Imaging of cognitive outcomes in patients with autoimmune encephalitis

Die Autoimmunenzephalitis ist eine kürzlich beschriebene entzündliche Erkrankung des zentralen Nervensystems, die Gedächtnisdefizite, Psychosen, oder epileptische Anfälle hervorrufen kann. Derzeit ist hingegen noch nicht ausreichend verstanden, welche pathologischen Veränderungen zu den kognitiven Defiziten führen und welche neuropsychologischen und bildgebenden Langzeitoutcomes zu erwarten sind. Anhand von strukturellen und funktionellen Bildgebungsanalysen zeigt diese Dissertation, dass kognitive Defizite auch nach der akuten Phase der Autoimmunenzephalitis fortbestehen können. Bei der LGI1-Enzephalitis gehen Gedächtnisdefizite mit fokalen strukturellen Läsionen im Hippocampus einher. Durch eine funktionelle Störung der Resting-State-Konnektivität des Default-Mode- und Salienznetzwerkes beeinträchtigen diese Hippocampusläsionen auch Hirnregionen außerhalb des limbischen Systems. Bei Patient:innen mit NMDA-Rezeptor-Enzephalitis finden sich in der longitudinalen neuropsychologischen Untersuchung trotz guter allgemeiner Genesung auch noch mehrere Jahre nach der Akutphase persistierende Defizite des Gedächtnisses und exekutiver Funktionen. Zuletzt zeigt eine transdiagnostische Analyse, dass der anteriore Hippocampus eine erhöhte Vulnerabilität gegenüber immunvermittelten pathologischen Prozessen aufweist. Diese Ergebnisse legen nahe, dass kognitive Symptome auch noch nach der Entlassung aus der stationären Behandlung fortbestehen können. Sowohl umschriebene strukturelle Hippocampusläsionen als auch Veränderungen in makroskopischen funktionellen Hirnnetzwerken tragen zur pathophysiologischen Erklärung dieser Symptome bei. Zudem erlauben diese Ergebnisse einen Einblick in neuroplastische Veränderungen des Gehirns und haben weitreichende Implikationen für die Langzeitversorgung und das Design zukünftiger klinischer Studien.Autoimmune encephalitis is a recently described inflammatory disease of the central nervous system that can cause memory deficits, psychosis, or seizures. The trajectory of cognitive dysfunction and the underlying long-term imaging correlates are, however, not yet fully understood. By using advanced structural and functional neuroimaging, this thesis shows that cognitive deficits persist beyond the acute phase. In LGI1 encephalitis, MRI postprocessing revealed that memory deficits are related to focal structural hippocampal lesions. These hippocampal lesions propagate to brain areas outside the limbic system through aberrant resting-state connectivity of the default mode network (DMN) and the salience network. In NMDA receptor encephalitis, a longitudinal analysis of neuropsychological data describes persistent cognitive deficits, especially in the memory and executive domains, despite good physical recovery several years after the acute disease. Lastly, a transdiagnostic analysis reveals that the anterior hippocampus is particularly vulnerable to immune-mediated damage. In conclusion, these results demonstrate that cognitive symptoms in autoimmune encephalitis can persist beyond discharge from neurological care. Both discrete structural hippocampal damage and changes in macroscopic functional networks shed light on the pathophysiological basis of these symptoms. These findings help to explain how the brain responds to pathological damage and have substantial implications for long-term patient care and the design of future clinical studies

Cerebellar contribution to Cognitive Impairment in early stages of Relapsing-Remitting Multiple Sclerosis: a conventional and rs-fMRI study

