Tesis sobre el tema "White matter structure"

The great amount of METH abuse all over the world causes enormous social and criminal justice problems. In the human brain the abuse of METH causes implications on both structures and functions given rise to acute as well as long term symptoms. In this essay the effects of METH abuse is described in the manner of the drug mechanism such as the impact on neurotransmitters, structural deficits with decreased and increased volumes and the implication on attention, memory, decision  making and emotions. Results from studies showing brain structural and cognitive impairments in METH abusers and in prenatal METH exposed children.

The structural integrity of the white matter is required for neuronal communication within the brain which is essential for normal cognitive function. Post-mortem and clinical imaging studies of elderly individuals have demonstrated that white matter integrity is weakened with increasing age which is proposed to underlie age-related cognitive decline. Whilst the exact mechanisms are unknown it is thought that modest age-related reductions in cerebral blood flow, termed chronic cerebral hypoperfusion, may contribute to white matter disruption and impaired cognition with ageing. Investigating the effects of white matter integrity in humans is limited as it is difficult to definitively ascertain a cause and effect relationship. Indeed, elderly individuals with cerebral hypoperfusion often have co-existing disease such as hypertension thus the effects of hypoperfusion in isolation cannot be determined. This has led to the development of a mouse model of chronic cerebral hypoperfusion which provides the opportunity to directly assess whether cerebral hypoperfusion results in disruption to white matter and cognitive impairment. This is achieved by applying small wire coils around both common carotid arteries of the mouse resulting in a global reduction in cerebral blood flow. Importantly the extent of blood flow reduction is dependent on the internal diameter of the coils meaning that differing severities of hypoperfusion can be studied. Previous studies using this model have demonstrated diffuse white matter pathology in white matter tracts including the corpus callosum, internal capsule and optic tract following 1 month of hypoperfusion which is accompanied by impaired spatial working memory. This thesis sought to test the hypothesis that chronic cerebral hypoperfusion would influence the structural integrity of nodal and paranodal domains of myelinated axons of the white matter and result in decreased numbers of oligodendroglial cells. It was additionally hypothesised that treatment with the anti-inflammatory and antioxidant drug dimethyl fumarate (DMF) would ameliorate structural and functional alterations to white matter following hypoperfusion. Aim 1 – To determine the impact of chronic cerebral hypoperfusion on the structural integrity of nodal and paranodal domains of myelinated axons The first aim of this thesis was to investigate the effects of chronic cerebral hypoperfusion on the structural integrity of nodal and paranodal domains of myelinated axons. This was addressed by examining key myelin and axonal proteins found at nodal, paranodal and internodal domains. This revealed significant alterations to the distribution of voltage-gated sodium (Nav1.6) channels at nodes of Ranvier which were differentially altered in response to increasing durations of chronic cerebral hypoperfusion. Specifically an increase in the Nav1.6+ domain length was observed in the corpus callosum following 3 days (p < 0.0001) and 1 month (p < 0.001) of chronic cerebral hypoperfusion but was not significantly different from sham controls following 6 weeks of hypoperfusion (p = 0.066). A significant decrease in Nav1.6 domain length was observed following 3 months of hypoperfusion (p = 0.003). Assessment of paranodal integrity was carried out by measuring nodal gap length and by ultrastructural analysis of paranodal domains. This revealed pronounced alterations to nodal gap length, loss of paranodal septate-like junctions and abnormal morphology of paranodal loops. Furthermore this study revealed a significant loss of myelin associated glycoprotein, a key protein involved in the maintenance of axon-glial integrity, as early as 3 days following the onset of hypoperfusion. A further aim of this study was to examine potential mechanisms underlying the observed alterations to nodal and paranodal domains following cerebral hypoperfusion. It was hypothesised that increased inflammation and accumulation of mitochondria at nodes of Ranvier would be observed following hypoperfusion. The extent of inflammation was assessed by counting numbers of microglia which revealed no significant difference between groups following 3 days of hypoperfusion (p = 0.425) but a significant increase in microglial number was observed following 1 month of hypoperfusion (p = 0.001). In addition, assessment of mitochondrial distribution along myelinated axons revealed decreased numbers of nodes containing mitochondria following 6 weeks of hypoperfusion (p = 0.03) with no difference between groups observed following 3 months (p = 0.742). Taken together the results from this study provide evidence that chronic cerebral hypoperfusion results in dynamic alterations in the localisation of Nav1.6 channels which are accompanied by disruption to paranodal domains and impaired axon-glial integrity. Furthermore microglial number does not appear to mediate nodal and paranodal disruption following 3 days but may contribute to ongoing pathology following 1 month of chronic cerebral hypoperfusion. Aim 2 – To determine the effects of chronic cerebral hypoperfusion on oligodendroglial populations. The second aim of this thesis was to determine the effect of chronic cerebral hypoperfusion on numbers of mature oligodendrocytes and oligodendrocyte precursor cells (OPCs). This revealed a significant decrease in numbers of both populations following 3 days of cerebral hypoperfusion however following 1 month numbers of OPCs were restored and a significant increase in mature oligodendrocyte number was observed. Assessment of OPC proliferation demonstrated low numbers of proliferating cells but revealed that a proportion of newly generated cells had differentiated into mature oligodendrocytes. To determine a potential mechanism involved in OPC differentiation following cerebral hypoperfusion the expression of the GPR17 receptor was examined which has recently been reported to mediate OPC differentiation in response to injury. The results demonstrated decreased expression of GPR17 following 3 days of hypoperfusion (p = 0.007) with no difference between groups observed following 1 month (p = 0.362) indicating that this receptor is not involved in differentiation of OPCs following hypoperfusion. Taken together the results from this study show that mature oligodendrocytes and OPCs are lost early in response to hypoperfusion but that these cells recover over time, highlighting the regenerative capacity of the white matter following cerebral hypoperfusion.Aim 3 – To investigate whether modulation of inflammation and oxidative stress could ameliorate alterations to white matter structure and function following severe chronic cerebral hypoperfusion The third and final aim of this thesis was to determine whether treatment with the anti-inflammatory and antioxidant drug DMF could ameliorate structural and functional alterations to white matter following severe chronic cerebral hypoperfusion. This was achieved by examining myelin and axonal integrity in addition to numbers of oligodendrocytes and OPCs following 7 days of severe chronic cerebral hypoperfusion. This revealed that myelin integrity was significantly decreased in vehicle-treated hypoperfused animals as compared to shams (p = 0.005). However no differences in myelin integrity were observed between sham and hypoperfused mice treated with DMF (p = 0.312). In contrast to the previous study, numbers of oligodendrocytes and OPCs were not altered following severe hypoperfusion however DMF treatment led to significantly increased numbers of oligodendrocytes in sham animals (p = 0.003). Assessment of white matter function using electrophysiology revealed that the conduction velocity of myelinated axons was significantly increased in DMF-treated hypoperfused animals as compared to those treated with vehicle (p = 0.04). Taken together the results of this study demonstrate that modulation of inflammation and oxidative stress may improve structural and functional white matter alterations following chronic cerebral hypoperfusion. Conclusions: The results presented in this thesis demonstrate that chronic cerebral hypoperfusion results in structural alterations to myelinated axons and to oligodendroglial populations within the white matter which are accompanied by impaired spatial working memory. Whilst previous studies using the model have reported that cerebral hypoperfusion results in diffuse white matter pathology, this study has highlighted the vulnerability of nodal and paranodal domains of myelinated axons as regions which are altered early in response to hypoperfusion. Furthermore, characterisation of oligodendroglial populations has revealed that these cells are replaced over time despite ongoing hypoperfusion which demonstrates the regenerative capacity of the white matter following cerebral hypoperfusion. Critically the results presented in this thesis demonstrate that treatment with DMF improved the function of myelinated axons in response to severe reductions in cerebral blood flow and thus may represent an appropriate therapeutic strategy for chronic cerebral hypoperfusion.

The present doctoral thesis is focused on describing the effects that different environmental and genetic modulators have on white matter pathways and its consequences measured with diffusion tensor imaging. We chose to focus on two examples of each type of modulators. Firstly, we selected as environment modulating factors: pollutants and video games. On one side, pollution as an external factor that enters passively the brain and may influence developmental trajectories. And on the other hand, we used video games as a good example of active behavior that can modify white matter tracts through practice. Secondly, Down syndrome and Prader-Willi syndrome were selected as representative genetic syndromes that may interfere on white matter growth because, although Down syndrome has higher incidence rate than Prader- Willi syndrome, both show behavioral and cognitive alterations, indicating an abnormal brain development. The results of this doctoral thesis lead to the conclusion that white matter pathways development is not an immutable process and it can be modified by diverse modulators. In the same way, diffusion tensor imaging is a good-quality technique to capture and identify those white matter changes through life.
La presente tesis doctoral se centra en describir los efectos que diferentes moduladores ambientales y genéticos tienen sobre las vías de la sustancia blanca y sus consecuencias a través de imágenes de tensor de difusión. Decidimos centrarnos dos ejemplos de cada tipo de moduladores. En primer lugar, se seleccionó como factores de modulación ambiental: contaminantes y videojuegos. Por un lado, la contaminación es un factor externo que penetra pasivamente el cerebro y puede influir en las trayectorias del desarrollo. Y por otro lado, los videojuegos son un buen ejemplo de comportamiento activo que puede modificar los tractos de la materia blanca a través de la práctica. En segundo lugar, se seleccionaron el síndrome de Down y síndrome de Prader-Willi como síndromes genéticos representativos que pueden interferir en el crecimiento de la materia blanca ya que, aunque el síndrome de Down tiene una tasa de incidencia superior al síndrome de Prader-Willi, ambos muestran alteraciones cognitivas y conductuales fruto de un subdesarrollo de las vías de sustancia blanca. Los resultados de esta tesis doctoral nos llevan a la conclusión de que el desarrollo de vías de sustancia blanca no es un proceso inmutable y puede ser modificado por diversos moduladores. De la misma manera, el tensor de difusión es una técnica adecuada para capturar e identificar los cambios en la sustancia blanca que acontecen a lo largo de la vida.

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.

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.

