Browsing by Author "Rypma, Bart"
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Item Assessment of Unconstrained Cerebrovascular Reactivity Marker for Large Age-Range fMRI Studies(Public Library of Science) Kannurpatti, S. S.; Motes, Michael A.; Biswal, B. B.; Rypma, BartBreath hold (BH), a commonly used task to measure cerebrovascular reactivity (CVR) in fMRI studies varies in outcome among individuals due to subject-physiology and/or BH-inspiration/expiration differences (i.e., performance). In prior age-related fMRI studies, smaller task-related BOLD response variability is observed among younger than older individuals. Also, a linear CVR versus task relationship exists in younger individuals which maybe useful to test the accuracy of CVR responses in older groups. Hence we hypothesized that subject-related physiological and/or BH differences, if present, may compromise CVR versus task linearity in older individuals. To test the hypothesis, empirical BH versus task relationships from motor and cognitive areas were obtained in younger (mean age = 26 years) and older (mean age = 58 years) human subjects. BH versus task linearity was observed only in the younger group, confirming our hypothesis. Further analysis indicated BH responses and its variability to be similar in both younger and older groups, suggesting that BH may not accurately represent CVR in a large age range. Using the resting state fluctuation of amplitude (RSFA) as an unconstrained alternative to BH, subject-wise correspondence between BH and RSFA was tested. Correlation between BH versus RSFA was significant within the motor but was not significant in the cognitive areas in the younger and was completely disrupted in both areas in the older subjects indicating that BH responses are constrained by subject-related physiology and/or performance-related differences. Contrasting BH to task, RSFA-task relationships were independent of age accompanied by age-related increases in CVR variability as measured by RSFA, not observed with BH. Together the results obtained indicate that RSFA accurately represents CVR in any age range avoiding multiple and yet unknown physiologic and task-related pitfalls of BH.Item Bolder than BOLD: Changes in Neurophysiologic Underpinnings of fMRI Signal With Age and Task Demand(2020-04-21) Turner, Monroe Patrick; Rypma, BartMany theories of mechanisms involved in brain aging are based on age differences in bloodoxygen-level-dependent (BOLD) signal as measured with functional magnetic resonance imaging (fMRI). The contour of the hemodynamic response function (HRF), the signature of the evolution of BOLD signal through time, reflects a combination of influences from neural, glial, and vascular systems. Each of these systems forms one tier of a three-tier model used here to describe the process of neural-vascular coupling (NVC). Based on a preponderance of evidence from physiologic research of the aging brain, the often-invoked assumption that NVC does not change in healthy aging is unlikely to be based in fact and could explain disparate and conflicting results in neurocognitive aging literature. The BOLD signal, comprising multiple physiologic factors including cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2), serves as an index of the health of the NVC system, the process that links these two quantities. Disentangling the physiologic factors underlying age-related changes in BOLD would allow formulation of more precise models of neurocognitive aging. Separate measurement and derivation of these quantities is possible through use of a calibrated fMRI paradigm that employs dual-echo pseudo-continuous arterial spin labeling and a hypercapnia manipulation. While these quantities have been measured individually in previous studies, the way in which they change with task frequency, and age-group differences therein, remains unresearched. Sixty participants (thirty-three younger and twenty-seven older participants) completed a hypercapnic breathing challenge as well as a visual stimulation paradigm that presented flickering radial checkerboards at three frequencies (2 Hz, 4 Hz, and 8 Hz). The deoxyhemoglobin dilution model was used to estimate the theoretical BOLD signal ceiling for each participant to calculate CMRO2. Results indicate that, for small regions of interest (ROIs; approximately 5,000 μL in volume) there was a significant linear effect of Flicker-Frequency of the checkerboard in both BOLD and CBF, as well as a significant negative quadratic effect of Flicker-Frequency in CMRO2 (increases from 2 Hz to 4 Hz, but decreases from 4 Hz to 8 Hz). There were also significant main effects of AgeGroup, with younger adults showing higher BOLD signal than older adults, but older adults showing higher CMRO2 than younger adults, in the presence of group-equivalent CBF. This replicated a prior study using a similar experimental paradigm and similarly sized ROI. AgeGroup × Flicker-Frequency interaction effects were not observed in any of these measures. However, a significant Age-Group × Flicker-Frequency interaction was observed in the NVC ratio, with younger adults showing activity-dependent NVC and older adults