Background. The cerebellum is a primary site of Multiple Sclerosis (MS) pathology. Structural and functional MRI studies have demonstrated the role of the posterior cerebellum in cognitive functions. To date, the “Cerebellar Cognitive Affective Syndrome” (CCAS) scale has never been used to test MS-related Cognitive Impairment (CI) and its association with cerebellar involvement. Objectives. We investigated the association of MRI structural and functional abnormalities of the cognitive cerebellum with CI and tested the role of the CCAS scale in detecting CI in a cohort of very early RRMS patients. Methods. 37 patients with early RRMS and 4 age- and sex-matched healthy controls (HC) were enrolled in this cross-sectional, exploratory study. Cognitive performances were assessed through BICAMS, D-KEFS ST, and CCAS scale. Using a CCAS scale score cut-off (based on a 50 HC sample), 26/37 (70%) patients were classified as “Normal-CCAS” and 11/37 (30%) as “Impaired-CCAS”. All subjects underwent a conventional and resting-state functional MRI (rs-fMRI) protocol. Comparisons between groups were assessed for structural and functional MRI parameters. Moreover, correlations between cognitive test scores and structural-functional MRI parameters were evaluated. Results. Patients with pathological score on CCAS also showed CVLT-II and D-KEFS ST low scores. A significant reduction in cerebellar volumetric parameters was found in the CCAS-impaired MS group compared to the normal one, albeit whole brain WM and thalamic volumes were also significantly reduced. The rs-fMRI analysis revealed higher functional connectivity (FC) between the cognitive cerebellum and most of the functional brain cortical networks in the CCAS-impaired group compared to the normal one. Conclusions. Our findings suggest that CI in early RRMS is associated with pathological alterations in both structural and functional MRI parameters. Higher FC between cerebellar-brain networks in CCAS-impaired patients might be the expression of a compensatory hyperactivation of altered cognitive cerebellar connections. Finally, although the CCAS scale has proven able to detect CI in MS patients, its specificity for cerebellar pathology needs to be further investigated

