Language skills increase as the brain matures and language specialization is linked to the left hemisphere. Among distinct language domains, sentence comprehension is particularly vital in language acquisition and, by comparison, requires a much longer time-span before full mastery in children. Although accumulating studies have revealed the neural mechanism underlying sentence comprehension acquisition, the development of the brain’s gray matter and its relation to sentence comprehension had not been fully understood. This thesis employs structural magnetic resonance imaging and diffusion-weighted imaging data to investigate the neural correlates of sentence comprehension in preschoolers both cross-sectionally and longitudinally. The first study examines how cortical thick- ness covariance is relevant for syntax in preschoolers and changes across development. Results suggest that the cortical thickness covariance of brain regions relevant for syntax increases from preschoolers to adults, whilst preschoolers with superior language abilities show a more adult-like covariance pattern. Reconstructing the white matter fiber tract connecting the left inferior frontal and superior temporal cortices using diffusion-weighted imaging data, the second study suggests that the reduced cortical thickness covariance in the left frontotemporal regions is likely due to immature white matter connectivity during preschool. The third study then investigated the cortical thickness asymmetry and its relation to sentence comprehension abilities. Results show that longitudinal cortical thick- ness asymmetry in the inferior frontal cortex was associated with improvements in sentence comprehension, further suggesting the crucial role of the inferior frontal cortex for sentence comprehension acquisition. Taken together, evidence from gray and white matter data provides new insights into the neuroscientific model of language acquisition and the emergence of syntactic processing during language development.

No description available.

During adolescence, the brain undergoes significant reorganization due to myelination and synaptic pruning. These changes are associated with risk-taking behaviors and the development of social relationships. Recent advancements in adolescent brain development can potentially enhance strategies for preventing and treating mental health disorders. This systematic review focuses on structural changes in the adolescent brain, specifically emphasizing a decrease in gray matter and an increase in white matter changes. Four longitudinal MRI studies were included in this systematic review to identify changes in brain volume among healthy adolescents with an age range of 10 to 19 years. The results revealed observable changes in gray and white matter volume in various brain regions during this period. A decrease in gray matter was observed in the frontal, temporal, and parietal cortex, and several subcortical regions. Contrary to our expectations, the amygdala displayed an increase in gray matter in early adolescence. We expected this findings to occur in late childhood. The results also indicated that males undergo more significant changes in the brain during this period than females. Considering the Social Process Network (SIPN) and triadic model, changes occurring in the frontal cortex and the amygdala could be linked to social behavior. While the changes in the thalamus, hippocampus, and amygdala may be linked to heightened risk-taking and mental health disorders. Further research is necessary to clarify the relationship between mental health disorders, behaviors, and developmental processes during adolescence.

No description available.

While evidence suggests there is indeed a relationship between arterial stiffness and changes in brain structure and function cross-sectionally, the longitudinal relationship between arterial stiffness and changes in brain structure and function is unclear. Also unclear is whether a regional effect of arterial stiffness on brain structure exists, or if the effect is homogenous across brain regions. Using a healthy cohort of the UK Biobank study (N = 1858, meanSD: 61  7 years), we investigated the longitudinal association between changes in arterial stiffness index (ASI) and brain structure (grey matter cortical thickness, whole brain grey matter volume, white matter hyperintensity volume) and function (cognitive performance in 6 tests) over 2.5  1 years. We also examined the association between baseline ASI and all structural and functional brain outcomes 8-11 years post-baseline (N = 630). Prior to post-hoc correction, we observed a significant effect of changes in ASI over 2.5  1 years on grey matter cortical thickness in 11 brain regions contributing to reductions between 0.0004-0.0024mm annually, but none of the 11 regions remained significant post-correction. Following correction there was also no effect of changes in ASI on whole brain grey matter volume (p = 0.76), white matter hyperintensity volume (p = 0.84), or cognitive performance in the domains of interest. Baseline ASI was not associated with regional grey matter cortical thickness, white matter hyperintensity volume, or cognitive function, but did have a significant negative association with whole brain grey matter volume 8.5  1.05 (p = 0.015) years later and 11  1.02 (p = 0.03) years later. Our findings suggest that taken with the effect of age, elevations in ASI may