showing activityindependent NVC. Further, when larger ROIs are examined, the main effect of Age-Group disappears in CMRO2, but a main effect of Age-Group emerges in CBF (greater in younger adults than in older adults). These results are interpreted as an empirical demonstration that the assumption of age-equivalent NVC is not valid, and that variability in the nature of the metabolic demands of different conditions of a task further complicate straightforward interpretation of BOLD signal as a faithful proxy of underlying neural activity.Item Cross-Modal Priming of Music Concepts: On the Metaphorical Nature of Musical Meaning(2018-05) Brigante, Ryan M.; Rypma, BartCross-modal correspondence is a cognitive phenomenon in which the perception of one dimension influences or coincides with the perception of another dimension. Some cases of cross-modal correspondence are thought to occur at the semantic/conceptual level of analysis. The present work tested the hypothesis that cross-modal correspondence occurs when there is a metaphorical relation between the interacting dimensions. In Experiments 1 and 2, participants listened to brief tones or chords while viewing a display that varied in color, and they provided subjective ratings of both auditory and visual brightness for the stimuli in each trial. In Experiment 3, participants underwent a mood induction procedure that temporarily increased their happiness or sadness, and then they judged the brightness of tones and chords. Using the terminology of conceptual metaphor theory, the target domains of interest were musical timbre and harmony, and the source domains were visual brightness (Experiments 1 and 2) and mood valence (Experiment 3). Experiment 1 found that participants rated tones as brighter in timbre and chords as brighter in harmony when viewing brighter (higher luminance) colors. An auditory-to-visual priming effect was also observed, but to a lesser extent than visual-to-auditory priming. Musically untrained participants were more influenced by cross-modal priming than were those with music training. Experiment 2 replicated the findings of Experiment 1 in the context of a pitch comparison task involving flat/sharp judgments. Experiment 3 found limited evidence that participants perceived tones and chords as brighter when their mood was happier and darker when sadder. These findings suggest that semantic networks have metaphoric structure, with activation spreading to metaphorically related concepts, which influences perception of the metaphorically related dimensions. Metaphoric connections are asymmetric, with source-to-target mappings weighted more heavily than target-to-source mappings. Expertise in the target domain might reduce the strength of metaphoric connections by establishing stronger literal connections within the target domain.Item fNIRS and Pupillometry Correlates of Attentional States(2020-12-01T06:00:00.000Z) Gunal, Mehmet; Krawczyk, Daniel; Evans, Julia; Liu, Hanli; Rypma, Bart; Wig, GaganThis dissertation aims to examine the localization and function of BA 10 specifically looking into its role in maintaining and switching between attentional states using functional near-infrared spectroscopy (fNIRS) and pupillometry. Previous findings from fMRI report a medial-lateral BA10 dissociation during stimulus-oriented (SO) and stimulus-independent (SI) tasks. Pupillometry has been previously used to investigate different attention states, dissociating focused, attention (on-task) trials from mind-wandered, distracted (off-task) states. However, so far there is no evidence that fNIRS hemodynamic responses (HR) and pupillary responses (PR) could be used to better characterize and identify attention states. Replacing fMRI with fNIRS, I divided SO and SI tasks into on-task and off-task groups and showed that fNIRS exhibit similar medial-lateral BA10 dissociations for SO tasks. I also showed that both HR and PR can be used to distinguish on-task SO from off-task SO groups. Finally, I explored whether fNIRS and pupillometry signals share similar biomarkers which may enhance the identification of these attention states using these measures simultaneously. This study was able to successfully characterize attention states and dissociate them on BA10 but did not confirm that simultaneous signal acquisition of these two methods would enhance the identification of attentional states.Item Hemodynamic Response Variability and its Relationship to the BOLD signal in Younger and Older Adults(August 2023) Taylor, Mackenzie Breann 1996-; Rypma, Bart; Rennaker, Robert; Spence, Jeffrey S.; Seaman, Kendra; Krawczyk, DanielStudies have shown age-related differences in blood-oxygen-level-dependent signal (BOLD) variability, specifically amplitude variability. However, results have been mixed. Little remains known about the sources contributing to this variability. Identifying these sources would have implications for underlying mechanisms contributing to BOLD measurement. Changes in BOLD yield a characteristic hemodynamic response function (HRF) that reflects a combination of blood flow and oxygenation changes that follow neural activity. In healthy aging, multiple