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Atrophy of the corpus callosum (CC) is a documented consequence of moderate-to-severe traumatic brain injury (TBI), which has been expressed as volume loss using quantitative magnetic resonance imaging (MRI). Other advanced imaging modalities such as diffusion tensor imaging (DTI) have also detected white matter microstructural alteration following TBI in the CC. The manner and degree to which macrostructural changes such as volume and microstructural changes develop over time following pediatric TBI and their relation to a measure of processing speed is the focus of this longitudinal investigation. As such, DTI and volumetric changes of the CC in participants with TBI and a comparison group at approximately three and 18 months post injury and their relation to processing speed were determined.

Background. Resilience is the capacity of individuals to resist mental disorders despite exposure to stress. Little is known about its neural underpinnings. The putative variation of white-matter microstructure with resilience in adolescence, a critical period for brain maturation and onset of high-prevalence mental disorders, has not been assessed by diffusion tensor imaging (DTI). Lower fractional anisotropy (FA) though, has been reported in the corpus callosum (CC), the brain’s largest white-matter structure, in psychiatric and stress-related conditions. We hypothesized that higher FA in the CC would characterize stress-resilient adolescents. Method. Three groups of adolescents recruited from the community were compared: resilient with low risk of mental disorder despite high exposure to lifetime stress (n = 55), at-risk of mental disorder exposed to the same level of stress (n = 68), and controls (n = 123). Personality was assessed by the NEO-Five Factor Inventory (NEO-FFI). Voxelwise statistics of DTI values in CC were obtained using tract-based spatial statistics. Regional projections were identified by probabilistic tractography. Results. Higher FA values were detected in the anterior CC of resilient compared to both non-resilient and control adolescents. FA values varied according to resilience capacity. Seed regional changes in anterior CC projected onto anterior cingulate and frontal cortex. Neuroticism and three other NEO-FFI factor scores differentiated non-resilient participants from the other two groups. Conclusion. High FA was detected in resilient adolescents in an anterior CC region projecting to frontal areas subserving cognitive resources. Psychiatric risk was associated with personality characteristics. Resilience in adolescence may be related to white-matter microstructure.

Objetivo: Caracterizar o perfil das habilidades de linguagem (oral e escrita) de indivíduos com Displasia Frontonasal com e sem anomalias do sistema nervoso central. Modelo: Análise perspectiva descrevendo os achados da avaliação de linguagem em indivíduos com sinais clínicos de Displasia Frontonasal. Local de execução: Setor de Genética Clínica, HRAC-USP. Participantes: 14 indivíduos, com faixa etária variável, sendo 9 do gênero feminino e 5 do gênero masculino. O GI constituído por 7 indivíduos com displasia frontonasal isolada e 7 com displasia frontonasal associada a anomalias estruturais do Sistema Nervoso Central. Resultados: No GI, 3 Indivíduos (43%) apresentaram alterações nas habilidades de linguagem (oral e escrita), enquanto que no GII, 5 (71%) apresentaram os mesmos achados Na avaliação complementar, os resultados foram parcialmente concordantes com a avaliação clínica, sendo que 43% do GI apresentaram escores abaixo do esperado e no GII foram 71%. Conclusão: Conclui-se que a DFN associada a anomalias estruturais do SNC, como corpo caloso, apresentam em sua maioria, alterações nas habilidades de linguagem oral e escrita em porcentagem bem maior a DFN isolada. Porém as alterações de linguagem/aprendizagem podem estar associadas a DFN, uma vez que esta afecção apresenta um quadro de características fenotípicas bem distintas. / Objective: To characterize the profile of language skills (oral and written) of patients with frontonasal dysplasia with and without central nervous system anomalies. Model: Analysis perspective describing the findings of the evaluation of language in individuals with clinical features of frontonasal dysplasia. Setting: Genetics Departament, HRAC-USP. Participants: 14 individuals with varying ages, 9 females and 5 males. The GI consist 7 individuals with isolated frontonasal dysplasia and 7 with frontonasal dysplasia associated with central nervous system anomalies. Results: In GI, 3 individuals (43%) showed alterations in language skills (oral and escreita), whereas in GII, five individuals (71%) showed the same results. On supplementary assessment, the findings were consistent to the clinical evaluation, and 43% had scores below in GI and 71% in GII. Conclusions: It is concluded that the FND associated with structural abnormalities of the CNS, such as the corpus callosum, have mostly changes in the skills of oral and written language in a much larger percentage DFN isolated. However the language / learning disabilities may be associated with DFN, since this disease presents with distinct phenotypic characteristics.