have an additive effect to accelerate changes in brain structure beyond the range that is to be expected as a part of normal aging. Our findings also suggest the relationship between ASI and reductions in whole brain grey matter volume may require long-term exposure to elevations in arterial stiffness in otherwise healthy older adults. / Thesis / Master of Science in Kinesiology / Arterial stiffening both accompanies the normal aging process and can progress due to acquired health conditions. As arteries begin to stiffen the ability to buffer high pressure blood flow is impaired and can put microvasculature at risk of damage. Microvascular damage in the brain can disrupt blood and subsequent oxygen delivery to the brain. When delivery to the brain does not meet the metabolic demand, changes in brain structure brain can occur. Changes in brain structure are associated with impaired brain function, as well as potentially accelerating the progression of neurological diseases. What remains unclear is whether arterial stiffness impacts brain structure differently across regions or all regions homogenously. The purpose of this thesis was to examine the relationship between arterial stiffness and structural and functional changes in the brain over time (objective 1: 2-5 years; objective 2: 8-11 years). Our observations suggest that the progression of arterial stiffness had an effect that was equivalent to approximately 30% of the rate of grey matter tissue loss associated with normal healthy aging (~0.25% reduction in grey matter per year). We found no effect of changes in arterial stiffness on the progression of total grey matter volume, white matter lesions or brain function. We did observe a significant negative relationship between arterial stiffness at baseline and total grey matter volume 8-11 years later. We found no relationship between baseline arterial stiffness and brain structure or function 8–11-years post-baseline. Taken with the effects of normal aging, the loss of tissue in select brain regions associated with changes in arterial stiffness may result in grey matter reductions beyond the range associated with what is considered healthy or normal aging. The association of arterial stiffness and total grey matter volume 8-11 years later suggests that changes in whole brain structure are the product of long-term exposure to arterial stiffness.

Accurate delineation of anatomical structures in the white matter of the human brain is of paramount importance for multiple applications, such as neurosurgical planning, characterization of neurological disorders, and connectomic studies. Diffusion Magnetic Resonance Imaging (dMRI) techniques can provide, in-vivo, a mathematical representation of thousands of fibers composing such anatomical structures, in the form of 3D polylines called streamlines. Given this representation, a task of invaluable interest is known as white matter bundle segmentation, whose aim is to virtually group together streamlines sharing a similar pathway into anatomically meaningful structures, called white matter bundles. Obtaining a good and reliable bundle segmentation is however not trivial, mainly because of the intrinsic complexity of the data. Most of the current methods for bundle segmentation require extensive neuroanatomical knowledge, are time consuming, or are not able to adapt to different data settings. To overcome these limitations, the main goal of this thesis is to develop a new automatic method for accurate white matter bundle segmentation, by exploiting, combining and extending multiple up-to-date supervised learning techniques. The main contribution of the project is the development of a novel streamline-based bundle segmentation method based on binary linear classification, which simultaneously combines information from atlases, bundle geometries, and connectivity patterns. We prove that the proposed method reaches unprecedented quality of segmentation, and that is robust to a multitude of diverse settings, such as when there are differences in bundle size, tracking algorithm, and/or quality of dMRI data. In addition, we show that some of the state-of-the-art bundle segmentation methods are deeply affected by a geometrical property of the shape of the bundles to be segmented, their fractal dimension. Important factors involved in the task of streamline classification are: (i) the need for an effective streamline distance function and (ii) the definition of a proper feature space. To this end, we compare some of the most common streamline distance functions available in the literature and we provide some guidelines on their practical use for the task of supervised bundle segmentation. Moreover, we investigate the possibility to include, in a streamline-based segmentation method, additional information to the typically employed streamline distance measure. Specifically, we provide evidence that considering additional anatomical information regarding the cortical terminations of the streamlines and their proximity to specific Regions of Interest (ROIs) helps to improve the results of bundle segmentation. Lastly, significant attention is paid to reproducibility in neuroscience. Following the FAIR (Findable, Accessible, Interoperable and Reusable) Data Principles, we have integrated our pipelines of analysis into an online open platform devoted to promoting reproducibility of scientific results and to facilitating knowledge discovery.

