistema de regulação do SUS como geradores de aumento da demanda nos serviços investigados; a falta de entendimento, por parte dos pacientes, de que a cura não ocorre quando atingido o controle da dor pela dose terapêutica, dificulta o acompanhamento. Considerações: A investigação das abordagens médicas e odontológicas frente a NT nos dois serviços investigados, identificou aspectos que podem motivar e aproximar aos mesmos e a potencialização dos recursos existentes, gerando resultados mais favoráveis aos indivíduos acometidos, à capacitação profissional, à pesquisa e a resolubilidade das ações do SUS.

A maioria dos pacientes que têm dor de origem dentária pulpar ou periapical tem dor referida, e algumas características da dor parecem influenciar este fenômeno. Por meio do preenchimento de fichas clínicas, com informações sobre as características da dor, investigamos, em 60 voluntários, a distribuição topográfica de áreas de dor referida de origem dentária. Por meio de métodos psicofísicos, comparamos a resolução espacial da dor com a resolução espacial de outras modalidades somestésicas (mecânica e térmica). Nossos resultados indicam que a intensidade da dor favorece o fenômeno da dor referida e interfere na sua dispersão topográfica. Dentes algógenos com polpa viva influenciam um maior espalhamento da dor. A organização hodológica do núcleo espinal do trigêmeo e mecanismos fisiológicos de integração neural podem explicar de maneira satisfatória várias características da dor referida. Além disso, observamos que a resolução espacial na localização da dor é maior que a resolução espacial da localização de outros estímulos somestésicos nos elementos dentários. / The majority of patients who suffer from toothache report referred pain to other sites in the head and neck. Thus, the aim of this study was to investigate the clinical and psychophysical characteristics of referred pain in the orofacial region and how factors such as intensity, duration and nature of odontogenic pain might modulate them. We employed psychophysical and clinical methods to correlate pain perception with the anatomy and physiology of the trigeminal system. Sixty patients reporting primary toothache were investigated as to the clinical and psychophysical aspects of their pains symptoms and signals (intensity, duration, location and state of the pulp inflammatory process). Pain intensity and state of irreversible pulp inflammation were found to significantly affect facilitate the incidence of referred pain and its spread across vertical laminations. Considering these results, we proposed a physiological model based on both neuronal integration (spatial and temporal summation) and the topographic organization of the trigeminal system, which is able to explain the observed characteristics of referred dental pain.

Une réduction de l'inhibition segmentaire contribue vraisemblablement à l'hypersensibilité douloureuse persistante – qui se manifeste par l'hyperalgie, l'allodynie, et la douleur spontanée – au cours d'états douloureux chroniques. L'association fréquente d'une allodynie avec la migraine – une céphalée épisodique – suggère qu'une perte de l'inhibition synaptique contribue aussi à la manifestation de la douleur migraineuse. Cependant, la grande prévalence de la migraine – plus de 10% de la population générale – soulève la question de savoir si le traitement des informations méningées par le réseau neuronal – associant interneurones excitateurs et inhibiteurs – dans le complexe trigéminal, premier relais sur les voies nociceptives de la face et des méninges, est le même que celui des autres informations, par exemple cutanées. Nous avons caractérisé l'effet du blocage pharmacologique des récepteurs à la glycine (GlyR) et des récepteurs GABAA (GABAAR) sur la transmission synaptique entre fibres afférentes primaires, cutanées ou méningées, et neurones de second ordre en enregistrant des potentiels de champ dans le sous-noyau caudal superficiel (Sp5C). Une stimulation électrique transcutanée évoque trois potentiels de champ négatifs dus à l'activation, du plus précoce au