Indiana University-Purdue University Indianapolis (IUPUI) / Negative urgency, defined as a tendency to act rashly under extreme negative emotion, is strongly associated with tobacco use. Despite the robust cross-sectional and experimental evidence linking negative urgency and tobacco use, neural correlates of negative urgency in tobacco use have not been studied. The purpose of the current study was to 1) identify neural circuits that differ between tobacco users and non-tobacco users and 2) explore the relationship between resting-state seed-based functional connectivity (rsFC) and negative urgency, both in the overall group and between tobacco users and non-tobacco users. Using negative urgency-related brain regions as seed regions (voxel level p = .005, cluster-level a < .05), compared to non-tobacco users (n = 21; mean age = 36.57, 62% female, 76% white), tobacco users (n = 22; mean age = 37.50, 64% female, 77% white) had stronger rsFC strengths in the right amygdala – left medial orbitofrontal cortex/ventromedial prefrontal cortex circuit and the right nucleus accumbens – right temporoparietal junction circuit. Additionally, rsFC in the bilateral temporal pole – left supramarginal gyrus circuits was positively correlated with negative urgency (Left temporal pole: r = .55, p < .001; Right temporal pole: r = .51, p < .001). The current study extends previous neuroimaging findings, which have mainly focused on how negative urgency is related to brain responses in localized, segregated brain regions, by examining the network-level interactions between different brain regions. This study provides prime preliminary data for future neuroimaging studies of negative urgency by providing potential target networks that would aid the development of novel intervention strategies for negative urgency-based maladaptive behaviors.

Magnetic resonance imaging of neuronal activity is one of the most promising techniques in modern psychiatric research. While clear functional links with phenotypic variables have been established and detailed networks of activity robustly identified, fMRI scans have not yet yielded the robust biomarkers of psychiatric diseases, such as schizophrenia, which would allow for their use as a clinical diagnostic tool. One possible explanation for the lack of such results is that neural activity is highly non- stationary, whereas most analysis techniques assume that signal properties remain relatively static over time. Time-frequency analysis is a family of analytic techniques which do not assume that data is stationary, and thus is well suited to the analysis of neural time series. Resting state fMRI scans from a publicly available dataset were decomposed using the Wavelet transform and Hilbert Huang Transform, techniques from time-frequency analysis. The results of these processes were then used as the basis for calculating several properties of the fMRI signal within each voxel. The wavelet transform, a simpler technique, generated measures which showed broad differences between patients with schizophrenia and healthy controls but failed to reach statistical significance in the vast majority of situations. The Hilbert Huang transform, in contrast, showed significant increases in certain measures throughout areas associated with sensory processing, dysfunction in which is a symptom of schizophrenia. These results support the use of analysis techniques able to capture the nonstationarities in neural data and encourages the use of such techniques to explore the nature of the neural differences in psychiatric disorders.

Major depressive disorder (MDD) is one of the most common psychiatric illnesses and causes significant disturbances in daily functioning. Research on heart-rate variability (HRV) biofeedback training suggests that HRV is an efficacious adjunct to psychotherapy in reducing depressive symptoms. The purpose of this study was to examine neurological changes in depressed individuals who were randomized to either a psychotherapy plus HRV biofeedback training or to a treatment as usual group. A control group with no history of depression was also studied. We collected psychological, physiological, and imaging data from 30 participants (10 in an experimental group, 10 in a treatment as usual group, and the other 10 in a healthy control group) at baseline and follow-up. Regions of interest (ROIs) included anterior cingulate cortex, hippocampus, and amygdala. Participants from the experimental group went through 5 weekly HRV trainings in conjunction with traditional psychotherapy approaches. The treatment as usual group only received psychotherapy. The healthy controls did not receive any HRV training or therapy services. Overall, we found significant improvements in the experimental group's depression score, overall distress level, and HRV measurements relative to the TAU and control groups. However, we did not find significant HRV and resting-state connectivity group differences among experimental group relative to healthy controls. Together, results suggest that HRV training helps to reduce depressed participants' overall distress level and depressive symptoms. However, findings do not show any changes in participants' imaging data. These findings serve as pilot data on literature related to HRV biofeedback training in a depressed population.