Abstract Recognition of individuals at highest risk for psychosis is challenging and no definitive biomarkers are yet available. Physical illnesses associated with a sedentary lifestyle are common in patients with severe mental illness. Both, bodyweight and risk for psychosis are associated with brain white matter (WM) abnormalities. There are several dysregulated pathways which are common in psychiatric illnesses and weight-related processes, but it is not known how weight and vulnerability for psychosis interact in the brain. The present study examines brain WM microstructure and its association to body mass index (BMI) in young adults with a familial risk for psychosis (FR). In addition, the level of physical activity and cardiorespiratory fitness in individuals vulnerable to psychosis was examined. Participants of the present study are members of the Northern Finland Birth Cohort 1986. Two separate clinical substudies were conducted. The first having been done when the participants were at age 15–16. At that time, physical activity was defined by postal questionnaire (n=6,987) and cardiorespiratory fitness was measured by a submaximal cycle ergometer test (n=4,803). Risk for psychosis was viewed from three perspectives, with possible overlap between groups: having familial risk for psychosis, existing prodromal symptoms at age 15–16, and development of hospital treated psychosis between the ages of 16 and 20 years. The latter substudy was conducted when the participants were aged between 20 and 25 years. Diffusion tensor imaging was performed on 108 participants. Our study showed that there was no difference in WM microstructure between FR and control groups suggesting that WM abnormalities are not a genetic feature for risk of psychosis in all populations. However, the association between BMI and WM microstructure differed significantly between the FR and control groups. We also demonstrated that the level of physical activity was lower before the onset of psychotic illness. Therefore, these results imply that it would be of great importance to consider weight and physical activity levels in subjects at risk for psychosis, in order to avoid the detrimental effects of a sedentary lifestyle on overall health
Tiivistelmä Korkeimmassa psykoosiriskissä olevien tunnistaminen on haastavaa, eikä kunnollisia biomarkkereita ole käytettävissä. Vähäiseen liikunta-aktiivisuuteen liitetyt fyysiset sairaudet ovat yleisiä vakavaa mielenterveyshäiriötä sairastavilla. Sekä kehonpaino että psykoosialttius on yhdistetty aivojen valkean aineen rakenteen poikkeavuuksiin. Useat kehon säätelymekanismien poikkeavuudet liittyvät sekä psykiatrisiin sairauksiin että painoon liittyviin prosesseihin, mutta ei ole olemassa tutkimustietoa siitä, miten paino ja psykoosialttius vaikuttavat yhdessä aivojen rakenteeseen. Tässä osajulkaisuväitöskirjassa tutkitaan aivojen valkean aineen mikrorakennetta nuorilla aikuisilla, jotka ovat sukuriskissä sairastua psykoosiin, sekä painon vaikutusta valkean aineen rakenteeseen psykoosiriskissä. Lisäksi tutkitaan psykoosialttiiden nuorten liikunta-aktiivisuutta ja kuntoa. Tutkittavat kuuluvat Pohjois-Suomen vuoden 1986 syntymäkohorttiin. Kaksi osatutkimusta toteutettiin, joista aikaisempi kliininen tutkimus tutkittavien ollessa 15–16-vuotiaita. Tuolloin selvitettiin liikunta-aktiivisuus postikyselyn avulla (n=6,987) ja aerobinen kunto mittaamalla hapenottokyky polkupyöräergometrilla (n=4,803). Psykoosialttiutta tarkasteltiin kolmella tavalla, ja ryhmien välillä esiintyi osittaista päällekkäisyyttä: sukurasitus, 15–16 v. iässä raportoidut psykoosinkaltaiset oireet ja sairaalahoitoon johtanut psykoosi 16–20 v. iässä. Toinen kliininen osatutkimus toteutettiin tutkittavien ollessa 20–25-vuotiaita. Tutkimuksen yhteydessä tehtiin aivojen diffuusiotensorikuvaus 108 osallistuneelle. Aivojen valkean aineen mikrorakenteessa ei havaittu eroa sukuriskissä olevien ja kontrollien välillä viitaten siihen, että poikkeavuudet valkean aineen rakenteessa eivät olisi psykoosiriskin geneettinen piirre kaikissa populaatioissa. Havaitsimme kuitenkin, että assosiaatio painoindeksin ja valkean aineen rakenteen välillä oli erilainen sukuriski- ja kontrolliryhmissä. Tutkimus osoitti myös, että liikunta-aktiivisuus on alentunut jo ennen psykoosisairauden puhkeamista. Psykoosiriskissä olevien liikuntatottumuksiin ja painoon tulisi kiinnittää erityistä huomiota jo varhaisessa vaiheessa elimellisten sairauksien ehkäisemiseksi

Older age is a primary risk factor for the development of cardiovascular disease in part through the stiffening of the large cardiothoracic elastic arteries (e.g., aorta, carotid arteries). Aging is also associated with reduced cognitive function, cerebrovascular reactivity and brain white matter integrity, but whether these changes in brain structure and function are associated with age-related large artery stiffness remains unclear. In contrast, older adults who have high aerobic fitness demonstrate attenuated large artery stiffness and better cognitive performance compared to their sedentary counterparts, but the effects of aerobic fitness on white matter integrity and cerebrovascular reactivity with aging are conflicting and limited. Moreover, whether high aerobic fitness-associated lower large artery stiffness in older adults is associated with, and perhaps mediates, the beneficial changes in cognitive function and white matter structure remains unknown. The purpose of this study was to investigate the extent to which high aerobic fitness is associated with preserved white matter structure, cerebrovascular reactivity, and cognitive performance in aged individuals, and if these changes in brain structure and function are associated with attenuated large artery stiffness. In young (n=19, 23.6 ± 2.5 years) and old (n=22, 64.4 ± 4.2 years) healthy adults, large elastic artery stiffness was measured by carotid-femoral pulse wave velocity (cfPWV, aortic stiffness) via non-invasive applanation tonometry of carotid and femoral pulse waveforms and carotid artery beta-stiffness index (β-stiffness index) and compliance using high-resolution ultrasound and carotid blood pressure via applanation tonometry. Aerobic fitness was measured as maximal exercise oxygen uptake (VO2max) using respiratory gas analysis on an upright cycle ergometer. Older subjects were stratified as high or low fit based on gender and age VO2max classification. Letter, pattern and N-Back cognitive tests were used to assess processing speed and working memory respectively. Fractional anisotropy (FA) from diffusion tensor images and Blood Oxygenation Level Dependent (BOLD) imaging was used to assess cerebrovascular reactivity (CVR) response to a breath hold and brain activation during a working memory task. The association between large artery stiffness and FA was then assessed using a voxel-wise general linear model approach and a region-of-interest analysis. Our results confirmed age-related increases in cfPWV, carotid β-stiffness index and central (carotid) but not brachial systolic blood pressure, and expected reductions in carotid compliance, VO2max, working memory and processing speed, and in white matter integrity in select brain regions (bilateral cingulate, frontal, occipital, temporal). In contrast, we found no age-associated differences in CVR to breath hold stimulus or change in BOLD response to the N-Back. In our cohort of health adults, we found that the age-related changes in large artery stiffness were not attenuated by high compared with low VO2max. Among older adults, large elastic artery stiffness was not associated with regional white matter integrity or cerebrovascular reactivity in any regions-of-interest. Greater carotid artery compliance and lower β-stiffness index was associated with higher processing speed, while compliance was related to higher d'Prime scores and lower reaction time on the 2-Back task among the older adults. CVR to a breath hold stimulus was not related to any measure of cognitive performance. VO2max was not associated with any measures of vascular function, brain structure, function or cognition, indicating relations between large artery stiffness and cognition were independent of aerobic fitness capacity. Taken together, these data suggest that select measures of cognitive performance, but not white matter structure or CVR, may be susceptible to age-related changes in carotid stiffness/compliance and that are unaffected by aerobic fitness. More work is needed to understand the mechanisms by which age-related declines in carotid artery compliance and increased carotid stiffness are associated with reductions in cognitive function in older adults.

The costs associated with diagnosis, treatment and care of Alzheimer’s disease (AD) patients places a significant financial and social strain on healthcare systems, patients and caregivers, especially in low-and middle-income countries (LAMICs). Traditional methods for diagnosing AD are time consuming and expensive, and treatments are often only effective in the early stages. These factors call for the development of alternative diagnostic methods. One such method that has gained attention due to its neural overlaps with AD is the measurement of intraindividual variability (IIV; the within-person variation in performance over multiple trials of a single task). IIV researchers have highlighted the role of white matter in increased IIV, and micro-structural white matter changes have been implicated in the early stages of AD. The current study examined the relationship between IIV on simple and choice reaction time tasks and micro-structural white matter changes, as indexed by fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (DA) and radial diffusivity (DR) in a sample of 16 AD patients and 20 healthy older adults. Across the entire sample, increased IIV on both the simple and choice reaction time tasks was significantly correlated with lower FA in an area of the right hemisphere inferior longitudinal fasciculus (R-ILF). Increased IIV on the choice reaction time task was significantly correlated with lower DA in the same area. Finally, IIV on the choice reaction time task contributed significantly and uniquely to variance in DA in the same area. These results suggest that further longitudinal studies into the diagnostic utility of IIV for neurological disorders might be of value for clinicians, patients and caregivers.

Le cerveau est organisé tel un réseau reliant différentes régions. Ce réseau est important pour le développement de fonctions comme le langage. Certains troubles cognitifs peuvent être expliqués par des problèmes de connexion entre régions plus qu’à des dommages de ces dernières. Malgré plusieurs décennies de travail sur ces réseaux, nos connaissances sur le sujet n’ont pas beaucoup évoluées depuis le début du siècle dernier. Récemment, un développement spectaculaire des techniques de l’imagerie par résonance magnétique (IRM) a permis l’étude vivant du cerveau humain. Une technique permettant l’exploration des faisceaux de la matière blanche (MB) in vivo est l’IRM de diffusion (IRMd). En particulier, la trajectographie à partir de l’IRMd facilite le traçage des faisceaux de la MB. C’est donc une technique prometteuse afin d’explorer l’aspect cognitif de l’anatomie humaine ainsi que de ses troubles. La motivation de cette thèse est la dissection in vivo de la MB. Cette procédure permet d’isoler les faisceaux de la MB, qui jouent un rôle particulier dans le fonctionnement du cerveau, de façon à pouvoir les analyser. L’exécution manuelle de cette tache requiert une grande connaissance du cerveau et demande plusieurs heurs de travail. Le développement d’une technique automatique est donc de la plus grande importance. Cette thèse contient plusieurs contributions : nous développons des moyens d’automatiser la dissection de la MB, c’est-à-dire le cadre mathématique nécessaire à sa compréhension. Ces outils nous permettent ensuite de développer des techniques d’analyse de la moelle épinière et de recherche de différences dans la MB entre des individus sains et schizophrènes
The brain is organized in networks that are made up of tracks connecting different regions. These networks are important for the development of brain functions such as language. Lesions and cognitive disorders are sometimes better explained by disconnection mechanisms between cerebral regions than by damage of those regions. Despite several decades of tracing these networks in the brain, our knowledge of cerebral connections has progressed very little since the beginning of the last century. Recently, we have seen a spectacular development of magnetic resonance imaging (MRI) techniques for the study of the living human brain. One technique for exploring white matter (WM) tissue characteristics and pathway in vivo is diffusion MRI (dMRI). Particulary, dMRI tractography facilitates the tracing the WM tracts in vivo. DMRI is a promising technique to explore the anatomical basis of human cognition and its disorders. The motivation of this thesis is the in vivo dissection of the WM. This procedure isolates the WM tracts that play a role in a particular function or disorder of the brain so they can be analysed. Manually performing this task requires a great knowledge of brain anatomy and several hours of work. Hence, the development of a technique to automatically perform the identification of WM structures is of utmost importance. This thesis has several contributions : we develop means for the automatic dissection of WM tracts from dMRI, this is based on a mathematical framework for the WM and its tracts ; using these tools, we develop techniques to analyse the spinal chord and to find group differences in the WM particulary between healthy and schizophrenic subjects

