Des anomalies macro et micro-structurales des réseaux cérébraux impliqués dans la régulation émotionnelle ont été observées chez des adolescents et des adultes présentant un trouble dépressif majeur. Cependant, on ignore si ces anomalies se développent au fur et à mesure de la maladie dépressive ou si elles sont présentes avant. La dépression sub-syndromique de l’adolescent étant associée à un risque élevé, mais non systématique, de développer ultérieurement un trouble dépressif majeur, l'étude des corrélats neuro-anatomiques qui lui sont associées pourrait apporter des informations sur la physiopathologie de la dépression. Nous avons utilisé les données cliniques et d’Imagerie par Résonance Magnétique pondérée en T1 et en diffusion de l’étude européenne IMAGEN portant sur 2131 adolescents recrutés en population générale à 14 ans, puis réévalués à 16 ans, afin de comparer les données d’adolescents présentant une dépression sub-syndromique à celles d’adolescents non déprimés. Nous avons mis en évidence des changements structuraux chez des adolescents présentant une dépression sub-syndromique dans des régions impliquées dans la dépression. La relation entre dépression sub-syndromique à 14 ans et dépression clinique à 16 ans était en partie expliquée par un plus petit volume de cortex préfrontal médian chez les filles et par de plus faibles valeurs de fraction d’anisotropie dans les faisceaux connectant le corps calleux au cortex cingulaire antérieur chez les deux sexes. A l’adolescence, des changements cérébraux dans des régions impliquées dans la régulation émotionnelle semblent être associés à un risque accru de transition vers des formes syndromiques de dépression. / Neuroimaging findings have been reported in emotional regions in both adults and adolescents with depression but it still remains unknown whether such brain alterations can be detected before depression onset or reflect disease progression. Although subthreshold-depression in adolescence is a condition at risk for Major Depressive Disorder, not all youths with subthreshold depression will develop full-syndrome depression. Thus, studying brain correlates of subthreshold-depression in adolescence may inform on the pathophysiology of depression. We used clinical and, T1 weighted and diffusion magnetic resonance imaging data from the IMAGEN study, an European and population-based cohort of 2131 adolescents recruited from secondary schools at age 14 and followed-up at age 16. Regional gray and white matter morphometry and white matter microstructure were compared between adolescents with subthreshold-depression and healthy control adolescents. Macro and micro structural brain changes were found in adolescents with subthreshold-depression in regions involved in Major Depressive Disorder. The relation between subthreshold-depression at baseline and clinical depression at follow-up was mediated by lower medial-prefrontal gray matter volume in girls and by lower fractional anisotropy in tracts projecting from the corpus callosum to the anterior cingulate cortex in both sexes. The findings suggest that subthreshold-depression in early adolescence is associated with structural volumetric and connectivity changes in emotion-regulation circuits, and that some of these changes might denote high risk for later clinical depression.

As epilepsias generalizadas idiopáticas (EGIs) associam-se a controle satisfatório de crises e a exames de neuroimagem convencionais normais. Métodos de neuroimagem avançada, como DTI (diffusion tensor imaging) e VBM (voxel based morphometry), permitiram melhor compreensão dos mecanismos envolvidos no comportamento clínico das EGIs. O objetivo do estudo foi avaliar diferenças clínicas entre pacientes com EGI não refratária e refratária, assim como avaliar as diferenças entre pacientes com EGI não refratária, refratária e indivíduos saudáveis através de ressonância por DTI e VBM. Avaliamos 40 pacientes com características clínicas e eletrencefalográficas de EGI, sendo 22 pacientes com EGI não refratária (GNR) e 18 pacientes com EGI refratária (GR). Participaram do estudo 20 indivíduos saudáveis, os quais compuseram o grupo controle (GC). O grupo GR apresentava maior número de pacientes usuários de fármacos benzodiazepínicos (p=0,01) e de fármacos antiepilépticos não-valproato (p=0,02). Pacientes do grupo GR também utilizavam doses maiores de VPA que os pacientes do grupo GNR (p=0,03) e recebiam maior carga total média de fármacos antiepilépticos (p=0,04). Observou-se, em relação aos 16 feixes e tratos avaliados nos índices de DTI (AF, DM, DR, DA) que houve diferença estatística do grupo GNR em relação ao GC em duas áreas do índice AF (anisotropia fracional), seis áreas do índice DM (difusividade média), seis áreas do índice DR (difusividade radial) e seis áreas do índice DA (difusividade