MRI of Perfusion-Diffusion Mismatch in Non-Human Primate (Baboon) Stroke: A Preliminary Report

The goal of this study was to develop a clinically relevant non-human primate (baboon) stroke model and multi-parametric MRI protocols on a clinical scanner with long-term goals to better model human stroke and facilitate clinical translations of novel therapeutic strategies. Baboons were chosen because of their relatively large brain volume and that they are evolutionarily close to humans. Middle cerebral artery occlusion (MCAO) was induced using a minimally invasive endovascular approach to guide an inflatable balloon catheter into the MCA and followed by permanently or transiently inflate the balloon. Using multimodal MRI, including perfusion and diffusion imaging, the spatiotemporal dynamic evolution of the ischemic lesions in permanent and transient occlusion experiments in baboons were investigated. Perfusion-diffusion mismatch, which approximates the ischemic penumbra, was detected. In the permanent MCAO group (n = 2), the mean infarct volume was 29 ml (17% of total brain volume) whereas in the transient MCAO group (n = 2, 60 or 90 min of occlusion), the mean infarct volume was 15 ml (9% of total brain volume). Substantial perfusion-diffusion mismatch tissue (~50%) was salvaged by reperfusion compared to permanent MCAO. This baboon stroke model has the potential to become a translational platform to better design clinical studies, guide clinical diagnosis and improve treatment time windows in patients

MRI Techniques and New Animal Models for Imaging the Brain

Chapitre 10absen

Effects of Hand Transplantation on Cortical Organization

Amputation induces substantial reorganization of the body part somatotopy in primary sensory cortex (S1), and these effects of deafferentation increase with time. Determining whether these changes are reversible is critical for understanding the potential to recover from deafferenting injuries. Here, we report evidence that the representation of a transplanted hand and digits can actually recapture the pre-amputation S1 hand territory in two transplant patients. With limited sensation 4 months post operation, one of the patient's (D.S.) palmar tactile stimulation evoked contralateral S1 responses that were indistinguishable in location and amplitude from those detected in healthy matched controls. The other patient (M.S.) demonstrated not only much improved sensation but also recovered ability to localize tactile stimuli 120+ months after the operation. The results described suggest that even decades after complete deafferentation, restoring afferent input to S1 leads to re-establishment of the gross hand and digits representations within their original territory. Stimulation of the deafferented cortical maps may play an important role in maintaining their viability until the afferent input is restored. Motor imagery and creation of virtual visual feedback of the absent hand with a mirror have been proposed as stimuli. We used fMRI to record neural activity while 11 unilateral hand amputees and matched controls performed aurally-paced thumb-finger sequencing movements with their intact hand (matching hand in case of controls) under visual guidance during four conditions: 1) intact hand (ME), 2) ME with motor imagery of the amputated hand, 3) ME with virtual visual feedback of the amputated hand, and 4) ME with motor imagery and the virtual visual feedback of the amputated hand. In contrast to controls, amputees showed increases in activity during all four conditions within the former functionally-defined sensorimotor hand territory. Movements of the intact hand likely increase activity in the former hand territory as a result of decreased interhemispheric inhibition. This stimulation may maintain deafferented hand representations that can recover soon after the afferent input is restored by hand transplantation

Spatio-Temporal and Multisensory Integration: the relationship between sleep and the cerebellum

Does the cerebellum sleep? If so, does sleep contribute to cerebellar cognition? In this thesis, the sleep contribution to the consolidation process of spatial-temporal and multisensory integration was investigated in relation to the human cerebellum. Multiple experimental approaches were used to answer research questions addressed in the various chapters. Summarizing the evidence of the electrophysiology and neuroimaging studies, in Chapter1 we present intriguing evidence that the cerebellum is involved in sleep physiology, and that cerebellar-dependent memory formation can be consolidated during sleep. In Chapter 2, using functional neuroimaging in healthy participants during various forms of the Serial interception sequential learning (SISL) task, i.e., predictive timing, motor coordination, and motor imagination, we assessed the cerebellar involvement in spatio-temporal predictive timing; and possible cerebellar interactions with other regions, most notably the hippocampus. In Chapter 3, we add to the findings of Chapter 2 that indicate the cerebellum and hippocampus are involved in the task, by showing that more than simply activated, the cerebellum is a necessary and responsible region for the establishment of the spatio-temporal prediction. This follows from the deficits in behavioral properties of the predictive and reactive timing in the cerebellar ataxia type 6 patients, using the modified version of the SISL task. In Chapter 4, we assessed the subsequent post-interval behavioral performances on the learning of the fixed and random timing sequences in the SISL task, comparing a sleep group and wake group in healthy participants. Our findings show that sleep consolidates the process of cerebellar-dependent spatio-temporal integration. In Chapter 5, we investigated the establishment of visual-tactile integration during sleep through the examination of tactile motion stimulation during sleep and showed that, subsequent to sleep, directional visual motion discrimination i