plus tardif, de fibres afférentes primaires de type Aβ, Aδ et C. Bloquer les GlyRs et/ou GABAARs segmentaires facilite les potentiels de champ polysynaptiques excitateurs évoqués par l'activation des fibres afférentes primaires de type A et, au contraire, inhibe, ou même abolit, les potentiels de champ C. Bloquer les récepteurs GABAB (GABABR) segmentaires prévient cette suppression. Il est intéressant de noter que bloquer les GABABRs, potentialise aussi les potentiels de champ C en condition controle. Une stimulation électrique méningée évoque deux potentiels de champ négatifs dus à l'activation, du plus précoce au plus tardif, des fibres afférentes primaires de type Aδ et C. Au contraire du potentiel de champ C cutané, le potentiel de champ C méningé est potentialisé après blocage des GlyRs et/ou GABAARs segmentaires. Ces résultats démontrent que le traitement des informations cutanées et méningées par le Sp5C est différent. Seule l'activation des fibres afférentes primaires cutanées de type A inhibe les inputs cutanés de type C vers le Sp5C par l'intermédiaire d'un circuit polysynaptique excitateur, d'interneurones GABAergiques de dernier ordre et de GABABRs présynaptiques. La théorie du "gate control" postule que l'activité des afférences non-nociceptives ferme la porte à la transmission des inputs nociceptifs vers les centres supérieurs. Nos résultats suggèrent que l'état de la porte dépend de l'activité non seulement dans les fibres afférentes primaires de type A mais aussi dans les circuits polysynaptiques excitateurs de la corne dorsale. / Pathological disruption of segmental inhibition is thought to contribute to persistent pain hypersensitivity – including hyperalgesia, allodynia and spontaneous pain – that occurs during chronic pain states. That allodynia is also often associated with migraine – an episodic headache – suggests that a loss of synaptic inhibition is also involved in the manifestation of headache pain. However, the very high prevalence of migraine – more than 10% of the general population – raises the question as to whether processing of meningeous inputs by local neuronal network – consisting of excitatory and inhibitory interneurons – within the trigeminal nucleus, the first relay station for incoming nociceptive signals of the face and meninges, is the same as that of others, for instance cutaneous. We sought to characterize how pharmacological blockade of glycine and GABAA receptors modifies synaptic transmission between either cutaneous or meningeous primary afferent fibers and second order neurons by recording field potentials in the rat superficial medullary dorsal horn (MDH). Transcutaneous electrical stimulation evokes three negative field potentials elicited by, from the earliest to the latest, Aβ-, Aδ- and C-fiber primary afferents. Blocking segmental glycine and/or GABAA receptors strongly facilitates A-fiber-activated polysynaptic excitatory field potentials but, conversely, inhibits, or even abolishes, C-fiber field potentials. Blocking segmental GABAB receptors reverses such suppression. Interestingly, it also potentiates C-fiber field potentials under control conditions. Meningeous electrical stimulation evokes two negative field potentials elicited by, from the earliest to the latest, Aδ- and C-fiber primary afferents. Unlike cutaneous C-fiber field potentials, meningeous ones are facilitated by blocking segmental glycine and/or GABAA receptors. These results demonstrate that MDH processing of cutaneous and meningeous inputs are different. Only activation of cutaneous A-fiber primary afferents inhibits cutaneous C-fiber inputs to the MDH by the way of polysynaptic excitatory pathways, last-order GABAergic interneurons and presynaptic GABAB receptors. In view of the gate control theory postulating that afferent volleys in non-nociceptive afferents close the gate to central transmission of nociceptive inputs, our results suggest that the state of the gate depends on firing activities of both A-fiber primary afferents and polysynaptic excitatory circuits, i.e. the inhibitory tone, within the dorsal horn.