Hypertension has been associated with causing deleterious effects to the cerebrovasculature, which are thought to underlie the formation of white matter lesions (WML) and predispose individuals to age related cognitive decline. In humans hypertension frequently occurs concomitantly with other vascular risk factors making it difficult to ascertain the primary mechanisms of hypertension in isolation. Animal models of hypertension have been used in an aid to establish the mechanisms of hypertension in isolation. To date the knowledge gleaned from animal models has undoubtedly provided an insight as to the role of hypertension and cerebrovasculature remodelling but, these models have limitations such as lack of genetically matched controls and the inability to control the severity of hypertension, restricting the understanding of the underlying mechanisms. All studies within this thesis used the Cyp1a1 Ren2 inducible hypertensive rat model, induced by dietary addition of Indole-3-carbinol (I3C), allowing the severity and duration of hypertension to be tightly controlled and compared to genetically matched controls. This thesis set out to address the hypothesis that sustained hypertension will lead to alterations to the structural integrity of the cerebrovasculature and white matter, which will be exacerbated with age and that hypertension will be associated with alterations to gene expression and cognitive function. Initially this thesis sought to investigate the effect of hypertension on the structural integrity of the vasculature in the Cyp1a1 Ren2 rat model. Firstly, blood pressure in the Cyp1a1 Ren2 rat model was characterised and it was found that the dietary addition of I3C, caused a sustained level of increased blood pressure in all three cohorts. Cerebrovascular alterations were found to consist of increased eNOS expression in the young brain, which progressed with increased duration of hypertension to vascular morphological alterations of decreased vessel width and a redistribution of tight junction protein claudin-5. With age, hypertensive vascular alterations consisted of increased eNOS expression and vascular density. Additionally, there was evidence that hypertension caused a vascular inflammatory response in the young and aged brain. Secondly, this thesis investigated the effect of hypertension on gene expression. Overall it was found that hypertension altered genes related to collagen growth factors, ion channels, eNOS related Map-Kinase pathway and inflammatory genes. Thirdly, this thesis sought to investigate the impact of hypertension on the overall structural integrity of the brain and white matter examining neurons, myelin, oligodendrocytes, axons and microglia, in several regions of the young and aged brain. In general, this study found that hypertension did not cause overt structural or myelin alterations in the majority of regions analysed, with only evidence of myelin alterations occurring within the subcortex of hypertensive animals from each of the young cohorts analysed. However, an adverse subcortical inflammatory response was found in hypertensive animals of the young 6-month cohort and also in hypertensive animals from the aged 4-month cohort, where the inflammatory response was not exclusive to the subcortex of hypertensive animals but also occurred in multiple white matter tracts. Lastly this thesis chose to examine the effect of hypertension on cognitive function, specifically spatial reference and working memory using the Morris water maze and found no evidence of alterations in the cognitive functions examined. Conclusions The results presented within this thesis demonstrated that hypertension in isolation leads to modest alterations to the integrity of the cerebrovasculature and white matter, with no evidence of alterations to specific cognitive functions examined, demonstrating the importance of studying hypertension in isolation. Additionally, this study highlights the initial hypertensive induced alterations to the cerebrovasculature, such as endothelial signalling, vascular structure and inflammation, providing a window for therapeutic intervention at a time point when there are minimal alterations to the overall structural integrity of the brain. Future studies in this model should concentrate on examining different severities of hypertension and also hypertension concomitantly with other vascular risk factors to try and recapitulate pathological alterations found in humans.

Objective: The purpose of this project was to evaluate white matter degeneration and its impact on hippocampal structural connectivity in patients with amnestic mild cognitive impairment, non-amnestic mild cognitive impairment and Alzheimer's disease.Methods: We estimated white matter fractional anisotropy, mean diffusivity and hippocampal structural connectivity in two independent cohorts. The ADNI cohort included 108 subjects [25 cognitively normal, 21 amnestic mild cognitive impairment, 47 non-amnestic mild cognitive impairment and 15 Alzheimer's disease]. A second cohort included 34 subjects [15 cognitively normal and 19 amnestic mild cognitive impairment] recruited in Montreal. All subjects underwent clinical and neuropsychological assessment in addition to diffusion and T1 MRI. Individual fractional anisotropy and mean diffusivity maps were generated using FSL-DTIfit. In addition, hippocampal structural connectivity maps expressing the probability of connectivity between the hippocampus and cortex were generated using a pipeline based on FSL-probtrackX. Voxel-based group comparison statistics of fractional anisotropy, mean diffusivity and hippocampal structural connectivity were estimated using Tract-Based Spatial Statistics. The proportion of abnormal to total white matter volume was estimated using the total volume of the white matter skeleton. Results: We found that in both cohorts, when compared to cognitively normal, amnestic mild cognitive impairment patients had 27-29% white matter volume showing higher mean diffusivity but no significant fractional anisotropy abnormalities. No fractional anisotropy or mean diffusivity differences were observed between non-amnestic between mild cognitive impairment patients and cognitively normal subjects. Alzheimer's disease patients had 66.3% of normalized white matter volume with increased mean diffusivity and 54.3% of the white matter had reduced fractional anisotropy. Reduced structural connectivity was found in the hippocampal connections to temporal, inferior parietal, posterior cingulate and frontal regions only in the Alzheimer's group. Conclusions: The severity of white matter degeneration appears to be higher in advanced clinical stages, supporting the construct that these abnormalities are part of the pathophysiological processes of Alzheimer's disease.
Anormalités dans la matière blanche et déconnections structurelles de l'hippocampe dans la Maladie d'Alzheimer et le Trouble Cognitif Léger avec amnésieObjectif: Ce projet a pour but d'évaluer la dégénérescence de la matière blanche et son impact sur la connectivité structurelle de l'hippocampe chez des patients avec un trouble cognitif léger avec ou sans amnésie ou la Maladie d'Alzheimer.Méthodes: Nous avons estimé l'anisotropie fractionnelle et la diffusivité moyenne de la matière blanche ainsi que la connectivité structurelle de l'hippocampe dans deux cohortes indépendantes. La cohorte ADNI incluait 108 sujets [25 cognitivement normaux, 21 avec trouble cognitif léger avec amnésie, 47 avec trouble cognitif léger sans amnésie et 15 Maladie d'Alzheimer]. Une deuxième cohorte incluait 34 sujets [15 cognitivement normaux et 19 avec trouble cognitif léger avec amnésie] recrutés à Montréal. Tous les sujets ont passé une évaluation clinique et neuropsychologique, en plus d'acquisitions IRM de diffusion et T1. Les images individuelles d'anisotropie fractionnelle et de diffusivité moyenne ont été générées avec FSL-DTIfit. Celles de connectivité structurelle de l'hippocampe, qui expriment la probabilité d'une connexion entre l'hippocampe et le cortex, ont été générées en utilisant une fonction basée sur FSL-probtractX. Les comparaisons statistiques au niveau du voxel pour l'anisotropie fractionnelle, la diffusivité moyenne et la connectivité structurelle de l'hippocampe ont été estimées en utilisant l'outil Tract-Based Spatial Statistics. La proportion d'anormalités dans la matière blanche a été estimée en utilisant le volume total du patron de matière blanche.Résultats: Dans les deux cohortes, on peut observer que les patients du groupe trouble cognitif léger avec amnésie ont 27-29% du volume de matière blanche avec une diffusivité moyenne plus élevée mais sans anormalité probante de l'anisotropie fractionnelle. Aucune différence d'anisotropie fractionnelle ou de diffusivité moyenne n'est observée entre le groupe avec trouble cognitif léger sans amnésie et celui cognitivement normal. Nous avons trouvé chez les patients avec la Maladie d'Alzheimer 66.3% de la matière blanche normalisée avec une augmentation de la diffusivité moyenne, et dans 54.3% une réduction d'anisotropie fractionnelle. Une réduction de la connectivité structurelle a été détectée dans les connections hippocampales aux régions frontales, temporales, pariétales inférieures et cingulaires postérieures dans le groupe Maladie d'Alzheimer seulement.Conclusions: La sévérité de la dégénérescence de la matière blanche apparaît être plus importante dans les stages cliniques avancées, ce qui supporte la théorie que ces anormalités font parties des processus pathophysiologiques de la Maladie d'Alzheimer.

Mild traumatic brain injury (mTBI) is a common and often inconspicuous wound that is frequently associated with chronic low-grade symptoms and cognitive dysfunction. Previous evidence suggests that daily blue wavelength light therapy may be effective at reducing fatigue and improving sleep in patients recovering from mTBI. However, the effects of light therapy on recovering brain structure remain unexplored. In this study, we analyzed white matter diffusion properties, including generalized fractional anisotropy, and the quantity of water diffusion in isotropic (i.e., isotropic diffusion) and anisotropic fashion (i.e., quantitative anisotropy, QA) for fibers crossing 11 brain areas known to be significantly affected following mTBI. Specifically, we investigated how 6 weeks of daily morning blue light exposure therapy (compared to an amber-light placebo condition) impacted changes in white matter diffusion in individuals with mTBI. We observed a significant impact of the blue light treatment (relative to the placebo) on the amount of water diffusion (QA) for multiple brain areas, including the corpus callosum, anterior corona radiata, and thalamus. Moreover, many of these changes were associated with improvements in sleep latency and delayed memory. These findings suggest that blue wavelength light exposure may serve as one of the potential non-pharmacological treatments for facilitating structural and functional recovery following mTBI; they also support the use of QA as a reliable neuro-biomarker for mTBI therapies.

In the first part of this thesis, an introduction of the main characteristics of the primary-progressive form of multiple sclerosis (PPMS) (Chapter I), and of the acquisition and post-processing of the conventional and quantitative magnetic resonance imaging techniques employed in the studies presented in this thesis (Chapter II), will be presented. In the second part of this thesis, several advanced imaging techniques will be employed to answer the following two key questions on PPMS: 1) Is there is a spatial and temporal link between the pathological processes occurring in the normal appearing white matter (WM) and in the grey matter (GM) of patients with PPMS?; 2) Which regions of WM and GM abnormalities significantly contribute to clinical progression and cognitive dysfunction over time in patients with PPMS? To answer the first question, I first used tract-based spatial statistics (TBSS) and voxel-based morphometry (VBM), to explore the spatial relationship between the damage occurring in the normal-appearing WM and GM in patients with early PPMS (Chapter III). Then, I moved onto exploring the temporal relationship linking the pathological changes affecting the two compartments, employing magnetization transfer imaging (MTI) and diffusion-based tractography (Chapter IV). To answer the second question, I first looked at the prognostic role of WM lesion location in a study conducted on a large population of patients with well- established PPMS who were followed-up for ten years in five different European centres (Chapter V). Then, using a novel approach which combines MTI and TBSS, I explored the regions of short-term accrual of microstructural damage in patients with early PPMS (Chapter VI). Finally, I moved onto examining the relative contribution of WM and GM damage to long-term motor and cognitive disability in PPMS (Chapter VII). In the final Chapter, I will summarise the results of the studies presented in this thesis, provide an answer to the two key questions on PPMS, and propose future directions for research.