Beyond language: The unspoken sensory-motor representation of the tongue in non-primates, non-human and human primates

The English idiom “on the tip of my tongue” commonly acknowledges that something is known, but it cannot be immediately brought to mind. This phrase accurately describes sensorimotor functions of the tongue, which are fundamental for many tongue-related behaviors (e.g., speech), but often neglected by scientific research. Here, we review a wide range of studies conducted on non-primates, non-human and human primates with the aim of providing a comprehensive description of the cortical representation of the tongue's somatosensory inputs and motor outputs across different phylogenetic domains. First, we summarize how the properties of passive non-noxious mechanical stimuli are encoded in the putative somatosensory tongue area, which has a conserved location in the ventral portion of the somatosensory cortex across mammals. Second, we review how complex self-generated actions involving the tongue are represented in more anterior regions of the putative somato-motor tongue area. Finally, we describe multisensory response properties of the primate and non-primate tongue area by also defining how the cytoarchitecture of this area is affected by experience and deafferentation

L’effet du stress sur la douleur aiguë et chronique

Objectif : Cette thèse a pour objectif de mieux comprendre l’effet du stress sur la douleur aiguë et chronique. Devis expérimental : 16 patients souffrant de douleur chronique lombalgique et 18 sujets contrôles ont participé à une étude d’imagerie par résonance magnétique (IRM) et ont collecté des échantillons de salive afin de quantifier les niveaux d’hormone de stress (i.e. cortisol) la journée de l’étude (réponse réactive) et durant les sept jours consécutifs suivants (réponse basale). Étude 1 : Une première étude a examiné le lien entre les niveaux de cortisol basal, le volume de l’hippocampe et l’activité cérébrale évoquée par la douleur thermique chez des patients souffrant de douleur chronique et les sujets contrôles. Les résultats révèlent que les patients souffrant de douleur chronique avaient des niveaux de cortisol plus élevés que ceux des sujets contrôles. Chez ces patients, un niveau élevé de cortisol était associé à un plus petit volume de l'hippocampe et à davantage d’activation dans le gyrus parahippocampique antérieure (une région impliquée dans l'anxiété anticipatoire et l'apprentissage associatif). De plus, une analyse de médiation a montré que le niveau de cortisol basal et la force de la réponse parahippocampique explique statistiquement l’association négative entre le volume de l'hippocampe et l'intensité de la douleur chronique. Ces résultats suggèrent que l’activité endocrinienne plus élevée chez les patients ayant un plus petit hippocampe modifie le fonctionnement du complexe hippocampique et contribue à l’intensité de la douleur chronique. Étude 2 : La deuxième étude a évalué la contribution de la réponse de stress réactif aux différences interindividuelles dans la perception de la douleur aiguë chez des patients souffrant de douleur chronique et chez des sujets normaux. Les deux groupes ont montré des augmentations significatives du niveau de cortisol en réponse à des stimulations nocives administrées dans un contexte d’IRM suggérant ainsi que la réactivité de l’axe hypothalamo-hypophyso-surrénalien est préservée chez les patients lombalgiques. De plus, les individus présentant une réponse hormonale de stress plus forte ont rapporté moins de douleur et ont montré une réduction de l'activation cérébrale dans le noyau accumbens, dans le cortex cingulaire antérieur (CCA), le cortex somatosensoriel primaire, et l'insula postérieure. Des analyses de médiation ont indiqué que la douleur liée à l'activité du CCA explique statistiquement la relation entre la réponse de stress et le désagrément de la douleur rapportée par les participants. Enfin, des analyses complémentaires ont révélé que le stress réduit la connectivité fonctionnelle entre le CCA et le tronc cérébral pendant la douleur aiguë. Ces résultats indiquent que le stress réactif module la douleur et contribue à la variabilité interindividuelle de l'activité cérébrale et la réponse affective à la douleur. Discussion : Conjointement, ces études suggèrent dans un premier temps que la douleur chronique peut être exacerbée par une réponse physiologique inadéquate de l'organisme exposé à un stress récurrent, et en un second temps, que le CCA contribuerait à l'analgésie induite par le stress. Sur le plan conceptuel, ces études renforcent le point de vue prédominant suggérant que la douleur chronique induit des changements dans les systèmes cérébraux régissant les fonctions motivationnelles et affective de la douleur.Goal : This thesis aimed at better understanding the impact of stress on acute and chronic pain. Experimental design: 16 patients with chronic low back pain pain and 18 control subjects participated in a functional magnetic resonance imaging (fMRI) study and collected saliva samples to quantify the levels of stress hormone (ie cortisol) the day of study (reactive response) and during the following 7 consecutive days (basal response). Study 