Early brain development is characterized by rapid growth and perpetual reconfiguration, driven by a dynamic milieu of heterogeneous processes. Moreover, potent postnatal brain plasticity engenders increased vulnerability to environmental stimuli. However, little is known regarding the ontogeny and temporal manifestations of inter- and intra-regional functional connectivity that comprise functional brain networks. Recently, resting-state functional magnetic resonance imaging (fMRI) emerged as a promising non-invasive neuroinvestigative tool, measuring spontaneous fluctuations in blood oxygen level dependent (BOLD) signal at rest that reflect baseline neuronal activity. Its application has expanded to infant populations in the past decade, providing unprecedented insight into functional organization of the developing brain, as well as early biomarkers of abnormal/ disease states. However, rapid extension of the resting-state technique to infant populations leaves many methodological issues need to be resolved prior to standardization of the technique. The purpose of this thesis is to describe a protocol for intrinsic functional connectivity analysis, and extraction of resting-state networks in infants <12 months of age using the data-driven approach independent component analysis (ICA). To begin, we review the evolution of resting-state fMRI application in infant populations, including the biological premise for neural networks. Next, we present a protocol designed such that investigators without previous knowledge in the field can implement the analysis and reliably obtain viable results consistent with previous literature. Presented protocol provides detailed, albeit basic framework for RSN analysis, with interwoven discussion of basic theory behind each technique, as well as the rationale behind selecting parameters. The overarching goal is to catalyze efforts towards development of robust, infant-specific acquisition and preprocessing pipelines, as well as promote greater transparency by researchers regarding methods used. Finally, we review the literature, current methodological challenges and potential future directions for the field of infant resting-state fMRI.

Orofacial clefts are among the most common congenital defects in the United States, affecting roughly 1 in 600 births annually. A majority of these cases are considered to be “isolated” clefts of the lip and/or palate (ICLP). However the term “isolated” is somewhat of a misnomer, as functional deficits frequently accompany ICLP. One of the most problematic yet understudied of these deficits involves the high prevalence of reading disabilities in this population. It has been estimated that as high as 46% of children with ICLP will be diagnosed with a reading disability, particularly dyslexia. Despite this high prevalence and the well-established neurological basis of dyslexia, relatively little attention has been paid to the role that brain development plays in the reading problems in ICLP. Previous studies from our lab have demonstrated significant changes in brain structure in children with ICLP (that have importantly correlated with functional measures). However we have yet to combine both a structural and functional neuroimaging study with an in-depth analysis of reading dysfunction in this population. The current study examined boys with ICLP, age 8-12 (boys have a higher prevalence of ICLP and show more significant reading problems that girls with ICLP) compared to healthy control boys. Measures of cognitive functioning were obtained with an emphasis on reading and language skills. In addition MRI scans were obtained which included volumetric measures, diffusion-weighted measures (DWI; white matter), and connectivity measures (resting-state fMRI). Even after controlling for the effect of socioeconomic status, boys with ICLP showed significant decreases in reading and language skills (particularly reading fluency). Boys with ICLP did not show significant differences on phonlogical measures (the primary cause of dyslexia). In addition, phonological measures were not predictive of reading fluency, while object naming tasks were predictive of reading fluency in boys with ICLP. For white matter integrity, measures of fractional anisotropy (FA) were found to be increased in the right occipital lobe for boys with ICLP indicating more organized white matter in this region. This increase in right occipital FA was also predictive of better reading outcomes, particularly reading fluency. For more specific white matter tracts, only the fornix and the tapetum (both associated with the temporal lobes) showed a significant difference with a decrease in FA for boys with ICLP. The decrease in FA in the tapetum was also predictive of better reading outcomes in ICLP. When looking at resting-state networks, boys with ICLP showed an increase in connectivity within posterior and subcortical regions when compared to healthy control boys, indicating stronger network connections within the posterior language regions of the brain. Taken together, these results point to differences in both structural and functional connectivity in the brains boys with ICLP. Furthermore, this pattern is different than that found in children with developmental dyslexia as there appears to be no disruption of the posterior reading systems. Cognitive measures also indicate normal phonological awareness in this group, further distinguishing them from dyslexic children. Boys with ICLP instead may be over-relying on these posterior, more visually oriented reading systems as a compensatory mechanism to overcome problems with the development of the typical “lexical route” of reading.