Temporomandibular disorders (TMD) are a family of prevalent chronic pain disorders affecting masticatory muscles and/or the temporomandibular joint. There is no unequivocally recognized peripheral aetiology for idiopathic TMD. The central nervous system (CNS) may initiate and/or maintain the pain in idiopathic TMD due to sustained or long-term nociceptive input that induces maladaptive brain plasticity, and/or to inherent personality-related factors that may reduce the brain's capacity to modulate nociceptive activity. The main aim of this thesis is to determine whether there are structural neural abnormalities in patients with TMD, and whether these abnormalities are related to TMD pain characteristics, or to neuroticism. The specific aims are to delineate in TMD: (1) gray matter (GM) brain abnormalities and the contribution of pain and neuroticism to abnormalities; (2) the contribution of abnormal brain GM aging in focal cortical regions associated with nociceptive processes; and (3) abnormalities in brain white matter and trigeminal nerve and the contribution of pain. In groups of 17 female patients with TMD and 17 age- and sex- matched controls, magnetic resonance imaging revealed that patients with TMD had: (1) thicker cortex in the somatosensory, ventrolateral prefrontal and frontal polar cortices than controls, (2) cortical thickness in motor and cognitive areas that was negatively related to pain intensity, orbitofrontal cortical thickness that was negatively correlated to pain unpleasantness, and thalamic GM volume correlated to TMD duration, (3) an abnormal relationship between neuroticism and orbitofrontal cortical thickness, (4) abnormal GM aging in nociceptive, modulatory and motor areas, (5) widespread abnormalities in white matter tracts in the brain related to sensory, motor and cognitive functions, (6) reduced trigeminal nerve integrity related to pain duration, and (7) abnormal connectivity in cognitive and modulatory brain regions. In sum, this thesis demonstrates for the first time abnormalities in both peripheral nerve and CNS in patients with TMD.

Temporomandibular disorders (TMD) are a family of prevalent chronic pain disorders affecting masticatory muscles and/or the temporomandibular joint. There is no unequivocally recognized peripheral aetiology for idiopathic TMD. The central nervous system (CNS) may initiate and/or maintain the pain in idiopathic TMD due to sustained or long-term nociceptive input that induces maladaptive brain plasticity, and/or to inherent personality-related factors that may reduce the brain's capacity to modulate nociceptive activity. The main aim of this thesis is to determine whether there are structural neural abnormalities in patients with TMD, and whether these abnormalities are related to TMD pain characteristics, or to neuroticism. The specific aims are to delineate in TMD: (1) gray matter (GM) brain abnormalities and the contribution of pain and neuroticism to abnormalities; (2) the contribution of abnormal brain GM aging in focal cortical regions associated with nociceptive processes; and (3) abnormalities in brain white matter and trigeminal nerve and the contribution of pain. In groups of 17 female patients with TMD and 17 age- and sex- matched controls, magnetic resonance imaging revealed that patients with TMD had: (1) thicker cortex in the somatosensory, ventrolateral prefrontal and frontal polar cortices than controls, (2) cortical thickness in motor and cognitive areas that was negatively related to pain intensity, orbitofrontal cortical thickness that was negatively correlated to pain unpleasantness, and thalamic GM volume correlated to TMD duration, (3) an abnormal relationship between neuroticism and orbitofrontal cortical thickness, (4) abnormal GM aging in nociceptive, modulatory and motor areas, (5) widespread abnormalities in white matter tracts in the brain related to sensory, motor and cognitive functions, (6) reduced trigeminal nerve integrity related to pain duration, and (7) abnormal connectivity in cognitive and modulatory brain regions. In sum, this thesis demonstrates for the first time abnormalities in both peripheral nerve and CNS in patients with TMD.

