Life Sciences Commons^™

Elucidating Neuroinflammation In Multiple Sclerosis By Network Analysis, Nora C. Welsh

Dartmouth College Ph.D Dissertations

Multiple sclerosis (MS) is a heterogeneous disease, differing on many variables, including disease course, sex, and overall activity. Key characteristics of the disease encompass demyelination, axonal damage, neuronal loss, glial cell activation, and the infiltration of peripheral immune cells. Molecular proxies of these functions are secreted proteins, including cytokines and immunoglobulins, which, in the central nervous system (CNS), can be secreted into the cerebrospinal fluid (CSF). A detailed analysis of these secreted proteins can offer insights into the evolving immunological and neurodegenerative features as the disease progresses. To understand the dynamic biological processes involved in MS, I used network analysis …

Target Selection And Enhancement During Attentional Tracking, Marvin R. Maechler

Dartmouth College Ph.D Dissertations

At any waking moment, we are bombarded with more sensory information than we can fully process. Attention is necessary to deal with the dynamic world we live in. One fundamental function of vision and attention is to keep track of moving objects, but what are the targets of attention during tracking?

One of the first theories of attentional tracking predicted that targets would be selected at early processing stages. By employing the double-drift illusion, which dissociates physical and perceived positions of moving objects, we investigated which of these positions is selected for tracking. Contrary to earlier theories and in line …

Dna Methylation-Based Epigenetic Biomarkers In Cell-Type Deconvolution And Tumor Tissue Of Origin Identification, Ze Zhang

Dartmouth College Ph.D Dissertations

DNA methylation is an epigenetic modification that regulates gene expression and is essential to establishing and preserving cellular identity. Genome-wide DNA methylation arrays provide a standardized and cost-effective approach to measuring DNA methylation. When combined with a cell-type reference library, DNA methylation measures allow the assessment of underlying cell-type proportions in heterogeneous mixtures. This approach, known as DNA methylation deconvolution or methylation cytometry, offers a standardized and cost-effective method for evaluating cell-type proportions. While this approach has succeeded in discerning cell types in various human tissues like blood, brain, tumors, skin, breast, and buccal swabs, the existing methods have major …

Oligodendrocyte 2phatal Reveals Dynamics Of Myelin Degeneration And Repair, Timothy W. Chapman

Dartmouth College Ph.D Dissertations

Oligodendrocytes are responsible for producing myelin in the central nervous system. This lipid-rich coating along axons helps to increase action potential velocity, provide metabolic support to axons, and facilitate fine-tuning of neuronal circuitry. Demyelination and/or myelin dysfunction is widespread in neurodegenerative diseases and aging. Despite this, we know very little about how individual oligodendrocytes, or the myelin sheaths they produce, degenerate. Myelin repair, carried out by resident oligodendrocyte precursor cells (OPCs), is known to occur following myelin damage in certain contexts. We sought to investigate the cellular dynamics of oligodendrocyte degeneration and repair by developing a non-inflammatory demyelination model, combining …

Self-Supervised Pretraining And Transfer Learning On Fmri Data With Transformers, Sean Paulsen

Dartmouth College Ph.D Dissertations

Transfer learning is a machine learning technique founded on the idea that knowledge acquired by a model during “pretraining” on a source task can be transferred to the learning of a target task. Successful transfer learning can result in improved performance, faster convergence, and reduced demand for data. This technique is particularly desirable for the task of brain decoding in the domain of functional magnetic resonance imaging (fMRI), wherein even the most modern machine learning methods can struggle to decode labelled features of brain images. This challenge is due to the highly complex underlying signal, physical and neurological differences between …

Complement System In Multiple Sclerosis: Its Role In Disease Course And Potential As A Therapeutic Target, Michael R. Linzey

Dartmouth College Ph.D Dissertations

Multiple sclerosis (MS) is a clinically heterogeneous neurological condition characterized by neuroinflammation and neurodegeneration. Relapsing-remitting MS, defined by inflammatory attacks, is the most common initial form of MS and there are currently 23 FDA-approved treatments for these patients. These therapies work primarily by reducing inflammation in the CNS; they do not work well in progressive disease. Therefore, an unmet medical need exists for effective therapeutic options to treat progressive MS (PMS).