The distribution of urotensin-II-immunoreactivity (irU-II) was studied in the rat brainstem and spinal cord with the use of an antiserum against the human urotensin II (U-II) peptide. A population of ventral horn neurons in the spinal cord, hypoglossal nucleus, dorsal motor nucleus of the vagus, facial motor nucleus, nucleus ambiguus, abducens nucleus and trigeminal motor nucleus exhibited irU-II of varying intensities. The number of irU-II motor neurons was higher in the lumbar segments as compared to that of cervical, thoracic and sacral segments. Double-labeling the sections with U-II- and choline acetyltransferase (ChAT)-antisera revealed that nearly all irU-II ventral horn and brainstem neurons were ChAT-positive. The result provides the first immunohistochemical evidence of the presence of irU-II in cholinergic motoneurons of the rat spinal cord and brainstem.

Trigeminal neuralgia is a painful neuralgia with a complicated pathology that is not clearly understood. Due to the ambiguity of the condition, patients often have to search for medical providers that specialize in trigeminal neuralgia, and even with the guidance of a specialist, some patients do not respond well to treatment.1 Despite the uncertainty surrounding the specifics of the disease, there are treatments available that can provide some level of pain relief for patients suffering from this disorder. When a patient does not respond well to medical therapy, surgery can be the next appropriate step in patient care management.2 However, while surgery can provide significant pain relief for patients who qualify, non-surgical treatments are needed during the interim, in the event of relapse, or for individuals who do not qualify for surgery. Cognitive behavioral therapy (CBT) is a well-researched treatment for chronic pain resulting from various diseases and disabilities.3 A systematic literature review was performed to identify if CBT decreases pain and improves the quality of life for patients diagnosed with classical, secondary, or idiopathic trigeminal neuralgia. More research is needed, but there is promising evidence in the literature that cognitive behavioral therapy can be useful for patients with trigeminal neuralgia to help them cope with their pain. In addition, there may be evidence that, while somewhat effective alone, cognitive behavioral therapy may be more effective in conjunction with another treatment such as medication. These results are encouraging for patients suffering with the chronic pain of trigeminal neuralgia, and future studies should further investigate the benefits of cognitive behavioral therapy for patients with trigeminal neuralgia.

The ophthalmic trigeminal placode (opV) is the birth place of one cell type of sensory neurons contributing to the trigeminal ganglion. Signals from the neural tube induce placodal identity within the surface ectoderm. Specified opV placode cells then up-regulate neuron differentiation markers and migrate to the ganglion. Several molecular pathways have been shown to act in opV placode cell development. Despite this, signals that specify individual neurons from within the opV placode remain unknown. However, it is known that components of the Notch signaling pathway are expressed in the opV placode. I tested the role of Notch signaling in opV placode development by separately inhibiting and over-activating the pathway. Using DAPT, an inhibitor of gamma-secretase, I inhibited Notch signaling in 13-15 somite stage chick embryo heads. Attenuated Notch signaling caused increased neuronal differentiation of opV cells at 13-15 somites. I also observed an increase in migratory opV placode (Pax3+) cells in the mesenchyme and expression of neuronal marker Islet1 in the ectoderm. Further, I activated Notch signaling by misexpressing the Notch intracellular domain (NICD) by in ovo electroporation of 10-12 somite stage chick embryos. This resulted in Pax3+ targeted cells failing to differentiate and remain instead in the ectoderm. Thus, Notch/Delta signaling plays an important role in selecting ophthalmic trigeminal cells to differentiate and migrate to the trigeminal ganglion.