components of the HRF (e.g., time-to-peak, rise slope, peak amplitude, full-width half-maximum, peak-to- trough, time-to-trough, fall slope, and trough amplitude) are susceptible to the mediating effects of age-related cerebrovascular alterations and underlying processes. Additionally, several studies have demonstrated that neuro-vascular coupling (NVC) differences in older adults are mirrored in HRF differences. To further explore these phenomena, the current study utilized the publicly available Cambridge Center for Aging and Neuroscience (CamCAN) dataset to estimate HRF variability in a visual-auditory task in 80 younger (18-30 years old; 44 Female/36 Male) and 212 older adults (54-74 years old; 100 Female/112 Male). The proposed study was carried out according to three aims: (1) examine intra-individual HRF variability in younger and older adults, (2) examine inter-individual HRF variability in younger and older adults, and (3) determine the relationship between HRF variability and cognitive performance in younger and older adults. Linear mixed models were used to assess individual and age-related differences in HRF features. I hypothesized that individuals, regardless of age, would have increased HRF variability in higher frequency task conditions compared to lower frequency conditions. For age- related differences, I hypothesized that older adults would have increased HRF feature variability, and that their HRF variability would be inversely related to canonical-derived BOLD voxel extent. Finally, I hypothesized that there would be an interaction between HRF variability, age, and cognitive performance such that low-performing older adults would have increased HRF variability compared to high-performing older and younger adults. For group differences in HRF feature variability, I found that increased/decreased HRF feature variability was associated with increasing auditory frequencies depending on the region examined. For group differences in mean HRF features, I found that increased mean HRF features were associated with increasing auditory frequencies, with the exception of fall slope which exhibited an inverse relationship. Older adults had increased HRF feature variability and mean HRF features, primarily in the precentral and temporal ROIs, compared to younger adults. Older adults’ increased voxel extent was associated with decreased variance of their rise slopes, full-width half-maxima, peak-to- troughs, and time-to-troughs. Finally, younger adults exhibited a significant relationship between their reaction times and mean HRF features in the highest frequency condition while the older adults did not. My results showed that HRF feature variability exhibits region- and task- dependent differences that need to be accounted for when performing age-group comparisons, the latter-half of the HRF evolution and underlying mechanisms are potential sources of additional variability in older adults, and the difference between HRF features in the precentral cortex and other sensory cortices may serve a mediatory role between age and processing speed ability. This study assessed features of BOLD HRF shape as a proxy of NVC to identify potential sources of altered age-related variability and their relationships to behavior.Item Higher-Order Cognitive Training Effects on Processing Speed-Related Neural Activity: A Randomized Trial(Elsevier) Yezhuvath, Uma S.; Aslan, Sina; Motes, Michael A.; Spence, Jeffrey S.; Rypma, Bart; Chapman, Sandra Bond; 0000 0003 5170 3614 (Chapman, SB); Motes, Michael A.; Aslan, Sina; Spence, Jeffrey S.; Rypma, Bart; Chapman, Sandra BondHigher-order cognitive training has shown to enhance performance in older adults, but the neural mechanisms underlying performance enhancement have yet to be fully disambiguated. This randomized trial examined changes in processing speed and processing speed-related neural activity in older participants (57-71years of age) who underwent cognitive training (CT, N= 12) compared with wait-listed (WLC, N= 15) or exercise-training active (AC, N= 14) controls. The cognitive training taught cognitive control functions of strategic attention, integrative reasoning, and innovation over 12weeks. All 3 groups worked through a functional magnetic resonance imaging processing speed task during 3 sessions (baseline, mid-training, and post-training). Although all groups showed faster reaction times (RTs) across sessions, the CT group showed a significant increase, and the WLC and AC groups showed significant decreases across sessions in the association between RT and BOLD signal change within the left prefrontal cortex (PFC). Thus, cognitive training led to a change in processing speed-related neural activity where faster processing speed was associated with reduced PFC activation, fitting previously identified neural efficiency profiles.Item Investigating the Neural Bases for Intra-Subject Cognitive Efficiency Changes using Functional Magnetic Resonance Imaging(Frontiers Research Foundation) Rao, Neena K.; Motes, Michael A.; Rypma, BartSeveral fMRI studies have examined brain regions mediating inter-subject variability in cognitive efficiency, but none have examined