Manual sleep scoring, executed by visual inspection of the EEG, is a very time consuming activity, with an inherent subjective decisional component. Automatic sleep scoring could ease the job of the technicians, because faster and more accurate. Frequency information characterizing the main brain rhythms, and consequently the sleep stages, needs to be extracted from the EEG data. The approach used in this study involves a wavelet filter bank for the EEG frequency features extraction. The wavelet packet analysis tool in MATLAB has been employed and the frequency information subsequently used for the automatic sleep scoring by means of an artificial neural network. Finally, the automatic sleep scoring has been employed for epoching the fMRI data, thus allowing for studying brain resting state networks during sleep. Three resting state networks have been inspected; the Default Mode Network, The Attentional Network and the Salience Network. The networks functional connectivity variations have been inspected in both healthy and narcoleptic subjects. Narcolepsy is a neurobiological disorder characterized by an excessive daytime sleepiness, whose aetiology may be linked to a loss of neurons in the hypothalamic region.

Our senses, while limited, shape our perception of the world and contribute to the functional architecture of the brain. This dissertation investigates the role of sensory modality and task demands in the cortical organization of healthy human adults using functional magnetic resonance imaging (fMRI). This research provides evidence for sensory modality bias in frontal cortical regions by directly contrasting auditory and visual sustained attention. This contrast revealed two distinct visual-biased regions in lateral frontal cortex - superior and inferior precentral sulcus (sPCS, iPCS) - anatomically interleaved with two auditory-biased regions - transverse gyrus intersecting precentral sulcus (tgPCS) and caudal inferior frontal sulcus (cIFS). Intrinsic (resting-state) functional connectivity analysis demonstrated that sPCS and iPCS fall within a broad visual-attention network, while tgPCS and cIFS fall within a broad auditory-attention network. Unisensory (auditory or visual) short-term memory (STM) tasks assessed the flexible recruitment of these sensory-biased cortical regions by varying information domain demands (e.g., spatial, temporal). While both modalities provide spatial and temporal information, vision has greater spatial resolution than audition, and audition has excellent temporal precision relative to vision. A visual temporal, but not a spatial, STM task flexibly recruited frontal auditory-biased regions; conversely, an auditory spatial task more strongly recruited frontal visual-biased regions compared to an auditory temporal task. This flexible recruitment extended to an auditory-biased superior temporal lobe region and to a subset of visual-biased parietal regions. A demanding auditory spatial STM task recruited anterior/superior visuotopic maps (IPS2-4, SPL1) along the intraparietal sulcus, but neither spatial nor temporal auditory tasks recruited posterior/interior maps. Finally, a comparison of visual spatial attention and STM under varied cognitive load demands attempted to further elucidate the organization of posterior parietal cortex. Parietal visuotopic maps were recruited for both visual spatial attention and working memory but demonstrated a graded response to task demands. Posterior/inferior maps (IPS0-1) demonstrated a linear relationship with the number of items attended to or remembered in the visual spatial tasks. Anterior/superior maps (IPS2-4, SPL1) demonstrated a general recruitment in visual spatial cognitive tasks, with a stronger response for visual spatial attention compared to STM.