La cartographie de la connectivité anatomique du cerveau humain est un défi scientifique majeur. Décrire la trajectoire et les connexions réalisées par les cent milliards de neurones qui composent le cerveau est une tâche titanesque et multi-échelle.Les grands faisceaux ont été décrits par des approches anatomiques classiques dès le 20ème siècle. Ces travaux ont également révélé l'existence de faisceaux plus courts, appelés superficiels, qui définissent la connectivité entre les régions anatomiques voisines. La taille réduite et la forme complexe de ces faisceaux posent un sérieux défi à leur visualisation, si bien que leur description demeure à ce jour débattue.Le premier axe de recherche de cette thèse vise à repousser les limites de l'IRM de diffusion et proposer un nouveau jeu de données ex-vivo du cerveau humain entier, intitulé Chenonceau, dédié à la caractérisation de la connectivité fine du cerveau.Le jeu de données est composé de deux acquisitions anatomiques pondérées en T2 à une résolution de 100 et 150 microns, ainsi que 175 jeux de données d'IRMd à une résolution de 200 microns et une pondération s'élevant jusqu'à 8000 s/mm2. Plus de 4500 heures d'acquisitions, réparties sur deux ans et demie ont été nécessaires pour acquérir ces données.Chenonceau met à profit la puissance de l'IRM pré-clinique Bruker 11.7T, doté à la fois d'un champ magnétique élevé et d'un tunnel de gradients puissants (780mT/m) permettant d'atteindre la résolution mésoscopique et une très forte pondération en diffusion.Pour concilier la taille imposante du cerveau humain avec l'imageur pré-clinique, un nouveau protocole d'acquisition est proposé. Celui-ci repose sur la séparation du cerveau en échantillons de taille réduite, qui sont sont imagés individuellement, puis réassemblés en post-traitement pour reconstituer le volume intégral.L'ensemble de la démarche est présenté, incluant le protocole de coupe et de préservation des pièces anatomiques, le détail des séquences IRM utilisées ainsi que la description du pipeline de traitement des images. Une attention particulière est portée à la définition de l'étape de recalage qui recompose le volume entier à partir des acquisitions individuelles.Les premières inférences de la connectivité anatomique issues de ce nouveau jeu de données sont également présentées. Les techniques de tractographie et de clustering permettent d'extraire non seulement les faisceaux longs de Chenonceau, mais également les faisceaux superficiels.La seconde partie de la thèse a porté sur le développement d'une nouvelle méthode de suivi de fibres, fondée sur l'utilisation d'un modèle de verres de spins.Ce dernier exprime le problème de tractographie sous la forme d'un ensemble de fragments de fibres, appelés spin, distribués dans l'échantillon et dont la position et l'orientation, ainsi que les connexions qu'ils établissent sont associés à une quantité d'énergie. La construction des tracts résulte du déplacement et de la connexion des spins, dans le but d'atteindre le minimum global d'énergie.Cette thèse propose de remplacer la méthode de Metropolis-Hastings utilisée pour l'optimisation par un agent entraîné dans un cadre d'apprentissage par renforcement.Cette nouvelle formulation vise à améliorer le choix des actions, qui ne seraient plus tirées aléatoirement, mais dictées par une stratégie apprise par l'agent, fruit de ses interactions passées avec des environnement semblables.Les capacités d'anticipation et de projection d'un tel agent apparaissent particulièrement adéquates pour proposer la trajectoire la plus pertinente dans des régions ou l'information de diffusion est ambiguë. De même, la possibilité pour l'algorithme d'apprendre au travers d'interactions permet de contourner la difficulté d'établir des ensembles de faisceaux considérées véritables
Mapping the structural connectivity of the human brain is a major scientific challenge. Describing the trajectory and connections made by the hundred billion neurons that make up the brain is a titanic and multi-scale task.The major fiber bundles have been described by classical anatomical approaches since the 20th century. These studies also revealed the existence of shorter bundles, called superficial bundles, that ensure the connectivity between neighboring anatomical regions. The small size and complex shape of these bundles set a serious challenge to their visualization, so that their description remains under discussion to this day.The first research axis of this thesis aims at pushing the limits of diffusion MRI and proposing a new ex-vivo dataset of the whole human brain, called Chenonceau, dedicated to the characterization of the fine connectivity of the brain.The dataset consists of two T2-weighted anatomical acquisitions at 100 and 150 micron resolution, as well as 175 dMRI datasets at 200 micron resolution with diffusion weighting reaching 8000 s/mm2. More than 4500 hours of acquisition, distributed across two and a half years were necessary to acquire this data.Chenonceau takes advantage of the Bruker 11.7T preclinical MRI system, equipped with both a high magnetic field and a powerful gradient tunnel (780mT/m) allowing to reach the mesoscopic resolution and a very high diffusion weighting.To reconcile the large size of the human brain with the preclinical system, a new acquisition protocol is proposed. It is based on the separation of the brain into smaller samples, which are imaged individually, then reassembled in post-processing to reconstitute the full volume.The whole process is presented, including the protocol for the cutting and the storage of the anatomical samples, the details of the MRI sequences and the description of the image processing pipeline. Special attention is dedicated to the definition of the registration step which recomposes the whole volume from the individual acquisitions.The first inferences of anatomical connectivity from this new dataset are also presented. Tractography associated with clustering techniques allow the extraction of the long and superficial bundles of Chenonceau.The second part of the thesis focused on the development of a new method for fiber tracking, based on the use of the spin glass model.The latter expresses the tractography problem as a set of fiber fragments, called spins, distributed in the sample and whose position and orientation, as well as the connections they establish, are associated with an amount of energy. The construction of the tracts results from the displacement and connection of the spins, with the aim of reaching the global minimum of energy.This thesis proposes to replace the Metropolis-Hastings method used for optimization by an agent trained in a reinforcement learning framework.This new formulation aims at improving the choice of actions, which would no longer be randomly drawn, but dictated by a strategy learned by the agent, fruit of its past interactions with similar environments.The anticipation and projection capacities of such an agent appear particularly adequate to propose the most relevant trajectory in regions where the diffusion information is ambiguous. Moreover, the possibility for the algorithm to learn through interactions allows to circumvent the difficulty of establishing datasets of ground-truth bundles

Diffusion tensor imaging (DTI) is a noninvasive MRI technique used to assess white matter (WM) integrity, fiber orientation, and structural connectivity (SC) using water diffusion properties. DTI techniques are rapidly evolving and are now having a dramatic effect on depression research. Major depressive disorder (MDD) is highly prevalent and a leading cause of worldwide disability. Despite decades of research, the neurobiology of MDD remains poorly understood. MDD is increasingly viewed as a disorder of neural circuitry in which a network of brain regions involved in mood regulation is dysfunctional. In an effort to better understand the neurobiology of MDD and develop more effective treatments, much research has focused on delineating the structure of this mood regulation network. Although many studies have focused on the structural connectivity of the mood regulation network, findings using DTI are highly variable, likely due to many technical and analytical limitations. Further, structural connectivity pattern analyses have not been adequately utilized in specific clinical contexts where they would likely have high relevance, e.g., the use of white matter deep brain stimulation (DBS) as an investigational treatment for depression. In this dissertation, we performed a comprehensive analysis of structural WM integrity in a large sample of depressed patients and demonstrated that disruption of WM does not play a major role in the neurobiology of MDD. Using graph theory analysis to assess organization of neural network, we elucidated the importance of the WM network in MDD. As an extension of this WM network analysis, we identified the necessary and sufficient WM tracts (circuit) that mediate the response of subcallosal cingulate cortex DBS treatment for depression; this work showed that such analyses may be useful in prospective target selection. Collectively, these findings contribute to better understanding of depression as a neural network disorder and possibly will improve efficacy of SCC DBS.

Mild cognitive impairment (MCI) is a transition phase between normal aging and Alzheimer’s disease. Individuals with MCI show impairment in cognition as well as corresponding damage to areas of their brain. Performance on tasks such as discriminating objects with ambiguous features has been associated with damage to the perirhinal cortex, while scenes with structural (spatial) elements have been associated with damage to the hippocampus. In addition, attention is regarded as one of the first non-memory domains to decline in MCI. A relatively new MRI technique called diffusion tensor imaging (DTI) is sensitive to white matter microstructural integrity and has been associated with changes due to cognitive decline. 18 MCI (14 amnesic, 4 vascular) and 12 healthy matched controls were assessed in feature ambiguity, attention and structural learning to assess associated deficits in MCI. Associations with white matter microstructural integrity were then investigated. The MCI groups were discovered to perform worse than controls on the test of structural learning. In addition, altered attention networks were found in MCI and were associated with white matter microstructural integrity. No significant differences were found for feature ambiguity. These findings suggest there may be specific damage to the hippocampus while the perirhinal cortex may be preserved in MCI. Furthermore, dysfunction in attention was found to be associated with white matter microstructural integrity. These experimental tests may be useful in assessing dysfunction in MCI and identifying degeneration in white matter microstructural integrity. Further studies with larger sample sizes are needed to validate these findings.

Telomeres are the outermost parts of linear chromosomes. They consist of tandemly repeated non-coding short nucleotide sequences (TTAGGG in all vertebrates), in humans spanning over the last 2 to 15 kilobase pairs of the chromosome. Due to the end-replication problem, telomeres shorten with each cellular division. A critically short telomere will trigger the cell to enter a state of cellular senescence or to apoptose. The rate of telomere shortening can be accelerated by factors such as oxidative stress and inflammation. Taken together, this contributed to making telomere length a candidate biomarker of health and aging. Studies have shown that leukocyte telomere length progressively shortens with age, and that it independent of age is associated with age-related morbidity, lifestyle factors, and mortality. This thesis was aimed at exploring the relationships of leukocyte telomere length with various functional and structural attributes of the brain. In Paper I, telomere length was shown to be longer among non-demented carriers of the apolipoprotein E (APOE) ε4 allele, a well-established risk factor for Alzheimer’s disease. However, the rate of telomere shortening was greater among the ε4 carriers, possibly due to the higher levels of oxidative stress and inflammation associated with this allele. Furthermore, performance on episodic memory tests was inversely related to telomere length among ε4 carriers. The results may contribute to a better understanding of the pathophysiology related to the APOE ε4 allele. The volume of the hippocampus, a structure in the brain critical for episodic memory function, was in Paper II found to be inversely related to telomere length among non-demented APOE ε3/ε3 carriers. No correlation between hippocampal volume and telomere length was discernible among ε4 carriers, but they fit the pattern exhibited by the ε3/ε3 carriers as they tended to have smaller hippocampi and longer telomere length compared with the ε3/ε3 carriers. The results are possibly explained by a low proliferative activity among subjects with smaller hippocampi, which might also explain the inverse association between telomere length and episodic memory performance in Paper I. In Paper III, we describe results corroborating earlier findings of shorter telomere length among individuals suffering from depression. Moreover, we found that the shorter telomere length among the patients to a large extent could be linked to a hypocortisolemic state; a state which has been associated with chronic stress. The findings corroborate the link between telomere length and stress, and underline the role of stress in depressive illness. Two prominent manifestations of the aging brain are atrophy and white matter hyperintensities. In Paper IV, we report that white matter hyperintensities and cerebral subcortical atrophy were associated with shorter telomere length in aged non-demented individuals. Cortical atrophy was not associated with telomere length. Inflammation may be the underlying cause of the associations, as it is linked to telomere attrition, subcortical atrophy, and white matter hyperintensities. Taken together, these results show that leukocyte telomere length has the potential of being used as a biomarker for structural and functional attributes of the brain. Furthermore, the findings can provide new insights into mechanisms of disease and aging of the brain

