No description available.

No description available.

L’imagerie fonctionnelle cérébrale détecte les changements hémodynamiques induits par un stimulus pour déterminer les zones d’activation neuronale. Plus particulièrement, l’imagerie BOLD en IRMf détecte les changements d’oxygénation du sang grâce aux propriétés paramagnétiques de la déoxyhémoglobine. L’oxygène n’est donc pas uniquement un substrat énergétique pour le tissu neuronal, il joue également un rôle majeur dans l’imagerie noninvasive du cerveau humain. Au cours de ma thèse, j’ai tout d’abord participé à la mise au point d’une nouvelle technique non-invasive d’imagerie de l’oxygène dans le cerveau d’animaux anesthésiés. Couplant un nouveau senseur phosphorescent de l’oxygène (Finikova et al., 2008) et la microscopie biphotonique, cette approche permet à la fois de cartographier l’oxygène en 3D avec une résolution spatiale et temporelle jusqu’alors inégalée, mais aussi de suivre simultanément l’oxygène et le flux sanguin dans les capillaires cérébraux au repos ou lors d’une activation neuronale (Lecoq et al., 2011). Tirant profit des nouvelles possibilités de cette technique, nous avons alors démontré: • la présence d’un shunt artério-veineux uniquement basé sur la diffusion de l’oxygène. Ce résultat, obtenu chez le rat dans la couche la plus superficielle du bulbe olfactif: la couche du nerf (ONL), confirme que l’oxygène ne diffuse pas uniquement à partir des capillaires et démontre que les artérioles contribuent significativement à l’oxygénation du tissu cérébral. Il démontre également qu’il n’est pas possible de déterminer ni la Po2 capillaire ni la Po2 tissulaire à partir de la Po2 veineuse. • l’existence de transitoires de Po2 associés à chaque globule rouge dans le compartiment capillaire, appelés EATs (erythrocyte-associated transients) (Hellums, 1977; Cabrales and Intaglietta, 2007). En bref, de part leur diamètre supérieur à celui de la lumière d’un capillaire, les globules rouges passent un à un dans la lumière des capillaires, laissant entre eux un espace de plasma. Cependant, la faible solubilité de l’oxygène dans le plasma crée une barrière à la diffusion, ce qui se traduit par une inhomogénéité de la Po2 capillaire: celle-ci est élevée au bord du globule rouge et décroit avec la distance pour atteindre un minimum à mi-distance entre deux globule rouges. Poursuivant l’étude des EATs (Parpaleix et al., 2013), nous avons observé les points suivants: • La Po2 tissulaire dans l’environnement immédiat d’un capillaire peut être déterminée à partir de la Po2 vasculaire à mi-distance entre deux érythrocytes. Ce résultat est intéressant en ce qu’il permettra d’effectuer des mesures non invasives de Po2 tissulaire, utile notamment chez l’animal éveillé. • L’amplitude des EATs est si large (35 mmHg en moyenne) que la Po2 capillaire moyenne ne reflète en rien la saturation en oxygène de l’hémoglobine. • Une empreinte filtrée des EATs vasculaires est détectable dans le tissu (_5 mmHg d’amplitude). • Au cours d’une stimulation neuronale, une diminution de la Po2 capillaire moyenne peut être détectée avant l’hyperémie fonctionnelle, un résultat jusqu’à présent controversé dans le domaine de l’imagerie BOLD en IRMf, mais important en ce que ce dip pourrait être un rapporteur très résolutif de l’activation neuronale. Parmi les questions restant en suspens et pouvant être étudiées finement avec notre approche, j’en citerai une principale: quel est le poids des différents facteurs (métaboliques, présynaptiques ou post-synaptiques) et du flux sanguin dans l’établissement de la Po2 cérébrale au repos? / In humans, functional mapping of brain activity mainly relies on the increase of cerebral blood flow (CBF) triggered by neuronal activation. This neurovascular coupling provides energy substrates such as oxygen and glucose to the activated area. The steady state concentration of oxygen, as well as its dynamics upon neuronal activation, have been investigated with numerous methods, however, none of them provided highly resolute measurements in depth. During my PhD, we combined a phosphorescence quenching approach with two-photon microscopy to detect, in depth and with a micrometer spatial resolution scale, the emission of phosphorescence by PtP-C343, a new oxygen nano-sensor designed for two-photon excitation. We first characterized the technique and then reported two biological results, using the olfactory bulb (OB) glomerulus as a model to study oxygen concentration, at rest and upon odor stimulation. We found an arterio-venous shunt, purely based on diffusion, in the superficial nerve layer of the OB, confirming the role of arterioles in brain oxygenation. Simultaneous measurements of Po2 and blood flow allowed us to reveal the presence of erythrocyte-associated transients (EATs), i.e. Po2 fluctuations that are associated with individual erythrocytes. Pursuing the investigation of EAT characteristics, we found that in capillaries, Po2 at mid-distance between two erythrocytes is at equilibrium with, and thus reports Po2 in the nearby neuropil. Finally, we could observe that even in capillaries, a small oxygen initial dip can be detected prior to functional hyperemia, upon odor activation.