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Early life stress (ELS) affects the developing brain and impacts capacity for self-regulation and risk for psychopathology. The high spatial resolution of functional magnetic resonance imaging (fMRI) confers an advantage for studying specific neural regions posited to link ELS with subsequent functioning. The first chapter in this dissertation reviews the literature establishing the feasibility and utility of fMRI research with infants and young children. This chapter examines methodological issues and outlines the potential for this technique to make unique contributions to understanding how ELS influences brain development. The next two chapters present results from a study that employed a functional activation paradigm and resting state functional connectivity MRI (rs-fcMRI) to examine associations between a common source of ELS, non-physical interparental conflict, and neural functioning during infancy. The functional activation paradigm focused on emotional tone of voice as a stimulus relevant to interparental conflict, which is likely salient to infants. Higher levels of interparental conflict (as reported by mothers) were associated with infants (6 to 12 months of age) showing greater reactivity to very angry versus neutral tone of voice in neural regions associated with processing and regulation of stress and emotion (hypothalamus and rostral anterior cingulate cortex). The rs-fcMRI analysis examined coordinated neural functioning in the absence of stimuli, focusing on the amygdala as a key region for understanding the impact of ELS and the posterior cingulate cortex as part of a group of regions that show higher levels of activity in the absence of stimuli (the default network). The results replicate previous work characterizing the default network in infants and provide novel evidence for the functional connectivity of the amydgala and amygdala subregions during infancy. Interparental conflict was associated with variation in the connectivity of both regions. Thus levels of interparental conflict were associated with neural reactivity to a stressor-relevant stimulus and with patterns of coordinated neural functioning in the absence of such stimuli. These results provide support for the utility of using fMRI with infants to examine early emerging associations between common forms of ELS and brain functioning. This dissertation includes previously published and co-authored material. / 2016-10-17

Basic science and early clinical trial evidence suggest the safe diuretic drug amiloride, may exert a neuroprotective effect in multiple sclerosis (MS) through blockade of the acid sensing ion channel. Neuroprotective treatments are a key unmet need in multiple sclerosis. Optic neuritis (ON) is a discrete CNS inflammatory event leading to neuro-axonal injury in the optic nerve and retina. The optic nerve is part of the visual system, one of the most functionally and structurally eloquent systems in the central nervous system, which affords a number of unique modalities to assess neurodegeneration and neuroprotection. The visual system can be classified into two parts, the anterior and posterior visual systems, which are defined by the lateral geniculate nucleus, where the two components synapse. The extent of neurodegeneration following ON in the anterior visual system can be imaged in vivo through scanning laser polarimetry (GDx) and optical coherence tomography (OCT). The posterior visual system can be imaged by quantitative and functional magnetic resonance imaging (MRI) of the brain, giving insights into white matter structural integrity and cortical plasticity over time. Combining these modalities in a longitudinal study, allows assessment of the impact of neurodegeneration in the anterior visual system on neurodegeneration downstream in the posterior visual system and on changes in functional connectivity over time in the visual cortex. Furthermore, in the clinical trial setting the neuroprotective effect of any intervention both on direct anterior neurodegeneration and downstream processes can be assessed. The functional relevance of changes in all of these biomarkers can be tested through a number of visual measures, including low contrast visual acuity. In MS, the contribution of transsynaptic neurodegeneration to the global neuronal loss experienced by patients is an area of incomplete understanding. In addition, the role of the visual cortex, through neuroplasticity, in aiding visual recovery from optic neuritis, is unclear. To address these issues, this thesis reports the results of the first clinical trial of amiloride in ON, and shows that despite the pre- and early clinical evidence of neuroprotection of amiloride, no neuroprotective benefit was found. It goes on to explore reasons for this lack of effect including the finding of early retinal neurodegeneration in ON, and the need for early recruitment windows in the future. From there, it makes a detailed assessment of the longitudinal changes in retinal OCT for 12 months following ON, including a novel finding of the temporal evolution of inner nuclear layer swelling, previously reported only cross-sectionally. Next, for the first time macular retinal neurodegeneration is shown to influence diffusion tensor MRI derived measures of white matter integrity in the optic radiations, indicating transsynaptic neurodegeneration. Finally, longitudinal changes in resting state functional connectivity following ON are found in the visual system for the first time. The interaction between this cortical functional, retinal neurodegeneration and visual recovery is probed.