axial), assim como houve diferença estatística do grupo GR em relação ao GC em duas áreas do índice AF, sete áreas do índice DM, seis áreas do índice DR e três áreas do índice DA. Entre as 94 regiões estudadas por VBM, observou-se redução volumétrica estatística em nove áreas de interesse no GNR quando em comparação ao GC e em sete áreas de interesse no GR quando em comparação ao GC. Não se observaram diferenças entre os grupos GNR e GR nos parâmetros avaliados por DTI ou por VBM. Como esperado, observamos que pacientes com EGI refratária mais frequentemente utilizam fármacos antiepilépticos de segunda linha ou não habituais a este tipo de epilepsia. O estudo permitiu concluir que o comprometimento encefálico nas EGIs analisadas é difuso e envolve áreas habitualmente não associadas a estas epilepsias, como o hipocampo e outras áreas temporais, e que os achados imagenológicos não se associam à refratariedade clínica dos pacientes / Generalized idiopathic epilepsies (IGEs) are usually associated with good seizure control and normal conventional neuroimaging exams. Advanced neuroimaging methods, such as DTI (diffusion tensor imaging) and VBM (voxel based morphometry) have provided a better understanding of the IGEs. This study´s primary objective was to evaluate clinical diferences between refractory and non-refractory IGEs, and to compare advanced MRI methods (DTI and VBM) findings in refractory and non-refractory IGE patients. Forty IGE patients were divided in two groups: 22 non-refratory (NRG) patients and 18 refractory (RG) patients. Twenty healthy subjects were enrolled as a control group (CG). RG patients received benzodiazepines (p=0,01) and non-valproate antiepileptic drugs (p=0,02) more often than NRG patients. RG group also received a higher mean total of antiepileptic drug load (p=0,04) than NRG group. Regarding neuroimaging methods, DTI index analysis (FA, MD, RD, AD) statiscally demonstrated that NRG group had two compromised areas on FA (fractional anisotropy) index, six areas on MD (mean diffusivity) index, six areas on RD (radial diffusivity) index and six areas on AD (axial diffusivity) index, when compared to CG. On RG group, DTI index analysis statiscally demonstrated that this group had two compromised areas on FA index, seven areas on MD index, six areas on RD index and three areas on AD index, when compared to CG, of 16 analyzed areas of interest. VBM analysis of 94 regions of interest showed reduced volumes in nine areas in the NRG group when compared to CG and in seven areas of interest in the RG group when compared to CG. We found no differences on DTI and VBM parameters comparing NRG and RG groups. As expected, refractory IGE patients received second line or non-usual antiepileptic drugs for this epilepsy type more often than non-refractory patients. We concluded that brain involvement´s in IGEs is diffuse and affects areas usually not related to this epilepsy type, such as the hipocampus and other temporal areas. Advanced neuroimaging findings in IGEs were not associated with clinical refractoriness

Fortschreitendes Alter geht häufig mit Leistungsabnahmen in kognitiven Aufgaben einher. Eine steigende Anzahl Studien zeigt, dass regelmäßige körperliche Aktivität negativen Alterseffekten entgegenwirken kann und somit zur Erhaltung kognitiver und zerebraler Funktionen im Alter beiträgt. Die vorliegende Dissertation untersuchte im Rahmen eines Ausdauertrainings die Zusammenhänge zwischen Veränderungen in der körperlichen Fitness und Veränderungen in Gehirn und Verhalten bei älteren Erwachsenen. Studie I zeigt, dass zuvor gefundene Vergrößerungen des Hippocampus auf Änderungen der Mikrostruktur des zugrundeliegenden Gewebes zurückgeführt werden können. Die Probanden, die ihre Fitness am meisten verbesserten, zeigten auch die stärkste Verdichtung des Hippocampusgewebes. Die Verdichtung des Gewebes stand wiederum in positivem Zusammenhang mit der Veränderung im Hippocampusvolumen. Diese Ergebnisse weisen darauf hin, dass Veränderungen im Volumen aus einer Vermehrung der Zellmembranen resultieren und nicht aus der Ausdehnung bereits vorhandener Zellen. In Studie II hingen Veränderungen in der Fitness zusammen mit Veränderungen in der Mikrostruktur eines präfrontalen Traktes der weißen Substanz, nämlich dem Forceps minor. Gleichermaßen hingen die Veränderungen in der Mikrostruktur des Forceps minor mit Veränderungen in einem zusammengesetzten Maß fluider kognitiver Fähigkeiten zusammen. Dieses Ergebnis zeigt, dass Veränderungen in der Mikrostruktur der weißen Substanz möglicherweise zu den positiven Auswirkungen von körperlicher Aktivität auf kognitive Fähigkeiten beitragen. Studie III zeigt, dass Veränderungen der Fitness positiv mit Veränderungen der neuronalen Spezifität korrelieren, welches als indirektes Maß für dopaminerge Neuromodulation