Stroke of the Visual Cortex

Stroke is the leading cause of homonymous visual field defect (VFD), resulting from irreversible damage of the post-chiasmatic visual pathway. From 6 to 13% of ischaemic strokes affect the supply area of the posterior cerebral artery, including the visual cortex in the occipital lobe. Besides ischaemic injury, the visual cortex can be damaged by intracerebral haemorrhage (ICH), 10% of which reside in the occipital lobe. Since occipital stroke almost always disturbs vision but can leave motor and language functions untouched, it may remain unrecognised in the acute phase, withholding the patients from receiving recanalisation treatments. Moreover, only up to 25% of stroke-related VFD recover spontaneously, whereas the rest continue to hinder patients’ independence in daily living and quality of life. Despite rigorous efforts, no evidence-based rehabilitation method to restore vision after stroke has been established. The aim of this thesis was to study the recognition, clinical characteristics, rehabilitation, neural mechanisms, and outcome of occipital stroke patients with VFD. The retrospective part of the thesis consists of two cohorts. The first cohort comprised 245 occipital ischaemic stroke patients admitted to the neurological emergency department of Helsinki University Hospital due to visual symptoms in 2010‒2015. We investigated their prehospital recognition and diagnostic delays and analysed the obstacles in their access to acute stroke treatment. The second retrospective cohort was the Helsinki ICH Study registry of 1013 consecutive non-traumatic ICH patients treated at Helsinki University Hospital in 2005‒2010, among whom we searched for isolated occipital ICH patients and analysed their clinical characteristics, aetiology, outcome, and incidence of post-stroke epilepsy in comparison to ICHs of other location. The prospective part of the thesis was based on the multicentre, randomised, sham-controlled exploratory REVIS (Restoration of Vision after Stroke) trial that studied rehabilitation of persistent VFD after chronic occipital stroke with different methods of non-invasive electrical brain stimulation. Altogether 56 patients were included in three 10-day experiments in three centres. The centres examined: 1) repetitive transorbital alternating current stimulation (rtACS) vs transcranial direct current stimulation preceding rtACS (tDCS/rtACS) vs sham in Germany, 2) rtACS vs sham in Finland, and 3) tDCS vs sham in Italy. In a functional magnetic resonance imaging spin-off study, resting-state functional connectivity of occipital stroke patients receiving rtACS or sham was compared to healthy control subjects at baseline and to each other after intervention. We found out that the prehospital delay of occipital stroke patients ranged between 20 minutes and 5 weeks and only 20% were admitted within the 4.5-hour time window of intravenous thrombolysis. Consequently, only 6.5% received thrombolysis, which is the mainstay of acute stroke treatment. One fourth of the patients arrived through at least two points of care and as many were assessed by an ophthalmologist before entering the neurological care, even though acute stroke patients should be transported directly to the neurological emergency department. The diagnostic delay was primarily caused by the patients’ late contact to health care but was also attributed to poor recognition and misdiagnosis by health-care professionals. The incidence of isolated occipital ICH was 1.9% of all non-traumatic ICHs and 5.3% of lobar ICHs. The patients with occipital ICH were younger and had more often vascular malformations as an aetiology of the bleeding than the non-occipital lobar ICH patients. They presented with milder symptoms and longer delay, and over 60% of the patients suffered solely from visual focal symptom. The haematoma volume in the occipital lobe was smaller and grew less compared to the non-occipital lobar haemorrhages. All in all, the occipital location of ICH was independently associated with favourable outcome at discharge among the patients with lobar ICH. The majority of the occipital ICH patients were able to return to independent activities of daily living, including driving a car and working, within a follow-up of a year. However, post-stroke epilepsy was as frequent as after non-occipital lobar ICH. In the prospective REVIS trial, rtACS was mostly ineffective in vision rehabilitation according to behavioural vision tests. Neither did it affect resting-state functional connectivity in comparison to sham. Transcranial DCS alone increased the monocular visual field measured with standard automated perimetry. The combined tDCS/rtACS propelled some improvements in the secondary visual outcome measures but did not differ from the sham stimulation. All the stimulation modalities were tolerated well. The functional connectivity of the chronic occipital stroke patients with VFD did not differ from the healthy control subjects when the whole brain network was considered in the analyses. However, a few occipital regions close to the infarct expressed lower local connectivity to the highly connected regions of the network according to the network graph metrics, whereas a lateral occipital region in the damaged hemisphere had higher network connectivity. These findings support the view that chronic ischaemic damage of the visual cortex affects functional connectivity within the visual network but leaves global connectivity unchanged. In conclusion, occipital stroke patients are insufficiently recognised, and thus the awareness of visual stroke symptoms should be raised especially among the public but also among health-care professionals to provide the patients with timely acute treatment and to prevent permanent disability. Occipital ICH patients have relatively favourable outcomes, but a structural cause of bleeding should be searched. Non-invasive electrical brain stimulation with the examined modalities does not cause robust improvement in vision or functional connectivity of the brain networks after a 10-day treatment, but further experiments with tDCS-based methods, potentially in combination with vision training, may be worth pursuing.Ihmisen näköaivokuori sijaitsee pääosin takaraivolohkossa ja sen vaurio johtaa tyypillisesti molempien silmien toispuoleiseen näkökenttäpuutokseen. Yleisin syy vaurioon on aivoverenkiertohäiriö: joko aivovaltimon tukoksesta johtuva infarkti tai verisuonen repeämästä aiheutuva aivoverenvuoto. Näkökenttäpuutos alentaa toiminta-, työ- ja ajokykyä ja heikentää elämänlaatua. Alle neljäsosa näkökenttäpuutoksista paranee täysin, eikä niiden kuntouttamiseksi ole kliiniseen käyttöön vakiintunutta menetelmää. Väitöskirjatyössä tutkittiin näköaivokuoren aivoverenkiertohäiriöiden tunnistamista, kliinistä kuvaa, kuntoutusta ja ennustetta. Tutkimuksessa selvisi, että ainoastaan 20,8 % HUS:in neurologian päivystyksessä vuosina 2010–2015 hoidetuista, näköoirein ilmenneen takaraivolohkon infarktin saaneista potilaista tuli hoitoon liuotushoidon mahdollistavassa aikaikkunassa ja vain 6,5 % sai liuotuksen. Viiveen yleisin syy oli potilaiden hidas hakeutuminen hoitoon, mutta kolmasosassa tapauksista myöskään terveydenhuoltohenkilökunta ei aluksi tunnistanut oireiden johtuvan aivoverenkiertohäiriöstä. Takaraivolohkoon rajautuvia aivoverenvuotoja esiintyi 1,9 %:lla HUS:issa 2005–2010 hoidetusta 1013 aivoverenvuotopotilaasta. Potilaat olivat nuorempia ja lieväoireisempia kuin muut vuotopotilaat, ja heidän vuotonsa johtuivat useammin verisuoniepämuodostumista. Vuodon sijainti takaraivolohkossa ennusti parempaa toimintakykyä sairaalasta kotiutuessa, ja suurin osa potilaista toipui vuoden sisällä päivittäistoiminnoissa itsenäisiksi. Epilepsian ilmaantuvuus ei eronnut pitkäaikaisseurannassa muista aivoverenvuotopotilaista. Satunnaistetussa, lumekontrolloidussa REVIS-monikeskustutkimuksessa selvitettiin kajoamattomien, heikkoa sähkövirtaa hyödyntävien stimulaatiomenetelmien tehoa takaraivolohkon aivoinfarktin aiheuttaman kroonisen näkökenttäpuutoksen kuntoutuksessa. Hoitokokeessa tasavirtastimulaatio (tDCS) pienensi vaurion vastapuoleisen silmän näkökenttäpuutosta verrattuna lumehoitoon, kun taas vaihtovirtastimulaatio (rtACS) oli tehotonta. Myöskään näiden yhdistelmällä (tDCS/rtACS) tulokset eivät eronneet lumeesta. Lisäksi toiminnallisella magneettikuvauksella tutkittiin 16 takaraivolohkon aivoinfarktipotilaan lepohermoverkostojen toiminnallista kytkeytyvyyttä verrattuna terveisiin koehenkilöihin. Tutkimus paljasti paikallisia muutoksia kytkeytyvyydessä potilaiden näköinformaation käsittelyyn osallistuvilla aivoalueilla, mutta laajemmin verkostojen toiminta ei eronnut verrokeista. Vaihtovirtastimulaatio ei muuttanut toiminnallista kytkeytyvyyttä