L’imagerie par résonance magnétique pondérée en diffusion est une modalité unique sensible aux mouvements microscopiques des molécules d’eau dans les tissus biologiques. Il est possible d’utiliser les caractéristiques de ce mouvement pour inférer la structure macroscopique des faisceaux de la matière blanche du cerveau. La technique, appelée tractographie, est devenue l’outil de choix pour étudier cette structure de façon non invasive. Par exemple, la tractographie est utilisée en planification neurochirurgicale et pour le suivi du développement de maladies neurodégénératives.Dans cette thèse, nous exposons certains des biais introduits lors de reconstructions par tractographie, et des méthodes sont proposées pour les réduire. D’abord, nous utilisons des connaissances anatomiques a priori pour orienter la reconstruction. Ainsi, nous montrons que l’information anatomique sur la nature des tissus permet d'estimer des faisceaux anatomiquement plausibles et de réduire les biais dans l’estimation de structures complexes de la matière blanche. Ensuite, nous utilisons des connnaissances microstructurelles a priori dans la reconstruction, afin de permettre à la tractographie de suivre le mouvement des molécules d’eau non seulement le long des faisceaux, mais aussi dans des milieux microstructurels spécifiques. La tractographie peut ainsi distinguer différents faisceaux, réduire les erreurs de reconstruction et permettre l’étude de la microstructure le long de la matière blanche. Somme toute, nous montrons que l’utilisation de connaissances anatomiques et microstructurelles a priori, en tractographie, augmente l’exactitude des reconstructions de la matière blanche du cerveau
Diffusion-weighted magnetic resonance imaging is a unique imaging modality sensitive to the microscopic movement of water molecules in biological tissues. By characterizing the movement of water molecules, it is possible to infer the macroscopic neuronal pathways of the brain. The technique, so-called tractography, had become the tool of choice to study non-invasively the human brain's white matter in vivo. For instance, it has been used in neurosurgical intervention planning and in neurodegenerative diseases monitoring. In this thesis, we report biases from current tractography reconstruction and suggest methods to reduce them. We first use anatomical priors, derived from a high resolution T1-weighted image, to guide tractography. We show that knowledge of the nature of biological tissue helps tractography to reconstruct anatomically valid neuronal pathways, and reduces biases in the estimation of complex white matter regions. We then use microstructural priors, derived from the state-of-the-art diffusionweighted magnetic resonance imaging protocol, in the tractography reconstruction process. This allows tractography to follow the movement of water molecules not only along neuronal pathways, but also in a microstructurally specific environment. Thus, the tractography distinguishes more accurately neuronal pathways and reduces reconstruction errors. Moreover, it provides the mean to study white matter microstructure characteristics along neuronal pathways. Altogether, we show that anatomical and microstructural priors used during the tractography process improve brain’s white matter reconstruction

Objectives: One of the most prominent features of schizophrenia is relatively lower general cognitive ability (GCA). An emerging approach to understanding the roots of variation in GCA relies on network properties of the brain. In this multi-center study, we determined global characteristics of brain networks using graph theory and related these to GCA in healthy controls and individuals with schizophrenia. Methods: Participants (N = 116 controls, 80 patients with schizophrenia) were recruited from four sites. GCA was represented by the first principal component of a large battery of neurocognitive tests. Graph metrics were derived from diffusion-weighted imaging. Results: The global metrics of longer characteristic path length and reduced overall connectivity predicted lower GCA across groups, and group differences were noted for both variables. Measures of clustering, efficiency, and modularity did not differ across groups or predict GCA. Follow-up analyses investigated three topological types of connectivity—connections among high degree “rich club” nodes, “feeder” connections to these rich club nodes, and “local” connections not involving the rich club. Rich club and local connectivity predicted performance across groups. In a subsample (N = 101 controls, 56 patients), a genetic measure reflecting mutation load, based on rare copy number deletions, was associated with longer characteristic path length. Conclusions: Results highlight the importance of characteristic path lengths and rich club connectivity for GCA and provide no evidence for group differences in the relationships between graph metrics and GCA.

This thesis work focuses on the dynamical properties of two-component galaxy models characterized by a stellar density distribution described by a Jaffe profile, and a galaxy (stars plus dark matter) density distribution following a r^(-3) shape at large radii. The dark matter (hereafter, DM) density profile is defined by the difference between the galaxy and the stellar profiles. The orbital structure of the stellar component is described by the Osipkov-Merritt (OM) radial anisotropy, and that of the DM halo is assumed isotropic; a black hole (BH) is also added at the center of the galaxy. The thesis is organized as follows. In Chapter 2 the main structural properties of the models are presented, and the conditions required to have a nowhere negative and monothonically decreasing DM halo density profile are derived; a discussion is also given of how the DM component can be built in order to have the same asymptotical behaviour, in the outer regions and near the center, as the Navarro-Frenk-White (NFW) profile. In Chapter 3 an investigation of the phase-space properties of the models is carried out, both from the point of view of the necessary and sufficient conditions for consistency, and from the direct inspection of the distribution function; the minimum value of the anisotropy radius for consistency is derived in terms of the galaxy parameters. In Chapter 4 the analytical solution of the Jeans equations with OM anisotropy is presented, together with the projection of the velocity dispersion profile at small and large radii. Finally, in Chapter 5 the global quantities entering the Virial theorem are explicitly calculated; these can be used for energetic considerations that are briefly mentioned, and allow us to determine the fiducial anisotropy limit required to prevent the onset of Radial Orbit Instability as a function of the galaxy parameters. The main results are summarized in Chapter 6, and some technical details are given in the Appendices.

L’ambition des très hauts champs magnétiques (≥ 7T) à forts gradients (≥ 300mT/m) est de dépasser la résolution millimétrique imposée à plus bas champ pour atteindre l’échelle mésoscopique en neuroimagerie. Etudier le cerveau à cette échelle est essentiel pour comprendre le lien entre fonction et substrat anatomique. Malgré les progrès réalisés sur les aimants cliniques à 7T, il n’en est pas de même des gradients. Cette thèse vise à cartographier le cerveau humain à l’échelle mésoscopique via l’étude de pièces anatomiques post mortem. Une approche alternative a été choisie, reposant sur l'utilisation d'imageurs précliniques à très hauts champs (7T et 11.7T) et forts gradients (780mT/m). Après une première étape de préparation (extraction et fixation) opérée au CHU de Tours, une pièce anatomique complète a été scannée à 3T, avant découpe de l’hémisphère gauche en sept blocs. Un protocole d’acquisition IRM ciblant une résolution mésoscopique a ensuite été mis en place à 11.7T. Ce protocole, incluant des séquences anatomiques, relaxométriques, et de diffusion, a été validé à l’aide de deux structures clé: un hippocampe et un tronc cérébral. Les données anatomiques et de diffusion acquises à une résolution mésoscopique sur l’hippocampe ont permis de segmenter ses sous-champs, d’extraire le circuit polysynaptique et d’observer l’existence d’un gradient de connectivité et de densité neuritique positif dans la direction postéro-antérieure de l’hippocampe. L’utilisation de modèles avancés d’étude de la microstructure a également révélé l’apport de ces techniques pour la segmentation de l’hippocampe, les cartes de densité neuritique révélant les trois couches des champs ammoniens. Un tronc cérébral a ensuite été scanné, avec une résolution atteignant la centaine de micromètres. Une segmentation de 53 de ses 71 noyaux a été réalisée au sein du CHU de Tours, permettant d’établir la cartographie IRM du tronc cérébral humain la plus complète à ce jour. Les principaux faisceaux de la substance blanche ont été reconstruits, ainsi que les projections du locus coeruleus, structure connue pour être atteinte dans le maladie de Parkinson. Forts de ces résultats, la campagne d'acquisition de l'hémisphère gauche, d’une durée de 10 mois, a été initiée. Le protocole d’acquisition à 11.7T intègre des séquences anatomiques (100/150µm) ainsi que des séquences d'imagerie 3D pondérées en diffusion (b=1500/4500/8000 s/mm², 25/60/90 directions) à 200µm. Des acquisitions complémentaires réalisées à 7T comprenant des séquence d’écho de spin rapide avec inversion-récupération ont par ailleurs permis d’étudier la myéloarchitecture du cortex cérébral et d’identifier automatiquement sa structure laminaire. Un nouveau modèle de mélange de Gaussiennes a été développé, intégrant les informations myéloarchitecturales issues de la cartographie T1 et les informations cytoarchitecturales issues de l’imagerie de diffusion. Il a ainsi pu être démontré que l’utilisation conjointe de ces deux informations permettait de mettre en évidence des couches du cortex visuel, l’information myéloarchitecturale favorisant l’extraction des couches externes et la densité neuritique celle des couches plus profondes. Enfin, l’exploitation des données IRM acquises à 11.7T sur les différents blocs a nécessité la mise en place d’une chaîne de prétraitements pour corriger les artéfacts d’imagerie et reconstruire l’hémisphère entier à l’aide de stratégies de recalage difféomorphe avancées. L’objectif de ce projet est l’obtention d’un jeu de données IRM de très haute résolution spatio-angulaire de l’hémisphère gauche. Ce jeu de données anatomique et de diffusion unique permettra à terme de constituer un nouvel atlas IRM mésoscopique de la structure, de la connectivité et de la cytoarchitecture du cerveau humain
The aim of ultra-high field strength (≥7T) and ultra-strong gradient systems (≥300mT/m) is to go beyond the millimeter resolution imposed at lower field and to reach the mesoscopic scale in neuroimaging. This scale is essential to understand the link between brain structure and function. However, despite recent technological improvements of clinical UHF-MRI, gradient systems remain too limited to reach this resolution. This thesis aims at answering the need for mapping the human brain at a mesoscopic scale by the study of post mortem samples. An alternative approach has been developed, based on the use of preclinical systems equipped with ultra-high fields (7T/11.7T) and strong gradients (780mT). After its extraction and fixation at Bretonneau University Hospital (Tours), an entire human brain specimen was scanned on a 3T clinical system, before separating its two hemispheres and cutting each hemisphere into seven blocks that could fit into the small bore of an 11.7T preclinical system. An MRI acquisition protocol targeting a mesoscopic resolution was then set up at 11.7T. This protocol, including anatomical, quantitative, and diffusion-weighted sequences, was validated through the study of two key structures: the hippocampus and the brainstem. From the high resolution anatomical and diffusion dataset of the human hippocampus, it was possible to segment the hippocampal subfields, to extract the polysynaptic pathway, and to observe a positive gradient of connectivity and neuritic density in the posterior-anterior direction of the hippocampal formation. The use of advanced microstructural models (NODDI) also highlighted the potential of these techniques to reveal the laminar structure of the Ammon’s horn. A high resolution anatomical and diffusion MRI dataset was obtained from the human brainstem with an enhanced resolution of a hundred micrometers. The segmentation of 53 of its 71 nuclei was performed at the Bretonneau University Hospital, making it the most complete MR-based segmentation of the human brainstem to date. Major white matter bundles were reconstructed, as well as projections of the locus coeruleus, a structure known to be impaired in Parkinson’s disease. Buoyed by these results, a dedicated acquisition campaign targeting the entire left hemisphere was launched for total scan duration of 10 months. The acquisition protocol was performed at 11.7T and included high resolution anatomical sequences (100/150μm) as well as 3D diffusion-weighted sequences (b=1500/4500/8000 s/mm², 25/60/90 directions, 200μm). In addition, T1-weighted inversion recovery turbo spin echo scans were performed at 7T to further investigate the myeloarchitecture of the cortical ribbon at 300µm, revealing its laminar structure. A new method to automatically segment the cortical layers was developed relying on a Gaussian mixture model integrating both T1-based myeloarchitectural information and diffusion-based cytoarchitectural information. The results gave evidence that the combination of these two contrasts highlighted the layers of the visual cortex, the myeloarchitectural information favoring the extraction of the outer layers and the neuritic density favoring the extraction of the deeper layers. Finally, the analysis of the MRI dataset acquired at 11.7T on the seven blocks required the development of a preprocessing pipeline to correct artifacts and to reconstruct the entire hemisphere using advanced registration methods. The aim was to obtain an ultra-high spatio-angular resolution MRI dataset of the left hemisphere, in order to establish a new mesoscopic post mortem MRI atlas of the human brain, including key information about its structure, connectivity and microstructure