Reappraisal — reinterpreting a situation to change emotional response — is an effective emotion regulation strategy that relies on cognitive control network activity, including engagement of the dorsolateral prefrontal cortex (dlPFC), to attenuate amygdala activity. Greater dlPFC-Amygdala functional connectivity predicts instructed reappraisal task success, and daily use of reappraisal for younger adults (Pico-Perez et al.., 2018) but not older adults (Opitz et al., 2012), while the connectivity of the vmPFC is predictive of physiological markers of ER success for all ages (Sakaki et al., 2016 & Urry et al., 2006). However, the relationship between Resting-State Functional Connectivity (RSFC) and reappraisal task success across the lifespan has yet to be investigated. Participants in the Cambridge Center for Aging Neuroscience study (N=299) completed an 8-minute resting-state fMRI scan. In each trial of an emotion regulation task, participants either viewed or reappraised a negative film and reported post-regulation positive affect. RSFC across bilateral amygdala and the mPFC, the left and the right dlPFC were calculated with Matlab’s CONN Toolbox. The hypothesis is that the strength of the amygdala-mPFC RSFC will predict lower negative and higher positive affect scores after reappraising, however, this study data failed to find evidence to support this hypothesis. The association between the amygdala-dlPFC RSFC and post-reappraisal negative affect scores was moderated by age. Positive affect was higher when there was a stronger negative RSFC in young and middle-aged adults, and this relationship was not significant at older ages (~72). Our results suggest that dlPFC-amygdala activity at rest may be a predictor of emotion regulation in younger and midlife adults but that dlPFC-amygdala activity may be less predictive of emotion regulation outcomes in later life.

Social Anxiety Disorder (SAD) is characterized by excessive concern or fear of negative evaluation in one or more social situations and ranks as one of the most common psychiatric disorders. SAD has also been characterized by significant deficits in social motivation and a lack of reactivity to pleasurable stimuli (i.e., positive affect; [PA]), particularly within social contexts. Recent neuroimaging work has shifted towards examining positively-valenced motivational systems in SAD focused on reward responses to social and nonsocial stimuli. These studies have revealed aberrant reward processing during social reward tasks in individuals with SAD. However, not all individuals with SAD exhibit reward circuitry dysfunction. Therefore, the current study aimed to examine if functional patterns of connectivity in the brain underlie heterogeneity in PA differences in individuals with SAD. Results revealed several functional connectivity strength differences between SAD and control groups within reward regions. Additionally, associations between regions of interest (ROIs)-couplings (i.e., OFC and insula, OFC and subgenual cingulate, insula and cingulate, and cingulate and subgenual cingulate) and diminished PA were present in individuals with SAD, but not controls. Lastly, results demonstrated that individuals with SAD had higher variability in their reward connectivity strength presentations and reports of PA as compared to controls. These results hold significance for the development of interventions for SAD that focus on the enhancement of PA to bolster social reward responsivity. / M.S. / Social Anxiety Disorder (SAD) is a common disorder where individuals experience persistent excessive fear of one or more social situations. Individuals with SAD also tend to show lower social motivation and a lack of reactivity to pleasurable activities/events (referred to broadly as positive affect; [PA]), particularly within social situations. Current work has focused on areas within the brain that are responsible for reward responses, and have indicated that individuals with SAD show different types of reward processing during social reward situations. However, not all individuals with SAD show these same patterns. Therefore, the current study aimed to examine if connections between reward regions in the brain underlie differences in PA differences in individuals with SAD. Results showed several differences between SAD and control groups within reward regions of the brain. Additionally, specific associations between brain regions of interest and low PA were present in individuals with SAD, but not controls. Lastly, results demonstrated that individuals with SAD had higher variability in their connections between reward regions and reports of PA as compared to controls. These results can help inform the development of treatments for SAD that focus on the improving PA in an attempt to increase responsiveness to social rewards.