In MS, intrathecal immunoglobulins synthesis (IIgS) correlates with disease progression. My goals for this dissertation were to establish the pathological role of IIgS and identify new potential therapeutic …

Behavioral And Neural Mechanisms Of Serotonin Modulation Of Impulsivity And Reward, Stephanie S. Desrochers

Dartmouth College Ph.D Dissertations

Despite its prevalence in many psychiatric disorders, such as attention deficit hyperactivity disorder, suicidal depression, schizophrenia, and aggression and motivational disorders, impulsivity and its biological bases remain poorly understood. Subdivisions of impulsivity, including impulsive action (reduced response inhibition) and impulsive choice (reduced delay of gratification), sometimes present in an uncorrelated manner. This complexity renders pathological impulsivity difficult to treat, as different underlying causes likely result in different phenotypic presentations, despite being placed under one umbrella term. In order to study the behavior and biology of one particular facet of impulsivity, this dissertation utilizes the serotonin 1B receptor (5-HT1BR; an inhibitory …

Gabaergic Interneurons And Prenatal Ethanol Exposure: From Development To Aging, Adelaide R. Tousley

Dartmouth College Ph.D Dissertations

Fetal Alcohol Spectrum Disorders are the most common non-genetic cause of neurodevelopmental disability worldwide. Individuals with Fetal Alcohol Spectrum Disorder experience clinical symptoms including differences in physical, cognitive and behavioral development beginning in early childhood, but continue to face challenges into adulthood. There is a critical need to examine the effects of prenatal ethanol exposure across early development, and to establish how the developmental effects of prenatal ethanol exposure may or may not progress in aging individuals. To contribute to these two areas, I asked how a binge-type prenatal ethanol exposure might affect: (1) early postnatal development of striatal neurons …

Accelerated Forgetting In People With Epilepsy: Pathologic Memory Loss, Its Neural Basis, And Potential Therapies, Sarah Ashley Steimel Phd

Dartmouth College Ph.D Dissertations

While forgetting is vital to human functioning, delineating between normative and disordered forgetting can become incredibly complex. This thesis characterizes a pathologic form of forgetting in epilepsy, identifies a neural basis, and investigates the potential of stimulation as a therapeutic tool. Chapter 2 presents a behavioral characterization of the time course of Accelerated Long-Term Forgetting (ALF) in people with epilepsy (PWE). This chapter shows evidence of ALF on a shorter time scale than previous studies, with a differential impact on recall and recognition. Chapter 3 builds upon the work in Chapter 2 by extending ALF time points and investigating the …

Mapping The Malleable Self: How Self-Views Are Represented And Learned Within The Social Brain, Sasha Carmela Brietzke

Dartmouth College Ph.D Dissertations

Humans possess a unique and wide-ranging ability to self-reflect that takes center stage in our everyday cognition. While many people believe their own self to be immutable, different contexts may warp how we perceive the self. The goal of this dissertation is to investigate two lenses through which we may view the self: (1) across time in the past and future, and (2) through the eyes of others via evaluative feedback. In Studies 1-3, I demonstrate that people’s ratings of their own personality become increasingly less differentiated as they consider more distant past and future selves. This effect was preferential …

Spatial Representation In Postrhinal Cortex, Patrick Lachance

Dartmouth College Ph.D Dissertations

Animals rely on a variety of internal and external cues to orient themselves when navigating their environments and determining their current spatial context. Information regarding these cues enters the brain from the navigator’s first-person perspective. Information of this type is considered to be egocentric, or self-centered. However, decades of behavioral, electrophysiological, and imaging research suggest that the brain contains a rich collection of spatial representations that are unrestricted by the animal’s first-person perspective, and instead are defined relative to the surrounding environment. These representations are considered allocentric, or world-centered. Despite an abundance of promising modeling work, the specific mechanisms by …

Genetic Heterogeneity In Schizophrenia And Contribution Of Context To Vowel Recognition, Eva Childers

Dartmouth College Ph.D Dissertations

This dissertation is composed of three chapters that address two distinct topics. Chapter 2 addresses the use of consonantal context in vowel perception. Previous studies have demonstrated that context is important for vowel identification, however, this effect may be an artifact of stimuli production. To address this potential confound, we used stimuli extracted from an audiobook and asked subjects to identify vowels encased in consonants and isolated by themselves. We show that subjects had improved vowel identification when the vowel is presented with a consonantal framing, suggesting there is information contained in the surrounding context that is important for phoneme …

Beyond Homogenous Decision-Making Models: Role Of Brain Areas Interaction And Heterogeneity, Mohsen Rakhshan

Dartmouth College Ph.D Dissertations

Most existing mechanistic models of decision making consider microcircuits within a homogenous brain area and fail to consider the distributed nature of this cognitive process. More specifically, these models do not take into account: a) how different types of information might influence choice in different stages of the process; and b) how interactions and the heterogeneity between circuits across different brain areas might be essential for the process. In this dissertation, I present a combination of experimental and modeling approaches to study distributed nature of the decision-making by examining both the distributed processing of information as well as the interaction …