932 research outputs found

    Hippocampal Volume and the Detection of Mild Cognitive Impairment in an Older Adult Population: Assessing Performance on Cognitive Screeners Administered In-Person and Electronically

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    The present study investigated how performance on in-person and electronic neuropsychological assessment measures predicted subcortical hippocampal volume and cognitive decline consistent with mild cognitive impairment. It was hypothesized that the Montreal Cognitive Assessment would display better predictive strength than the Cogstate Brief Battery when evaluating subcortical hippocampal volume measured via structural magnetic resonance imaging. It was further hypothesized that the Montreal Cognitive Assessment would be more sensitive to predicting group membership to the diagnostic classification of mild cognitive impairment compared to the Cogstate Brief Battery. The sample included 445 older adult participants selected from the Alzheimer’s Disease Neuroimaging Initiative 3. Participants met criteria for diagnostic classifications of cognitively normal and mild cognitive impairment and had undergone neuropsychological testing consisting of the Montreal Cognitive Assessment and Cogstate Brief Battery, as well as structural magnetic resonance imaging scans of the hippocampus at baseline testing. The learning/working memory composite from the Cogstate Brief Battery was the only substantial predictor for total subcortical hippocampal volume. When evaluating predictive strength relative to group membership of either cognitively normal or mild cognitive impairment, the Montreal Cognitive Assessment was the most substantial predictor of diagnostic classification, specifically mild cognitive impairment. The learning/working memory composite from the Cogstate Brief Battery was also a good predictor of group membership, though the Montreal Cognitive Assessment was observed to be more sensitive overall. The results of this study maintained the effectiveness of in-person neuropsychological assessment, while also supporting the use of electronic measures with older adults when evaluating cognitive status. The data also contributes additional information that is helpful in the early detection of progressive neurodegenerative diseases, such as Alzheimer’s disease

    Feasibility of functional MRI on point-of-care MR platforms

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    Magnetic resonance imaging (MRI) has proven to be a clinically valuable tool that can produce anatomical and functional images with improved soft tissue contrast compared to other imaging modalities. There has recently been a surge in low- and mid-field scanners due to hardware developments and innovative acquisition techniques. These compact scanners are accessible, offer reduced siting requirements and can be made operational at a reduced cost. This thesis aims to implement blood-oxygen-level-dependent (BOLD) resting-state functional MRI (fMRI) at such a mid-field point-of-care scanner. The availability of this technique can be beneficial to get neurological information in cases of traumatic brain injury, stroke, epilepsy, and dementia. This technique was previously not implemented at low- and mid-field since signal-to-noise ratio and the contrast scale with field strength. Studies were conducted to gauge the performance of an independent component analysis (ICA) based platform (GraphICA) to analyze artificially added noisy resting state functional data previously collected with a 3T scanner. This platform was used in later chapters to preprocess and perform functional connectivity studies with data from a mid-field scanner. A single echo gradient echo echoplanar imaging (GE-EPI) sequence is typically used for BOLD-based fMRI. Task-based fMRI experiments were performed with this sequence to gauge the feasibility of this technique on a mid-field scanner. Once the feasibility was established, the sequence was further optimized to suit mid-field scanners by considering all the imaging parameters. Resting-state experiments were conducted with an optimized single echo GE-EPI sequence with reduced dead time on a mid-field scanner. Temporal and image signal-to-noise ratio were calculated for different cortical regions. Along with that, functional connectivity studies and identification of resting-state networks were performed with GraphICA which demonstrated the feasibility of this resting-state fMRI at mid-field. The reliability and repeatability of the identified networks were assessed by comparing the networks identified with 3T data. Resting-state experiments were conducted with a multi-echo GE-EPI sequence to use the dead time due to long T2* at mid-field effectively. Temporal signal-to-noise was calculated for different cortical regions. Along with that, functional connectivity studies and identification of resting-state networks were performed with GraphICA which demonstrated the feasibility of this resting-state fMRI at mid-field

    Identification of different MRI atrophy progression trajectories in epilepsy by subtype and stage inference

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    Artificial intelligence (AI)-based tools are widely employed, but their use for diagnosis and prognosis of neurological disorders is still evolving. Here we analyse a cross-sectional multicentre structural MRI dataset of 696 people with epilepsy and 118 control subjects. We use an innovative machine-learning algorithm, Subtype and Stage Inference, to develop a novel data-driven disease taxonomy, whereby epilepsy subtypes correspond to distinct patterns of spatiotemporal progression of brain atrophy.In a discovery cohort of 814 individuals, we identify two subtypes common to focal and idiopathic generalized epilepsies, characterized by progression of grey matter atrophy driven by the cortex or the basal ganglia. A third subtype, only detected in focal epilepsies, was characterized by hippocampal atrophy. We corroborate external validity via an independent cohort of 254 people and confirm that the basal ganglia subtype is associated with the most severe epilepsy.Our findings suggest fundamental processes underlying the progression of epilepsy-related brain atrophy. We deliver a novel MRI- and AI-guided epilepsy taxonomy, which could be used for individualized prognostics and targeted therapeutics