Objetivo: Avaliar a atrofia do corpo caloso (CC) em pacientes com doença de Alzheimer (DA) e comprometimento cognitivo leve (CCL) e quantificar quais regiões dessa estrutura são mais acometidas nessa doença como uso de técnicas quantitativas de ressonância magnética. Metodologia: O estudo contou com a participação de 75 indivíduos sendo 22 controles normais (CN), 30 com CCL e 23 com DA. O volume total do corpo caloso e suas 3 diferentes sub regiões foram delimitadas em cortes sagitais de imagem de ressonância magnética. Os volumes obtidos foram corrigidos para a variação de volume intracraniano. As mascaras foram co-registradas a mapas de relaxometria e transferência de magnetização para analise quantitativa. Resultados: Encontramos atrofia e redução dos valores de relaxometria e transferência de magnetização nos pacientes do grupo DA. As tres sub regiões do corpo caloso apresentaram redução de volume na doença sendo que a atrofia foi maior nas regiões anteriores. Não encontramos diferença significativa nos parâmetros estudados entre CCL e CN. Conclusões: Embora o corpo caloso esteja envolvido no processo de desconexão cortical presente na doença de Alzheimer seu envolvimento não é precoce. / Objective: To evaluate the atrophy of the corpus callosum (CC) in patients with Alzheimer disease (AD) and mild cognitive impairment (CCL) and quantify which regions of this structure are most affected in this disease as using quantitative MRI techniques. Methodology: The study counted on the participation of 75 individuals being 22 normal controls (CN), 30 with CCL and 23 with AI). The total volume of the corpus callosum and its v 3 different sub regions were delimited in sagittal sections of magnetic resonance imaging. The volumes obtained were corrected for intracranial volume variation. The masks were recorded with maps of relaxometry and transfer of magnetization for quantitative analysis. Results: We found atrophy and reduced values of relaxometry and magnetization transfer in patients in the AD group. The three sub regions of the corpus callosum showed volume reduction in the disease, with atrophy being greater in the anterior region. We found no significant difference in the parameters studied between CCL and CN fit .Conclusions: Although the corpus callosum is involved in the process of cortical detachment present in Alzheimer\'s disease, its involvement is late.

The corpus callosum, the major interhemispheric fiber tract, mediates communication between homotopic regions within the primary somatosensory cortex (S1). Recently, in 1- to 6-day-old neonatal rats, brief bursts of high-frequency, oscillatory activity - called spindle-bursts (SBs) - were described in S1 following sensory feedback from endogenously generated sleep-related myoclonic twitch movements and exogenously generated peripheral stimulation. To determine whether interhemispheric communication via the corpus callosum modulates the expression of SBs during this early period of development and contributes to cortical organization and plasticity, we investigated the endogenous (spontaneous) expression and exogenous (evoked) activity of SBs in neonatal rats with intact or surgically severed callosal fibers (i.e., callosotomy; CCx). We used Ag/AgCl cortical surface electrodes in the S1-forelimb region of the cortex to measure neurophysiological and behavioral activity in both intact and CCx subjects across the sleep-wake cycle during the first two postnatal weeks of development. Our results demonstrate, for the first time, that the corpus callosum modulates spontaneous and evoked activity between homotopic regions in S1 as early as 24-hours after birth. In addition, CCx disinhibits cortical activity, nearly doubling the rate of spontaneous SBs through, but not after, postnatal day 6 (P6). CCx also significantly and reliably disrupts the evoked response to peripheral stimulation of the forepaw. To examine the role of sleep-related twitches and their associated sensory feedback (SBs in S1) - modulated by the corpus callosum - in cortical development and plasticity, we performed CCx or sham surgeries at P1, P6, or P8, and tested subjects the day of surgery or over the ensuing week of recovery. Regardless of age, CCx immediately disrupted SBs evoked by forepaw stimulation. The P1 and P6 CCx groups exhibited full recovery after one week; in contrast, the P8 group did not exhibit recovery of function, thus indicating an abrupt decrease in cortical plasticity between P6 and P8. Together, these results provide the first evidence that sleep-related myoclonic twitches and the associated sensory feedback in S1 (SBs) contribute to cortical development, plasticity, and recovery of function after interhemispheric communication is disrupted by callosotomy. CCx-induced disinhibition of spontaneous SBs is a transient phenomenon whose disappearance coincides with the onset of increased intrinsic connectivity, establishment of excitatory-inhibitory balance, and diminished plasticity in S1. Our findings indicate that CCx-induced disinhibition of spontaneous twitch-related SBs and disruption of evoked response to peripheral stimulation serve as a bioassay of somatosensory cortical plasticity during the early postnatal period.