Les Glioblastomes (GBM, grade IV selon l’OMS) sont les tumeurs cérébrales primaires les plus agressives et sont caractérisées par une néovascularisation importante associée à l’hypoxie et à la nécrose. L’origine cellulaire des GBM est controversée, mais des sous-populations de cellules multipotentes ont été identifiées au sein des tumeurs, et seraient responsables de la radio/chimiorésistance des GBM. Ces cellules souches de glioblastome (GSC) contrôlent activement la vascularisation tumorale par leur interaction étroite avec les cellules vasculaires composant les niches tumorales. La voie Notch est une signalisation canonique essentielle au développement et à l’homéostasie du système nerveux central et son réseau vasculaire associé. Dans le contexte des GBM, cette cascade serait nécessaire à la gliomagénèse, par le maintien du réservoir de GSC au sein de la niche périvasculaire. Cependant, le mode d’action moléculaire de Notch dans les GBM reste encore à démontrer, du fait de résultats divergents observés dans plusieurs études. Dans la première partie de mon travail de thèse, j’ai contribué à l’exploration de la signalisation Notch1 dans des cultures de GSC établies et caractérisées au sein du laboratoire. Le niveau basal d’activation de Notch1 étant faible dans nos GSC, l’approche a été d’activer constitutivement cet axe par transduction lentivirale. Suite à cette activation forcée, les GSC subissent un changement phénotypique majeur et se différencient en cellules périvasculaires ou cellules « pericyte-like ». Cette transition neurovasculaire des GSC promeut la vascularisation active des tumeurs par la normalisation du réseau vasculaire in vivo. Par la suite, j’ai posé la question des mécanismes moléculaires en aval de Notch1 ; par l’étude des facteurs de transcription TAL1 et SLUG, deux candidats potentiels au contrôle de cette plasticité neurovasculaire. Dans ce but, j’ai examiné leur contribution au phénotype vasculaire des GSC dans un modèle in vitro de la niche périvasculaire ; et in vivo par l’analyse d’échantillons humains de GBM. Enfin, j’ai également observé que l’activation de Notch1 module l’activité de la machinerie du protéasome, ce qui pourrait contribuer activement à la transition moléculaire observée dans les GSC. Ces travaux mettent en avant la plasticité phénotypique des GSC: une meilleure compréhension de ces processus pourrait mener à la conception de thérapies ciblant efficacement les GSC et leur vascularisation associée. / Glioblastomas (GBM, WHO grade IV) are highly aggressive brain tumors in which extensive vascularization is associated with hypoxia and necrosis. GBM cell of origin is controversial; however multipotent stem-like subpopulations have been identified within tumors, and could account for GBM radio/chemoresistance. These glioblastoma stem-like cells (GSC) actively promote tumoral vascularization processes by closely interacting with vascular cells composing tumoral niches. The Notch cascade is a canonical signaling pathway required during developmental stages and adult homeostasis of the central nervous system and the associated vascular network. In the context of GBM, this molecular axis could induce gliomagenesis by promoting GSC maintenance in the perivascular niche. However, Notch-induced molecular mechanisms controlling GBM progression still remain elusive, due to divergent results observed in numerous reports. During the first part of my thesis work, I contributed to the assessment of Notch1 functions in GSC cultures isolated and characterized in our lab. Given a low Notch1 basal activation status in our GSCs, our approach was to constitutively activate this axis via lentiviral transduction. Following this forced activation, GSCs undergo drastic phenotypic changes and differenciate into perivascular-like or “pericyte-like” cells. This neurovascular transition of GSCs induces active tumoral vascularization by promoting normalization of the vascular network in vivo. Consequently, I questioned the molecular mechanisms downstream of Notch1 by focusing on TAL1 and SLUG transcription factors, two potential candidates controlling this neurovascular plasticity. For this purpose, I examined their contribution to the GSC vascular-like phenotype in an in vitro model of the perivascular niche; and in vivo by analyzing human GBM samples. Finally, I also observed that Notch1 activation modulates the activity of the proteasomal machinery, which could actively contribute to the molecular transition occurring in GSCs. This work highlights GSC phenotypic plasticity: a better understanding of these processes could lead to the design of therapies efficiently targeting GSCs and their associated vasculature.

