京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20796号 / 医博第4296号 / 新制||医||1025(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 中山 健夫, 教授 富樫 かおり, 教授 鈴木 実 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Inhibitory control refers to a person’s ability to control responses and impulses. Deficits in inhibitory control have been found in the neurodevelopmental disorder of Attention deficit hyperactivity disorder (ADHD), though this has mainly been studied in children. This thesis is a systematic review of how inhibition is impacted in adults with ADHD and which neural correlates that are associated with inhibitory control. Only peer-reviewed original articles that used adults above the age of 18 were included. All articles used a between subject design, meaning healthy participants were compared to participants with ADHD. To measure inhibitory control, articles which used either the Stroop Task or Go/No-go task were examined. Nine articles were included in this systematic review. Through functional magnetic resonance imaging (fMRI) altered neural activation was seen in several brain regions, such as the dorsolateral prefrontal cortex, fronto-basal ganglia networks, anterior cingulate cortex, posterior cingulate cortex, parietal lobe and inferior frontal gyrus. Many of these regions have previously been linked to inhibitory control, while others hint at possible compensatory pathways for inhibition in ADHD. In summary, subtle impairments in inhibition networks appear to underlie the disorder all the way into adulthood.

Thesis advisor: Scott D. Slotnick / Sex differences exist in both brain anatomy and neurochemistry (Cahill, 2006). Many differences have been identified in brain regions associated with long-term memory including the dorsolateral prefrontal cortex, hippocampus, and visual processing regions (Andreano & Cahill, 2009). There is, however, a paucity of research investigating whether and how these differences translate into differences in functional activity. Part 1 investigated sex differences in the patterns of functional activity in the brain during spatial long-term memory, item memory, memory confidence, and false memory. In addition, a meta-analysis was conducted to identify whether there were consistent sex differences in the brain across different long-term memory types. Part 2 determined whether there were sex differences in the patterns of functional connectivity in the brain during spatial long-term memory. Specifically, differences in functional connectivity between the hippocampus and the rest of the brain in addition to the thalamus and the rest of the brain were investigated. Finally, Part 3 investigated whether the observed differences in the patterns of activity (identified in Chapter 1) had sufficient information to classify the sex of individual participants. The results of Part 3 argue against the popular notion that the average female brain and average male brain are not significantly different (Joel et al., 2015). More broadly, the studies presented in this dissertation argue against the widespread practice of collapsing across sex in cognitive neuroscience. / Thesis (PhD) — Boston College, 2021. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Psychology.

The goal of this study is to advance the utility of functional brain imaging as a tool for the diagnosis and treatment of neurological disorders by creating a statistical database of functional MRI (fMRI) brain activation patterns collected from neurologically and psychiatrically unimpaired subjects. Continuous fMRI scans have been obtained from each subject while s/he performed a variety of cognitive tasks that are commonly found in standard neurological and cognitive assessment batteries. The collected fMRI data has been processed, analyzed, and converted into database which can be used as a reference of reliable indices of normal brain activity patterns for a wide range of cognitive functions.

The hippocampus is thought to be involved in memory formation and consolidation, with computational models proposing the process of pattern separation as a means for encoding overlapping memories. Previous research has used semantically related targets and lures to investigate hippocampal responses to mnemonic interference. Here, we attempted to define the response function of the hippocampus and its inputs during pattern separation by parametrically varying target-lure similarity in a continuous recognition task. We also investigated the effect of task demands (intentional versus incidental encoding) on pattern separation processes. We collected functional magnetic resonance imaging (fMRI) data while participants were shown a series of objects. In the intentional paradigm, participants identified objects as "new" (novel stimuli), "old" (exact repetitions), or "rotated" (previously seen objects that were subsequently rotated by varied degrees). In the incidental paradigm, participants were shown the same stimuli but identified objects as "toy" or "not toy". Activation in the hippocampus was best fit with a power function, consistent with predictions made by computational models of pattern separation processes in the hippocampus. The degree of pattern separation was driven by the information most relevant to the task—pattern separation was seen in the left hippocampus when semantic information was more important to the task and seen in the right hippocampus when spatial information was more important. We also present data illustrating that top-down processes modulate activity in the ventral visual processing stream.