Les acouphènes subjectifs chroniques concernent entre 10 et 15% de la population des pays industrialisés. Ils peuvent entraîner des modifications visibles du comportement, une détérioration très nette de la qualité de vie et dans des cas extrêmes des troubles nerveux post-traumatiques ou un état dépressif clinique (Berrios & Rose, 1992; Berrios et al, 1988) pouvant mener à des pensées suicidaires (Dobie, 2003). Les acouphènes peuvent provenir de différents relais des voies auditives périphériques ou centrales, cependant la grande majorité des acouphènes chroniques est liée à une perte auditive, presbyacousie, ou exposition au bruit. En effet, approximativement 90% des acouphènes chroniques sont liés à une perte auditive (Nicolas-Puel et al. 2006).Les acouphènes peuvent entraîner des changements importants dans le fonctionnement de certains réseaux cérébraux. Même en cas de lésion périphérique, l’anomalie perceptive qui en résulte peut à terme entraîner une modification de l’activité des structures cérébrales, par des phénomènes de plasticité. Malheureusement aujourd’hui compte tenu des divergences constatées aux niveaux des résultats obtenus par les différentes études effectuées chez les sujets acouphéniques, aucun consensus n’a pu être établi quant à l’établissement d’un modèle de la physiopathologie des acouphènes liés à une perte auditive.L’objectif général de ce travail est donc de mettre en place un protocole multimodal robuste afin de détecter des d’anomalies d’activation cérébrales chez des sujets souffrants d’acouphènes unilatéraux liés à une perte auditive par rapport à des sujets normo-entendants. Ce protocole comprend :- un paradigme permettant de réaliser des acquisitions fonctionnelles avec et sans acouphènes perçus, grâce à l’inhibition résiduelle des acouphènes,- un paradigme d’IRM fonctionnelle de repos,- un paradigme d’IRM fonctionnelle avec stimulation sonores,- une mesure du débit sanguin cérébral régional.Notre étude a permis de mettre en évidence l’implication du réseau du mode par défaut et notamment du précunéus dans la perception d’acouphènes. En effet, les résultats de notre étude montrent selon plusieurs modalités que ce réseau est hypo-activé chez les sujets présentant des acouphènes liés à une perte auditive. L’hypoactivité de ces régions pourrait être réduite de façon temporaire par le masquage des acouphènes par une stimulation sonore. De plus, l’inhibition résiduelle des acouphènes conduit à l’hyper-activations des régions du réseau du mode par défaut et notamment du précunéus. / Chronic subjective tinnitus concern 10 to 15% of the population in industrialized countries. They can cause visible changes in behavior, a sharp deterioration in the quality of life and in extreme cases of post-traumatic stress disorder or clinical depression (Berrios & Rose, 1992; Berrios et al, 1988) that could lead to suicidal thoughts (Dobie, 2003). Tinnitus may originate from different peripherical nodes or central auditory pathways, however the majority of chronic tinnitus is associated with hearing loss, presbycusis, or exposure to noise. Indeed, approximately 90% of chronic tinnitus is associated with hearing loss (Nicolas-Puel et al. 2006).Tinnitus can cause significant changes in the activity of brain networks. Even in case of peripherical lesions, the perceptual abnormality that results can ultimately lead to a change in the activity of brain structures, by plasticity phenomena. Unfortunately today given the discrepancies in the levels of results obtained by different studies in the affected persons, no consensus has been established regarding the establishment of a model of the pathophysiology of tinnitus associated with a loss hearing.The general objective of this work is to develop a robust multimodal protocol to detect cerebral activation abnormalities in subjects suffering from unilateral tinnitus associated with hearing loss compared to normal-hearing subjects. This protocol includes:- An acquisition paradigm with and without perceived tinnitus through the residual inhibition,- A resting state fMRI paradigm,- A sound evoked fMRI paradigm (with sound stimulation),- A measure of the regional cerebral blood flow.Our study has permitted to highlight the involvement of the default mode network including the precuneus in the perception of tinnitus. Indeed, the results of our study show as many terms as the network is hypo-activated in subjects with tinnitus associated with hearing loss. Hypoactivity of these areas could be reduced temporarily by masking the tinnitus by sound stimulation. In addition, residual inhibition of tinnitus leads to hyper-activation regions of the default mode of the network and in particular precuneus.