No description available.

Functional hyperaemia is an important mechanism by which increased neuronal activity is matched by a rapid and regional increase in blood supply. This mechanism is facilitated by a process known as “neurovascular coupling” – the orchestrated communication system involving the cells that comprise the neurovascular unit (neurons, astrocytes and the smooth muscle and endothelial cells lining arterioles). Blood flow regulation and neurovascular coupling are altered in several pathological states including hypertension, diabetes, Alzheimer’s disease, cortical spreading depression and stroke. By adapting and extending other models found in the literature, we create, for the first time, a mathematical model of the entire neurovascular unit that is capable of simulating two separate neurovascular coupling mechanisms: a potassium- and EET-based and a NO-based mechanism. These models successfully account for several observations seen in experiment. The potassium/EET-based mechanism can achieve arteriolar dilations similar in magnitude (3%) to those observed during a 60-second neuronal activation (modelled as a release of potassium and glutamate into the synaptic cleft). This model also successfully emulates the paradoxical experimental finding that vasoconstriction follows vasodilation when the astrocytic calcium concentration (or perivascular potassium concentration) is increased further. We suggest that the interaction of the changing smooth muscle cell membrane potential and the changing potassium-dependent resting potential of the inwardly rectifying potassium channel are responsible for this effect. Furthermore, our simulations demonstrate that the arteriolar behaviour is profoundly affected by depolarization of the astrocytic cell membrane, and by changes in the rate of perivascular potassium clearance or the volume ratio between the perivascular space and astrocyte. In the modelled NO-based neurovascular coupling mechanism, NO exerts its vasodilatory effects via neuronal and endothelial cell sources. With both sources included, the model achieves a 1% dilation due to a 60-second neuronal activation. When the endothelial contribution to NO production is omitted, the arteriole is more constricted at baseline. Without the endothelial NO contribution, the arteriolar change in diameter during neuronal activity is greater (6%). We hypothesize that NO has a dual purpose in neurovascular coupling: 1) it dixxxvi rectly mediates neurovascular coupling through release by neuronal sources, and 2) it indirectly modulates the size of the neurovascular coupling response by determining the baseline tone. Our physiological models of neurovascular coupling have allowed us to replicate, and explain, some of the phenomena seen in both neurovascular coupling-oriented and clinicallyoriented experimental research. This project highlights the fact that physiological modelling can be used as a tool to understand biological processes in a way that physical experiment cannot always do, and most importantly, can help to elucidate the cellular processes that induce or accompany our most debilitating diseases.