Work focusing on the combination of EMG and fMRI in skeletal muscle. / Two commonly used diagnostic techniques for examining muscle function in vivo are functional magnetic resonance imaging (fMRI) and electromyography (EMG). EMG allows for examination of the functional, electrical activity of muscle during force production. Comparatively, fMRI or more specifically blood oxygen level dependant imaging can be applied to visualize muscle activation and recovery post-exercise. It is a combination of oxygenation, metabolism, blood flow and blood volume. The proposed method combines both techniques in simultaneous data acquisition to provide greater muscle physiological information during exercise. Additionally, both techniques are non-invasive making repeated measurements feasible. EMG hardware filtering was designed and constructed to facilitate EMG measurements alongside MRI scans during simultaneous acquisition. Next, a complex artifact subtraction method called fMRI artifact slice template removal (FASTR) was implemented. With custom scripts and small adaptations to FASTR, it was modified for use with EMG/fMRI, specifically, with a echo planar imaging (EPI) BOLD sequence. Several experiments were then performed to test it's capabilities improving the signal-to-noise ratio (SNR) of the EMG data from 2.8 to 46 in one case. After EMG hardware and software were developed and implemented, a simple exercise protocol was developed to investigate changes in concurrent BOLD/EMG, recording before, during and following exercise. A linear correlation analyses was performed to compare EMG and BOLD results. A strong correlation between the EMG root-mean-square (RMS) peak amplitude and the length of time to recover back to baseline was noted (r=0.681, n=3). For future studies, multiple EMG measurements should be applied to improve the amount of information collected during voluntary exercise. Lastly, this technique may have usage with not just BOLD MRI scans, but with various other techniques such as near infrared spectroscopy (NIRS), and diffusion tensor imaging (DTI) in order to further probe muscle physiology. / Thesis / Master of Applied Science (MASc) / Two commonly used methods for detecting disease and injury in muscle are magnetic resonance imaging (MRI), and electromyography (EMG). EMG provides information about the electrical activity of muscle during exercise, while MRI scans give two or three dimensional images of the body. Using these two techniques at the same time, provides the opportunity to obtain greater physiological information of muscle during and after exercise. The goal of this work was to design and create an EMG system that functioned alongside MRI scans. However, combining these two techniques presented several challenges that needed to be solved before this was possible. These issues were resolved and diminished by utilizing specific hardware and software solutions alongside rigorous testing. Additionally, results from the combination of these two techniques have demonstrated there is great potential for future studies. In conclusion, using EMG and MRI together is feasible, and allows for further investigation into muscle physiology.

To make decisions, plan, and act appropriately in a complex world, the brain formulates internal models of how the world works. As we change our goals, shift to novel environments, or as the world simply evolves around us, these models must flexibly adapt. Impairments in the formation of such flexible models are present in numerous disorders such as schizophrenia, Parkinson’s, and Alzheimer’s Disease and plague even the most sophisticated artificial agents. Therefore, understanding how the brain structures efficient internal models is of critical importance. Previous findings indicate that the information extracted from past experiences is organized and encoded into relational structured knowledge by the prefrontal cortex (PFC) and the medial temporal lobe (MTL). This process requires balancing two complementary computations in response to overlap. The first is to generalize the commonalities shared across overlapping experiences. The second is to separate overlapping experiences that fundamentally differed along a critical dimension, such as their outcomes, required actions, or time. How the brain balances these functions when faced with overlap remains poorly understood. In this thesis, I proposed that the analysis of the geometry of neural representational spaces offers valuable insights into the brain’s solution to optimally disambiguate and generalize overlapping experiences. I tested this proposal through the analysis of three functional magnetic resonance imaging (fMRI) experiments leveraging data-driven multivariate techniques to probe the dimensionality, structure, and content of these spaces. The first experiment (chapter 2) explored how PFC subregions respond to partially overlapping spatial environments during goal-directed virtual navigation. Based on previous research conducted in our lab that showed prefrontal activity in response to spatial overlap, we analyzed the dimensionality, structure, and content of prefrontal representations while participants learned a virtual navigation task. These analyses demonstrated compressed and highly orthogonalized codes early in learning that shifted over time towards more integrated and schematic codes. Critically, both prospective and retrospective information was bound to the representations of overlapping routes, with greater weight given to prospective information early in learning to help separate overlap. Based on these results, I advanced the idea that PFC subregions tune the geometry of their representations based on task demands and argued that prefrontal attention acts as a filter to promote both the separation and generalization of overlap. Building on the first experiment, a second study (chapter 3) focused on the re-analysis of a high-resolution fMRI study centered on the MTL that examined how MTL subregions handle prospective spatial overlap when planning routes in the same task. Based on previous research in our lab, we knew that the parahippocampal cortex (PHC) and hippocampal subfields CA1 and CA3/DG likely play a role in disambiguating overlapping routes during planning. We probed the geometry of their representations using the same methods used in experiment 1. The results demonstrated a segregation of roles between compressed schematic codes in PHC and expanded orthogonalized codes in CA3/DG that formed over the course of learning in response to overlap. Importantly, the degree of pattern separation observed in CA3/DG depended on the amount of initial overlap. These findings lead to the conclusion that generalization and separation are balanced in the MTL by distributing these functions to different subregions. Furthermore, the results suggest that MTL integration is supported by compression, whereas its separation is achieved via expansion. The third experiment (chapter 4) further examined how PFC and MTL regions balance generalization and separation processes when faced with abstract overlap between context-dependent rules. An analysis of the geometry of representational spaces in a context-dependent rule learning task found that successful rule learning was characterized by maintaining a balance between high and low dimensional spaces over learning. This equilibrium likely enabled the formation of relational knowledge representations that captured the latent structure of the task rules. Importantly, the only level of abstraction observed was one that perfectly matched the maximal amount of abstraction necessary to perform the task, and this structure only appeared later in learning in the hippocampus relative to extra-hippocampal regions. These results suggest that the brain employs an efficient and flexible coding scheme to respond to task demands. The results also suggest an important interplay between prefrontal and hippocampal codes over the course of learning. These three experiments demonstrate the promise that representational geometries offer in understanding the computations of the brain. Specifically, the results show that the flexible equilibrium between generalization and separation is accompanied by the fine-tuning of the dimensionality, structure, and content of representational spaces across a distributed network of MTL and PFC subregions. In the conclusion chapter, I discuss how these insights fit into existing frameworks regarding efficient and distributed codes.

