On the basis of a strong body of data, the Institute of Medicine currently recommends at least 60 minutes of exercise per day to prevent body weight gain overtime. Previous studies have shown that there is no compensatory increase in food intake with this dose of exercise. Ultimately, the brain decides whether to alter food intake. Surprisingly, no published studies have assessed the impact of exercise on brain activation. Using functional magnetic resonance imaging (fMRI) and an appetite questionnaire, we investigated the effects of a single bout of aerobic exercise on brain responses to visual food cues and subjective appetite responses. After an overnight fast, 30 (17M, 13W), healthy, habitually active subjects (22.0±3.8 years, 23.6±2.4 kg/m2, 44.3±8.3 mL∙kg-1∙min-1) either rested or exercised for 60 minutes, in a counterbalanced crossover design. Immediately after each condition, blood oxygen dependent levels were determined in response to visual food cues of different energy value during an fMRI scan. Exercise showed significantly greater activation (P < .005, uncorrected) in regions implicated in food inhibition (superior frontal gyrus, medial surface), and visual attention (precuneus, superior temporal gyrus, middle temporal gyrus and fusiform gyrus) regions. However, exercise did show a greater activation in a food reward region (medial orbitofrontal cortex). The rest condition only showed greater activation in a visual center (fusiform gyrus) and the midbrain. In addition, relative to no-exercise, subjective appetite responses were suppressed following the exercise bout. Taken altogether, these data suggest exercise may impact the brain in a direction expected to suppress food intake and increase food attention, which is in line with previous behavioral, biological and fMRI data. These findings may explain, at least partially, why aerobic exercise does not lead to a compensatory increase in food intake.

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.

The larynx is the mammalian organ of vocalization. Humans have a degree of control over this organ considerably beyond the abilities of other primates, most notably in our control over the larynx during speech. Although there is an abundance of research on the neural basis of speech, relatively little of this research has focused on the control of the larynx. First, I performed a meta-analysis to search for brain areas responsible for making explicit judgments about affective prosody to identify candidate premotor areas in prefrontal cortex that may also plan the affective component of affective prosody (Chapter 2). The inferior frontal gyrus pars orbitalis was the only prefrontal region preferentially engaged by affective vocalizations. Second, I used functional magnetic resonance imaging to determine whether there are discrete neural systems for producing innate-affective versus arbitrary non-affective vocalizations in the human brain, as has been predicted from non-human primate models (Chapter 3). The vocal-motor system demonstrated a lack of specialization since both types of vocalizations engaged the entire network. Third, I searched for brain areas that were preferentially engaged during vocal imitation (Chapter 4), which is a key process in vocal learning. Vocal imitation preferentially engaged a cortico-striate network similar to that predicted from avian models of vocal imitation. Finally, I performed a meta-analysis to explore the neural basis of persistent developmental stuttering (Chapter 5), a speech disorder that is associated with poor control of the laryngeal muscles. Among other brain areas, primary motor regions controlling the larynx were abnormally activated in the brains of people who stutter. Together these studies advance our knowledge of the human vocal-motor system, how it relates to that in other species, and how this system may be disrupted in persistent developmental stuttering. I discuss remaining gaps in our knowledge that will be the focus of my future research. / Dissertation / Doctor of Philosophy (PhD) / One hallmark of the human species is our ability to talk. This dissertation describes a body of research that uses modern brain imaging technology ¬to study the brain systems that underlie this ability in humans –referred to as the vocal-motor system. It then compares this system in humans to the closest equivalent in monkeys, since monkeys lack this ability but share relatively recent common ancestry with humans. It also makes comparisons with the brains of songbirds, since the ability of juvenile songbirds to learn songs may share similarities with the human ability to learn speech. Finally, it looks at the potential dysfunction of this system in the brains of people who stutter.