angenommen wird. Zusammenfassend erweitern die Ergebnisse dieser Dissertation die Literatur über positive Effekte von körperlicher Aktivität auf Alterungsprozesse und stärken den Kenntnisstand über zugrundeliegende Mechanismen. / Advanced age has been consistently linked to performance deterioration in cognitive tasks targeting the ability to mentally manipulate information. A growing body of literature suggests that regular physical exercise alleviates the adverse effects of age and helps to preserve cognitive and cerebral capacities in old age. The present dissertation investigated associations between changes in fitness and changes in cerebral and cognitive measures within a group of older adults who participated in an exercise intervention. Paper I shows that previously reported increases in hippocampal volume can be linked to exercise-induced changes in the underlying tissue microstructure. The participants who improved most in fitness showed most increments in hippocampal tissue density. Changes in tissue density were in turn positively associated with changes in hippocampal volume. This finding suggests that volumetric changes result from an increase in the bulk of cell membranes, and not from a mere dilation of existing cells. In Paper II, changes in fitness were associated with changes in the microstructure of a prefrontal white matter tract, namely the forceps minor. Likewise, changes in forceps minor microstructure were related to changes in a composite score of fluid cognitive abilities. This result indicates that changes in white matter microstructure may contribute to the beneficial effects of exercise on cognition. Paper III demonstrates that changes in fitness are positively correlated with changes in neural specificity, presumably an indirect marker of dopaminergic neuromodulation. In summary, findings from the present dissertation extend the literature on beneficial effects of exercise on age-related deterioration and add knowledge regarding the underlying mechanisms.

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: O acesso cirúrgico ao corno temporal do ventrículo lateral (CTVL) é realizado para tratamento de lesões temporais mediais, dentre as quais se destaca a esclerose hipocampal que leva à epilepsia, e pode ser realizado através das superfícies lateral ou inferior do lobo temporal ou pelo sulco lateral do cérebro (fissura silviana). O parênquima cerebral subcortical localizado entre o sulco limitante inferior da ínsula (SLI) e o CTVL é composto por importantes feixes de fibras brancas, os quais podem eventualmente ser lesionados nos acessos cirúrgicos trans-silvianos. OBJETIVO: Descrever a localização dos principais feixes de fibras brancas na região entre o SLI e o CTVL. MÉTODOS: Os principais feixes de fibras brancas subcorticais foram examinados em 14 hemisférios cerebrais cadavéricos adultos utilizando a técnica de dissecção de Klingler, sendo possível descrever suas posições em relação à extremidade anterior do SLI (nomeado de Ponto Temporal do Límen - PTL). RESULTADOS: Os principais feixes de fibras identificados profundamente ao SLI formam um arranjo multilaminar e podem ser divididos de acordo com a profundidade em que são encontrados. As fibras de associação curta da cápsula extrema, que continuam em direção aos opérculos, formam a camada subcortical mais superficial e foram encontradas sob todo o SLI. As fibras da cápsula externa são encontradas mais profundamente, em uma camada formada por três principais feixes em uma disposição anteroposterior sequencial: o fascículo uncinado (encontrado desde o PTL até 10,0 ± 2.2 mm posteriormente), o fascículo fronto-occipital inferior (encontrado entre 10,0 ± 2,2 mm e 35,5 ± 2,7 mm posterior ao PTL) e fibras claustro-corticais (encontradas desde 35,5 ± 2,7 mm posterior ao PTL até o final desse sulco). A extensão lateral da comissura anterior está logo abaixo dessa camada e suas fibras foram encontradas entre 8,4 ± 1,8 mm e 22,0 ± 6,8 mm posterior ao PTL. A camada mais profunda é formada pelas fibras da cápsula interna/corona radiata, onde se destacam as radiações ópticas cujas fibras foram encontradas entre 10,6 ± 3,4 mm e 34,5 ± 3,5 mm posterior ao PTL. CONCLUSÕES: O fascículo uncinado é aproximadamente encontrado sob o terço anterior do segmento anterior do SLI (entre o PTL e o corpo geniculado lateral), enquanto o fascículo fronto-occipital inferior e as fibras da radiação óptica são encontrados sob os dois terços posteriores deste segmento. Os resultados sugerem que na abordagem trans-silviana transinsular, uma incisão através do SLI, começando no PTL e se estendendo até 6 mm posteriormente, irá atravessar o fascículo uncinado, mas não o fascículo fronto-occipital inferior e as radiações ópticas / INTRODUCTION: The surgical approach to the temporal horn of the lateral