Older bilingual adults typically perform better than monolinguals in tasks of executive control, and are diagnosed later with dementia. Studies have also shown structural and functional brain differences between bilinguals and monolinguals. However, it remains poorly understood how language history influences the functional organization of the aging brain. The current study investigated; 1) differences in resting-state functional connectivity between monolinguals and bilinguals in the Default Mode Network (DMN), Frontoparietal Network (FPN), Executive Control Network (ECN), Language Network (LANG), and a network consisting of structures associated with tasks of executive control coined the Bilingual Control Network (BCN); 2) the relationship of cognitive performance with functional connectivity of the BCN; and 3) whether proficiency, age of second language acquisition, degree of second language exposure, and frequency of language use predicts the network’s functional connectivity. Healthy older bilinguals (N=10) were matched pairwise for age, sex and education to healthy older monolinguals (N=10). All participants completed a battery of cognitive tests, a language history questionnaire, and a 6-minute functional scan during rest. Results showed that groups did not differ in cognitive performance, or in the functional connectivity of the FPN, ECN, LANG, or BCN. However, monolinguals had significantly stronger functional connectivity in the DMN compared to bilinguals. Later age of second language acquisition and lower proficiency were also associated with greater DMN functional connectivity. None of these variables predicted BCN’s functional connectivity. However, bilinguals showed stronger functional connectivity with other structures outside of the canonical networks compared to monolinguals. Finally, vocabulary scores, local switch cost accuracy and reaction time were negatively correlated with BCN’s functional connectivity. Overall, these findings illustrate differences in functional brain organization associated with language experience in the DMN, while challenging the “bilingual advantage” hypothesis. The results also suggest a possible neural mechanism by which bilingualism might mediate cognitive reserve.

This thesis gives an overview on how to estimate changes in functional brain networks using graph theoretical measures. It explains the assessment and definition of functional brain networks derived from fMRI data. More explicitly, this thesis provides examples and newly developed methods on the measurement and visualization of changes due to pathology, external electrical stimulation or ongoing internal thought processes. These changes can occur on long as well as on short time scales and might be a key to understanding brain pathologies and their development. Furthermore, this thesis describes new methods to investigate and visualize these changes on both time scales and provides a more complete picture of the brain as a dynamic and constantly changing network.

Emotional intelligence (EI) is defined as an individual's capacity to accurately perceive, understand, reason about, and regulate emotions, and to apply that information to facilitate thought and achieve goals. Although EI plays an important role in mental health and success in academic, professional and social realms, the neurocircuitry underlying this capacity remains poorly characterized, and no study to date has yet examined the relationship between EI and intrinsic neural network function. Here, in a sample of 54 healthy individuals (28 women, 26 men), we apply independent components analysis (ICA) with dual regression to functional magnetic resonance imaging (fMRI) data acquired while subjects were resting in the scanner to investigate brain circuits (intrinsic resting state networks) whose activity is associated with greater self-reported (i.e. Trait) and objectively measured (i.e. Ability) EI. We show that higher Ability EI, but not Trait EI, is associated with stronger negatively correlated spontaneous fMRI signals between the basal ganglia/limbic network (BGN) and posterior default mode network (DMN), and regions involved in emotional processing and regulation. Importantly, these findings suggest that the functional connectivity within and between intrinsic networks associated with mentation, affective regulation, emotion processing, and reward are strongly related to ability EI.