The blood oxygen level dependent functional MRI (BOLD-fMRI) signal is an indirect measure of the neuronal activity that most BOLD studies are interested in. This thesis uses generative embedding algorithms to investigate some of the challenges and opportunities that this presents for BOLD imaging. It is standard practice to analyse BOLD signals using general linear models (GLMs) that assume fixed neurovascular coupling. However, this assumption may cause false positive or negative neural activations to be detected if the biological manifestations of brain diseases, disorders and pharmaceutical drugs (termed "neuromodulations") alter this coupling. Generative embedding can help overcome this problem by identifying when a neuromodulation confounds the standard GLM. When applied to anaesthetic neuromodulations found in preclinical imaging data, Fentanyl has the smallest confounding effect and Pentobarbital has the largest, causing extremely significant neural activations to go undetected. Half of the anaesthetics tested caused overestimation of the neuronal activity but the other half caused underestimation. The variability in biological action between anaesthetic modulations in identical brain regions of genetically similar animals highlights the complexity required to comprehensively account for factors confounding neurovascular coupling in GLMs generally. Generative embedding has the potential to augment established algorithms used to compensate for these variations in GLMs without complicating the standard (ANOVA) way of reporting BOLD results. Neuromodulation of neurovascular coupling can also present opportunities, such as improved diagnosis, monitoring and understanding of brain diseases accompanied by neurovascular uncoupling. Information theory is used to show that the discriminabilities of neurodegenerative-diseased and healthy generative posterior parameter spaces make generative embedding a viable tool for these commercial applications, boasting sensitivity to neurovascular coupling nonlinearities and biological interpretability. The value of hybrid neuroimaging systems over separate neuroimaging technologies is found to be greatest for early-stage neurodegenerative disease.

Les athlètes utilisent les suppléments nutritionnels avec pour objectif d'améliorer leur performance sportive. La performance sportive dépend de facteurs physiques, mais également de facteurs cognitifs. Les suppléments nutritionnels riches en flavanols issu du cacao (CF) peuvent stimuler la fonction vasculaire, réduire le stress oxydant et améliorer la fonction cognitive. L'objectif de cette thèse est donc d’analyser les effets d'une consommation aigue, ou pendant une semaine, de CF, sur la performance physique et cognitive chez des athlètes, chez des sujets actifs et chez des personnes ayant un diabète de type 1 (DT1). De plus, l’objectif est d’investiguer les effets des CF en altitude simulé, où l’hypoxie limite la performance cognitive et physique.La consommation aigue de 900 mg CF (dont 196 mg d'épicatéchine) suscite une augmentation de l’oxygénation cérébrale, mais pas de la concentration de BDNF sérique et n'a pas d’effet sur la fonction cognitive chez des sportifs sains. L’effet bénéfique des CF sur l’oxygénation cérébrale au repos est dépassé par l’ampleur de l’augmentation de la perfusion et de l’oxygénation cérébrale à l’exercice physique et n'est donc plus visible en post-exercice.En hypoxie (altitude simulée de 4000 m), la consommation aigue de 530 mg CF (dont 100 mg d'épicatéchine) augmente la réponse hémodynamique du cortex préfrontal durant une tâche cognitive, mais n’affecte pas l’activité neuronale. Les CF améliorent la pensée abstraite en normoxie, mais n’améliorent aucun autre domaine des fonctions cognitives. Seule la précision lors du test de Stroop est diminuée par l’hypoxie. De plus, la réponse hémodynamique du cortex préfrontale et l’activité neuronale ne diffèrent pas en hypoxie vs. en normoxie.Le diabète de type 1 (DT1) est associé avec une dysfonction endothéliale, qui constitue un des facteurs de déclin cognitif lié au diabète. Dans une 3ième étude, la fonction cognitive n’est pas altérée chez les patients DT1, en comparaison des sujets sains, alors que l'activation cérébrale diffère entre ces 2 groupes. Cette différence d'activation cérébrale pourrait alors jouer un rôle compensatoire chez les patients DT1. La consommation aigue de CF peut améliorer les fonctions exécutives chez des patients DT1 et des sujets sains, et peut augmenter le signal BOLD dans les régions du cerveau activées par les tâches cognitives.Ainsi, la consommation aigue de CF augmente la vasoréactivité cérébrale. Ces changements sont associés avec une meilleure fonction cognitive chez des patients DT1, alors que ce n’est pas le cas chez des sujets entraînés, ni au niveau de la mer, ni en hypoxie. Malgré ces effets bénéfiques des CF, l’exercice physique semble rester un moyen beaucoup plus efficace pour stimuler la vasoreactivité cérébrale et les fonctions cognitives.Nous