Concussions impact the cognitive abilities and emotional wellbeing of adolescents. More specifically, adolescents exhibit signs of executive dysfunction and depressive symptoms following concussion. Evidence suggests a link between cognitive performance and depressive symptoms in concussed populations; however, concussion research has focused mostly on cognitive deficits and emotional dysregulation in singularity, rather than as an integrated system. Therefore, the purpose of this thesis is to explore the clinical and biological relationship between depressive symptoms and executive dysfunction following mild traumatic brain injury (mTBI) or concussion in pediatric populations. Chapter 1 provides an overview of the literature surrounding children and youth with concussive injury as it pertains to executive dysfunction and depressive symptoms. Chapter 2 describes the clinical nature of the relationship between depressive symptoms and executive dysfunction. The results demonstrate that individuals with elevated depressive symptoms had comparable performance to individuals with normal levels of depressive symptoms on executive function scores. This included their performance on an inhibitory control task in which emotional distractors were presented. Regardless of levels of depressive symptoms, adolescents with concussive injury displayed impaired executive functioning compared to normative data, which emphasizes the importance of evaluating executive function following concussion. Chapter 3 involves the use of functional brain imaging to explore the physiological differences between adolescents with average and elevated depressive symptoms on emotion-mediated inhibitory control processes. The group as whole did not display activity in the frontostriatal regions that are associated with inhibitory control, which suggests a potential impairment in this network. Adolescents with elevated depressive symptoms displayed fewer areas of activity compared to adolescents with average levels of depressive symptoms. As a number of individuals (particularly those with elevated depressive symptoms) were injured in the occipital region of the skull, the coup-contrecoup impact may have resulted in frontal lobe injury. Faces were used to evoke emotional processing throughout the inhibitory control task. The results revealed that adolescents with elevated depressive symptoms were more likely to engage in brain regions subserving evaluative processing of social interactions. This might suggest that depressive symptoms display differences in physiology when emotional stimuli are present. These findings provide insight into the role the environment plays in contributing to the cognitive demands placed on adolescents recovering from concussion. Chapter 4 reviews the key messages derived from these results and describes their clinical relevance. This exploration may lead to a more holistic understanding of concussion and a better approach to injury management, particularly for adolescents who express higher levels of depressive symptoms following concussion. / Thesis / Master of Science (MSc)

The rapid advancements in the field of machine learning and artificial intelligence has led to the emergence of technologies like the Brain Computer Interface (BCI), which has revolutionized rehabilitation protocols. However, given the neural basis of BCIs and the dependence of its performance on cognitive factors, BCIs may be used to characterize the functional capacity of the user. A resting state segment can also be considered for characterization of the functional network integrity, creating a two part framework that probes the functional networks and their cognitive manifestations. This thesis explores such a two part framework using a simultaneous EEG-fMRI setup on a healthy population. The BCI accuracies for all subjects increased over the course of the scan and is thought to be due to learning processes on the subject's part. Since such learning processes require cognitive faculties such as attention and working memory, these factors might modulate the BCI performance profile, making it a potential metric for the integrity of such cognitive factors. The resting state analysis identified four EEG Microstates that have been previously found to be associated with verbal, visual, saliency and attention reorientation tasks. The proportion of each microstate that composed the corresponding fMRI resting state networks (RSN) were identified, opening up the potential for predicting fMRI-based RSN information, from EEG microstates alone. The developed protocol can be used to diagnose potential conditions that negatively affect the functional capacity of the user by using the results from this study as healthy control data. This is the first known BCI based system for characterization of the user's functional integrity, opening up the possibility of using BCIs as a metric for diagnosing a neuropathology. / Thesis / Master of Applied Science (MASc)

京都大学 / 新制・論文博士 / 博士(医学) / 乙第13570号 / 論医博第2296号 / 新制||医||1069(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 花川 隆, 教授 渡邉 大, 教授 高橋 淳 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 新制・課程博士 / 博士(情報学) / 甲第24931号 / 情博第842号 / 新制||情||141(附属図書館) / 京都大学大学院情報学研究科知能情報学専攻 / (主査)教授 神谷 之康, 教授 熊田 孝恒, 教授 西田 眞也 / 学位規則第4条第1項該当 / Doctor of Informatics / Kyoto University / DFAM