ventricle (CTVL) is performed for treatment of medial temporal lesions, among which hippocampal sclerosis leading to epilepsy is emphasized, and can be performed through the lateral or inferior surfaces of the temporal lobe or through the sylvian fissure. The subcortical cerebral parenchyma located between the inferior limiting sulcus of the insula (SLI) and the CTVL is composed of important white matter fiber bundles, which may eventually be injured in transsylvian surgical approaches. OBJECTIVES: To describe the location of the main white matter fiber bundles in the region between SLI and CTVL. METHODS: The main subcortical white matter fiber bundles were examined in 14 adult cadaveric cerebral hemispheres using the Klingler dissection technique, and it was possible to describe their positions in relation to the anterior end of the SLI (named Temporal Limen Point - PTL). RESULTS: The main white matter fiber bundles identified deeply to the SLI form a multi-laminar arrangement that can be understood according to the depth in which they are found. The short association fibers of the extreme capsule, which continue toward the opercula, form the most superficial subcortical layer and were found underneath all the SLI. The external capsule fibers were found more deeply, in a layer formed by three main fiber bundles organized in a sequential anterior-posterior disposition: the uncinate fascicle (found from the PTL to 10.0 ± 2.2 mm posteriorly), the inferior fronto-occipital fascicle (found between 10.0 ± 2.2 mm and 35.5 ± 2.7 mm posterior to the PTL) and claustrocortical fibers (found from 35.5 ± 2.7 mm posterior to PTL to the end of this sulcus). The lateral extension of the anterior commissure was below this layer and its fibers were found between 8.4 ± 1.8 mm and 22.0 ± 6.8 mm posterior to the PTL. The deepest layer is formed by the fibers of the internal capsule/corona radiata, where the optical radiation fibers were distinguished and found between 10.6 ± 3.4 mm and 34.5 ± 3.5 mm posterior to the PTL. CONCLUSIONS: The uncinate fascicle is approximately found under the anterior third of the anterior SLI segment (between the PTL and the lateral geniculate body), while the inferior fronto-occipital fascicle and fibers of the optical radiation are found under the posterior two thirds of this segment. The results suggest that at the transsylvian-transinsular approach, an incision at the SLI, from the PTL to 6 mm posteriorly, will cross the uncinate fascicle, but not the inferior fronto-occipital fascicle and optical radiation fibers

As epilepsias generalizadas idiopáticas (EGIs) associam-se a controle satisfatório de crises e a exames de neuroimagem convencionais normais. Métodos de neuroimagem avançada, como DTI (diffusion tensor imaging) e VBM (voxel based morphometry), permitiram melhor compreensão dos mecanismos envolvidos no comportamento clínico das EGIs. O objetivo do estudo foi avaliar diferenças clínicas entre pacientes com EGI não refratária e refratária, assim como avaliar as diferenças entre pacientes com EGI não refratária, refratária e indivíduos saudáveis através de ressonância por DTI e VBM. Avaliamos 40 pacientes com características clínicas e eletrencefalográficas de EGI, sendo 22 pacientes com EGI não refratária (GNR) e 18 pacientes com EGI refratária (GR). Participaram do estudo 20 indivíduos saudáveis, os quais compuseram o grupo controle (GC). O grupo GR apresentava maior número de pacientes usuários de fármacos benzodiazepínicos (p=0,01) e de fármacos antiepilépticos não-valproato (p=0,02). Pacientes do grupo GR também utilizavam doses maiores de VPA que os pacientes do grupo GNR (p=0,03) e recebiam maior carga total média de fármacos antiepilépticos (p=0,04). Observou-se, em relação aos 16 feixes e tratos avaliados nos índices de DTI (AF, DM, DR, DA) que houve diferença estatística do grupo GNR em relação ao GC em duas áreas do índice AF (anisotropia fracional), seis áreas do índice DM (difusividade média), seis áreas do índice DR (difusividade radial) e seis áreas do índice DA (difusividade axial), assim como houve diferença estatística do grupo GR em relação ao GC em duas áreas do índice AF, sete áreas do índice DM, seis áreas do índice DR e três áreas do índice DA. Entre as 94 regiões estudadas por VBM, observou-se redução volumétrica estatística em nove áreas de interesse no GNR quando em comparação ao GC e em sete áreas de interesse no GR quando em comparação ao GC. Não se observaram diferenças entre os grupos GNR e GR nos parâmetros avaliados por DTI ou por VBM. Como esperado, observamos que pacientes com EGI refratária mais frequentemente utilizam fármacos antiepilépticos de segunda linha ou não habituais a este tipo de epilepsia. O estudo permitiu concluir que o comprometimento encefálico nas EGIs analisadas é difuso e envolve áreas