Despite the success of available medical and psychosocial treatments, a sizable subgroup of individuals with commonly co-occurring disorders, generalized anxiety disorder (GAD) and major depressive disorder (MDD), fail to make sufficient treatment gains thereby prolonging their deficits in life functioning and satisfaction. Clinically, these patients often display temperamental features reflecting heightened sensitivity to underlying motivational systems related to threat/safety and reward/loss (e.g., somatic anxiety) as well as inordinate negative self-referential processing (e.g., worry, rumination). This profile may reflect disruption in two important neural networks associated with emotional/motivational salience (e.g., salience network) and self-referentiality (e.g., default network, DN). Emotion Regulation Therapy (ERT) was developed to target this hypothesized profile and its neurobehavioral markers. In the present study, 22 GAD patients (with and without MDD) completed resting state MRI scans before receiving 16 sessions of ERT. To test study these hypotheses, we examined the associations between baseline patterns of intrinsic functional connectivity (iFC) of the insula and of hubs within the DN (anterior and dorsal medial prefrontal cortex [MPFC] and posterior cingulate cortex [PCC]) and treatment-related changes in worry, somatic anxiety symptoms and decentering. Results suggest that greater treatment linked reductions in worry were associated with iFC clusters in both the insular and parietal cortices. Greater treatment linked gains in decentering, a metacognitive process that involves the capacity to observe items that arise in the mind with healthy psychological distance that is targeted by ERT, was associated with iFC clusters in the anterior and posterior DN. The current study adds to the growing body of research implicating disruptions in the default and salience networks as promising targets of treatment for GAD with and without co-occurring MDD.

Early life stress (ELS) affects the developing brain and impacts capacity for self-regulation and risk for psychopathology. The high spatial resolution of functional magnetic resonance imaging (fMRI) confers an advantage for studying specific neural regions posited to link ELS with subsequent functioning. The first chapter in this dissertation reviews the literature establishing the feasibility and utility of fMRI research with infants and young children. This chapter examines methodological issues and outlines the potential for this technique to make unique contributions to understanding how ELS influences brain development. The next two chapters present results from a study that employed a functional activation paradigm and resting state functional connectivity MRI (rs-fcMRI) to examine associations between a common source of ELS, non-physical interparental conflict, and neural functioning during infancy. The functional activation paradigm focused on emotional tone of voice as a stimulus relevant to interparental conflict, which is likely salient to infants. Higher levels of interparental conflict (as reported by mothers) were associated with infants (6 to 12 months of age) showing greater reactivity to very angry versus neutral tone of voice in neural regions associated with processing and regulation of stress and emotion (hypothalamus and rostral anterior cingulate cortex). The rs-fcMRI analysis examined coordinated neural functioning in the absence of stimuli, focusing on the amygdala as a key region for understanding the impact of ELS and the posterior cingulate cortex as part of a group of regions that show higher levels of activity in the absence of stimuli (the default network). The results replicate previous work characterizing the default network in infants and provide novel evidence for the functional connectivity of the amydgala and amygdala subregions during infancy. Interparental conflict was associated with variation in the connectivity of both regions. Thus levels of interparental conflict were associated with neural reactivity to a stressor-relevant stimulus and with patterns of coordinated neural functioning in the absence of such stimuli. These results provide support for the utility of using fMRI with infants to examine early emerging associations between common forms of ELS and brain functioning. This dissertation includes previously published and co-authored material. / 2016-10-17

Childhood maltreatment can have detrimental consequences on individual well-being and cognitive functioning. One type of childhood maltreatment that remains stigmatized and under-researched among men is child sexual abuse (CSA). Research examining the neurophysiological consequences of CSA in males is limited even further. This dissertation presents three original research articles which provide preliminary evidence of the lasting neurophysiological impact of CSA in men. We recruited all male participants, of those who experienced CSA, some had PTSD (CSA+PTSD) others did not have PTSD (CSA-PTSD) allowing for the examination of differences in males with histories of CSA (but no PTSD) versus those who have CSA histories and PTSD. We also recruited control males with no CSA histories nor PTSD. Three functional MRI tasks and one resting state functional scan were obtained. The letter n-back, and an emotional picture n-back task were used in the first study as a measure of working memory and emotional processing. The first study highlights the lasting impact CSA can have on men, regarding brain activity during working memory, and working memory when negative emotional stimuli are involved. The second study examined how negative/traumatic memories are re-experienced. Results from the second study demonstrate that CSA impacts the neurophysiology of autobiographical memory for traumatic experiences. In the final study, resting state functional connectivity was examined within the default mode, salience and limbic networks, and differences in functional connectivity within the networks were observed. Together, these findings highlight the long-term neural impact of CSA and can validate the experience of men who have lived through CSA. They can also guide researchers and clinicians to potential avenues of support for the well-being of these men. These studies highlight the need for more research with men who have experienced CSA so we can fully understand their altered neurophysiological responses, and how this knowledge can be used to support their mental health and continued wellness throughout their lives.