The field of neuroimaging has truly become data rich, and as such, novel analytical methods capable of gleaning meaningful information from large stores of imaging data are in high demand. Those methods that might also be applicable on the level of individual subjects, and thus potentially useful clinically, are of special interest. In this dissertation we introduce just such a method, called nonlinear functional mapping (NFM), and demonstrate its application in the analysis of resting state fMRI (functional Magnetic Resonance Imaging) from a 242-subject subset of the IMAGEN project, a European study of risk-taking behavior in adolescents that includes longitudinal phenotypic, behavioral, genetic, and neuroimaging data. Functional mapping employs a computational technique inspired by biological evolution to discover and mathematically characterize interactions among ROI (regions of interest), without making linear or univariate assumptions. Statistics of the resulting interaction relationships comport with recent independent work, constituting a preliminary cross-validation. Furthermore, nonlinear terms are ubiquitous in the models generated by NFM, suggesting that some of the interactions characterized here are not discoverable by standard linear methods of analysis. One such nonlinear interaction is discussed in the context of a direct comparison with a procedure involving pairwise correlation, designed to be an analogous linear version of functional mapping. Another such interaction suggests a novel distinction in brain function between drinking and non-drinking adolescents: a tighter coupling of ROI associated with emotion, reward, and interceptive processes such as thirst, among drinkers. Finally, we outline many improvements and extensions of the methodology to reduce computational expense, complement other analytical tools like graph-theoretic analysis, and possibly allow for voxel level functional mapping to eliminate the necessity of ROI selection.

The development of functional connectivity is often described as changing from local to distributed connections which give rise to the functional brain networks observed in adulthood. In contrast to the well-explored pattern found in functional connectivity, no research has been published describing effective connectivity development. Also, there is a plethora of literature describing functional connectivity patterns in a variety of neurodevelopmental and internalizing disorders, but there is little consistency in the connectivity patterns discovered for each disorder. Hence, this study aimed to describe functional and effective resting-state connectivity during adolescent development in a typically developing adolescent (TDA) group (n = 128) and to determine how adolescents with comorbid neurodevelopmental disorders (CND) (n = 46) differed. This was accomplished through functional and effective connectivity analysis within and between four networks: the Default Mode Network (DMN), the Salience Network (SN), the Dorsal Attention Network (DAN), and the Frontal Parietal Control Network (FPCN). The results from this study indicate that within-network connectivity decreased across age in the TDA group, which is in opposition to previous work which suggests strengthening within-network connectivity. The CND group displayed hyper-connectivity compared to the TDA group in between-network connectivity with no effect of age. The effective connectivity in the TDA group displayed decreasing connectivity within networks with increasing age, a novel effect not previously reported in the literature. The CND group’s effective connectivity was overall hyper-connected (for within- and between-networks). The functional connectivity patterns in the TDA group suggest that functional connectivity has subtle developmental change during adolescence. Further, the CND group consistently displayed hyper-connectivity in functional and effective connectivity. The CND group, and perhaps similar comorbid groups, may have less efficient networks which could contribute to their disorder(s).