L’Imagerie par résonance magnétique (IRM) est un outil fondamental pour l’exploration in vivo du développement du cerveau chez le fœtus, le bébé et l’enfant. Elle fournit plusieurs paramètres quantitatifs qui reflètent les changements des propriétés tissulaires au cours du développement en fonction de différents processus de maturation. Cependant, l’évaluation fiable de la maturation de la substance blanche est encore une question ouverte: d'une part, aucun de ces paramètres ne peut décrire toute la complexité des changements sous-jacents; d'autre part, aucun d'eux n’est spécifique d’un processus de développement ou d’une propriété tissulaire particulière. L’implémentation d’approches multiparamétriques combinant les informations complémentaires issues des différents paramètres IRM devrait permettre d’améliorer notre compréhension du développement du cerveau. Dans ce travail de thèse, je présente deux exemples de telles approches et montre leur pertinence pour l'étude de la maturation des faisceaux de substance blanche. La première approche fournit une mesure globale de la maturation basée sur la distance de Mahalanobis calculée à partir des différents paramètres IRM (temps de relaxation T1 et T2, diffusivités longitudinale et transverse du tenseur de diffusion DTI) chez des nourrissons (âgés de 3 à 21 semaines) et des adultes. Cette approche offre une meilleure description de l’asynchronisme de maturation à travers les différents faisceaux que les approches uniparamétriques. De plus, elle permet d'estimer les délais relatifs de maturation entre faisceaux. La seconde approche vise à quantifier la myélinisation des tissus cérébraux, en calculant la fraction de molécules d’eau liées à la myéline (MWF) en chaque voxel des images. Cette approche est basée sur un modèle tissulaire avec trois composantes ayant des caractéristiques de relaxation spécifiques, lesquelles ont été pré-calibrées sur trois jeunes adultes sains. Elle permet le calcul rapide des cartes MWF chez les nourrissons et semble bien révéler la progression de la myélinisation à l’échelle cérébrale. La robustesse de cette approche a également été étudiée en simulations. Une autre question cruciale pour l'étude du développement de la substance blanche est l'identification des faisceaux dans le cerveau des enfants. Dans ce travail de thèse, je décris également la création d'un atlas préliminaire de connectivité structurelle chez des enfants âgés de 17 à 81 mois, permettant l'extraction automatique des faisceaux à partir des données de tractographie. Cette approche a démontré sa pertinence pour l'évaluation régionale de la maturation de la substance blanche normale chez l’enfant. Pour finir, j’envisage dans la dernière partie du manuscrit les applications potentielles des différentes méthodes précédemment décrites pour l’étude fine des réseaux de substance blanche dans le cadre de deux exemples spécifiques de pathologies : les épilepsies focales et la leucodystrophie métachromatique
Magnetic Resonance Imaging (MRI) is a fundamental tool for in vivo investigation of brain development in newborns, infants and children. It provides several quantitative parameters that reflect changes in tissue properties during development depending on different undergoing maturational processes. However, reliable evaluation of the white matter maturation is still an open question: on one side, none of these parameters can describe the whole complexity of the undergoing changes; on the other side, neither of them is specific to any particular developmental process or tissue property. Developing multiparametric approaches combining complementary information from different MRI parameters is expected to improve our understanding of brain development. In this PhD work, I present two examples of such approaches and demonstrate their relevancy for investigation of maturation across different white matter bundles. The first approach provides a global measure of maturation based on the Mahalanobis distance calculated from different MRI parameters (relaxation times T1 and T2, longitudinal and transverse diffusivities from Diffusion Tensor Imaging, DTI) in infants (3-21 weeks) and adults. This approach provides a better description of the asynchronous maturation across the bundles than univariate approaches. Furthermore, it allows estimating the relative maturational delays between the bundles. The second approach aims at quantifying myelination of brain tissues by calculating Myelin Water Fraction (MWF) in each image voxel. This approach is based on a 3-component tissue model, with each model component having specific relaxation characteristics that were pre-calibrated in three healthy adult subjects. This approach allows fast computing of the MWF maps from infant data and could reveal progression of the brain myelination. The robustness of this approach was further investigated using computer simulations. Another important issue for studying white matter development in children is bundles identification. In the last part of this work I also describe creation of a preliminary atlas of white matter structural connectivity in children aged 17-81 months. This atlas allows automatic extraction of the bundles from tractography datasets. This approach demonstrated its relevance for evaluation of regional maturation of normal white matter in children. Finally, in the last part of the manuscript I describe potential future applications of the previously developed methods to investigation of the white matter in cases of two specific pathologies: focal epilepsy and metachromatic leukodystrophy

Intracerebral hemorrhage (ICH) results in secondary brain injury caused partially by blood and its metabolites. Survivors of ICH are often left with severe disabilities, therefore, decreasing the extent of this secondary injury may improve functional outcome of patients. Incubation of mouse brain slices with partially oxidized bilirubin, a neurotoxic blood breakdown product, caused a dose- and time-dependent decrease in axonal function, suggesting a reduced number of conducting myelinated axons. These effects did not occur when tissue was incubated with non-oxidized bilirubin. Injection of bilirubin into the corpus callosum of mice caused functional impairment of unmeylinated axons; however, immunohistochemical staining of the tissue showed evidence of structural damage to both oligodendrocytes and axons. This data provides evidence for functional and structural damage to white matter in the presence of partially oxidized bilirubin Therefore, diminishing the duration of presence of bilirubin and its oxidation in the brain warrants study as a means of decreasing secondary brain injury after ICH.

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.

博士
國立臺灣大學
生命科學系
105
Gray matter and white matter of the human brain degenerate with age. Using neuroimaging to characterize age-associated degenerative patterns in normal and pathological brain aging processes can help define normal aging and set up a reference for brain health exam. Previous neuroimaging studies on white matter fiber changes in healthy old people or patients with mild cognitive impairment (MCI) reported alteration of the tracts in the temporal-limbic regions and commissural fibers. The present thesis assumes that white matter tracts may be viewed as an inter-dependent network system, rather than isolated entities. We hypothesized that the degenerative patterns of white matter systems were different between normal aging and pathological aging. We investigated this hypothesis in the temporal-limbic fiber system and commissural fiber system. We conducted a cross-sectional study to investigate fiber degeneration patterns in three groups of participants, i.e. healthy young group, healthy old group and MCI group. The investigation entailed three separate studies including normal aging study (comparison between healthy young and healthy old groups), MCI study (comparison between healthy old and MCI groups) and abnormal aging study (comparison between healthy young and MCI groups). We used the template-based automatic analytical method (TBAA) to generate the profiles of generalized fractional anisotropy (GFA) index of the six tracts in the temporal-limbic fiber system and 18 tracts in the commissural fiber system. We used three statistical methods, i.e. mean GFA comparison, threshold-free cluster weighted (TFCW) method, and tract covariance analysis, to analyze fiber degeneration patterns in each of the studies. With this study design, we expect to identify the detailed patterns of fiber degeneration under healthy and pathological aging processes. We found heterogeneous aging effects and different patterns of age-associated changes in the two fiber systems. The degeneration pattern of the temporal-limbic fiber system adheres to the normal aging process, whereas that of the commissural fiber system is prone to pathological aging process. Specifically, the temporal-limbic fibers degenerated with age, whereas the callosal fibers degenerated more severely in MCI. The tract covariance of the commissural fiber system decreased with age and became more obvious in pathological aging. Our results suggest that the degeneration patterns of the commissural fiber system could serve as a promising biomarker of pathological aging. The present thesis demonstrates different age-associated patterns of fiber degeneration in two fiber systems. This knowledge may shed light on the complex pathological mechanisms of brain aging.