nous sommes aussi intéressés aux effets de CF sur la capacité antioxydante, le stress oxydant et la production de NO pendant l’exercice, ainsi que sur les implications pour la performance physique et la récupération, chez des athlètes. La consommation aigue de 903 mg CF augmente la capacité antioxydante au repos et pendant l’exercice, mais sans réduire le stress oxydant et la production de NO. La consommation pendant une semaine de 530 mg CF (dont 100 mg d'épicatéchine) atténue la peroxydation lipidique induite par l’exercice, mais n’influence pas la capacité antioxydante. Les CF ne modifient pas la production et la biodisponibilité du NO pendant un exercice en normoxie et en hypoxie (altitude simulée de 3000 m). La consommation de CF pendant une semaine peut augmenter la fonction endothéliale de repos, et peut réduire les effets nuisibles de l'hypoxie sur l’oxygénation préfrontale au repos et pendant l’exercice modéré. Par contre, cet effet disparait pendant l’exercice intense. La consommation aigue, et pendant une semaine, de CF n’augmente pas la performance physique, ni en normoxie, ni en hypoxie. / Sports performance depends on physical factors, but also on cognitive functioning. Nutritional supplements as potential ergogenic aids can impact muscle, but also the brain. Cocoa flavanols (CF) have antioxidant capacities, can stimulate vascular function, and potentially enhance cognitive function. CF intake might thus improve exercise performance and recovery by reducing oxidative stress, increasing NO availability and/or boosting cognitive function. It is the purpose of this PhD to identify the effects of CF on physical and cognitive performance in healthy athletes at sea level and altitude, as well as in patients with type 1 diabetes. Our systematic review showed that CF can reduce exercise-induced oxidative stress, but without improving exercise performance. Combining CF intake and exercise training improves cardiovascular risk factors and vascular function in healthy and overweight participants, but evidence on the synergistic effects of CF and exercise training on oxidative stress, inflammation and fat and glucose metabolism is lacking.In a randomized, placebo-controlled, double blind cross-over study, we showed that 900 mg CF intake increased prefrontal oxygenation in athletes, but without affecting executive function. BDNF was not affected by CF intake. The effects of high-intensity exercise largely overruled the effects of CF intake: large beneficial effects of exercise on prefrontal oxygenation and cognitive function were observed and CF supplementation did not enlarge these effects. In a 2nd study, the effect of acute CF intake (530 mg CF) on performance on a demanding cognitive test was assessed in normoxia and hypoxia (simulated altitude 4000 m). Electroencephalogram and fNIRS were used to analyse neuronal activity and hemodynamic changes. Acute CF intake improved the neurovascular response, but did not affect neuronal activity and cognitive performance in normoxia and hypoxia. Most cognitive functions, the cerebrovascular response and neuronal activity, were not altered in hypoxia in healthy subjects. In a 3rd study, we found that acute intake of 900 mg CF enhanced cognitive performance on the Flanker test in patients with type 1 diabetes, and their healthy matched controls. CF intake increased the BOLD response in brain areas activated during this specific task. While cognitive performance was not deteriorated in patients with type 1 diabetes, a different brain activation pattern during the cognitive task was observed, compared to healthy controls and this brain activation pattern was altered by CF intake. To conclude, acute CF intake improves prefrontal oxygenation and cerebrovascular responsiveness. This can be associated with better cognitive function in patients with type 1 diabetes, but does not result in improved executive function in healthy persons. Compared to exercise, the magnitude of the CF-induced neurovascular changes is small.Two studies were conducted examining the effects of CF on exercise-induced oxidative stress, NO availability and its implications for exercise performance, in well-trained cyclists. We found that acute CF (900 mg) improved the exercise-induced increase in total antioxidant capacity, but did not reduce the exercise-induced increase in lipid peroxidation. One week CF intake (530 mg CF) improved vascular function at rest, and prefrontal oxygenation at rest and during low-intensity exercise, but did not influence muscular oxygenation. One week CF intake partially restored the hypoxia-induced decline in prefrontal oxygenation during rest and low-intensity exercise, but not during high-intensity exercise. One week CF intake reduced exercise-induced lipid peroxidation, but did not alter total antioxidant capacity. Both acute and 1-week CF intake did not improve exercise performance and recovery and do not change NO production during exercise (in normoxia and hypoxia) in well-trained athletes.