This dissertation is divided into three chapters, each discussing the study of different regulatory molecules involved in sensory neurogenesis occurring in the trigeminal placode. Chapter one is a spatiotemporal description of Notch pathway genes in chick opV placode by stage-specific expression analysis, showing expression of many Notch pathway genes and effectors in the opV placode. Notch pathway gene expression is primarily confined to the ectoderm with highest expression of these genes at the beginning stages of peak neuronal differentiation. This information preceded studies of the functional roles that Notch signaling has in the opV placode and how it may affect the transcription factor, Pax3. Chapter two is a study of the transcription factor Pax3 and its role in opV placode development and sensory neuron differentiation. Pax3 is known to activate or repress gene transcription, and its activity may be dependent on the splice variant or isoform present. We show through RT-PCR that alternative splice forms of Pax3 are present at stages of chick development corresponding to cellular competence, cellular differentiation and ingression, and cellular aggregation. We have named these splice forms, Pax3V1 and Pax3V2. Using quantitative RT-PCR we show that Pax3V2 is consistently expressed at lower levels compared to Pax3 during cellular competence and differentiation. In order to determine the function of the three splice forms, we misexpressed them in the opV placode and analyzed the effect on neurogenesis. We looked at markers for neuronal differentiation of targeted cells after in ovo electroporation of Pax3, Pax3V1, and Pax3V2, which showed a significant difference between the control and each construct, but not between the groups of constructs. To enhance the process of neurogenesis we exposed the electroporated embryos to DAPT, a Notch signaling inhibitor that enhances sensory neurogenesis. Using this method we found that misexpression of Pax3 and Pax3V1 resulted in cells failing to differentiate, while Pax3V2 misexpression more closely resembles the neuronal differentiation seen in controls. These results show that the Pax3V2 isoform allows for neuronal differentiation of opV placodal cells after misexpression, while the Pax3 isoform and the Pax3V1 isoform block neuronal differentiation. Chapter three is a study of the necessity of Wnt signaling originating from the neural tube to induce Pax3 expression in the opV placode. A double knockout of Wnt1 and Wnt3a was produced to determine the necessity of these genes in opV placode development. Pax3 expression in the opV placode at E8.5 and E9.5 was markedly reduced in the double mutants when compared to wild type mice. This study shows that Wnt1 and Wnt3a genes are necessary for normal Pax3 expression, but that other signals may contribute to its induction.

Hintergrund: Der Geruchssinn spielt eine wichtige Rolle in unserem täglichen Leben, während sein Fehlen erhebliche Auswirkungen auf das Leben von Menschen mit Geruchsstörungen hat, einschließlich Veränderungen in ihrer geistigen, sozialen und körperlichen Gesundheit. Der Verlust des Geruchssinns kann eine Vorstufe zu schweren neurodegenerativen Erkrankungen wie Parkinson und Alzheimer sein, und kann mit depressiven Symptomen einhergehen. Daher sollten Menschen mit Riechverlust adäquat untersucht und behandelt werden. In den drei zu einer Arbeit zusammengefassten Veröffentlichungen wurde die MRT zur Untersuchung der Riechfunktion und ihrer Plastizität eingesetzt, vor allem bei Patienten mit Riechstörungen. Publikation 1 befasste sich mit der Verbesserung bestehender Methoden zur Bewertung des Volumens des Bulbus olfactorius (OB) hinsichtlich der strukturellen Bewertung der Riechfunktion. Publikation 2 befasste sich mit der funktionellen Plastizität des olfaktorischen