habitualmente não associadas a estas epilepsias, como o hipocampo e outras áreas temporais, e que os achados imagenológicos não se associam à refratariedade clínica dos pacientes / Generalized idiopathic epilepsies (IGEs) are usually associated with good seizure control and normal conventional neuroimaging exams. Advanced neuroimaging methods, such as DTI (diffusion tensor imaging) and VBM (voxel based morphometry) have provided a better understanding of the IGEs. This study´s primary objective was to evaluate clinical diferences between refractory and non-refractory IGEs, and to compare advanced MRI methods (DTI and VBM) findings in refractory and non-refractory IGE patients. Forty IGE patients were divided in two groups: 22 non-refratory (NRG) patients and 18 refractory (RG) patients. Twenty healthy subjects were enrolled as a control group (CG). RG patients received benzodiazepines (p=0,01) and non-valproate antiepileptic drugs (p=0,02) more often than NRG patients. RG group also received a higher mean total of antiepileptic drug load (p=0,04) than NRG group. Regarding neuroimaging methods, DTI index analysis (FA, MD, RD, AD) statiscally demonstrated that NRG group had two compromised areas on FA (fractional anisotropy) index, six areas on MD (mean diffusivity) index, six areas on RD (radial diffusivity) index and six areas on AD (axial diffusivity) index, when compared to CG. On RG group, DTI index analysis statiscally demonstrated that this group had two compromised areas on FA index, seven areas on MD index, six areas on RD index and three areas on AD index, when compared to CG, of 16 analyzed areas of interest. VBM analysis of 94 regions of interest showed reduced volumes in nine areas in the NRG group when compared to CG and in seven areas of interest in the RG group when compared to CG. We found no differences on DTI and VBM parameters comparing NRG and RG groups. As expected, refractory IGE patients received second line or non-usual antiepileptic drugs for this epilepsy type more often than non-refractory patients. We concluded that brain involvement´s in IGEs is diffuse and affects areas usually not related to this epilepsy type, such as the hipocampus and other temporal areas. Advanced neuroimaging findings in IGEs were not associated with clinical refractoriness

Doctor of Philosophy (PhD) / Schizophrenia is a severe mental illness that affects approximately 1% of the population worldwide, and which typically has a devastating effect on the lives of its sufferers. The characteristic symptoms of the disease include hallucinations, delusions, disorganized thought and reduced emotional expression. While many of the early theories of schizophrenia focused on its psychosocial foundations, more recent theories have focused on the neurobiological underpinnings of the disease. This thesis has four primary aims: 1) to use magnetic resonance imaging (MRI) to identify the structural brain abnormalities present in patients suffering from their first episode of schizophrenia (FES), 2) to elucidate whether these abnormalities were static or progressive over the first 2-3 years of patients’ illness, 3) to identify the relationship between these neuroanatomical abnormalities and patients’ clinical profile, and 4) to identify the normative relationship between longitudinal changes in neuroanatomy and electrophysiology in healthy participants, and to compare this to the relationship observed between these two indices in patients with FES. The aim of Chapter 2 was to use MRI to identify the neuroanatomical changes that occur over adolescence in healthy participants, and to identify the normative relationship between the neuroanatomical changes and electrophysiological changes associated with healthy periadolescent brain maturation. MRI and electroencephalographic (EEG) scans were acquired from 138 healthy participants between the ages of 10 and 30 years. The MRI scans were segmented into grey matter (GM) and white matter (WM) images, before being parcellated into the frontal, temporal, parietal and occipital lobes. Absolute EEG power was calculated for the slow-wave, alpha and beta frequency bands, for the corresponding cortical regions. The age-related changes in regional tissue volumes and regional EEG power were inferred with a regression model. The results indicated that the healthy participants experienced accelerated GM loss, EEG power loss and WM gain in the frontal and parietal lobes between the ages of 10 and 20 years, which decelerated between the ages of 20 and 30 years. A linear relationship was also observed between the maturational changes in regional GM volumes and EEG power in the frontal and parietal lobes. These results indicate that the periadolescent period is a time of great structural and electrophysiological change in the healthy human