1: The first study examined the associations between basal levels of cortisol, the hippocampal volumes, and brain activation to thermal stimulations in the low back pain patients and the healthy controls. Results showed that CBP patients have higher levels of cortisol than controls. In these patients, higher cortisol was associated with smaller hippocampal volume and stronger pain-evoked activity in the anterior parahippocampal gyrus (PHG), a region involved in anticipatory-anxiety and associative learning. Importantly, the results revealed that the cortisol levels and phasic pain responses in the PHG of the patients mediated a negative association between the hippocampal volume and the chronic pain intensity. These findings support a stress model of chronic pain suggesting that the higher levels of endocrine activity observed in individuals with a smaller hippocampii induces changes in the function of the hippocampal complex that may contribute to the persistent pain states. Study 2: The second study assessed the magnitude of the acute stress response to the noxious thermal stimulations administered in a MRI environment and tested its possible contribution to individual differences in pain perception. The two groups showed similar significant increases in reactive cortisol across the scanning session when compared to their basal levels, suggesting normal hypothalamic–pituitary–adrenal axis reactivity to painful stressors in chronic back pain patients. Critically, individuals with stronger cortisol responses reported less pain unpleasantness and showed a reduction of BOLD activation in nucleus accumbens at the stimulus onset and in the anterior mid-cingulate cortex (aMCC), the primary somatosensory cortex, and the posterior insula during heat pain. Mediation analyses indicated that pain-related activity in the aMCC mediated the relationship between the reactive cortisol response and the pain unpleasantness reported by the participants. Psychophysiological interaction further revealed that stress reduced functional connectivity between the aMCC and the brainstem during pain. These findings indicate that acute stress responses modulate pain in humans and contribute to individual variability in pain affect and pain-related brain activity. Discussion: Taken together, these studies firstly support recent theories suggesting that chronic pain could be partly maintained by maladaptive physiological responses of the organism facing a recurrent stressor and secondly revealed the neural correlates of stress-induced analgesia. On a conceptual level, these findings are important because they strengthen the predominant view that chronic pain does not disrupt the acute response to stress and the sensory dimension of pain, but rather induces long-term changes in neural systems underlying affective-motivational functions

Diffusion tensor imaging and resting state functional connectivity as advanced imaging biomarkers of outcome in infants with hypoxic-ischaemic encephalopathy treated with hypothermia

Therapeutic hypothermia confers significant benefit in term neonates with hypoxic-ischaemic encephalopathy (HIE). However, despite the treatment nearly half of the infants develop an unfavourable outcome. Intensive bench-based and early phase clinical research is focused on identifying treatments that augment hypothermic neuroprotection. Qualified biomarkers are required to test these promising therapies efficiently. This thesis aims to assess advanced magnetic resonance imaging (MRI) techniques, including diffusion tensor imaging (DTI) and resting state functional MRI (fMRI) as imaging biomarkers of outcome in infants with HIE who underwent hypothermic neuroprotection. FA values in the white matter (WM), obtained in the neonatal period and assessed by tract-based spatial statistics (TBSS), correlated with subsequent developmental quotient (DQ). However, TBSS is not suitable to study grey matter (GM), which is the primary site of injury following an acute hypoxic-ischaemic event. Therefore, a neonatal atlas-based automated tissue labelling approach was applied to segment central and cortical grey and whole brain WM. Mean diffusivity (MD) in GM structures, obtained in the neonatal period correlated with subsequent DQ. Although the central GM is the primary site of injury on conventional MRI following HIE; FA within WM tissue labels also correlated to neurodevelopmental performance scores. As DTI does not provide information on functional consequences of brain injury functional sequel of HIE was studied with resting state fMRI. Diminished functional connectivity was demonstrated in infants who suffered HIE, which associated with an unfavourable outcome. The results of this thesis suggest that MD in GM tissue labels and FA either determined within WM tissue labels or analysed with TBSS correlate to subsequent neurodevelopmental performance scores in infants who suffered HIE treated with hypothermia and may be applied as imaging biomarkers of outcome in this population. Although functional connectivity was diminished in infants with HIE, resting state fMRI needs further study to assess its utility as an imaging biomarker following a hypoxic-ischaemic brain injury.Open Acces