    Advancing the Study of Functional Connectome Development

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    A better understanding of functional changes in the brain across childhood offers the potential to better support neurodevelopmental and learning challenges. However, neuroimaging tools such as functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) are vulnerable to head motion and other artifacts, and studies have had limited reproducibility. To accomplish research goals, we need to understand the reliability and validity of data collection, processing, and analysis strategies. Neuroimaging datasets contain individually unique information, but identifiability is reduced by noise or lack of signal, suggesting it can be a measure of validity. The goal of this thesis was to use identifiability to benchmark different methodologies, and describe how identifiability associates with age across early childhood. I first compared several different fMRI preprocessing pipelines for data collected from young children. Preprocessing techniques are often controversial due to specific drawbacks and have typically been assessed with adult datasets, which have much less head motion. I found benefits to the use of global signal regression and temporal censoring, but overly strict censoring can impact identifiability, suggesting noise removed must be balanced against signal retained. I also compared several different EEG measures of functional connectivity (FC). EEG can be vulnerable to volume conduction artifacts that can be mitigated by only considering shared information with a time delay between signals. However, I found that mitigation strategies result in lower identifiability, suggesting that while removing confounding noise they also discard substantial signal of interest. Individual experiences may shape development in an individually unique way, which is supported by evidence that adults have more individually identifiable patterns of FC than children. I found that across 4 to 8 years of age, identifiability increased via increased self-stability, but without changes in similarity-to-others. In the absence of ground truth, it is difficult to argue for or against analysis decisions based solely on a theoretical framework and need to also be validated. My work highlights the importance of not thinking about techniques in a valid-invalid dichotomy; certain methods may be sub-optimal while still being preferable to alternatives if they better manage the trade off between noise removed and signal retained

    Chronic traumatic encephalopathy - neuroimaging markers and brain function

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    Geometric Data Analysis: Advancements of the Statistical Methodology and Applications

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    Data analysis has become fundamental to our society and comes in multiple facets and approaches. Nevertheless, in research and applications, the focus was primarily on data from Euclidean vector spaces. Consequently, the majority of methods that are applied today are not suited for more general data types. Driven by needs from fields like image processing, (medical) shape analysis, and network analysis, more and more attention has recently been given to data from non-Euclidean spaces–particularly (curved) manifolds. It has led to the field of geometric data analysis whose methods explicitly take the structure (for example, the topology and geometry) of the underlying space into account. This thesis contributes to the methodology of geometric data analysis by generalizing several fundamental notions from multivariate statistics to manifolds. We thereby focus on two different viewpoints. First, we use Riemannian structures to derive a novel regression scheme for general manifolds that relies on splines of generalized Bézier curves. It can accurately model non-geodesic relationships, for example, time-dependent trends with saturation effects or cyclic trends. Since Bézier curves can be evaluated with the constructive de Casteljau algorithm, working with data from manifolds of high dimensions (for example, a hundred thousand or more) is feasible. Relying on the regression, we further develop a hierarchical statistical model for an adequate analysis of longitudinal data in manifolds, and a method to control for confounding variables. We secondly focus on data that is not only manifold- but even Lie group-valued, which is frequently the case in applications. We can only achieve this by endowing the group with an affine connection structure that is generally not Riemannian. Utilizing it, we derive generalizations of several well-known dissimilarity measures between data distributions that can be used for various tasks, including hypothesis testing. Invariance under data translations is proven, and a connection to continuous distributions is given for one measure. A further central contribution of this thesis is that it shows use cases for all notions in real-world applications, particularly in problems from shape analysis in medical imaging and archaeology. We can replicate or further quantify several known findings for shape changes of the femur and the right hippocampus under osteoarthritis and Alzheimer's, respectively. Furthermore, in an archaeological application, we obtain new insights into the construction principles of ancient sundials. Last but not least, we use the geometric structure underlying human brain connectomes to predict cognitive scores. Utilizing a sample selection procedure, we obtain state-of-the-art results

    Ovarian hormones shape brain structure, function, and chemistry: A neuropsychiatric framework for female brain health