Working memory (WM) is often described as a mental workspace where information can be maintained and manipulated in the service of ongoing cognition. Theoretical accounts describe the focus of attention as a state within working memory where a limited number of items can be briefly maintained in a heightened status of awareness. Ongoing debate and conflicting empirical evidence surrounds the capacity and characteristics of the focus of attention. Substantial recency effects are reported in a group of WM studies, and these recency effects are interpreted as a marker of the focus of attention (e.g., Nee & Jonides, 2008; Oztekin, Davachi, & McElree, 2010). The present work considers whether these findings are specific to parameters of these particular studies or whether they generalize across a broader range of tasks. An initial behavioral experiment tested performance across two tasks (judgment of recency and judgment of primacy), two information types (verbal and spatial), and two self-reported strategies (maintenance-based and retrieval-based). Central analyses averaged trials by the serial position of the correct item, and compared the accuracy and speed of retrieval of trials in different serial positions. Results showed evidence of both recency effects and primacy effects in all four types of task (verbal judgment of recency, verbal judgment of primacy, spatial judgment of recency, and spatial judgment of primacy). Moreover, a significant task by effect-type interaction showed that the size of recency and primacy effects shifted with the demands of the task (e.g., larger recency effects in judgment of recency than in judgment of primacy). Some similarities and some differences were found between verbal and spatial domains, while no differences were found across self-reported strategy. A subsequent fMRI experiment examined the neural correlates of verbal judgment of recency and primacy. Again, behavioral results showed a task by effect-type interaction where there was a larger recency effect in judgment of recency and a larger primacy effect in judgment of primacy. FMRI results showed no distinct correlates of a recency effect. In other words, , contrasts comparing fMRI signal during retrieval of recency item trials and middle item trials did not reveal above threshold clusters of activation. In contrast, neural correlates of primacy were found in frontal lobe brain regions (BA 4, 6, 32) associated with active maintenance of information. Moreover, the precise neural correlates of primacy were task-specific. In sum, two experiments demonstrate that the behavioral and neural signatures of WM, specifically related to primacy and recency effects, are dependent on task-demands. Accounts of the architecture of WM should address these observations, which inform how competing claims are supported across studies of WM. / Psychology