Orofacial clefts are among the most common congenital defects in the United States, affecting roughly 1 in 600 births annually. A majority of these cases are considered to be “isolated” clefts of the lip and/or palate (ICLP). However the term “isolated” is somewhat of a misnomer, as functional deficits frequently accompany ICLP. One of the most problematic yet understudied of these deficits involves the high prevalence of reading disabilities in this population. It has been estimated that as high as 46% of children with ICLP will be diagnosed with a reading disability, particularly dyslexia. Despite this high prevalence and the well-established neurological basis of dyslexia, relatively little attention has been paid to the role that brain development plays in the reading problems in ICLP. Previous studies from our lab have demonstrated significant changes in brain structure in children with ICLP (that have importantly correlated with functional measures). However we have yet to combine both a structural and functional neuroimaging study with an in-depth analysis of reading dysfunction in this population. The current study examined boys with ICLP, age 8-12 (boys have a higher prevalence of ICLP and show more significant reading problems that girls with ICLP) compared to healthy control boys. Measures of cognitive functioning were obtained with an emphasis on reading and language skills. In addition MRI scans were obtained which included volumetric measures, diffusion-weighted measures (DWI; white matter), and connectivity measures (resting-state fMRI). Even after controlling for the effect of socioeconomic status, boys with ICLP showed significant decreases in reading and language skills (particularly reading fluency). Boys with ICLP did not show significant differences on phonlogical measures (the primary cause of dyslexia). In addition, phonological measures were not predictive of reading fluency, while object naming tasks were predictive of reading fluency in boys with ICLP. For white matter integrity, measures of fractional anisotropy (FA) were found to be increased in the right occipital lobe for boys with ICLP indicating more organized white matter in this region. This increase in right occipital FA was also predictive of better reading outcomes, particularly reading fluency. For more specific white matter tracts, only the fornix and the tapetum (both associated with the temporal lobes) showed a significant difference with a decrease in FA for boys with ICLP. The decrease in FA in the tapetum was also predictive of better reading outcomes in ICLP. When looking at resting-state networks, boys with ICLP showed an increase in connectivity within posterior and subcortical regions when compared to healthy control boys, indicating stronger network connections within the posterior language regions of the brain. Taken together, these results point to differences in both structural and functional connectivity in the brains boys with ICLP. Furthermore, this pattern is different than that found in children with developmental dyslexia as there appears to be no disruption of the posterior reading systems. Cognitive measures also indicate normal phonological awareness in this group, further distinguishing them from dyslexic children. Boys with ICLP instead may be over-relying on these posterior, more visually oriented reading systems as a compensatory mechanism to overcome problems with the development of the typical “lexical route” of reading.