Ein bezüglich Datenakquisition und Nachverarbeitung optimiertes Visualisie-rungsprotokoll zur dreidimensionalen Darstellung der Hirnnerven V-VIII im Be-reich der basalen Zisternen wird vorgestellt. Auf der Basis von hochauflösen-den MRT Daten und unter Verwendung der Volume-Rendering-Technik entstanden insgesamt 10 Standardansichten der genannten Hirnnerven, die deren vollständige und zeiteffektive intrazisternale Abbildung mit besonderer Beachtung pathophysiologisch relevanter Zonen ermöglichen. Das Protokoll zeigte in der Evaluation an Patienten mit neurovaskulären Konflikten und an-deren neuralen Kompressionssyndromen im Bereich des Kleinhirnbrücken-winkels seine Eignung bezüglich Bildqualität und diagnostischer Wertigkeit. Probleme traten vor allem aufgrund von Pulsations- und Bewegungsartefakten im akquirierten MRT-Datensatz, sowie zu enger Zisternen auf der Höhe der virtuellen Kameraposition auf. Diese ließen sich in den meisten Fällen jedoch durch leichte Parametervariationen beheben. Zur genauen Identifikation der Gefäße und zur Vermeidung der Weitergabe von Fehlzuordnungen war zu-sätzlich zu den Rekonstruktionen die Betrachtung des Originaldatensatzes er-forderlich. Die Nachverfolgung der mit dem beschriebenen Protokoll virtuell zisternoskopisch untersuchten Patienten ergab bei der weit überwiegenden Zahl der verfolgbaren Patienten Konsequenzen hinsichtlich Diagnose und/oder Therapie. Die Korrelation mit intraoperativen Befunden konnte nur bei zwei Patienten mit Akustikusneurinomen erfolgen, wobei hier eine Über-einstimmung festgestellt werden konnte. Ursache für die nur geringe Zahl der zur Verfügung stehenden intraoperativen Befunde ist die lange Latenz zwi-schen Bildgebung und neurochirurgischer Intervention bei neurovaskulären Konflikten. Zusammenfassend lässt sich feststellen dass die virtuelle Zister-noskopie nach dem vorgestellten Protokoll eine komplementäre Bildgebungs-technik ist, die wichtige räumliche Informationen zu neurovaskulären Interakti-onen in den basalen Zisternen liefert. Weitere Untersuchungen, insbesondere die intraoperative Befundkorrelation, sind jedoch erforderlich. / The following thesis presents a protocol for the three-dimensional visualization of the cranial nerves V-VIII within the basal cisterns, being optimized with regard to data acquisition and postprocessing. Based on high resolution MRI datasets and using the volume rendering technique, 10 standardized views of the aforementioned cranial nerves were developed. Thus, the complete and time effective intracisternal depiction was intended to be made possible, focussing on pathophysiological important areas of the nerves. The protocol showed its suitability concerning image quality and diagnostic value in evaluation of patients with neurovascular conflicts or other neural compression syndromes in the cerebello-pontine angle. Problems mainly occurred as a result of pulsation and motion artefacts in the MR dataset and narrow cisterns in the level of the virtual camera position. In most cases they could be solved by slight variations of the postprocessing parameters. To guaranty the correct identification of the vessels and to avoid the risk of giving incorrectly assigned anatomic information to subsequent readers, the additional inspection of original dataset is necessary. In the follow up of the examined patients consequences in diagnosis and/or therapy were found in the most cases. The correlation of the virtual cisternoscopic images with the intraoperative results could only be performed in two patients with acoustic neuromas and was successful. The reason for the small amount of available intraoperative results is the latency between imaging and neurosurgical intervention in neurovascular conflicts. Concluding the virtual cisternoscopy following the introduced protocol is a complementary imaging technique that provides important spatial information about neurovascular interactions within the basal cisterns. Yet further investigations, especially the intraoperative correlation of the results, are necessary.