Le traumatisme crânien (TC) représente un des problèmes majeurs de santé publique, pour lequel à l’heure actuelle il n’existe aucun traitement. Le TC induit une neuro-inflammation délétère qui pourrait contribuer à l’apparition des lésions de la substance blanche (SB). Ces dernières sont à l’origine de lourdes conséquences neurologiques chez les patients victimes de TC. Néanmoins, très peu d’études se sont intéressées à ces lésions bien que plus sévères que les lésions de la substance grise. Ainsi une meilleure connaissance de leur évolution et des causes devient indispensable. L’hyperactivation de la poly(ADP ribose)polymérase (PARP) joue un rôle délétère dans les conséquences post-traumatiques, notamment sur la neuro-inflammation. Ainsi son inhibition pourrait être bénéfique le développement des lésions de la SB. Dans ce contexte, l’objectif de notre travail a été d’évaluer le rôle de la PARP dans les lésions de la SB dans un modèle expérimental de TC induit par impact cortical contrôlé chez la souris. Dans une première partie, nous avons étudié l’évolution de la démyélinisation dans le corps calleux, une structure riche en SB, entre 6 heures et 3 mois post-TC. Parallèlement, les évolutions de la lésion cérébrale, des déficits sensorimoteurs, de la neuro-inflammation et de l’œdème cérébral ont été étudiées. Le TC induit (1) une démyélinisation dès 7 jours et au moins jusqu’à 3 mois post-TC, précédée par (2) une lésion cérébrale entre 24 et 72 heures suivie par une cicatrisation, (3) une neuro-inflammation entre 6 heures et 7 jours et (4) un œdème cérébral entre 6 et 72 heures post-TC. De plus, le TC induit des déficits sensorimoteurs à 6 heures et 3 mois. Ces résultats montrent que ce modèle est adapté pour étudier les lésions de la SB post-TC, et que la neuro-inflammation et l’œdème cérébral pourrait être impliqués dans la démyélinisation. Dans une deuxième partie, nous avons étudié le rôle de la PARP dans les lésions de la SB suite à TC à l’aide de souris knockout (KO) et wild-type (WT) pour le gène de la PARP. Nous avons mis en évidence que les souris KO ne présentent pas de démyélinisation bilatérale du corps calleux après un TC par rapport aux souris WT à 7 jours post-TC, démontrant pour la première fois l’implication de cette enzyme dans les lésions de la SB consécutives à un TC. De plus, nous avons constaté que les souris KO non traumatisées présentent une diminution de myélinisation comparativement aux souris WT non traumatisées, suggérant un rôle de la PARP dans le processus physiologique de la myélinisation.En conclusion, l’ensemble de ce travail expérimental a permis (1) une meilleure caractérisation de la démyélinisation post-TC et des mécanismes potentiellement impliqués dans cette dernière, et (2) de démontrer pour la première fois le rôle délétère de la PARP dans la démyélinisation induite par un TC. Nos travaux suggèrent le potentiel de l’inhibition de la PARP comme stratégie thérapeutique pour la prévention des lésions de la SB post-traumatiques. / Traumatic brain injury (TBI) is a leading cause of death and disability for which there is no neuroprotective treatment up to date. It results in neuroinflammation that may participate in lasting motor and cognitive impairments accompanied by changes in white matter (WM) tracts. WM lesions, evidenced by demyelination, are associated with neurological disorders and in clinical studies are common consequences in patients with chronic TBI. Several studies suggest a contribution of an overactivation of the poly(ADP-ribose) polymerase (PARP) to the neuroinflammatory response which may lead to demyelination. The first part of this study was dedicated to a detailed in vivo assessment of the evolution over time of neurological disorders, cerebral lesion and edema, neuroinflammation and white matter injury induced by controlled cortical impact (CCI) between 6 hours and 12 weeks post-TBI. Notably in the corpus callosum, a significant demyelination starting at 7 days appeared to be a major consequence to post-traumatic neuroinflammation associated with motor dysfunctions. The second part of this study was dedicated to the evaluation of PARP’s role in WM lesions post-TBI, using PARP knockout (KO) mice. Our main findings reveal a diminished demyelination in the corpus callosum of TBI PARP KO as opposed to TBI PARP wildtype specimens. Hence, these data suggest for the first time PARP’s deleterious role in post-traumatic demyelination. In conclusion, taken together these data give an overall view of motor/sensorimotor deficits, neuroinflammation and demyelination in a CCI model of TBI that could help to validate pharmacological strategy for preventing post-traumatic WM injury. Notably, PARP’s inhibition seems to be a valid candidate as this enzyme participates in the establishment of a demyelinating process.