brain. The aim of Chapter 3 was to identify the GM abnormalities present in patients with FES, both at the time of their first presentation to mental health services (baseline), and over the first 2-3 years of their illness (follow-up). MRI scans were acquired from 41 patients with FES at baseline, and 47 matched healthy control subjects. Of these participants, 25 FES patients and 26 controls returned 2-3 years later for a follow-up scan. The analysis technique of voxel-based morphometry (VBM) was used in conjunction with the Statistical Parametric Mapping (SPM) software package in order to identify the regions of GM difference between the groups at baseline. The related analysis technique of tensor-based morphometry (TBM) was used to identify subjects’ longitudinal GM change over the follow-up interval. Relative to the healthy controls, the FES patients were observed to exhibit widespread GM reductions in the frontal, parietal and temporal cortices and cerebellum at baseline, as well as more circumscribed regions of GM increase, particularly in the occipital lobe. Furthermore, the FES patients lost considerably more GM over the follow-up interval than the controls, particularly in the parietal and temporal cortices. These results indicate that patients with FES exhibit significant structural brain abnormalities very early in the course of their illness, and that these abnormalities progress over the first few years of their illness. Chapter 4 employed the same methodology to investigate the white matter abnormalities exhibited by the FES subjects relative to the controls, both at baseline and over the follow-up interval. Compared to controls, the FES patients exhibited volumetric WM deficits in the frontal and temporal lobes at baseline, as well as volumetric increases at the fronto-parietal junction bilaterally. Furthermore, the FES patients lost considerably more WM over the follow-up interval than did the controls in the middle and inferior temporal cortex bilaterally. While there is substantial evidence indicating that abnormalities in the maturational processes of myelination play a significant role in the development of WM abnormalities in FES, the observed longitudinal reductions in WM were consistent with the death of a select population of temporal lobe neurons over the follow-up interval. The aim of Chapter 5 was to investigate the clinical correlates of the GM abnormalities exhibited by the FES patients at baseline. The volumes of four distinct cerebral regions where 31 patients with FES exhibited reduced GM volumes relative to 30 matched controls were calculated and correlated with patients’ scores on three primary symptom dimensions: Disorganization, Reality Distortion and Psychomotor Poverty. The results indicated that the greater the degree of atrophy exhibited by the FES patients in three of these four ‘regions-of-reduction’, the less severe their degree of Reality Distortion. These results suggest that an excessive amount of GM atrophy may in fact preclude the formation of hallucinations or highly systematized delusions in patients with FES. The aim of Chapter 6 was to identify the relationship between the longitudinal changes in brain structure and brain electrophysiology exhibited by 19 FES patients over the first 2-3 years of their illness, and to compare it to the normative relationship between the two indices reported in Chapter 2. The methodology employed for the parcellation of the MRI and EEG data was identical to Chapter 2. The results indicated that, in contrast to the healthy controls, the longitudinal reduction in GM volume exhibited by the FES patients was not associated with a corresponding reduction in EEG power in any brain lobe. In contrast, EEG power was observed to be maintained or even to increase over the follow-up interval in these patients. These results were consistent with the FES patients experiencing an abnormal elevation of neural synchrony. Such an abnormality in neural synchrony could potentially form the basis of the dysfunctional neural connectivity that has been widely proposed to underlie the functional deficits present in patients with schizophrenia. The primary aim of Chapter 7 was to assimilate the findings from the preceding empirical chapters with the theoretical framework provided in the literature, into an integrated and testable model of schizophrenia. The model emphasized dysfunctions in brain maturation, specifically in the normative processes of synaptic ‘pruning’ and axonal myelination, as playing a key role in the development of disintegrated neural activity and the subsequent onset of schizophrenic symptoms. The model concluded with the novel proposal that disintegrated neural activity arises from abnormal elevations in the synchrony of synaptic activity in patients with first-episode schizophrenia.