Systems bei Patienten mit angeborener und erworbener Anosmie, wenn der olfaktorische Input fehlt. Publikation 3 befasste sich mit der Plastizität des chemosensorischen Systems am Beispiel der gewohnheitsmäßigen Exposition zu trigeminalen Gerüchen. Methoden: In Publikation 1 wurden 52 Probanden einer 3-T-MRT Untersuchung des Gehirns unterzogen. Alle Probanden wurden mit der 'Sniffin' Sticks'-Testbatterie auf ihre orthonasale Riechfunktion hin getestet. Mit Hilfe der AMIRA®-Software berechneten zwei geschulte Beobachter das OB-Volumen mit einem manuellen Segmentierungsverfahren, der planimetrischen manuellen Konturierung (PMC) (Fläche in mm3). Mit ITK-SNAP®-Software verwendeten die gleichen Beobachter die neue Methode 'box-frame' zur Berechnung des OB-Volumens. Zunächst wurde die Anzahl der Schichten (Länge) mit deutlicher Erkennbarkeit des OB notiert. Bei der Box-Methode wurde angenommen, dass Höhe und Breite der Markierungen in einem Winkel von 90° zueinander stehen. Das Volumen wurde als Vielfaches von L x B x H (Scheibendicke in mm3) berechnet. Bei divergenten Befunden wurde ein dritter Beobachter herangezogen, und die zwei am nächsten liegenden Volumina mit weniger als 10 % Unterschied zur weiteren Betrachtung ausgewählt. In Publikation 2 wurden 40 Probanden mit 3-T-fMRT untersucht. Davon waren 18 gesunde Probanden, 14 waren Probanden mit kongenitaler Anosmie und 8 hatten eine idiopathische Anosmie. Den Probanden wurden 36 Wörter mit starker olfaktorischer Assoziation (OW) und 36 Kontrollwörter mit geringer oder keiner olfaktorischen Assoziation (CW) präsentiert. Die Teilnehmer wurden angewiesen, die Anweisungen und Wörter zu lesen. Vor den Wortblöcken wurden die Teilnehmer darauf hingewiesen, sich auf die olfaktorischen Aspekte der angezeigten Wörter zu konzentrieren, um eine Erwartung für im Folgenden gezeigten Wörter zu wecken und um die OW- von den CW-Blöcken klar zu trennen. Geruchsbezogene semantische Unterschiede wurden als Kriterium für die Unterscheidung zwischen den Aktivierungen gewählt. Wir verglichen vor allem Aktivierungsphasen, in denen OW erwartet wurden mit denjenigen, in denen OW gelesen wurden. In Publikation 3 nahmen 40 gesunde Probanden an einer fMRT-Untersuchung teil. Ein Teil der Probanden kaute regelmäßig Kaugummi mit Minzegeschmack (GC, n = 20), ein anderer Teil verwendete nie bzw. sehr selten Kaugummi oder andere Lebensmittel mit Minzgerüchen, z.B. Pfefferminztee (N'GC, n = 20). Mit Hilfe eines computergesteuerten Olfaktometers wurden den Probanden in vier separaten Sitzungen zwei „trigeminale Gerüche“ (Pfefferminze und Minze) und zwei „olfaktorische Gerüche“ (Kirsche und Erdbeere) verabreicht. Nach jeder Sitzung bewerteten die Probanden die Intensität und die Angenehmheit der angebotenen Gerüche. Ergebnisse: In Publikation 1 berechneten wir die OB-Volumina mit beiden Techniken und fanden vergleichbare Ergebnisse. Für die von beiden Beobachtern berechneten Volumina wurde eine hohe Korrelation festgestellt. Für die manuelle Segmentierung betrug Cronbachs α 0,91 bzw. 0,93 für das rechte bzw. linke OB-Volumen, während für die Box-Frame-Methode α 0,94 bzw. 0,90 für das rechte bzw. linke OB-Volumen betrug. In Publikation 2 zeigten die Teilnehmer mit idiopathischer und congenitaler Anosmie während der Erwartung der OW eine stärkere Aktivierung im posterioren OFC, die sich bis zur rechten Insula, dem Caudatum und dem fronto-medialen OFC erstreckte. Während des Lesens der OW zeigten Teilnehmer mit congenitaler Anosmie eine stärkere Aktivierung im posterioren OFC, die bis zur Insula reichte. In Publikation 3 zeigte die GC-Gruppe eine höhere trigeminale Empfindlichkeit im Vergleich zur N'GC-Gruppe. Olfaktorische Gerüche aktivierten den bilateralen insulären Kortex und die Amygdala. Neben den olfaktorischen Bereichen (Amygdala, insulärer Kortex) führten trigeminale