regions mediating intra-subject variability in efficiency. Thus, the present study was designed to identify brain regions involved in intra-subject variability in cognitive efficiency via participant-level correlations between trial-level reaction time (RT) and trial-level fMRI BOLD percent signal change on a processing speed task. On each trial, participants indicated whether a digit-symbol probe-pair was present or absent in an array of nine digit-symbol probe-pairs while fMRI data were collected. Deconvolution analyses, using RT time-series models (derived from the proportional scaling of an event-related hemodynamic response function model by trial-level RT), were used to evaluate relationships between trial-level RTs and BOLD percent signal change. Although task-related patterns of activation and deactivation were observed in regions including bilateral occipital, bilateral parietal, portions of the medial wall such as the precuneus, default mode network regions including anterior cingulate, posterior cingulate, bilateral temporal, right cerebellum, and right cuneus, RT-BOLD correlations were observed in a more circumscribed set of regions. Positive RT-BOLD correlations, where fast RTs were associated with lower BOLD percent signal change, were observed in regions including bilateral occipital, bilateral parietal, and the precuneus. RT-BOLD correlations were not observed in the default mode network indicating a smaller set of regions associated with intra-subject variability in cognitive efficiency. The results are discussed in terms of a distributed area of regions that mediate variability in the cognitive efficiency that might underlie processing speed differences between individuals.Item Multiple Sclerosis and Healthy Aging: a Comparative Analysis of Structure and Function(2022-12-01T06:00:00.000Z) Abdelkarim, Dema; Rypma, Bart; Evans, Julia; Krawczyk, Daniel; Spence, Jeffrey; Hart Jr., JohnThe relationship between healthy, normal aging and the neurodegenerative disease Multiple Sclerosis (MS) is a subject of ongoing debate. Parallels between the two include vascular and metabolic decline in addition to cognitive decline. In particular, processing speed declines are seen in both aging and MS. In aging, previous work has suggested that processing speed decline is thought to be the basis for all age-related cognitive decline. Whereas neurovascular and neurovascular effects of MS and aging have previously been studied separately, they have not been studied in parallel. In addition, the relationships between these effects and MS- and age- related cognitive decline have not previously been investigated. In the studies presented here, I explore the relationships between neurovascular and neurometabolic function in aging and in MS as well as their effects on cognitive and brain volume using multiple regression analysis. I found that cerebrovascular reactivity is associated with cognitive decline in aging, but not in MS, despite significantly lower arterial reactivity in MS. I also found that task-evoked neurovascular and neurometabolic dynamics are associated with brain volume in MS, but not in aging. Lastly, I do not find any relationships between processing speed and white matter integrity in any group. These results indicate that processing speed decline is a diffuse phenomenon that can arise from the dysfunction of many different systems. It is also indicative of divergent effects of vascular pathology and signaling dysfunction on MS patients and older adults. This work shows that despite similarities in pathological processes, vascular and metabolic associations with cognitive decline and brain volume differ between MS and aging.Item Neural and Cognitive Mechanisms of Trait Mindfulness and Their Relationships to Negatively-Valenced Emotional Reactivity(2021-07-21) Himes, Lyndahl; Rypma, BartMindfulness, an attentive non-judgmental awareness and focus on present moment experiences (Kabat-Zinn, 1994), can be used to refer to a particular type of meditation practice, a state achieved during meditation practice (alternately referred to here as a mindful state, or states of mindfulness), or an enduring and stable personality trait. While mindfulness is often viewed as a type of skill one can develop and cultivate during meditation practice, untrained individuals can vary in trait mindfulness. Trait mindfulness refers to one’s predisposition toward presentmoment attention and awareness in everyday life (Baer et al., 2006) and can change with experience and practice (e.g., Nyklicek et al., 2013; Shapiro et al., 2011). One's predisposition to be mindful in everyday life can be increased by evoking mindful states consistently (e.g., Davidson, 2010), and psychological health benefits are thought to result from increased trait mindfulness due to mindfulness meditation practice (Kiken et al., 2015). High trait mindfulness is associated with an increased ability to release negative thoughts (e.g., Frewen et al., 2008) and more effective and flexible emotion regulation (e.g., Roemer et al., 2015). While improved emotion regulation is generally associated with higher levels of trait mindfulness, research has been inconclusive