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This thesis first explored the effects of concurrent spatial attention and working memory task performance on over-ground gait in healthy young and older adults. It then compared over-ground gait parameters and working memory performance in mild Alzheimer’s Disease (AD) and normal controls (NC) and investigated costs of dual-tasking on working memory performance and cadence during treadmill walking at preferred walking speed in the two groups. Furthermore, it explored these differences in AD and NC groups in relation to their subcortical hyperintensities (SH) that were rated using standardized scales on MRI. Reaction times and accuracy on working memory performance measures were collected under single and dual task conditions. Over-ground gait parameters were measured on an automated walkway. Costs of dual-tasking on gait parameters and working memory performance were measured at a constant velocity on a treadmill. The hypotheses that working memory influences gait performance and that a higher SH burden negatively influences over-ground gait and costs of dual-task conditions, were supported in a series of experiments. Gait slowed down while performing working memory and spatial attention tasks in young and older adults. Patients with mild AD, compared to NC, had a slower gait velocity, shorter stride length and lower cadence on the walkway. When the two groups were subdivided into higher and lower SH groups based on their median SH score, the NC group with lower SH burden walked significantly faster with a higher cadence and a longer stride length than the other three groups. Lastly, a higher SH burden negatively influenced working memory performance in NC while in mild AD patients, it had negative influences on adaptive changes in gait while dual-tasking. These results suggest that, in dual-task condition, SH interfere with processing speed in NC and on gait in AD. These findings provide new insights in to tradeoffs during dual tasking in relation to cerebrovascular disease. This has ecological implications because of the prevalence of small vessel disease in aging and dementia, may impact on predicting falls in AD.

Functional magnetic resonance imaging (fMRI) is a widely used, noninvasive technique to map brain activation, and has provided considerable insight into human brain function over the past two decades. Until recently, fMRI studies have focused on gray matter; however, reports of fMRI activation in white matter are mounting. White matter fMRI activation has the potential to greatly expand the breadth of brain connectivity research, as well as improve the assessment and diagnosis of white matter and connectivity disorders. Despite these potential benefits, white matter fMRI activation remains controversial. The controversy is partially due to the existence of incompletely understood facets of fMRI signals in white matter. This thesis describes three experiments that aim to refine what is currently known about white matter fMRI activation. In the first experiment, one of the main concerns about fMRI activation in white matter was addressed; namely, whether white matter has sufficient cerebrovascular reactivity to support hemodynamic changes that can be measured with fMRI. It was demonstrated that white matter has the capacity to support detectable hemodynamic changes in the absence of partial volume effects. In the second experiment, the effect of static magnetic field strength on sensitivity to white matter fMRI activation was explored as a possible cause of the relative paucity of reports of white matter fMRI activation. The results showed greater sensitivity to white matter fMRI activation at 4 T relative to 1.5 T MRI. In the third experiment, the relationship between white matter activation and the activated network of gray matter regions was explored. This was accomplished using fMRI-guided tractography in which structural connections between activated clusters are evaluated. Structural connectivity between white matter fMRI activation and regions of gray matter activation was demonstrated, providing evidence of the functional significance of fMRI activation in white matter. These experiments provide important insights, which will allow for improved investigations of white matter fMRI activation in the future. In addition, it is posited that experimenter bias, via selective reporting of activation clusters, has contributed to the slow acceptance of fMRI activation in white matter.