Introdução: As doenças cerebrovasculares constituem-se um sério problema de saúde, e dados sobre sua prevalência mundial são alarmantes. A doença aterosclerótica dos vasos cervicais é um importante fator etiológico de isquêmica cerebral, por mecanismos que envolvem fenômenos embólicos e hipofluxo cerebral. Enquanto o manejo dos pacientes com estenose carotídea sintomática geralmente requer procedimentos cruentos como a endarterectomia e a angioplatia com stent carotídeo, não estão bem definidos o espectro clínico e o manejo adequado dos pacientes com estenoses carotídeas ditas assintomáticas (sem evidência de evento cerebrovascular ipsilateral). Neste contexto, é possível que a presença de déficits cognitivos e as alterações estruturais e funcionais na ressonância magnética cerebral possam ser úteis para a estratificação e o manejo destes pacientes. Objetivos: constitui objetivo principal do presente estudo investigar associações entre biomarcadores de ressonância magnética e desempenho cognitivo, em sujeitos com estenose carotídea assintomática unilateral. Métodos: foram incluídos na pesquisa 13 voluntários, com diagnóstico de doença aterosclerótica assintomática unilateral com comprometimento >= 70% da luz do vaso, recrutados nos ambulatórios de neurologia e cirurgia vascular, do Hospital das Clínicas, da Faculdade de Medicina de Ribeirão Preto - FMRP/ USP. Participaram do grupo controle 13 voluntários, sem antecedentes de doenças cerebrovasculares. A avaliação neuropsicológica consistiu na aplicação do Subteste Dígitos (WAIS); Trail Making Test; Stroop Test; Teste das Figuras Complexas de Rey; provas de fluência verbal fonêmica e categoria semântica; e o Mini Exame do Estado Mental, edições 1 e 2. Para a composição da avaliação de neuroimagem por ressonância magnética, foram inclusas: (1) imagens FLAIR (fluid attenuated inversion recovery) para avaliação de carga de lesão de substância branca; (2) imagens de ASL (arterial spin labeling), ponderadas em perfusão sanguínea, para quantificação do fluxo sanguíneo cerebral; e (3) imagens baseadas no contraste BOLD (blood oxygenation level dependent), em repouso, para avaliação da conectividade funcional. Análises estatísticas foram realizadas pelo Stata 15.1, em que as variáveis foram testadas para normalidade usando o teste de normalidade de Shapiro-Wilk. O teste t de amostras independentes e o teste U de Mann-Whitney foram utilizados para analisar as diferenças entre os grupos. As diferenças hemisféricas na carga de WMH foram testadas pelo teste t pareado, ou Wilcoxon. Testes Chi-squared ou Teste Exato de Fisher foram utilizados na análise de variáveis categóricas. Os coeficientes decorrelação de Pearson ou Spearman foram utilizados para explorar correlações entre escores cognitivos, volume de substância branca, carga de WMH, CBF e conectividade funcional. Resultados: O volume de substância branca (SB) em pacientes com estenose carotídea assintomática mostrou-se marcadamente reduzido, enquanto hiperintensidade de sinal em SB esteve significativamente aumentada em relação a indivíduos controles (p < 0,01). O hemisfério ipsilateral à estenose assintomática grave apresentou carga mais expressiva de lesão em SB (p = 0,01). Neste contexto, a presença de estenose assintomática esteve independentemente associada à hiperintensidade de SB. Análises de CBF não revelaram diferenças entre os grupos clínicos e controle, embora o CBF tenha sido associado ao desempenho das funções cognitivas em todos os domínios avaliados por este estudo. Não foram identificadas diferenças de fluxo sanguíneo global em territórios das artérias cerebrais anterior, média e posterior, entre sujeitos com estenose de artéria carótida assintomática e controles. Pacientes apresentaram prejuízos de conectividade em redes cerebrais de repouso (RSBNs), especialmente frontotemporal, saliência e rede atencional dorsal, em relação aos controles (p-FDR < 0,01). A performance cognitiva de pacientes com estenose carotídea foi inferior ao grupo controle, para todas as medidas, com diferenças significativas em domínios mnemônicos, atencionais e funções executivas (p<0.05), estes relacionados com RSBNs. Conclusões: Nós identificamos anormalidades pré-clínicas no volume de SB, CBF, conectividade funcional e no desempenho cognitivo de pacientes com estenose carotídea assintomática. Biomarcadores de neuroimagem na RM, combinados à avaliação cognitiva têm um grande potencial para identificação de pacientes com estenose carotídea assintomática sob risco elevado de AVC e declínio cognitivo. / Background: Cerebrovascular diseases are an important health problem worldwide with high prevalence, mortality and morbidity. Among its etiological subtypes, atherosclerotic disease involving the carotid artery is strongly associated with ischemic stroke due to arterial embolism and hemodynamic compromise. The management of symptomatic carotid stenosis generally requires carotid endarterectomy or stenting. Nevertheless, the management of asymptomatic carotid stenosis and patient selection for these procedures is still largely debated. It is possible that the presence of cognitive impairment, alterations on functional and structural magnetic resonance imaging (MRI) biomarkers of cerebrovascular disease could help the stratification and management of these patients. Objetives: to investigate the association between MRI biomarker of cerebrovascular disease and cognitive function in patient with unilateral asymptomatic carotid stenosis. Methods: we evaluated 13 patients with unilateral carotid stenosis >= 70% recruited from a tertiary academic outpatient clinic in Brazil and 13 control subjects without carotid stenosis or history of cerebrovascular diseases paired by age and sex. The neuropsycological evaluation included the WAIS, Trail Making Test; Stroop Test; Rey complex figures test; verbal fluency and categorical semantic fluency; and the minimental state 1 and 2. The MRI evaluation included: (1) FLAIR evaluation of white matter (WM) burden; (2) ASL evaluation of cerebral blood flow (CBF); (3) resting-state BOLD for evaluation of functional connectivity. Statistical analyses were performed with the Stata 15.1 package. Normality of the distribution of the variables was assessed with the Shapiro-Wilk test. We also used the student t test, Mann-whytney test, Chi-squared test and Fisher exact test as appropriate for univariate analyses. Pearson and Spearman correlation coefficients were used to explore the correlations among cognitive performance scores, WM volume, burden of WM hyperintensities, CBF and brain functional connectivity. Results: the global WM volume was markedly reduced and the global WM hyperintensity was significantly increased within the ipsilateral hemisphere in patients with unilateral carotid stenosis, when compared to controls (p < 0,01). CBF evaluated by ASL was associated with cognitive function but it was not significantly different between patients and controls within the arterial territories of the major intracranial arteries. Patients with carotid stenosis showed marked compromise of the brain connectivity within the frontotemporal, attentional and salience networks when compared to controls (p-FDR < 0,01). The cognitive performance was inferior for patients with unilateral carotid stenosis compared to controls in several cognitivedomains including executive function, attention and mnemonic domains. Conclusions: patients with asymptomatic carotid stenosis have high frequency of pre-clinical abnormalities on structural and functional MRI biomarkers and cognitive impairment. Evaluation of cognitive function, structural and functional MRI biomarkers of cerebrovascular disease may have a role to improve patient stratification and selection for interventions among patients with unilateral carotid stenosis.