regarding the relationship between mindfulness and emotional reactivity in the face of a negatively-valenced stressor, especially in non-meditators. The overarching purpose of the studies presented here is to ascertain the behavioral and brain bases of these emotion-mood relationships across 3 separate studies. In the first two studies, I examined the relationships between trait mindfulness and negatively-valenced emotional reactivity following a negative mood induction in non-meditators (Himes et al., 2021). The underlying mechanisms of this emotional self-regulation and flexibility cannot be understood by behavioral examination alone, and neuroimaging literature reveals that there are structural and functional brain differences between meditators and non-meditators in regions associated with emotional and self-regulatory processing. It remains unclear whether these differences are solely due to training effects brought on by meditation practices or to trait effects that might be present in non-meditators based on their intrinsic level of mindfulness. By examining functional and structural brain differences in individuals with varying levels of trait mindfulness, a greater understanding of how trait mindfulness impacts emotion processing, and its brain bases, can be gained. To address this question, I examined whether, in a sample of non-meditators, individual differences in trait mindfulness are associated with structural and functional differences in brain regions associated with emotional, self-referential, and self-regulatory processing.Item Physiologic Characterization of Multiple Sclerosis and Its Clinical Implications(2020-03-26) Sivakolundu, Dinesh Keran; Rypma, Bart; Spiro, StephenMultiple sclerosis (MS) is a central nervous system autoimmune disorder that features cognitive impairment as a prominent symptom in almost 70% of these patients. Little remains known about the pathophysiology of this impairment. Our understanding of mechanisms that underlie MS-related cognitive impairment mainly emerge from structural magnetic resonance imaging (sMRI) studies. Clinicians also depend on sMRI for MS diagnosis, treatment choice, and disease surveillance. These sMRI techniques, however, are limited in providing information regarding MS-related physiologic or metabolic alterations, disease origin, and the extent of underlying tissue injury. Lack of such information has hindered our ability to better understand the mechanisms that underlie cognitive impairment in MS. Such limitations often have repercussions in the management of MS and are reflected as misdiagnosis and inappropriate treatment. In this dissertation, I describe a set of studies that assess physiologic and metabolic changes in MS patients using novel functional MRI techniques. These techniques permitted me to investigate how such changes contribute to the development of MS-related cognitive impairment, and to evaluate the translational ability of such physiologic metrics to clinical practice.Item Prediction of Task-Related BOLD fMRI with Amplitude Signatures of Resting-State fMRIKannurpatti, S. S.; Rypma, Bart; Biswal, B. B.Blood oxygen contrast-functional magnetic resonance imaging (fMRI) signals are a convolution of neural and vascular components. Several studies indicate that task-related (T-fMRI) or resting-state (R-fMRI) responses linearly relate to hypercapnic task responses. Based on the linearity of R-fMRI andT-fMRI with hypercapnia demonstrated by different groups using different study designs, we hypothesized that R-fMRI andT-fMRI signals are governed by a common physiological mechanism and that resting-state fluctuation of amplitude (RSFA) should be linearly related to T-fMRI responses. We tested this prediction in a group of healthy younger humans where R-fMRI, T-fMRI, and hypercapnic (breath hold, BH) task measures were obtained form the same scan session during resting state and during performance of motor and BH tasks. Within individual subjects, significant linear correlations were observed between motor and BH task responses across voxels. When averaged over the whole brain, the subject-wise correlation between the motor and BH tasks showed a similar linear relationship within the group. Likewise, a significant linear correlation was observed between motor-task activity and RSFA across voxels and subjects. The linear rest-task (R-T) relationship between motor activity and RSFA suggested that R-fMRI and T-fMRI responses are governed by similar physiological mechanisms. A practical use of the R-T relationship is its potential to estimateT-fMRI responses in special populations unable to perform tasks during fMRI scanning. Using the R-T relationship determined from the first group of 12 healthy subjects, we predicted theT-fMRI responses in a second group of 7 healthy subjects. RSFA in both the lower and higher frequency ranges robustly predicted the magnitude ofT-fMRI responses at the subject and voxel levels. We propose thatT-fMRI responses are reliably predictable to the voxel level in situations where only R-fMRI measures are possible, and may be useful for assessing neural activity in task non-compliant clinical populations. © 