La mémoire de reconnaissance nous permet à la fois de détecter rapidement un stimulus précédemment perçu (familiarité), et de récupérer des informations relatives au contexte de notre rencontre avec ce stimulus (recollection). Les modèles neuro-anatomiques d'Aggleton et Brown (1999) puis d'Aggleton et al. (2011) postulent que le noyau antérieur (NA) du thalamus et le tractus mamillo-thalamique (TMT) du fait de leurs connexions avec l'hippocampe font partie du circuit de la recollection tandis que le noyau dorso-médian (DM) participerait à la familiarité en raison de ses connexions avec le cortex périrhinal. Dans cette thèse nous avons testé cette hypothèse d'indépendance. 12 patients avec un infarctus thalamique gauche ont été recrutés ainsi qu'un groupe de sujets contrôles appariés. Tous les participants ont été soumis à un bilan neuropsychologique, à trois tâches expérimentales de mémoire de reconnaissance et à un examen d'IRM morphologique et d'IRM fonctionnelle de repos. Selon les tâches nous avons estimé la contribution de la recollection et de la familiarité à la réponse sur la base de la verbalisation de la source, du degré de confiance dans la réponse ou de la catégorisation des réponses. Les lésions thalamiques ont été quantifiées et localisées automatiquement grâce à une nouvelle approche méthodologique que nous avons développée. Le profil neuropsychologique des patients a mis en évidence une amnésie antérograde verbale et un trouble exécutif modéré (Etude 1). Les lésions atteignaient principalement le DM alors que le NA était intact chez tous. Le TMT était lésé chez les 7 patients les plus amnésiques (Etudes 1 et 2). La recollection était altérée chez les patients quelle que soit la tâche alors que la familiarité était préservée. De plus l'indice de recollection corrélait avec la lésion du DM (Etude 2). Enfin, des corrélations ont été trouvées dans l'étude en connectivité fonctionnelle entre la disconnexion thalamo-frontale et la recollection (Etude 3). En somme, ces résultats signifient i\ qu'une lésion du NA n'est pas nécessaire pour causer une amnésie ii\ qu'une lésion du DM est suffisante pour causer un défaut de recollection mais pas nécessaire pour atteindre la familiarité iii\ qu'une lésion du TMT prédit une amnésie sévère, enfin iv\ que le réseau reliant fonctionnellement le DM au cortex préfrontal semble être impliqué dans l'expérience subjective de la mémoire de reconnaissance plutôt que dans ses contenus. Ils suggèrent de plus que le modèle d'Aggleton et al (2011) devrait être révisé en ce qui concerne la relation familiarité / DM. / Recognition memory allows determining whether a stimulus has been previously encountered based on either a rapid detection process (familiarity) or a longer retrieval of the context associated with the stimulus (recollection). Aggleton and Brown's model (1999) and Aggleton and colleagues (2011) postulated that recollection and familiarity are anatomically and functionally independent. They hypothesized that the anterior nucleus (AN) / mamillothalamic tract (MTT) complex of the thalamus would be critical for recollection due to its connections with the hippocampus. The Mediodorsal (MD) nucleus would support familiarity owing to its links with the perirhinal cortex. In this thesis we tested this independence hypothesis. The 12 subjects with a pure left thalamic infarction were included along with a healthy matched control group. Every subject underwent a neuropsychological assessment, three experimental verbal recognition memory tasks, a high-resolution structural volumetric MRI scan and resting state functional imaging. Recollection and familiarity estimations were derived from subjective reports or responses categorization. We specifically developed the methods used to automatically analyse the volume and localization of the lesions. Patients performed worse than controls on verbal memory and to a lesser extent on executive tasks (Study 1). Most of the lesions were located in the MD while no lesion of the AN was found. The seven patients exhibiting MTT damage had the lowest memory performance (Studies 1 and 2). Recollection was lower in patients than in controls in all the three tasks whereas familiarity was systematically normal. In addition we found a significant correlation between the recollection index and the DM damage, suggesting that DM is directly involved in recollection (Article 2). Finally the functional connectivity results showed a correlation between recollection and a pattern of thalamofrontal disconnection in the patients, helping to understand the DM-recollection relationship. Overall, the findings of the different studies mean that i\ AN damage is rare and is not necessary to cause an amnesia, ii\ MD damage is sufficient to cause a recollection impairment but not necessary to impair familiarity, iii\ MTT damage predicts the severity of the amnesia, iv\ the network linking functionally the MD with the prefrontal cortex seems to be involved in the subjective experience associated with recognition memory.

Converging evidence from a variety of fields, including psychiatry, suggests that the temporal correlates of the brain’s resting state could serve as essential markers of a healthy and efficient brain. We use ketamine to induce schizophrenia-like states in 32 healthy individuals to examine the brain’s resting states using fMRI. We found a global reduction in temporal variability quantified by the time series’ standard deviation and an increase in scale-free properties quantified by the Hurst exponent representing the signal self-affinity over time. We also found network-specific and frequency-specific effects of ketamine on these temporal measures. Our results confirm prior studies in aging, sleep, anesthesia, and psychiatry suggesting that increased self-affinity and decreased temporal variability of the brain resting state could indicate a compromised and inefficient brain state. Our results expand our systemic view of the temporal structure of the brain and shed light on promising biomarkers in psychiatry