Predictability of threat is one of the key modulators of neural activity in fear and anxiety-related threat processes and there is a considerable number of studies focusing on the exact contribution of centromedial amygdala and Bed nucleus of stria terminalis (BNST) in animals as well as in humans. In this research field, some studies already investigated the differential involvement of both areas during temporally predictable and unpredictable threat processes in humans. However, these studies showed several limitations e.g. small sample size, no predictable threat conditions, no separation of anticipation and confrontation processes, which should be addressed in future studies. Furthermore, evidence for group-based inter-individual differences of amygdala and BNST activity during predictable and unpredictable threat processes have not been studied extensively. Several studies suggest a relevant role of the amygdala and BNST activity in phobic processes in patients with specific phobia, but no study so far has investigated the exact contribution of centromedial amygdala (CM) and BNST during temporally predictable and unpredictable threat processes in specific phobia. This thesis consisted of three studies and aimed to evaluate the exact contribution of CM and BNST during temporally predictable and unpredictable threat anticipation and confrontation with the use of an optimized functional magnetic resonance imaging (fMRI) paradigm, which aimed to solve methodological limitations of recent studies. Study 1 used a large sample of healthy participants who were grouped based on NPSR1 genotype, and study 2 and study 3 used a sample of patients with spider phobia. In sum, the results of all three studies indicated, that BNST is more relevant for anticipation processes as compared to the CM. Contrary, during the confrontation phase the CM displays a greater relevance for threat confrontation processes. In recent years, various studies have investigated the extent to which treatment success can be predicted in patients with anxiety disorders based on pre-treatment fMRI activity. Therefore, this was investigated for the first time in study 3 in patients with spider phobia during temporally predictable and unpredictable threat processes. Results indicated that independent of temporal predictability lower anterior cingulate cortex (ACC) activity during threat anticipation and engaged BNST during threat confrontation might be benefitting factors for successful therapy response in spider phobia. / Die Vorhersagbarkeit der Bedrohung ist einer der wichtigsten Modulatoren der neuronalen Aktivität bei angst- und furchtbezogenen Bedrohungsprozessen, und es gibt eine beträchtliche Anzahl von Studien, die sich mit der unterschiedlichen Beteiligung der zentromedialen Amygdala (CM) und des Bed nucleus of stria terminalis (BNST) während dieser Prozesse sowohl bei Tieren als auch beim Menschen beschäftigen. In diesem Forschungsfeld untersuchten bereits einige Studien die exakte Beteiligung beider Areale während zeitlich vorhersehbarer und unvorhersehbarer Bedrohungsprozesse beim Menschen. Diese Studien wiesen jedoch einige Limitationen auf (z.B. geringe Stichprobengröße, keine vorhersagbaren Bedrohungsbedingungen, gemeinsame Analyse der Aktivierung über Antizipations- und Konfrontationsphasen hinweg), die in zukünftigen Studien verbessert werden sollten. Zudem gibt es bisher wenige Studien, welche die unterschiedliche Beteiligung der Amygdala und des BNST während Bedrohungsprozessen auf Grundlage gruppenbasierter inter-individueller Unterschiede untersucht haben. Mehrere Studien deuten auf eine erhöhte Aktivierung sowohl der Amygdala als auch des BNST während phobischer Angstprozesse bei Patient*Innen mit einer spezifischen Phobie hin. Allerdings hat bisher jedoch noch keine Studie die Aktivierung der CM und des BNST während zeitlich vorhersagbarer und unvorhersagbarer phobischer Bedrohungsprozesse bei Patient*Innen direkt verglichen. Unter Verwendung eines optimierten funktionelle Magnetresonanztomographie (fMRT)-Paradigmas, das darauf abzielte, methodische Probleme der bisherigen Studien zu lösen, wurde in dieser Arbeit die unterschiedliche Aktivierung von CM und BNST während zeitlich vorhersehbarer und unvorhersehbarer Bedrohungsantizipation und -konfrontation in einer großen Stichprobe gesunder Teilnehmer, die anhand des NPSR1-Genotyps gruppiert wurden (Studie 1), und Patient*Innen mit einer Spinnenphobie untersucht (Studie 2 und Studie 3). In Summe zeigten die Ergebnisse aller drei Studien, dass im Vergleich zur CM der BNST für Antizipationsprozesse relevanter ist. Hingegen zeigte die CM in der Konfrontationsphase mit einer Bedrohung eine größere Aktivierung als der BNST. In den letzten Jahren haben verschiedene Studien untersucht, inwieweit der Behandlungserfolg bei Patient*Innen mit einer Angststörung anhand der fMRT-Aktivität vor der Behandlung vorhergesagt werden kann. Daher wurde in Studie 3 dies erstmals bei Patient*Innen mit einer Spinnenphobie während zeitlich vorhersehbarer und unvorhersehbarer Bedrohungsprozesse untersucht. Die Ergebnisse deuteten darauf hin, dass eine geringere Aktivität im anterioren cingulären Cortex (ACC) während phobischen Antizipationsprozessen und eine höhere Aktivierung im BNST während der Konfrontation mit phobischen Stimuli günstige Faktoren für den Therapieerfolg bei Spinnenphobie sein könnten.