The Dynamics of Central-Peripheral Stress Responses after Acute Psychosocial Stress: a Multimodal Perspective

An acute stress response is a complex interaction of central and peripheral psychophysiological systems with unique temporal characteristics. Interestingly, the interaction represents a unique temporal characteristic. Investigating the dynamics of both brain and body signals during and after an encounter with a stressor allows us to understand the underlying principle of the acute stress response, which has been shown to be atypical in various psychiatric disorders. However, a detailed understanding of stress response is rarely investigated. Therefore, this thesis investigates two major approaches for understanding the acute stress response dynamics using simultaneous electroencephalography (EEG)-photoplethysmographyfunctional magnetic resonance imaging experiments in 39 subjects before and after the ScanStress task. The EEG-derived vigilance indexes reveal a continuous decline at rest. Given the role of alertness in an efficient stress response, the effects of acute stress induction on EEG-derived vigilance metrics are of interest. Therefore, the first approach uses the dynamic analysis of psychophysiological stress responses after the acute psychosocial stress induction. The first study investigates the carry-over effect of acute psychosocial stress on vigilance and its modulation by the multicomponent over-thecounter drug neurexan, which has been shown to modulate the neuroendocrine stress response. By using dynamic analysis, six vigilance scores were calculated every two minutes before and after the stress induction during the resting state. The study revealed that stress delays the continuous decline of vigilance at rest. In addition, the stress-induced increase in mean vigilance levels at rest was correlated positively with the levels of perceived stress during the last month. In addition, the mean vigilance level exhibited a decrease after neurexan treatment compared to placebo intake. Heart rate variability (HRV) can be viewed as an indicator of how well the adaptive regulation system in the brain reacts the peripheral environment. However, the relationship between the HRV and functional connectivity patterns in the brain networks in stressful situations is rarely investigated. Therefore, the second approach uses the multimodal approach to examine the interaction between different stress response systems. The study investigated the temporal association between HRV and FC between the three core brain networks, namely the central executive network, salience network, and default mode network at baseline and after the psychosocial stress induction. In this study, the functional connectivity between three core brain networks and the HRV was examined by taking 60s window length. Furthermore, the temporal association between HRV and functional connectivity was investigated. A significant association was found between HRV and default mode network-central executive network functional connectivity at rest, which was significantly reduced after acute stress induction compared to baseline. These findings suggest that HRV cofluctuates with the core brain networks selectively depending on the stress conditions. In summary, acute psychological stress affects brain dynamics by exhibiting a delay in the continuously declining vigilance and keeping the brain in a more alert state even after the stressor disappears. Furthermore, the results suggest that EEG-derived vigilance metrics index not only stress-response but also the temporal dynamics of vigilance regulation. It can serve as a potential biomarker for the diagnosis and prognosis for stress-related disorders disrupting temporal characteristics of stress response dynamics and showing atypical stress response. In addition, the study revealed that stress affects the interactions among the core large-scale functional networks and physiological dynamics of the heart. The dynamic adaptation of the resources is crucial in a stressful situation; therefore, the stress alters the interaction between the brain and heart. The perturbation in this interaction may play an important role in developing and maintaining stress-related disorders. The thesis work provides novel insights and an understanding of the central and peripheral stress response dynamics, which show a huge potential for the diagnosis, prognosis, and therapeutic planning of individuals with neuropsychiatric disorders