O nervo alveolar inferior (Nai), o mais espesso ramo do nervo mandibular (V par craniano), está funcionalmente relacionado à inervação da mandíbula e dentes inferiores, além de parte dos tecidos moles circunjacentes. Seu estudo morfológico, sobretudo em mandíbulas adultas, foi sistematicamente realizado, contudo, sem ainda haver um consenso definitivo para o seu padrão de ramificação. Desse modo, considerando-se a importância em se demonstrar um modelo de constituição básica para o Nai, realizou-se o presente estudo em fetos humanos da 19ª a 36ª semana de vida intrauterina. Foram utilizados 86 hemimandíbulas, de ambos os sexos, em que se avaliou o padrão morfológico intraósseo do Nai e de seus ramos, seus envoltórios conjuntivos e suas relações com as estruturas vasculares, utilizando-se de microdissecção e microscopia eletrônica de varredura (MEV). Relativamente ao padrão morfológico do segmento intramandibular do Nai, foram propostos 4 tipos de ramificação: Tipo I (16%), onde o Nai emite 3 ramos principais, os nervos alveolares inferiores posterior (Naip), médio (Naim) e anterior (Naia); Tipo II (34%), semelhante ao anterior, porém ausente o Naim; Tipo III (30%), semelhante ao primeiro, porém ausentes Naim e o Naia; e o Tipo IV (20%), a forma clássica do Nai, onde somente o Naia se ramifica a partir dele. Verificou-se uma série de conexões entre todos os feixes nervosos, sobretudo entre o Naip e o Nai, sendo que os ramos dentais e peridentais partem, em sua maioria, do Naip, Naim e Naia. Sobre os envoltórios conjuntivos, verificou-se que se espessam à medida que o feto se desenvolve, notando também a presença de uma bainha neurovascular comum a envolver o feixe vasculonervoso alveolar inferior. Quanto ao posicionamento da artéria alveolar inferior, adjacente ao forame da mandíbula, cruza o feixe nervoso, em sua maioria, pela face medial (41%) ou pela lateral (55%), para logo em seguida alcançar sua posição definitiva sobre a face superior do feixe nervoso. Quanto às veias alveolares inferiores, em número de 1 a 3, posicionam-se posteromedialmente às outras estruturas do feixe vasculonervoso. Para a veia de Serres, observada em todos os espécimes e envolta por um canal ósseo, propôs-se a terminologia veia paramandibular. / The inferior alveolar nerve (Nai), the thickest branch of the mandibular nerve (V pair of cranial nerve), is functionally related to jaw and lower teeth innervation as well as, being part of the surrounding smooth tissue. The Nai morphology has been systematically studied in mandible of adults however, no definitive consensus has been reached in relation to its branched pattern. Therefore, this study was been performed in 19 to 36 week-gestation fetuses, due to the importance of determining a basic model of Nai as available data refers only to its arrangement in adults. Micro dissection and Scanner Electron Microscopy (MEV) were performed on 86 human hemi-mandibles of both sexes in order to evaluate the morphological intraosseous pattern of Nai and its branches, its connective tissue and their relationship with vascular structures. In connection with the morphological pattern of intramandibular segment of Nai, four types of branches were proposed: Type I (16%) where Nai give rise to 3 main branches: posterior inferior alveolar nerve (Naip), medium (Naim), and anterior (Naia); Type II (34%), similar to Type I but Naim was absent; Type III (30%), similar to the first, however Naim and Naia were absent; and type IV (20%),the classic form of Nai, from which only Naia was raised. A series of connections was verified among all of the nervous bundles, especially between Nai and Naip. besides dental and periodontal branches commonly arising from Naip, Naim and Naia. In relation with the connective tissues, it was shown that they became thicker as the fetuses are developing; at this stage it was also noted one neurovascular sheath covering nerve bundles and blood vessels. Relatively to the inferior alveolar artery position, adjacent to mandible foramen, it can, frequently, cross the nerve bundle through medial (41%) or lateral surface (55%), reached after its final position on the superior surface of nerve bundle; the inferior alveolar veins (1 to 3), are posterior-medially positioned to the neurovascular bundle other structures. The terminology paramandibular vein was proposed to the Serres vein observed in all specimens studied which was surrounded by bone channel.