2012 Kannurpatti, Rypma and Biswal.Item The Cognitive, Neurophysiologic, and Connectivity Effects of Multiple Sclerosis on Information Processing Speed and Memory(2022-08-01T05:00:00.000Z) Zuppichini, Mark Daniel; Owen, Margaret Tresch; Rypma, Bart; Spence, Jeffrey; Filbey, Francesca; Hart Jr., JohnMultiple sclerosis (MS) is an autoimmune disease of the central nervous system that can negatively impact both motor and cognitive ability. About 70% of MS patients experience cognitive impairment with reduced information processing speed (IPS) and memory decrements as the most prevalent. IPS, defined as the amount of time needed to process elementary cognitive operations, might be especially critical for cognitive functions that require the coordination of widely distributed brain regions. Current models of working memory posit that it is a widely distributed system involving persistent neural activity in various brain regions during memory delays. In my dissertation, I first hypothesize that reduced IPS in MS disrupts the timely coorination needed between the brain regions associated with working memory function and that this reduced IPS underlies memory declines in MS patients. Furthermore, MS-related neuroinflammation might lead to a strain on oxygen resource availability that can cause neurologic and neurocognitive deficits. Therefore, my second hypothesis is that MS-related metabolic resource constraints impede the ability of neurons to fire persistently and are associated with MS-related reductions in IPS performance. Additionally, timely coordination of interregional connectivity is critical for IPS and memory function. Therefore, dysfunction to the persistent neural activity within a region could affect interregional connectivity. Therefore, my third hypothesis is that, due to altered metabolic resource availability, connectivity between brain regions involved in cognitive function is adversely affected. To test these hypotheses, MS and healthy control (HC) participants underwent extensive neuropsychological evaluation and then advanced dual-echo functional magnetic resonance imaging (fMRI) to obtain measures of blood-oxygen-level-dependent (BOLD) signal, cerebral blood flow, maximum blood-oxygen capacity (the factor M), and cerebral metabolic rate of oxygen (CMRO2) while they performed an IPS task. Participants also underwent resting-state fMRI and structural diffusion imaging to investigate functional and structural connectivity. Neuropsychological evaluation results showed that MS-related variability in IPS explained variability in verbal episodic and working memory ability in MS patients even after controlling for motor, visual, disease and demographic variables, and after using a composite variable to attenuate task-specific variability. Neurophysiologic results showed that levels of metabolism in the dorsolateral prefrontal cortex (dlPFC), and area known to be associated with IPS, significantly predicted IPS ability in MS patients. Connectivity analysis results showed that MS-related changes in prefrontal metabolism that significantly explained IPS ability were explained by MS-related changes in resting-state connectivity from the cerebellum. Furthermore, disrupted functional and structural connectivity between the cerebellum and parahippocampal gyri was associated with verbal learning and episodic memory impairment. These results suggest that MS-related metabolic disruptions in an executive area, the dlPFC, are associated with reduced IPS and connectivity changes in MS, and that this disruption has negative effects on episodic and working memory.Item Three‐Dimensional Lesion Phenotyping and Physiologic Characterization Inform Remyelination Ability in Multiple Sclerosis(American Society of Neuroimaging) Sivakolundu, Dinesh K.; Hansen, Madison R.; West, Kathryn L.; Wang, Yeqi; Stanley, Thomas; Wilson, Andrew; McCreary, Morgan; Turner, Monroe P.; Pinho, Marco C.; Newton, Braeden D.; Guo, Xiaohu; Rypma, Bart; Okuda, Darin T.; Sivakolundu, Dinesh K.; West, Kathryn L.; Wang, Yeqi; Stanley, Thomas; Wilson, Andrew; Turner, Monroe P.; Guo, Xiaohu; Rypma, BartBACKGROUND AND PURPOSE Multiple sclerosis (MS) clinical management is based upon lesion characterization from 2‐dimensional (2D) magnetic resonance imaging (MRI) views. Such views fail to convey the lesion‐phenotype (ie, shape and surface texture) complexity, underlying metabolic alterations, and remyelination potential. We utilized a 3‐dimensional (3D) lesion phenotyping approach coupled with imaging to study physiologic profiles within and around MS lesions and their impacts on lesion phenotypes. METHODS Lesions were identified in 3T T₂‐FLAIR images and segmented using geodesic active contouring. A calibrated fMRI sequence permitted measurement of cerebral blood flow (CBF), blood‐oxygen‐level‐dependent signal (BOLD), and cerebral metabolic rate of oxygen (CMRO₂). These metrics were measured within lesions and surrounding tissue in concentric layers exact to the 3D‐lesion shape. BOLD slope was calculated as BOLD changes from a lesion to its surrounding perimeters. White matter integrity was measured using diffusion kurtosis imaging. Associations