From Photography to fMRI

Hysteria, a mysterious disease known since antiquity, is said to have ceased to exist. Challenging this commonly held view, this is the first cross-disciplinary study to examine the current functional neuroimaging research into hysteria and compare it to the nineteenth-century image-based research into the same disorder. Paula Muhr's central argument is that, both in the nineteenth-century and the current neurobiological research on hysteria, images have enabled researchers to generate new medical insights. Through detailed case studies, Muhr traces how different images, from photography to functional brain scans, have reshaped the historically situated medical understanding of this disorder that defies the mind-body dualism

Functional network correlates of language and semiology in epilepsy

Epilepsy surgery is appropriate for 2-3% of all epilepsy diagnoses. The goal of the presurgical workup is to delineate the seizure network and to identify the risks associated with surgery. While interpretation of functional MRI and results in EEG-fMRI studies have largely focused on anatomical parameters, the focus of this thesis was to investigate canonical intrinsic connectivity networks in language function and seizure semiology. Epilepsy surgery aims to remove brain areas that generate seizures. Language dysfunction is frequently observed after anterior temporal lobe resection (ATLR), and the presurgical workup seeks to identify the risks associated with surgical outcome. The principal aim of experimental studies was to elaborate understanding of language function as expressed in the recruitment of relevant connectivity networks and to evaluate whether it has value in the prediction of language decline after anterior temporal lobe resection. Using cognitive fMRI, we assessed brain areas defined by parameters of anatomy and canonical intrinsic connectivity networks (ICN) that are involved in language function, specifically word retrieval as expressed in naming and fluency. fMRI data was quantified by lateralisation indices and by ICN_atlas metrics in a priori defined ICN and anatomical regions of interest. Reliability of language ICN recruitment was studied in 59 patients and 30 healthy controls who were included in our language experiments. New and established language fMRI paradigms were employed on a three Tesla scanner, while intellectual ability, language performance and emotional status were established for all subjects with standard psychometric assessment. Patients who had surgery were reinvestigated at an early postoperative stage of four months after anterior temporal lobe resection. A major part of the work sought to elucidate the association between fMRI patterns and disease characteristics including features of anxiety and depression, and prediction of postoperative language outcome. We studied the efficiency of reorganisation of language function associated with disease features prior to and following surgery. A further aim of experimental work was to use EEG-fMRI data to investigate the relationship between canonical intrinsic connectivity networks and seizure semiology, potentially providing an avenue for characterising the seizure network in the presurgical workup. The association of clinical signs with the EEG-fMRI informed activation patterns were studied using the data from eighteen patients’ whose seizures and simultaneous EEG-fMRI activations were reported in a previous study. The accuracy of ICN_atlas was validated and the ICN construct upheld in the language maps of TLE patients. The ICN construct was not evident in ictal fMRI maps and simulated ICN_atlas data. Intrinsic connectivity network recruitment was stable between sessions in controls. Amodal linguistic processing and the relevance of temporal intrinsic connectivity networks for naming and that of frontal intrinsic connectivity networks for word retrieval in the context of fluency was evident in intrinsic connectivity networks regions. The relevance of intrinsic connectivity networks in the study of language was further reiterated by significant association between some disease features and language performance, and disease features and activation in intrinsic connectivity networks. However, the anterior temporal lobe (ATL) showed significantly greater activation compared to intrinsic connectivity networks – a result which indicated that ATL functional language networks are better studied in the context of the anatomically demarked ATL, rather than its functionally connected intrinsic connectivity networks. Activation in temporal lobe networks served as a predictor for naming and fluency impairment after ATLR and an increasing likelihood of significant decline with greater magnitude of left lateralisation. Impairment of awareness served as a significant classifying feature of clinical expression and was significantly associated with the inhibition of normal brain functions. Canonical intrinsic connectivity networks including the default mode network were recruited along an anterior-posterior anatomical axis and were not significantly associated with clinical signs

From Photography to fMRI: Epistemic Functions of Images in Medical Research on Hysteria

Hysteria, a mysterious disease known since antiquity, is said to have ceased to exist. Challenging this commonly held view, this is the first cross-disciplinary study to examine the current functional neuroimaging research into hysteria and compare it to the nineteenth-century image-based research into the same disorder. Paula Muhr's central argument is that, both in the nineteenth-century and the current neurobiological research on hysteria, images have enabled researchers to generate new medical insights. Through detailed case studies, Muhr traces how different images, from photography to functional brain scans, have reshaped the historically situated medical understanding of this disorder that defies the mind-body dualism