Les progrès dans le domaine de la neuroimagerie cérébrale ont permis une certaine compréhension des maladies mentales comme la schizophrénie. Cependant, peu de résultats sont cohérents et ils sont souvent contradictoires, ce qui rend difficile de tirer des conclusions concrètes par rapport à la maladie. Plusieurs facteurs jouent un rôle dans les résultats divergents et convergents : Les différentes techniques d'imagerie et les analyses, le nombre de patients inclus dans les études, l'âge des patients, l'âge de l’'apparition de la maladie, les critères de diagnostic, les effets du traitement antipsychotique, le statut social, ainsi que les comorbidités, font partie de ces facteurs. Bien que les différences cérébrales entre femmes et hommes « normaux » sont bien établies, ce n’est que ces dernières années que des études en neuroimagerie de la schizophrénie ont abordé les différences homme-femme comme une explication potentielle des résultats discordants de l’imagerie cérébrale. L'objectif de cette thèse est de comprendre le rôle du sexe (genre féminin et masculin) dans les anomalies anatomiques observées dans la schizophrénie; ceci, en réalisant des études qui contrôlent, autant que possible, l'effet de différentes variables confondantes et en utilisant des analyses d’IRM automatisées chez des patients et des sujets sains de même âge et du même sexe. Une brève revue globale des résultats actuels dans le domaine de la schizophrénie ainsi que des résultats liés aux différences entre les sexes dans la schizophrénie vont être présentés. La première étude visait à étudier l'influence des différences de sexe sur des mesures de la gyrification corticale de la schizophrénie. Étant donné que la schizophrénie est une maladie dont les «symptômes cliniques » ont un impact négatif sur la qualité de vie des patients qui en souffrent, nous avons exploré la relation entre la gyrification corticale et les différents symptômes de la schizophrénie chez les hommes et les femmes atteints de ce trouble psychiatrique. Le rôle du sexe sur la gyrification corticale et son association aux symptômes a été à peine étudié chez les patients atteints de schizophrénie ; c’est pour cette raison que, nous croyons que cette étude est d’une importante valeur. Dans cette première étude, des images 3T T1 ont été acquises auprès de 48 patients atteints de schizophrénie (24 hommes [SZ-M] et 24 femmes [SZ-F]) et 48 volontaires sains (24 hommes [NC-M] et 24 femmes [NC-F]), appariés en fonction de l'âge et du sexe. Des mesures d’indice de gyrification (IG) pour chaque hémisphère et les quatre lobes cérébraux (frontaux, temporal, pariétal, et occipital) ont été effectuées en utilisant le pipeline de CIVET, lequel est entièrement automatisé. Plusieurs résultats intéressants ont émergé: les patients avaient des valeurs inférieures importantes de l’IG global par rapport aux témoins; SZ-M avaient des valeurs d'IG hémisphériques significativement inférieurs par rapport à NC-M, cela n'a pas été observé dans les groupes de femmes. Aucune différence entre les sexes dans les valeurs de diminution de l’IG avec l'âge n’a été observés chez les témoins sains par contre, une diminution de la valeur de l’IG avec l’âge chez les patients était plus importante chez les patients homme que les patients femmes. Une détérioration plus progressive dans l'hémisphère droit dans les deux groupes de patients a été observée, tout comme des réductions significatives des valeurs d’IG en relation avec la durée de la maladie chez SZ-M, mais pas chez SZ-F. Dans les groupes de patients, on observe des diminutions des valeurs d’IG dans les lobes frontaux bilatéraux et, le lobe occipital droit; le groupe SZ-M a montré une valeur d’IG significativement plus élevée par rapport à NC-M dans le lobe temporal droit; SZ-F a montré des valeurs d’IG significativement plus faibles dans les lobes bilatéraux frontaux, temporaux, pariétaux et le lobe occipital droit, par rapport à NC-F. Aucune corrélation significative n'a été trouvée entre les valeurs de l'IG et le profil de la symptomatologique dans les deux groupes de patients. Etant donné que l’IG reflète, en partie, des altérations dans le développement et la connectivité cérébrale, la diminution de l’IG observée chez les patients est en accord avec le modèle de développement neurobiologique de disconnectivité dans la schizophrénie. De plus, nous soulignons l'importance de l'âge ainsi que la durée de la maladie lorsque nous comparons les hommes et les femmes atteints de schizophrénie. Cependant, nous n'avons pas observé de corrélation significative n'a été trouvée entre les valeurs de l'IG et les symptômes, ce qui est d'un intérêt particulier et inattendu compte tenu des résultats de la neuroimagerie montrant par exemple certaines corrélations entre les symptômes positifs et certaines anomalies du lobe temporal dans la schizophrénie. Considérant ces résultats, nous avons décidé d'investiguer, dans notre deuxième étude, l'association entre les symptômes et les densités de matière grise (DMG) et de matière blanche (DMB) à la place des mesures de gyrification corticale. Nous avons utilisé la morphométrie basée sur le voxel "Voxel Based Morphometry (VBM8.0 with Diffeomorphic Anatomical Registration (Through Exponentiated Lie Algebra [DARTEL])" et la modélisation linéaire automatique (SPSS21.0 ALM) sur les images 3T T1 MPRAGE acquises auprès de 40 patients atteints de schizophrénie (SZ) et 41 témoins sains (NC). Nous avons trouvé que les patients atteints de schizophrénie avaient une DMG réduite dans le cortex cingulaire antérieur, le cortex temporal médian gauche et une DMG plus élevée dans le cortex cingulaire postérieur gauche par rapport aux sujets sains. Une diminution significative de DMB dans la région fronto-rectal inférieure gauche et la région pariétale postérieure gauche a été observée chez les patients comparés aux sujets sains. Nous avons trouvé des corrélations positives entre les symptômes positifs et la DMG dans l'insula gauche et le noyau caudé droit; et entre les symptômes négatifs et la DMG dans le cortex frontal médian droite et le lobe postérieur de cervelet droit. Nous avons aussi trouvé des corrélations négatives de DMG dans la région pariétale droite (précuneus), le lobe postérieur du cervelet gauche et les symptômes positifs; ainsi qu'entre la DMG du lobe antérieur du cervelet gauche et les symptômes négatifs. En outre, des corrélations positives ont été trouvées entre la DMB dans le cortex frontal médian droit et les symptômes positifs et entre le DMB dans la région frontale supérieure droite et les symptômes négatifs. Des corrélations négatives ont été trouvées entre les symptômes positifs et la DMB dans la région occipitale inférieure droite et le cunéus occipital droit, tandis que des corrélations négatives ont été trouvées entre la DMB et la région frontale supérieure gauche. Il est intéressant de noter que lorsque les symptômes ont été analysés par regroupement, nous avons trouvé que le symptôme de la désorganisation conceptuelle corrélait positivement avec la DMG totale et la DMB totale. L’augmentation de DMG a été associée à une diminution de la gravité des hallucinations et du manque de spontanéité; tandis que l'augmentation de DMB totale a été associée à la diminution de la sévérité de l'hostilité et des idées de grandeur. Une comparaison entre les groupes d'hommes a montré une diminution de la DMG chez les patients schizophrènes, tandis qu’aucune différences n’a été observée dans les groupes de femmes. Nous n’avons trouvé aucune corrélation entre la DMG, la DMB, le liquide cérébro-spinal, le volume total du cerveau, les symptômes individuels et la schizophrénie chez les sujets féminins. Chez les hommes atteints de schizophrénie, on observe des corrélations négatives importantes entre les idées de grandeur et la DMB; des corrélations positives entre la désorientation et la DMB. De plus on observe des corrélations entre et les déficits d'attention et de DMG et DMB. Nos résultats montrent que ces associations sont différentes chez les hommes et les femmes atteints de la schizophrénie. La symptomatologie de schizophrénie est un mélange de déficits cognitifs et socio-affectifs. Dans ce contexte, le but de notre troisième étude est d'étudier chez les patients atteints de la schizophrénie des DMG et DMB et leur relation avec l’acuité mnésique avec des contenus émotionnelles (négatives, positives et neutres) ainsi que étudier l'effet des différences de sexe sur nos résultats. Quarante et un patients droitiers, traités par antipsychotique, souffrant de schizophrénie (SZ) et 40 témoins sains (NC), tous droitiers, ont participé à l’étude. Nous avons utilisé des images de l'International Affective Picture System (IAPS), une banque d'images émotionnelles, et de l’IRM. On observe chez les témoins sains des corrélations entre les valeurs élevées de DMG du cortex pariétal postérieur, du lentiform, du putamen, noyau caudé, le cortex orbitofrontal inférieur gauche et la reconnaissance des images négatives. On observe des corrélations entre la DMG dans la région temporale gauche, fusiforme et la reconnaissance des images positives ; et également dans le cervelet antérieur gauche et l’acuité des images neutres. Chez les patients on observe des valeurs élevées des DMG dans le cortex occipital inférieur gauche et la reconnaissance des images négatives, mais aucune corrélation entre la capacité de reconnaissance des images positives ou neutres. Nous avons observé chez les témoins sains: des relations significatives entre la DMB dans le cortex pariétal postcentral gauche et la capacité de reconnaître des images négatives; dans le cortex temporal inferieur gauche, le cortex pariétal gauche (précuneus), le cortex frontal gauche et la capacité de reconnaissance des images positives; des valeurs de DMB du cortex temporel médian et l’acuité des images neutres. Les patients atteints de schizophrénie ont montré des relations significatives entre de DMB dans le cortex occipito-lingual gauche et la reconnaissance des images négatives ; dans le cortex pariétal angulaire gauche et la reconnaissance des images positives ; et dans le cortex temporal supérieur droit et les images neutres. Les différences de sexe dans la schizophrénie ont été observées : chez les patients de sexe masculin, des corrélations négatives ont été trouvées entre les DMB et la capacité de reconnaître des images négatives et positives. Chez les hommes sains, nous avons trouvé des corrélations positives entre des valeurs totales de DMG et la capacité de reconnaître des images négatives. Nous n’avons pas observé de corrélations dans les groupes de femmes. Ces résultats soutiennent l'hypothèse de l'atrophie fronto-temporale régionale chez les patients schizophrènes. Toutefois, nous notons qu’ils ont des augmentations relatives des valeurs de DMB dans le cortex occipito-pariétal. Nous avançons l'hypothèse que les déficits mnésiques chez les patients sont liés à des perturbations dans la coordination des réseaux cérébraux, ce qui peut être affecté par des déficits structuraux plus évidents chez les patients masculins. Par conséquent, nous préconisons que les futures études devraient utiliser le connectome ou l’approche « réseaux cérébraux » pour étudier l’impact du sexe (genre masculin-féminin) sur les déficits cognitifs et symptomatologiques dans la schizophrénie. Nos résultats globaux soulignent l'importance de la différence entre homme et femme dans la modulation de manifestations cliniques et fonctionnelles de la schizophrénie. Ainsi, nous croyons que le contrôle des covariables comme l'âge, la durée de la maladie et le statut social est insuffisant et que les études futures sur la schizophrénie devraient systématiquement séparer les hommes des femmes, afin de mieux comprendre cette maladie mentale complexe et dévastatrice.
Advances in cerebral neuroimaging techniques have helped our understanding of mental illnesses, such as schizophrenia. Few findings remain consistent and are often contradictory, making it difficult to draw informative conclusions about the disease. Several factors play a role in both diverging and converging results. Imaging technique and analyses, number of patients involved, age of patients, age at onset of the disease, diagnostic criteria, antipsychotic treatment effects, social status, comorbidities, are among some of the reasons. Despite well established cerebral sex differences in healthy population, it is only in recent years that neuroimaging studies in schizophrenia have addressed sex differences as a major possible explanation for discrepant neuroimaging finding. The aim of this thesis is to help understand the role of sex on brain structures in schizophrenia, by conducting studies that control as much as possible for other variables and by using MRI automated analyses for patients and controls matched for age and sex. This work will briefly present findings in schizophrenia in general, and then an extensive review of the literature on sex differences in schizophrenia will be presented. From it, we are able to conclude that sex differences have been reported with rare exception in almost all aspects involved in the life of patients with schizophrenia. Chapters 1. The first study investigated sex differences in cortical gyrification in schizophrenia patients (SZ). In addition, considering that schizophrenia is a disease of “clinical symptoms” that determine the quality of life of patients afflicted by it, we explored the relation between cortical gyrification and symptoms in males and females with schizophrenia. The role of sex on cortical gyrification and its association with symptoms has been scarcely investigated in patients with schizophrenia. In this study, 3T T1 images were acquired from 48 schizophrenia patients (24 males [SZ-M] and 24 females [SZ-F]) and 48 normal controls [NC] (24 males [NC-M] and 24 females [NC-F]) matched for age, sex, and handedness. Gyrification Index (GI) analyses for each hemisphere and four cerebral regions (frontal, temporal, parietal, and occipital) were performed using the fully automated CIVET pipeline. Patients had significant lower values of the overall GI relative to normal controls and SZ-M had significant lower right hemispheric GI values compared to NC-M. This was not observed in either NC-F or in SZ. No gender difference in GI values decreases with age were observed in NC. In patients, GI decreases with age were greater in SZ-M than SZ-F, with a more progressive deterioration in the right hemisphere in both patient groups. Significant GI value reductions in association with duration of illness were observed in SZ-M but not in SZ-F. Patient groups had lower GI in bilateral frontal, temporal, and parietal lobes than controls. SZ-F had significant lower GI values in left frontal, bilateral temporal and left parietal lobe compared to NC-F. No significant correlations were found between GI values and symptom scores in either group of patients. Since GI reflects, in part, alterations in cerebral development and connectivity, the decrease in GI observed in patients is in agreement with the neurodevelopmental model of disconnectivity in schizophrenia, and may explain the worse prognosis and social outcome observed in male patients. Furthermore, we emphasize the importance of age and duration of illness when comparing males and females with schizophrenia. Observed differences between male and female patients may reflect a more diffuse and generalized cortical loss in males. Female patients had cortical loss in specific regions, while preserving cortical gyrification in compensatory regions. Our latter finding -no significant correlation between GI values and symptom scores- was of particular interest and was unexpected in view of neuroimaging findings of correlations between positive symptoms and temporal lobe abnormalities. 2. In the second study, we examined the association between symptoms and brain structure using gray (GMD) and white matter (WMD) densities. Voxel-based morphometry (VBM8.0 with Diffeomorphic Anatomical Registration Through Exponentiated Lie Algebra [DARTEL]) and Automatic Linear Modeling (SPSS21.0 ALM) were used on 3T T1 MPRAGE images acquired from 40 schizophrenia patients (SZ) and 41 normal controls (NC). We found that SZ had lower GMD in the anterior cingulate cortex and left middle temporal gyrus, and higher GMD in the left posterior cingulate in comparison to NC. SZ had significantly lower WMD in the left inferior fronto-rectal and the left posterior parietal regions in comparison to NC. Significant positive correlations were found between positive symptoms and GMD in the left insula and right caudate, and between negative symptoms and GMD in the right middle frontal and the posterior lobe of the right cerebellum (uvula). Inverse relationships between GMD in the right parietal (precuneus), the left posterior lobe of the cerebellum (uvula) and positive symptoms, and between GMD in the left anterior lobe of the cerebellum and negative symptoms were observed in SZ. In addition, positive correlations were found between WMD in the right middle frontal lobe, and between positive symptoms and WMD in the right superior frontal region with negative symptoms. Negative correlations were found between positive symptoms and WMD in the right inferior occipital and the right occipital cuneus, while negative symptoms correlated negatively with the WMD of the left superior frontal. When symptom clusters were analyzed, conceptual disorganization symptom positively correlated with both total GMD and WMD. While increases in GMD were associated with decreased severity of lack of spontaneity and hallucinations symptom, increases in total WMD were associated with decreased severity of hostility and grandiosity symptoms. Comparison between male subjects revealed decreased GMD in male schizophrenia patients, while no differences were observed between females across groups. No correlations were found in female groups between GMD, WMD, CSF, or total brain volume and individual symptoms. In males with schizophrenia, significant negative correlation between ideas of grandiosity and WMD, a positive correlation between disorientation and WMD, and attention deficits and GMD and WMD were found. The current data suggest region-specific GMD and WMD association with negative and positive symptoms. In addition, it reveals that such associations are different in male and female schizophrenia patients. 3. The third study investigated the relationships of GMD and WMD with memory accuracy for emotionally negative, positive, and neutral pictures in schizophrenia patients relative to normal controls. Schizophrenia is characterized by an amalgam of cognitivo-socio-emotional deficits. The relationship between emotion processing on cognition and neurobiological underpinnings merit more attention than it has received so far. Memory deficits are among the most common deficits in schizophrenia and have a widespread impact on cognition in general. Additionally, consistently with the major theme of the present thesis, we investigated the effect of gender on the observed effect. Forty one, right-handed medicated patients with schizophrenia (SZ) and 40 right-handed normal controls (NC) matched by age and sex were assessed for memory accuracy using negative, positive and neutral pictures taken from the International Affective Picture System (IAPS). Imaging methods and analyses were similar to our second study. Fifteen minutes after presentation of selected IAPS images (incidental encoding), subjects were asked to recognize the previously seen images among other images. We found higher GMD in NC in the right posterior parietal cortex, lentiform, putamen, and caudate, as well as the left inferior orbitofrontal cortex, in relation with the negative images accuracy. NC had higher GMD in the left temporal and fusiform regions in relation with the positive images accuracy, and higher GMD in the left anterior cerebellum in relation with neutral images. Schizophrenia subjects had higher GMD in the left inferior occipital cortex in relation with the negative images accuracy, but GMD was not correlated with positive or neutral images accuracy in this group. WMDs correlations were higher in NC in the left postcentral parietal region for negative images; in the left inferior temporal, left precuneus parietal, and left frontal regions for positive images; and in the left middle temporal region for neutral images. Schizophrenia patients had higher WMD in the left lingual occipital for negative images; in the left angular parietal for positive images; and in the right superior temporal region for neutral images. While examining the two sexes separately, we observed inverse correlations between WMD and both negative and positive pictures in male patients. In addition, only in male controls, GMD positively correlated with negative pictures and this correlation was absent in female SZ subjects and NC females. These findings support the hypothesis of fronto-temporal regional atrophy in schizophrenia. Schizophrenia patients have relatively increased occipito-parietal WMD, advancing the hypothesis that the core pathophysiological problem underlying recall memory in SZ may be related to disruptive alterations in the coordination of large-scale brain networks, and this may be affected by structural deficits that are more evident in male patients. It is recommended that future studies should use the connectomes or the brain networks approach to investigate the effect of sex on memory deficits in schizophrenia. Our overall findings point out to the importance of sex in modulating the clinical and functional manifestations of schizophrenia. We believe that controlling for covariates as age, duration of illness, social status, etc. is insufficient and that future studies in schizophrenia should systematically separate male and female findings, if we wish to understand this complex and devastating mental illness.