Food choice and preference have been linked to post-ingestive consequences of food consumption. Many ultra-processed foods deliver calories rapidly and are highly rewarding. In literature surrounding substances of abuse, the speed at which a drug reaches the brain affects its abuse potential; this is known as the "rate hypothesis." Here, we test whether the rate hypothesis of addiction may apply to food, specifically whether caloric availability, or the speed at which carbohydrate becomes available for use, contributes to food reward and preference. To do this, we use beverages with novel flavors (conditioned stimulus (CS)) mixed with either a slow metabolizing carbohydrate (maltodextrin and inulin; CS+Slow), a fast-metabolizing carbohydrate (sucrose; CS+Fast), or no carbohydrate (sucralose; CS-). Participants are given each of these drinks 6 times to consume (conditioning period). 2 of these consumption periods occur during in-lab sessions. In one session, blood glucose is measured over one hour post-consumption. In another, we perform indirect calorimetry to assess post-consumption changes in substrate oxidation rates. At the post-testing session, changes in self-reported liking, wanting, and ad libitum intake of each beverage are recorded. Brain response to each flavor cue (without calories) is measured using fMRI at the post-test. We hypothesize the flavor paired with the CS+Fast will be the most liked, wanted, and consumed. We expect greater BOLD (blood oxygenated level dependent) activation to the CS+Fast relative to the CS+Slow and CS- in the nucleus accumbens and hypothalamus. This is an ongoing study and, here, we present our preliminary analysis of the data. / Doctor of Philosophy / People make food choices every day throughout their lives, but why? Research in the past has shown that there are aspects of an individual's life that may be affecting their preferences for foods. One of the aspects investigated in this analysis is metabolism. The way and speed that the body uses carbohydrates plays a large role in how an individual views food options. Here, we test if the speed at which the body is able to use carbohydrates affects their choices of food and if there are any neural components to these food options. To do this, we tested multiple carbohydrates to determine which were the best for comparisons of slow- and fast-metabolizing. These carbohydrate groups were tested against a drink containing no carbohydrates in two metabolic measurements: blood glucose and energy expenditure. We then used a magnetic resonance imaging scan to test brain activity when participants are given small amounts of each drink without carbohydrates. Each carbohydrate condition was paired with a novel flavor so participants wouldn't have a preconceived idea about the caloric load. We found drinks with sucrose, a common household sugar, had the fastest change in metabolic measures. Additionally, areas in the brain related to rewards and learning were activated by flavors associated with sucrose. This leads us to believe that carbohydrates that are quickly used by your body are more rewarding in the brain and may have implications for preferences down the line.

Adolescence is a transition period during which individuals have increasing autonomy in decision-making for themselves (Casey, Jones, and Hare, 2008), often choosing among options about which they have little knowledge and experience. This process of individuation and independence is reflected as real-world risk taking behaviors (Silveri et al., 2004), including higher motor accidents, unwanted pregnancies, sexually transmitted diseases, drug addictions, and death (Casey et al., 2008). The extent to which adolescents continue to display increased behaviors with negative consequences during this period of life depends critically on their ability to explore and learn potential consequences of actions within novel environments. This learning is not limited to the value of the outcome associated with making choices, but extends to the levels of risk taken in making those choices. While the existing adolescence literature has focused on neural substrates of risk preferences, how adolescents behaviorally and neurally learn about risks remain unknown. Success or failure to learn the potential variability of these consequences, or the risks involved, in ambiguous decisions is hypothesized to be a crucial process to allow the individuals to make decisions based on their risk preferences. The alternative in which adolescents fail to learn about the risks involved in their decisions leaves the adolescent in a state of continued exploration of the ambiguity, reflected as continued risk-taking behavior. This dissertation comprises 2 papers. The first paper is a perspective paper outlining a paradigm that risk taking behavior observed during adolescents may be a product of each adolescent's abilities to learn about risk. The second paper builds on the hypothesis of the perspective paper by first examining neural correlates of risk learning and quantifying individual risk learning abilities and then examining longitudinal risk learning developmental trajectories in relation to real-world risk-trajectories in adolescent individuals. / Doctor of Philosophy / Adolescence is a transition period during which individuals have increasing autonomy in decision-making for themselves, often choosing among options about which they have little knowledge and experience. This process of individuation and independence begins with the adolescent exploring their world and those options they are ignorant of. This is reflected as real-world risk-taking behaviors, including higher motor accidents, unwanted pregnancies, sexually transmitted diseases, drug addictions, and death. We hypothesized and tested the premise that whether adolescents who succeeded or fail to learn about the negative consequences of their actions while exploring will continue to partake in behaviors with negative consequences. This learning is not limited to the value of the outcome associated with making choices, but extends to the range of possible outcomes of the choices or the risks involved. Indeed, the failure to learn the risks involved in decisions with no known information show continued and greater risk-taking behavior, perhaps remaining in a state of continued exploration of the unknown.