La perte auditive est le trouble sensoriel le plus commun avec 40 % des personnes de plus de 65 ans affectées, entraînant, chez ces patients une dégradation de leur qualité de vie et un isolement sociale. Les principales causes sont le vieillissement ou l'exposition au bruit, mais les mutations génétiques sont aussi à l'origine de déficits auditifs. Parmi ces surdités, le Syndrome de Chudley McCullough (CMCS) est une maladie rare caractérisée par une surdité sévère et précoce associée à des anomalies cérébrales (Chudley et al., 1997). Récemment, des mutations du gène GPSM2 (G protein signaling modulator 2) ont été décrites comme étant responsables de cette pathologie sans que l'on en connaisse les mécanismes (Walsh et al., 2010). A l'aide d'un modèle d'étude murin de cette pathologie, nous avons identifié les bases moléculaires de la pathologie ainsi qu’une nouvelle fonction moléculaire pour Gpsm2 sur la modulation du cytosquelette d’actine. La perturbation de cette fonction affect à la fois la maturation des cellules auditives et la croissance des jeunes neurones, pouvant expliquer les surdités et l’hypoplasie du corps calleux décrits chez ces patients (Mauriac et al., 2017). De plus, nous avons identifié les partenaires de Gpsm2, les protéines Gαi, comme indispensables à la fonction auditive (Beer-Hammer et al., 2018). Au niveau moléculaire, nous avons découvert une nouvelle interaction de Gpsm2 avec une protéine essentielle à la maturation des cellules auditives et impliquées dans les surdités de type Usher, la Whirlin.Par conséquent, notre étude a permis de clarifier l’étiologie du CMCS et de montrer que sa complexité et son aspect multisyndromique sont dus au rôle multifonctionnel du complexe Gpsm2/G⍺i non seulement sur la dynamique de la tubuline dans des cellules en prolifération et en post-mitotiques (Ezan et al., 2013), mais aussi sur la dynamique d’actine (Mauriac et al., 2017). / Hearing loss is the most common sensory disorder, affecting 40% of people over 65 years old, leading for these patients, to the deterioration of their quality of life and to their social isolation. The main causes are aging or exposure to noise. However, many genes can also cause deafness. Among these deafnesses, the Chudley McCullough Syndrome (CMCS) is a rare disease characterized by severe and early deafness associated with brain abnormalities (Chudley et al., 1997). Recently, mutations in the GPSM2 (G protein signaling modulator 2) gene were found to be causative of this pathology, but the molecular basis were unknown (Walsh et al., 2010). Using a murine model of this pathology, we identified the molecular basis of this pathology as well as a new molecular function for Gpsm2 on the modulation of actin cytoskeleton. The disruption of this function leads to defect of the maturation of auditory hair cells and the reduction of the outgrowth of young neurons which may explain the deafness and the hypoplasia of the corpus callosum described in these patients (Mauriac et al., 2017). In addition, we identified partners of Gpsm2, Gαi proteins, as essential for auditory function (Beer-Hammer et al., 2018). At the molecular level, we have discovered a new interaction of Gpsm2 with a protein essential for the maturation of auditory cells and involved in Usher type deafness, Whirlin.Therefore, our study clarified the etiology of CMCS and show that the complexity and multisyndromic aspect of this pathology is due to the multifunctional role of the complex Gpsm2/G⍺i not only on tubulin dynamics in proliferating cells and post-mitotic cells (Ezan et al., 2013), but also on actin dynamics (Mauriac et al., 2017).

The interrelationships between brain, cognition, and behaviour are complex but can be more clearly characterised by studying disorders with an underlying genetic basis. This thesis examined these interrelationships in the context of Williams syndrome (WS), a neurodevelopmental genetic disorder that affects aspects of cognition, behaviour, and brain structure. The principal aims of this thesis were to evaluate the cognitive, behavioural, and neuroanatomical profile of WS individuals and to explore the relationships between aspects of the cognitive and behavioural profile and the neuroanatomical changes that are evident in WS. Three general hypotheses, and 10 specific hypotheses, were postulated as a means of exploring these aims. The first general hypothesis predicted that WS individuals would demonstrate distinct features within their cognitive and behavioural profile. Specifically, it was predicted that WS individuals would show relative strengths on verbal tasks and significant deficits on visuospatial and mathematical tasks, in contrast to control participants who were predicted to show a more even profile. It was also predicted that WS individuals would show evidence of heightened affect in response to music and demonstrate hypersociability as compared to control participants

Diffusion Tensor Imaging (DTI) can quantify tissue integrity in normal-appearing white matter (NAWM). NAWM abnormalities present at the earliest time point implicate neurodegeneration operative from the outset of multiple sclerosis (MS). DTI scans were obtained at first attacks from 6 children later diagnosed with MS and 6 children with monophasic demyelination, and from 6 controls, matched for age. DTI scans were also obtained from 22 children with established MS with clinical onset before age 12 years and compared to age-matched controls. Atlas- and tractography-based image processing methods were utilized. DTI metrics distinguished MS patients from patients with monophasic demyelination and from controls at the first attack. Differences in NAWM between children with established early-onset MS and controls were only notable when DTI was obtained in adolescence. DTI provides valuable insights into NAWM in children with MS, although in the youngest patients such changes may require time to develop.

Diffusion Tensor Imaging (DTI) can quantify tissue integrity in normal-appearing white matter (NAWM). NAWM abnormalities present at the earliest time point implicate neurodegeneration operative from the outset of multiple sclerosis (MS). DTI scans were obtained at first attacks from 6 children later diagnosed with MS and 6 children with monophasic demyelination, and from 6 controls, matched for age. DTI scans were also obtained from 22 children with established MS with clinical onset before age 12 years and compared to age-matched controls. Atlas- and tractography-based image processing methods were utilized. DTI metrics distinguished MS patients from patients with monophasic demyelination and from controls at the first attack. Differences in NAWM between children with established early-onset MS and controls were only notable when DTI was obtained in adolescence. DTI provides valuable insights into NAWM in children with MS, although in the youngest patients such changes may require time to develop.