Multiple sclerosis (MS) is a widespread inflammatory, demyelinating and neurodegenerative disease of the central nervous system (CNS). Various lines of evidence from magnetic resonance image (MRI) have proven that MS results in multiple structural abnormalities, in terms of grey matter (GM) atrophy, white matter (WM) lesions and microstructural damage as well as in functional connectivity abnormalities. Recently, some studies suggested that WM damage may be spatially linked with subsequent cortical and deep GM atrophy in primary progressive and longstanding MS. Other studies showed that most of the cortical GM atrophy may be partially independent from the WM lesions in both early and progressive MS. Few recent studies have revealed in MS, at the level of “patterns” (i.e., co-varying structurally and/or functionally related regions of the human brain), the presence of GM atrophy or WM microstructural damage, through source-based morphometry (SBM), a novel model-free and data-driven multivariate MRI-based approach, allowing grouping brain structural abnormalities into spatial patterns, well beyond the traditional assessment of single brain regions. We used here SBM on MRI data of a MS patient cohort with relatively mild disability in order to assess whether and to what extent distinct spatial patterns of GM atrophy and WM microstructural damage exist and may be inter-related. Given the alterations found in both structural and functional MRI modalities in MS, integration across such modalities might provide a more comprehensive view of the pathogenic substrates, by revealing important “hidden” relationships that could not be detected from a single MRI modality. Despite the development of different MRI techniques has improved the evaluation of the relationship between structure and function in MS brain, there is still a need to bridge the gap in linking such structural/functional changes in order to better clarify the picture of the MS pathogenic mechanisms. Multimodal neuroimaging data-driven approach, by searching for common information across modalities, could identify co-occurring changes across various brain measures, and thus yield a more comprehensive picture of the multiple underlying pathogenic mechanisms of disease. In this regard, we aimed to uncover in MS the hidden relationships between brain structural damage and functional alterations and the shared pathophysiology across different MRI modalities from a system-level perspective, through the multivariate analysis of multimodal brain MRI data. Our results reinforce previous findings on single MRI modalities and, furthermore, allow to investigate more efficiently the intimate pathogenic mechanism of WM and GM damage in terms of coexisting structural and functional changes, even at early disease stage.

Verbal memory deficits are among the most prominent cognitive sequelae in individuals with left temporal lobe epilepsy (LTLE). However, relationships between verbal memory function and white matter integrity (WMI) in the left temporal lobe remain unclear. Current study aims included determining fractional anisotropy (FA) and mean diffusivity (MD) differences as an index of WMI between participants with left temporal lobe epilepsy (LTLE), participants with right TLE (RTLE), and controls, establishing group differences based on verbal memory function between TLE groups, and describing relationships between WMI and verbal memory function within TLE groups. Probabilistic tractography defined the left fornix (FRX), left uncinate fasciculus (UF), left parahippocampal cingulum (PHC), and a control region, the left corticospinal tract (CST), in 26 LTLE, 29 RTLE, and 20 control participants. The LTLE group demonstrated significantly lower fractional anisotropy (FA) along the PHC compared with controls. LTLE and RTLE groups did not differ significantly on measures of verbal memory until analyses were restricted to participants with left-lateralized language functioning. PHC FA was negatively correlated with semantic memory function in LTLE, but positively associated with episodic memory functioning in RTLE. Overall, findings highlight the PHC as vulnerable in LTLE, and differentially related to verbal memory functioning based on TLE group. Both findings are likely secondary to left-lateralized white matter disruption in LTLE. The current study also highlighted the importance of identifying homogenous groups to more clearly identify brain-behavior relationships. Current findings further define left-lateralized white matter alternations and related verbal memory deficits in TLE. Implications for these findings are presented in context with previous TLE literature, and future directions for further study are discussed.

Dissertação de mestrado integrado em Psicologia
Psychopathy is a personality disorder marked by deficit in emotional processing, antisocial behavior, interpersonal manipulation and impulsive and erratic lifestyle. Functional and structural imaging studies have been used for analyses in cortical thinning and volume of grey and white matter in brain structures to identify the underlying abnormalities in psychiatric disorders. Previous studies indicate that individuals with psychopathy show an impaired response in the insula when processing emotional information, and this has been hypothesized to contribute to their callous-unemotional behavior. In parallel, it has also been found that these individuals display structural alterations in this region. Psychopathy is regarded as a dimensional construct and evidence points to continuities in the neurocognitive mechanisms that underlie the disorder. However, it is yet unknown whether the functional and structural abnormalities found in clinical and forensic samples can also be verified in subclinical groups or even if the same impaired processes are applied. Furthermore, it is still uncertain if the structural variation associated with psychopathic traits contribute to the etiology of the disorder or not. The objective of this study was to test if the same pattern of insula structural alterations was associated with the variance in psychopathic traits in the general population. Using a community sample (n=58) and measures of grey matter and white matter computed of T1 MRI data, our results show that the grey matter volume in the right insula and the white matter volume bilaterally is negatively associated with several psychopathic traits, indicating continuities in the neuro correlates of this disorder.

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.

碩士
國立臺灣大學
物理治療學研究所
105
Background: Gait performance and white matter tracts both decline with age. However, the relationship between the degeneration of white matter tracts and gait performance in middle-aged and older adults has not been comprehensively studied. Therefore, the aims of this study were to investigate whether spatiotemporal gait parameters under single- and dual-task walking conditions in cognitively normal middle-aged and older adults could be classified into independent domains, and whether the integrity of specific cerebral white matter tracts independently correlated with the these gait domains. Methods: One-hundred-and-three cognitively normal middle-aged and older adults over the age of 50 years (mean 64.3 ± 5.6 years) participated in this study. All participants received assessments of mental status, motor function, gait performance of comfortable-speed walking under single-task, motor dual-task and cognitive dual-task conditions, and brain MRI scans, including the T1-weighted, T2-weighted, and diffusion spectrum imaging (DSI). The GaitMatIITM was used for collection and analysis of spatiotemporal gait parameters and their stride-to-stride variabilities under the three conditions. Quantified brain volume measures and the visual rating of white matter lesions were obtained from T1-weighted and T2-weighted imaging, respectively. Values of general fractional anisotropy (GFA), which indicated the microstructural integrity of white matter fiber tracts, of 76 white matter fiber tracts were obtained from the DSI, using a validated tract-based automatic analysis technique. Principle component analysis (PCA) was used to classify gait domains under the three conditions. Univariate regression analyses were used to determine the tracts independently correlated with scores of gait domains under each condition, and multivariate regression analyses were used to determine the most important tracts that independently affacted scores of gait domains. Eight covariates were used in all regression analyses. Results: The gait domains emerged from the PCA of single-task gait were: pace, rhythm, phase, base of support, pace variability, and rhythm variability-phase variability; and those emerged from the PCA of motor and cognitive dual-task gait were: rhythm, phase, base of support, pace variability-rhythm variability, and phase variability. Multivariate regression analyses showed that the integrity of the right corticospinal tract (β = 0.236, p = 0.018), right arcuate fasciculus (β =－0.205, p = 0.035), and left uncinate fasciculus (β = 0.236, p = 0.015) independently contributed to the pace, phase, and base of support domains of single-task gait performance, respectively. The integrity of the left frontostriatal tracts (β = 0.216, p = 0.025), left corticospinal tract (β = 0.206, p = 0.049), left cingulate bundle (β = 0.359, p = <0.001), and callosal tract (β =－0.251, p = 0.006) independently contributed to the phase, base of support, pace variability-rhythm variability, and phase variability domains of motor dual-task gait performance, respectively. The integrity of the the right superior longitudinal fasciculus (β = 0.241, p = 0.014), right cingulate bundle (β = 0.234, p = 0.017), and left thalamic radition (β =－0.309, p = 0.003) independently contributed to the phase, base of support, and phase variability domains of cognitive dual-task gait performance, respectively. Discussion & Conclusions: Spatiotemporal gait parameters of single-task and dual-task walking in middle-aged and older adults could be categorized into different independent domains. The single-task gait performance correlated mainly with the integrity of white matter tracts of the motor and limbic systems. The better the integrity of white matter tracts related to the motor cortex, basal ganglia, and corpus callosum was, the better the motor dual-task gait performance was. The better the white matter tracts integrity of cortico-cortical and cortico-subcortical tracts integrating cognitive, sensory, and motor systems, the better the cognitive dual-task gait performance was.