between these metrics and 3D‐lesion phenotypes were studied. RESULTS One hundred nine lesions from 23 MS patients were analyzed. We identified a noninvasive biomarker, BOLD slope, to metabolically characterize lesions. Positive BOLD slope lesions were metabolically active with higher CMRO₂ and CBF compared to negative BOLD slope or inactive lesions. Metabolically active lesions with more intact white matter integrity had more symmetrical shapes and more complex surface textures compared to inactive lesions with less intact white matter integrity. CONCLUSION The association of lesion phenotypes with their metabolic signatures suggests the prospect for translation of such data to clinical management by providing information related to metabolic activity, lesion age, and risk for disease reactivation and self‐repair. Our findings also provide a platform for disease surveillance and outcome quantification involving myelin repair therapeutics.Item Time-varying Sources and Vascular Contributions to Age-accompanied Functional Brain Network Re-organization(2022-12-01T06:00:00.000Z) Han, Liang; Wig, Gagan; Stillman, Robert D; Rugg, Michael D.; Rypma, Bart; Gel, YuliaThe brain is a complex network of interacting brain areas that can be further divided into segregated functional systems. Resting-state system segregation is a feature of brain network organization that has relevance to brain function in both health and disease across adult lifespan. It is unclear what gives rise to system segregation and the individual differences in this brain network measure. In this dissertation, two aspects of this important question are investigated: (1) Do vascular factors contribute to relationships between age and system segregation across the adult lifespan? and (2) Can sources of time-varying information help account for relationships between aging and system segregation? The interplay between these questions reveals how the temporal evolution of system re-configuration at a short time scale impacts more stable individual features of large-scale network organization, in the context of differences in vascular health of adult individuals. This dissertation was accomplished by incorporating data from a total of 894 unique participants, over 3 independent studies (age range: 20 – 100 years) and including multiple neuroimaging modalities and measures of participant health and demographics. The contribution of vascular factors towards relationships between age and resting-state system segregation is first investigated. There exist relationships between age and vascular measures, including cardiovascular health (CVH) and cerebrovascular reactivity (CVR). Age-related decreases of system segregation persist after controlling for vascular-related variance. This is demonstrated by (i) computing system segregation regional CVR-corrected signals within each participant, and (ii) including CVH as a participant-level covariate in the models. These results demonstrate that age-related differences in system segregation cannot be fully attributed to differences in cerebrovascular and cardiovascular factors. To examine the contribution of time-varying information to system segregation, I examine the relationship between resting-state BOLD signal variability and system segregation. After controlling for vascular confounds by (i) estimating BOLD variability using CVR-corrected signals, (ii) including CVH as a covariate in the model, there is an absence of a relationship between age and BOLD variability, revealing that vascular factors serve as a major source of variance explaining previously reported relationships between age and resting-state BOLD signal variability. Further, with correction of vascular factors, BOLD variability does not relate to system segregation. An additional source of time-varying information is evaluated in relation to system segregation, focused on co-fluctuation amplitude of the resting-state time-series. Moments of greater co- fluctuation pattern across edges are identified (events), during which functional brain networks are highly modular relative to non-event moments. I demonstrate that the number of events that are present in an individual’s resting-state time-series is related to their system segregation. However, I next demonstrate that age-accompanied decreases of system segregation are evident across all the moments, irrespective of co-fluctuation amplitude of edges. Collectively, these findings reveal that while high co-fluctuation moments (events) may contribute towards establishing an individual’s system segregation, brain network re-organization exists across all time points of a resting-state scan. In sum, this dissertation provides important support that resting-state system segregation measures brain network re-organization across the adult lifespan. This measure is independent from vascular differences within individuals, and provides critical evidence of brain aging that is consistently evident across periods of rest. Serving as a biomarker of functional brain network integrity, system segregation further supports the application of this approach towards measuring individual brain health across the lifespan.