This thesis gives an overview on how to estimate changes in functional brain networks using graph theoretical measures. It explains the assessment and definition of functional brain networks derived from fMRI data. More explicitly, this thesis provides examples and newly developed methods on the measurement and visualization of changes due to pathology, external electrical stimulation or ongoing internal thought processes. These changes can occur on long as well as on short time scales and might be a key to understanding brain pathologies and their development. Furthermore, this thesis describes new methods to investigate and visualize these changes on both time scales and provides a more complete picture of the brain as a dynamic and constantly changing network.:1 Introduction 1.1 General Introduction 1.2 Functional Magnetic Resonance Imaging 1.3 Resting-state fMRI 1.4 Brain Networks and Graph Theory 1.5 White-Matter Lesions and Small Vessel Disease 1.6 Transcranial Direct Current Stimulation 1.7 Dynamic Functional Connectivity 2 Publications 2.1 Resting developments: a review of fMRI post-processing methodologies for spontaneous brain activity 2.2 Early small vessel disease affects fronto-parietal and cerebellar hubs in close correlation with clinical symptoms - A resting-state fMRI study 2.3 Dynamic modulation of intrinsic functional connectivity by transcranial direct current stimulation 2.4 Three-dimensional mean-shift edge bundling for the visualization of functional connectivity in the brain 2.5 Dynamic network participation of functional connectivity hubs assessed by resting-state fMRI 3 Summary 4 Bibliography 5. Appendix 5.1 Erklärung über die eigenständige Abfassung der Arbeit 5.2 Curriculum vitae 5.3 Publications 5.4 Acknowledgements

Indiana University-Purdue University Indianapolis (IUPUI) / The social cognitive ability to identify another’s internal state and social affective ability to share another’s emotional experience, known as empathy, are integral to healthy social functioning. During tasks, neural systems active when adolescents empathize include cognitive (medial prefrontal cortex and posterior cingulate cortex with the dorsolateral prefrontal cortex) and affective (anterior insula and anterior cingulate cortex) regions that are consistent with the adult task-based literature implicating the default mode, salience, and frontoparietal networks. However, task-based studies are limited to examining neural regions probed by the task; thus, do not capture broader patterns of information processing associated with complex processes, such as empathy. Methods of functional connectivity capture broader patterns of information processing at the level of network connectivity. Although it has clear advantages in identifying neural vulnerabilities to disorder, functional connectivity has yet to be used in adolescent investigations of empathy. Via parent- and self-report, deficits in either cognitive or affective processes central to empathy associate with the most widely agreed on classifications of behavioral disorders in adolescents – transdiagnostic symptoms of internalizing and externalizing. However, this evidence relies exclusively on self-report measures and research has yet to examine the neural connectivity underlying transdiagnostic symptoms in relation to cognitive and affective empathy. What has yet to be known is (1) how the social cognitive and affective processes of empathy are functionally connected across a heterogeneous sample of adolescents and (2) the association of cognitive, affective, and imbalanced empathy with transdiagnostic symptoms. Addressing these gaps in knowledge is an important incremental step for specifying vulnerabilities not fully captured via subjective report alone. This information can be used to improve prevention and intervention strategies. The present study will examine the functional connectivity of neural networks underlying empathy in early to mid-adolescents and their association with transdiagnostic symptoms.