IRM fonctionnelle chez le rat (défis méthodologiques)

L'imagerie par résonance magnétique fonctionnelle (IRMf ) permet de détecter sur le cerveau entier des activations neuronales en réponse à un stimulus, par le biais de l'observation des modifications hémodynamiques occasionnées. En particulier, l'IRMf est un outil de choix pour l'étude des mécanismes de la stimulation cérébrale profonde et de la stimulation du nerf vague qui sont encore mal connus. Cependant, cette technique n'est pas facilement utilisable chez l'homme en raison des problèmes de sécurité vis-à-vis de l'action des champs magnétiques intenses utilisés en IRM au niveau des électrodes implantées. Les développements méthodologiques chez l'animal sont donc nécessaires. L'objectif principal de cette thèse est l'étude des mécanismes à distance de la stimulation du système nerveux central et périphérique par IRMf chez le rat. Nous présentons dans un premier temps les séquences IRM rapides utilisées en IRMf, comme l'Echo-Planar Imaging multishot, permettant d'imager le cerveau entier en 1 à 2 secondes seulement, ainsi que les différents problèmes posés par l'utilisation de ces séquences, comme les artefacts de susceptibilité magnétique. Le couplage des séquences développées durant cette thèse avec des mesures électrophysiologiques a notamment permis l'imagerie des réseaux épileptiques chez le rat. Dans un second temps, nous développons les problèmes posés par la préparation animale, particulière en IRMf de par le fait que le couplage neurovasculaire doit être préservé sous anesthésie afin de préserver les activations neuronales. Après comparaison avec les anesthésies à l'isoflurane et la kétamine, nous avons déduit que la médétomidine constituait un anesthésique de choix pour l'IRMf du rongeur, et précisons le protocole de préparation animale utilisé pour l'imagerie. De plus, les électrodes utilisées en stimulation intracérébrale induisent des artefacts importants en imagerie, et des électrodes constituées de matériaux amagnétiques sont nécessaires. Nous expliquons pourquoi nous avons choisi des électrodes en carbone, et présentons le protocole de fabrication utilisé. Nous avons ensuite validé ces développements méthodologiques par des expériences d'IRMf de challenges hypercapniques et de stimulation de la patte chez le rat. Puis nous avons conduit une étude IRMf approfondie des mécanismes d'action de la stimulation du nerf vague, en s'intéressant à la distinction entre activations neuronales et effets cardiovasculaires confondants par modélisation causale dynamique. Nous présentons aussi des résultats en IRMf de la stimulation électrique intracérébrale chez le rat. Plusieurs cibles ont été stimulées (noyau géniculé dorso-latéral, gyrus dentelé, striatum et thalamus), et des activations ont été obtenues à distance de l'électrode, conformément aux connaissances actuelles sur les connexions neuroanatomiques de ces noyaux. Ainsi, nous avons mis au point et validé l'IRMf du rat et son application à la stimulation électrique du système nerveux périphérique et central.Functional magnetic resonance imaging (fMRI) can detect neuronal activations in the entire brain, in response to a stimulus, through the observation of subsequent hemodynamic changes. In particular, fMRI is a good tool for studying the mechanisms of deep brain stimulation and vagus nerve stimulation, which are still poorly understood. However, this technique is not readily usable in humans because of safety concerns towards the action of the strong magnetic fields used in MRI on implanted electrodes. Indeed, methodological developments in animals are needed. The main goal of this thesis is to study the mechanisms of central and peripheral nervous system stimulation in rats by fMRI. First, fast MRI sequences used in fMRI are exposed, such as multishot Echo-Planar Imaging, allowing to image the entire brain in a couple of seconds. Various imaging problems posed by these sequences, such as magnetic susceptibility artifacts, are also presented. These sequences, developed during this thesis, associated with electrophysiological measurements, allowed imaging of epileptic networks in the rat. Secondly, animal preparation is developped, as it is peculiar in fMRI : neuronal activations, as well as neurovascular coupling, must be preserved under anesthesia. Compared to anesthesia by isoflurane and ketamine, it was concluded that medetomidine was an anesthetic of choice for fMRI of the rodent, and the protocol used for animal preparation for imaging is specified. Furthermore, the electrodes used in deep brain stimulation induce significant artifacts in MRI images, and electrodes made of amagnetic materials are needed. Our choice of carbon electrodes is explained, and the manufacturing protocol used is exposed. These methodological developments were then validated in fMRI experiments of hypercapnic challenges and forepaw stimulation. Finally, an fMRI experiment studying mechanisms of action of vagus nerve stimulation was conducted, focusing on the distinction between neuronal activations and confounding cardiovascular effects by dynamic causal modeling. Also, results on fMRI of deep brain stimulation in rats are presented. Several targets were stimulated (dorsolateral geniculate nucleus, dentate gyrus, striatum and thalamus), and activations were obtained at a distance from the electrode. Results were in accordance with current knowledge on neuroanatomical connections of these nuclei. Thus, we developed and validated fMRI of the rat and its application to electrical stimulation of peripheral and central nervous system.SAVOIE-SCD - Bib.électronique (730659901) / SudocGRENOBLE1/INP-Bib.électronique (384210012) / SudocGRENOBLE2/3-Bib.électronique (384219901) / SudocSudocFranceF