Unlike other domains of cognition, the acquisition of procedural skills (e.g., the "how to" of memory) is spared by age. However, the consolidation (i.e., the transformation from labile memory to long-term storage) of this type of memory is compromised by age. Optimal memory consolidation for procedural skills is dependent on sleep. Sleep is also negatively impacted by normal, healthy aging. Recent research has identified the neural markers of the lost benefit of sleep for reduced memory consolidation with age. While this is relatively well-established for procedural memory, and for cognitively simple motor skills, the impact of age-related changes in sleep on cognitively complex procedural memory consolidation (i.e., novel cognitive strategies required for "problem-solving skills") remains to be investigated. Furthermore, reduced capacity to solve problems with age has serious mental health-related consequences, including increased depression and suicide attempts, as well as disability in depressed, cognitively impaired older adults. Moreover, problem-solving therapy has been found to improve quality of life in older adults. As such, the aims of these series of studies were to investigate: 1) the behavioural consequences of age on sleep-dependent memory consolidation, 2) identify the electrophysiological markers during sleep of the lost benefit of sleep, 3) identify the age-related changes in brain structure and how this relates to and behavioural outcomes and sleep, and, 4) identify the impact of age on sleep-dependent consolidation of the memory trace for problem-solving skills. Using an innovative combination of EEG, MRI, and behavioural testing in healthy young and older adults, these series of studies revealed novel insights into the breakdown of the normal processes that occur during sleep that support memory. The main objective of this thesis is to identify the neural markers of the very earliest signs under optimal conditions of age-related cognitive decline for problem-solving skills. Investigating the neurophysiological and behavioral consequences of age-related changes in sleep, and their impact on problem-solving skills, will help reveal therapeutic targets for future research that will improve quality of life for seniors. Furthermore, this research will ultimately lead to the development of early interventions targeting sleep that could delay or lessen the severity of the onset of clinically significant cognitive impairment; as those who sleep better, may also age better cognitively.

Although the cerebellum has been traditionally thought of as a motor processing brain region, recent evidence suggests that the cerebellum is functionally diverse. The posterior cerebellum in particular has been shown to play a role in social cognitive processes, and recent work has proposed that this region helps fine tune mental models of social cognition to, for example, to ensure accurate selection of actions in a social scenario. Social interactions with strangers are difficult, in part because we are constantly trying to gauge whether the other person likes or dislikes us without much information for our mental models to help us. From a reward processing standpoint, this requires tracking the value (positive or negative) of people’s valence to us and ensuring that our predictions about people’s affect towards us are correct. The aim of this project was to specify how the posterior cerebellum uniquely contributes to social reward processing, and to distinguish this contribution from regions that are canonically part of the reward and social brain regions. Participants, ages 12-36, completed a well-matched social and monetary reward task in the scanner. In the monetary condition, participants were asked to select which of two doors would result in winning money, and in other trials losing money. In the social condition, participants were asked to select which of two faces representing people would like or dislike them. Representational similarity analysis was used to compare the responses of reward and social brain regions to conditions in which participants either won or lost money and were either liked or disliked by others. We found that portions of the posterior cerebellum were sensitive to social reward, and treated positive social rewards more similarly to negative social rewards than the striatum. These results suggest that these regions in the posterior cerebellum has a dissociable contribution to social reward processing compared to other brain regions. / Psychology