Background: Methamphetamine (MA) abuse is a global crisis that exacerbates sociopolitico-economic burdens in South Africa. MA use is associated with a myriad of neural abnormalities of structure and function, with associated neurocognitive deficits, particularly executive function (EF). Working memory (WM) training has been identified as a potential adjunct to treatment of substance use disorder (SUD) to improve EF in the hope of reducing relapse rates. Neuroimaging suggests MA alters intrinsic resting state functional connectivity (rsFC), and this may contribute to neuropsychological deficits observed in methamphetamine use disorder (MUD). Methods: This nested study analysed data described in Brooks et al. (2016), in which WM training was used as an adjunct to inpatient treatment of MUD. Healthy controls (HC, N = 25) were compared to two MUD groups, one receiving treatment as usual (TAU, N = 17), and one receiving additional cognitive training (CT, N = 24) in the form of a modified version of the ‘N-back' task (C-Ya). This task was also used to assess WMA in the neural scanner, using conditions of 0-back and 1-back across groups. The current research explored these data in a novel manner through examining rsFC. Hypotheses: It was predicted that: 1) HC and MUD participants would differ on measures of WMA, but WMA would improve in MA groups at follow-up compared to baseline and this would be augmented in the CT group; 2) rsFC networks of neural regions supporting WM would be predictive of ability to perform well and improve on WM tasks; and 3) MA groups would display heightened rsFC activity within and between resting state neural networks of the default mode network (DMN) and canonical cognitive control networks (CCNs). Results: Significant differences were observed between HC and MA groups in race and level of education, but not on WMA as tested in the scanner. The CT group, who completed WMA 3-back conditions, demonstrated significant improvement on this task post- intervention. Exploratory regression models showed the WM rsFC network did not demonstrate significant relationships with any clinical, demographic, or WM variables when controlling for multiple comparisons. Heightened connectivity within and between the DMN and CCNs was observed in the MUD compared to the HC group, which provided support for hypothesis 3. Exploratory multivariate regression models demonstrated race, age, education, duration of drug use, and an interaction of group and abstinence may impact rsFC in these networks. Post-hoc analyses identified pairwise network combinations affected by these variables. Conclusions: Despite limitations of this small study, it offers tentative preliminary insights into the largely unexplored field of rsFC in MA populations. This study supports limited research demonstrating hyperconnectivity within and between CCNs and DMN of MA users. This study also offers support for recent research suggesting that easier conditions of the Nback task may not reliably test all aspects of WM function. Exploratory analyses of covariates potentially affecting rsFC provide a platform for directions of future research.

Les objectifs de cette thèse étaient de caractériser les corrélats neuronaux fonctionnels et structurels de l'abolition de la conscience observés pendant le coma et d'identifier les signatures neuronales précoces de la récupération neurologique à partir de cet état. Pour atteindre ce but, nous avons étudié des patients cérébrolésés, recrutés au stade aigu du coma, à l'aide de l'IRM fonctionnelle au repos et IRM structurale. Nos résultats indiquent une réorganisation topologique globale du cerveau des patients, reflétée par une dédifférenciation et une réduction de la résilience des réseaux fonctionnels au repos d'ordre élevé. Ces anomalies sont accompagnées d'une perte de connexions fronto-pariétales à longue distance. Au niveau régional, nous avons observé un schéma complexe de diminution et d'augmentation de la densité de connexion fonctionnelle entre le cortex postéromédial et le cortex préfrontal médial : régions précédemment décrites pour avoir un rôle critique dans la conscience. De manière intéressante, ces modifications de densité de connexion étaient significativement liées à la récupération des patients trois mois après le coma. Enfin, l'analyse multimodale a permis de démontrer une association significative entre la connectivité fonctionnelle et l'intégrité structurelle cérébrales antéro-postérieure, fournissant des informations importantes sur le lien structure/fonction au décours de ces troubles acquis de la conscience. / The aim of the present thesis was to characterize the functional and structural neural correlates of acute consciousness abolition induced by severe brain injury and identify early neural signatures of long-term neurological recovery. To do so, we studied brain-injured patients, recruited in the acute stage of coma, using resting-state functional and structural MRI. Our findings indicated a global topological brain reorganization in coma patients, reflected in dedifferentiated and less resilient high-order resting-state functional networks, paralleled with a loss of long-range fronto-parietal connections. On a regional level, we found a complex pattern of voxel-wise decrease and increase in functional connection density between the posteromedial cortex and the medial prefrontal cortex, regions previously described to have a critical role in conscious processing. These connection density patterns seemed to permit outcome prediction in patients, assessed three months post-coma. Furthermore, the multi-modal MRI analysis demonstrated a significant association between antero-posterior functional connectivity and structural integrity, providing further insights into the pathological underpinning of conscious processing.