Gerüche auch zu Aktivierungen im rechten Thalamus und der rechten Substantia nigra. In der GC-Gruppe führten olfaktorische Gerüche zu einer stärkeren bilateralen Aktivierung des insularen Kortex als in der N‘GC-Gruppe, während für trigeminale Gerüche keine derartigen Unterschiede beobachtet wurden. GC-Probanden schienen auf trigeminale chemosensorische Reize empfindlicher zu reagieren. Schlussfolgerungen: Mit der Veröffentlichung 1 konnten wir eine neue zuverlässige Methode vorstellen, die plastische Veränderungen auf der Ebene des OB auf effiziente Weise messbar macht. Die Methode ist zeitsparend und erfordert nur einen geringen technologischen Aufwand, was in die klinische Routine bedeutsam ist. Damit können strukturelle plastische Veränderungen des zentralnervösen Riechsystems zu diagnostischen Zwecken effektiv genutzt werden. In Publikation 2 fanden wir funktionelle Plastizität bei Patienten mit angeborener und erworbener Anosmie. Dieser Ansatz zeigte eine Aktivierung in den sekundären Geruchsregionen wie dem posterioren OFC, die sich bei Menschen mit angeborener Anosmie im Vergleich zu Riechgesunden bis zur Insula ausdehnte. Diese Aktivität ist am ehesten im Zusammenhang mit multisensorischer Integration zu sehen, was wiederum auf kompensatorische Mechanismus für die Verarbeitung semantischer Geruchsinformationen bei fehlendem Riechvermögen schließen lässt. In Publikation 3 untersuchten wir die Plastizität des chemosensorischen Systems bei gewohnheitsmäßiger Exposition zu trigeminalen Gerüchen. Gegenüber selektiv olfaktorischen Aktivierungen gibt es Überlappungen aber auch deutliche Unterschiede in der Peripherie und im ZNS, wie trigeminale Gerüche verarbeitet werden. Erwartungsgemäß schienen Teilnehmer mit habituellem Minzgebrauch empfindlicher auf trigeminale chemosensorische Reize zu reagieren. Dies führte jedoch nicht zu Unterschieden in der zentralnervösen Aktivierung für trigeminale Reize. Vielmehr erschienen trigeminale Gerüche für die Gruppe mit geringem Minzkonsum bedeutungsvoller und erregender. In der Summe zeigen die Arbeiten, dass das chemosensorische System außerordentlich plastisch ist, auf stuktureller und funktioneller Ebene und wir uns ständig an unsere Umwelt anpassen.:List of Abbreviations 1 List of figures 1 List of Tables 3 Introduction 4 Olfactory system 4 Olfactory dysfunction 5 Anatomy of olfactory system 6 Chemosensory assessment 8 Psychophysical olfactory tests 8 Psychophysical Trigeminal tests 9 Electrophysiological tests - olfactory event related potentials (OERP) 10 Functional magnetic resonance imaging (fMRI) 10 Publication 1: Assessment of structural plasticity by measuring OB volume 11 Publication 2: Assessing functional plasticity using bottom- up and top- down olfactory processing 12 Publication 3: Assessing plasticity of chemosensory system 12 Methods 13 Method 1 13 Publication 1- A novel technique for olfactory bulb measurements 13 Method 2 18 Publication 3- Habitual Exposure to Trigeminal Stimuli and Its Effects on the processing of Chemosensory Stimuli 18 Contributions in publications 20 Publication 1: 20 Publication 2: 20 Publication 3: 20 Abstract of publication 1 21 Publication 2 (Second study): Neural processing of olfactory‑related words in subjects with congenital and acquired olfactory dysfunction 31 Abstract of publication 2 31 Publication 3 (Third study) Habitual Exposure to Trigeminal Stimuli and Its Effects on the processing of Chemosensory Stimuli 40 Abstract of publication 3 40 Discussion and Outlook 49 Summary in German 55 Hintergrund 55 Methoden 55 Ergebnisse 56 Schlussfolgerungen 56 Summary in English 58 Background 58 Hypothesis 58 Methods 59 Results 59 Conclusions 60 References 61 Curriculum vitae 80 List of scientific publications 82 Anlage 1 84 Anlage 2 85

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