La mémoire de reconnaissance nous permet à la fois de détecter rapidement un stimulus précédemment perçu (familiarité), et de récupérer des informations relatives au contexte de notre rencontre avec ce stimulus (recollection). Les modèles neuro-anatomiques d'Aggleton et Brown (1999) puis d'Aggleton et al. (2011) postulent que le noyau antérieur (NA) du thalamus et le tractus mamillo-thalamique (TMT) du fait de leurs connexions avec l'hippocampe font partie du circuit de la recollection tandis que le noyau dorso-médian (DM) participerait à la familiarité en raison de ses connexions avec le cortex périrhinal. Dans cette thèse nous avons testé cette hypothèse d'indépendance. 12 patients avec un infarctus thalamique gauche ont été recrutés ainsi qu'un groupe de sujets contrôles appariés. Tous les participants ont été soumis à un bilan neuropsychologique, à trois tâches expérimentales de mémoire de reconnaissance et à un examen d'IRM morphologique et d'IRM fonctionnelle de repos. Selon les tâches nous avons estimé la contribution de la recollection et de la familiarité à la réponse sur la base de la verbalisation de la source, du degré de confiance dans la réponse ou de la catégorisation des réponses. Les lésions thalamiques ont été quantifiées et localisées automatiquement grâce à une nouvelle approche méthodologique que nous avons développée. Le profil neuropsychologique des patients a mis en évidence une amnésie antérograde verbale et un trouble exécutif modéré (Etude 1). Les lésions atteignaient principalement le DM alors que le NA était intact chez tous. Le TMT était lésé chez les 7 patients les plus amnésiques (Etudes 1 et 2). La recollection était altérée chez les patients quelle que soit la tâche alors que la familiarité était préservée. De plus l'indice de recollection corrélait avec la lésion du DM (Etude 2). Enfin, des corrélations ont été trouvées dans l'étude en connectivité fonctionnelle entre la disconnexion thalamo-frontale et la recollection (Etude 3). En somme, ces résultats signifient i\ qu'une lésion du NA n'est pas nécessaire pour causer une amnésie ii\ qu'une lésion du DM est suffisante pour causer un défaut de recollection mais pas nécessaire pour atteindre la familiarité iii\ qu'une lésion du TMT prédit une amnésie sévère, enfin iv\ que le réseau reliant fonctionnellement le DM au cortex préfrontal semble être impliqué dans l'expérience subjective de la mémoire de reconnaissance plutôt que dans ses contenus. Ils suggèrent de plus que le modèle d'Aggleton et al (2011) devrait être révisé en ce qui concerne la relation familiarité / DM. / Recognition memory allows determining whether a stimulus has been previously encountered based on either a rapid detection process (familiarity) or a longer retrieval of the context associated with the stimulus (recollection). Aggleton and Brown's model (1999) and Aggleton and colleagues (2011) postulated that recollection and familiarity are anatomically and functionally independent. They hypothesized that the anterior nucleus (AN) / mamillothalamic tract (MTT) complex of the thalamus would be critical for recollection due to its connections with the hippocampus. The Mediodorsal (MD) nucleus would support familiarity owing to its links with the perirhinal cortex. In this thesis we tested this independence hypothesis. The 12 subjects with a pure left thalamic infarction were included along with a healthy matched control group. Every subject underwent a neuropsychological assessment, three experimental verbal recognition memory tasks, a high-resolution structural volumetric MRI scan and resting state functional imaging. Recollection and familiarity estimations were derived from subjective reports or responses categorization. We specifically developed the methods used to automatically analyse the volume and localization of the lesions. Patients performed worse than controls on verbal memory and to a lesser extent on executive tasks (Study 1). Most of the lesions were located in the MD while no lesion of the AN was found. The seven patients exhibiting MTT damage had the lowest memory performance (Studies 1 and 2). Recollection was lower in patients than in controls in all the three tasks whereas familiarity was systematically normal. In addition we found a significant correlation between the recollection index and the DM damage, suggesting that DM is directly involved in recollection (Article 2). Finally the functional connectivity results showed a correlation between recollection and a pattern of thalamofrontal disconnection in the patients, helping to understand the DM-recollection relationship. Overall, the findings of the different studies mean that i\ AN damage is rare and is not necessary to cause an amnesia, ii\ MD damage is sufficient to cause a recollection impairment but not necessary to impair familiarity, iii\ MTT damage predicts the severity of the amnesia, iv\ the network linking functionally the MD with the prefrontal cortex seems to be involved in the subjective experience associated with recognition memory.

De récentes études ont montré que l'activité spontanée du cerveau observée au repos permet d'étudier l'organisation fonctionnelle cérébrale en complément de l'information fournie par les protocoles de tâches. A partir de ces signaux, nous allons extraire un atlas fonctionnel du cerveau modélisant la variabilité inter-sujet. La nouveauté de notre approche réside dans l'intégration d'a-prioris neuroscientifiques et de la variabilité inter-sujet directement dans un modèles probabiliste de l'activité de repos. Ces modèles seront appliqués sur de larges jeux de données. Cette variabilité, ignorée jusqu'à présent, cont nous permettre d'extraire des atlas flous, donc limités en terme de résolution. Des challenges à la fois numériques et algorithmiques sont à relever de par la taille des jeux de données étudiés et la complexité de la modélisation considérée. / Recent studies have shown that resting-state spontaneous brain activity unveils intrinsic cerebral functioning and complete information brought by prototype task study. From these signals, we will set up a functional atlas of the brain, along with an across-subject variability model. The novelty of our approach lies in the integration of neuroscientific priors and inter-individual variability in a probabilistic description of the rest activity. These models will be applied to large datasets. This variability, ignored until now, may lead to learning of fuzzy atlases, thus limited in term of resolution. This program yields both numerical and algorithmic challenges because of the data volume but also because of the complexity of modelisation.