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    There are robust sex differences in brain anatomy, function, as well as neuropsychiatric and neurodegenerative disease risk (1-6), with women approximately twice as likely to suffer from a depressive illness as well as Alzheimer’s Disease. Disruptions in ovarian hormones likely play a role in such disproportionate disease prevalence, given that ovarian hormones serve as key regulators of brain functional and structural plasticity and undergo major fluctuations across the female lifespan (7-9). From a clinical perspective, there is a wellreported increase in depression susceptibility and initial evidence for cognitive impairment or decline during hormonal transition states, such as the postpartum period and perimenopause (9-14). What remains unknown, however, is the underlying mechanism of how fluctuations in ovarian hormones interact with other biological factors to influence brain structure, function, and chemistry. While this line of research has translational relevance for over half the population, neuroscience is notably guilty of female participant exclusion in research studies, with the male brain implicitly treated as the default model and only a minority of basic and clinical neuroscience studies including a female sample (15-18). Female underrepresentation in neuroscience directly limits opportunities for basic scientific discovery; and without basic knowledge of the biological underpinnings of sex differences, we cannot address critical sexdriven differences in pathology. Thus, my doctoral thesis aims to deliberately investigate the influence of sex and ovarian hormones on brain states in health as well as in vulnerability to depression and cognitive impairment:Table of Contents List of Abbreviations ..................................................................................................................... i List of Figures .............................................................................................................................. ii Acknowledgements .....................................................................................................................iii 1 INTRODUCTION .....................................................................................................................1 1.1 Lifespan approach: Sex, hormones, and metabolic risk factors for cognitive health .......3 1.2 Reproductive years: Healthy models of ovarian hormones, serotonin, and the brain ......4 1.2.1 Ovarian hormones and brain structure across the menstrual cycle ........................4 1.2.2 Serotonergic modulation and brain function in oral contraceptive users .................6 1.3 Neuropsychiatric risk models: Reproductive subtypes of depression ...............................8 1.3.1 Hormonal transition states and brain chemistry measured by PET imaging ...........8 1.3.2 Serotonin transporter binding across the menstrual cycle in PMDD patients .......10 2 PUBLICATIONS ....................................................................................................................12 2.1 Publication 1: Association of estradiol and visceral fat with structural brain networks and memory performance in adults .................................................................................13 2.2 Publication 2: Longitudinal 7T MRI reveals volumetric changes in subregions of human medial temporal lobe to sex hormone fluctuations ..............................................28 2.3 Publication 3: One-week escitalopram intake alters the excitation-inhibition balance in the healthy female brain ...............................................................................................51 2.4 Publication 4: Using positron emission tomography to investigate hormone-mediated neurochemical changes across the female lifespan: implications for depression ..........65 2.5 Publication 5: Increase in serotonin transporter binding across the menstrual cycle in patients with premenstrual dysphoric disorder: a case-control longitudinal neuro- receptor ligand PET imaging study ..................................................................................82 3 SUMMARY ...........................................................................................................................100 References ..............................................................................................................................107 Supplementary Publications ...................................................................................................114 Author Contributions to Publication 1 .....................................................................................184 Author Contributions to Publication 2 .....................................................................................186 Author Contributions to Publication 3 .....................................................................................188 Author Contributions to Publication 4 .....................................................................................190 Author Contributions to Publication 5 .....................................................................................191 Declaration of Authenticity ......................................................................................................193 Curriculum Vitae ......................................................................................................................194 List of Publications ................................................................................................................195 List of Talks and Posters ......................................................................................................19

    Functional connectivity and dendritic integration of feedback in visual cortex

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    A fundamental question in neuroscience is how different brain regions communicate with each other. Sensory processing engages distributed circuits across many brain areas and involves information flow in the feedforward and feedback direction. While feedforward processing is conceptually well understood, feedback processing has remained mysterious. Cortico-cortical feedback axons are enriched in layer 1, where they form synapses with the apical dendrites of pyramidal neurons. The organization and dendritic integration of information conveyed by these axons, however, are unknown. This thesis describes my efforts to link the circuit-level and dendritic-level organization of cortico-cortical feedback in the mouse visual system. First, using cellular resolution all-optical interrogation across cortical areas, I characterized the functional connectivity between the lateromedial higher visual area (LM) and primary visual cortex (V1). Feedback influence had both facilitating and suppressive effects on visually-evoked activity in V1 neurons, and was spatially organized: retinotopically aligned feedback was relatively more suppressive, while retinotopically offset feedback was relatively more facilitating. Second, to examine how feedback inputs are integrated in apical dendrites, I optogenetically stimulated presynaptic neurons in LM while using 2-photon calcium imaging to map feedback-recipient spines in the apical tufts of layer 5 neurons in V1. Activation of a single feedback-providing input was sufficient to boost calcium signals and recruit branch-specific local events in the recipient dendrite, suggesting that feedback can engage dendritic nonlinearities directly. Finally, I measured the recruitment of apical dendrites during visual stimulus processing. Surround visual stimuli, which should recruit relatively more facilitating feedback, drove local calcium events in apical tuft branches. Moreover, global dendritic event size was not purely determined by somatic activity but modulated by visual stimuli and behavioural state, in a manner consistent with the spatial organization of feedback. In summary, these results point toward a possible involvement of active dendritic processing in the integration of feedback signals. Active dendrites could thus provide a biophysical substrate for the integration of essential top-down information streams, including contextual or predictive processing
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