From Photography to fMRI

Hysteria, a mysterious disease known since antiquity, is said to have ceased to exist. Challenging this commonly held view, this is the first cross-disciplinary study to examine the current functional neuroimaging research into hysteria and compare it to the nineteenth-century image-based research into the same disorder. Paula Muhr's central argument is that, both in the nineteenth-century and the current neurobiological research on hysteria, images have enabled researchers to generate new medical insights. Through detailed case studies, Muhr traces how different images, from photography to functional brain scans, have reshaped the historically situated medical understanding of this disorder that defies the mind-body dualism

Violence Exposure and Social Deprivation: Neural Connectivity Correlates and Protective Factors

Dimensions of early adversity, such as violence exposure and social deprivation, may have different effects associated with socioemotional functioning in the developing brain and different factors may be protective. This dissertation examined the downstream effects of childhood violence exposure and social deprivation in data from the Fragile Families and Child Wellbeing Study at birth, and ages 1, 3, 5, 9, and 15 years. Study one examined the association between violence exposure, social deprivation, and amygdala-prefrontal cortex white matter connectivity, a crucial circuit for emotion regulation. High violence exposure coupled with high social deprivation related to less amygdala–OFC white matter connectivity. Violence exposure was not associated with white matter connectivity when social deprivation was at mean or low levels (i.e., relatively socially supportive contexts). Therefore, social deprivation may exacerbate the effects of childhood violence exposure on the development of white matter connections involved in emotion processing and regulation. Conversely, social support may buffer against them. Study two investigated the association between violence exposure, social deprivation, and adolescent resting-state functional connectivity in two resting-state networks involved in socioemotional functioning (salience network, default mode network) using a person-specific modeling approach. Childhood violence exposure, but not social deprivation, was associated with reduced adolescent resting-state density of the salience and default mode networks. A data-driven algorithm, blinded to childhood adversity, identified youth with heightened violence exposure based on resting-state connectivity patterns. Childhood violence exposure was associated with adolescent functional connectivity heterogeneity, which may reflect person-specific neural plasticity and should be considered when attempting to understand the impacts of early adversity on the brain. Study three examined whether school connectedness was protective against violence exposure and social deprivation when predicting symptoms of internalizing and externalizing psychopathology and positive function and if school connectedness was uniformly protective against both dimensions of adversity. Results suggest that school connectedness is broadly related to better outcomes and may confer additional protection against social deprivation. These findings highlight the important role that the school environment can play for youth who have been exposed to adversity in other areas of their lives. Additionally, the interactive effect of school connectedness with social deprivation, but not violence exposure, supports modeling risk and resilience processes using dimensional frameworks to better identify specific groups of youth that may benefit from interventions that boost social connectedness at school in future research. Overall, this dissertation provides evidence for the complex and person-specific ways through which risk and resilience relate to development and points to considerations for future research. This research has implications for understanding how dimensions of adversity affect the brain and behavior during development and what factors can be protective, which can inform future neuroscience-informed policy interventions.PHDPsychologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/167957/1/lcgayle_1.pd

Developing and Validating Open Source Tools for Advanced Neuroimaging Research

Almost all scientific research relies on software. This is particularly true for research that uses neuroimaging technologies, such as functional magnetic resonance imaging (fMRI). These technologies generate massive amounts of data per participant, which must be processed and analyzed using specialized software. A large portion of these tools are developed by teams of researchers, rather than trained software developers. In this kind of ecosystem, where the majority of software creators are scientists, rather than trained programmers, it becomes more important than ever to rely on community-based development, which may explain why most of this software is open source. It is in the development of this kind of research-oriented, open source software that I have focused much of my graduate training, as is reflected in this dissertation. One software package I have helped to develop and maintain is tedana, a Python library for denoising multi-echo fMRI data. In chapter 2, I describe this library in a short, published software paper. Another library I maintain as the primary developer is NiMARE, a Python library for performing neuroimaging meta-analyses and derivative analyses, such as automated annotation and functional decoding. In chapter 3, I present NiMARE in a hybrid software paper with embedded tutorial code exhibiting the functionality of the library. This paper is currently hosted as a Jupyter book that combines narrative content and code snippets that can be executed online. In addition to research software development, I have focused my graduate work on performing reproducible, open fMRI research. To that end, chapter 4 is a repli- cation and extension of a recent paper on multi-echo fMRI denoising methods Power et al. (2018a). This replication was organized as a registered report, in which the introduction and methods were submitted for peer review before the analyses were performed. Finally, chapter 5 is a conclusion to the dissertation, in which I reflect on the work I have done and the skills I have developed throughout my training