Investigating Neurovascular Function in Pre-Clinical Models of Alzheimer’s Disease & Atherosclerosis

Background: Neurovascular coupling (NVC) is essential to brain health and the breakdown of NVC is proposed to be a key pathological factor in the development of Alzheimer’s disease (AD), vascular dementia (VaD) and other cerebrovascular diseases. Importantly; as we age, the presence of two or more comorbidities is common and this often leads to clinical complications. Whilst preclinical models of human disease are numerous and have supported basic and translational neuroscience immensely over the past few decades, models of comorbidity are few and often neglected when it is important to study comorbidity to reflect clinical presentations in patients. This project will focus on examining neurovascular function in 3 different preclinical models of AD, atherosclerosis (ATH) and comorbid AD & ATH (MIX). Aims & Objectives: I) To investigate neurovascular function at an early-AD timepoint (6m) in the J20-hAPP model of AD (J20-AD); when amyloid-beta deposits begin to form, using a chronic surgery recovered animal protocol. Neurovascular function will be assessed by 2D- optical imaging spectroscopy (2D-OIS) to measure cortical haemodynamics, in addition to using multichannel microelectrodes to obtain neural multi-unit activity (MUA). II) To investigate neurovascular function in a novel experimental model of ATH using the rAAV8-mPCSK9- D377Y + Western Diet model (PCSK9-ATH). III) To create a mixed comorbid model of AD and ATH (J20-PCSK9-MIX) and to investigate neurovascular function in this novel model. IV) To assess neuropathology and neuroinflammation from brain tissue in the 3 disease models. Results: Firstly, at an early stage, J20-AD mice exhibit enhanced evoked-haemodynamic responses associated with neural hyperexcitability. They also display a unique time- dependent elevation of baseline blood volume under normobaric hyperoxia. Secondly, PCSK9-ATH display reduced evoked-responses and show signs of neurovascular dysfunction associated with increased IL1β & TNFα-neuroinflammation. Thirdly, J20-PCSK9-MIX comorbid mice have a trebling of Aβ plaques in the hippocampus, although, without any further worsening of neurovascular function in the cortex compared to J20-AD mice, although all 3 disease models show a trend towards the reduced washout of HbR, which indicates metabolic inefficiency and inadequate oxygen delivery to neurons. Finally, electrode insertion into the brain (causing mild brain injury) leads to cortical spreading depression (CSD) to occur in all mice, with the most severe CSD occurring in J20-AD and PCSK9-ATH mice, and this may be related to levels of IL1β neuroinflammation, though this needs to be confirmed. Conclusions: These results provide novel insights in all 3 disease models which have important translational implications by highlighting distinct therapeutic targets and strategies. The results also show the importance of neurovascular function in dementia and targeting impairments to neurovascular function early on may be key to slowing down the onset and progression of dementia