Silvia A. Bunge - US grants

Introduction: Fast Spin Echo (FSE) is incompatible with ordered phase encoded respiratory compensation. For patients incapable of breath-holds or when additional SNR or resolution is desired, signal averaging, respiratory triggering and multiple breath-holds techniques are available. We propose an easily implemented method that requires no patient cooperation. We have modified the diminishing variance algorithm (DVA) to work on long TR, multiple slice sequences without a navigator echo. Methods: We use pneumatic bellows to provide respiratory position information instead of navigator echos. Though navigators are more accurate, navigators leave a signal loss band across the abdomen and require additional processing time. Bellows information is available easily and at a higher sampling rate. During the first pass through the sequence, the respiratory position and its corresponding excitation are stored in a separate histogram for each slice. After completing the first pass, information from all the histograms is used to determine the subject's most common respiratory position (mode). Thereafter, the histogram of each individual slice is narrowed about the mode during a reacquisition period. Prior to each reacquisition excitation, the bellows provide a respiratory position. If this position will narrow the slice's histogram, then the slice's worst excitation is reacquired. The reacquisition period continues until all histograms are sufficiently narrow or the scan reaches a pre-defined time limit. Results: Though DVA and respiratory triggering have similar objectives, DVA guarantees the smallest variance of respiratory positions for a fixed scan time. DVA also allows a consistent TR independent of respiration rate. Conclusions: DVA compensation for FSE reduces motion artifacts while efficiently using scan time. It is easy to implement, works with uncooperative subjects, and does not limit other gating or contrast parameters.

To produce meaningful, goal-directed behavior, it is necessary to be able to keep relevant information in mind and to mentally manipulate this information as needed (i.e., use working memory). It is also necessary to remember and use rules that specify how to respond under different circumstances and to switch flexibly between tasks and rules as the circumstances change. Working memory manipulation and the ability to use and switch flexibly between task rules are among the functions referred to as cognitive control functions, in that they enable us to control our thoughts and actions. Cognitive control is thought to rely on prefrontal cortex (PFC) and its interactions with other brain regions. However, brain imaging research in adults suggests that different control functions may rely on different brain regions. Moreover, behavioral research on the development of cognitive control over childhood suggests that these functions may mature at different rates. Dr. Silvia A. Bunge, with support of NSF, is examining the changes in brain activity over childhood that give rise to developmental improvements in specific cognitive control functions. To this end, functional magnetic resonance imaging (fMRI) data is being acquired while children and young adults (ages 8-25) perform tasks that require working memory and flexible rule use.

Characterizing developmental changes in the neural mechanisms underlying cognitive control will further our understanding of normal cognitive development and lead to insights regarding control mechanisms in the adult brain. These findings will lay the foundation for understanding how cognitive control development is compromised in neurodevelopmental disorders, and how teaching in schools might be modified to benefit children with disordered control. This project will provide research training and mentoring to a number of students, including a graduate student, a research assistant, and several undergraduates. The project will promote the scientific careers of at several female scientists. The findings will be disseminated via neuroscience conferences and child development conferences, and will be published in peer-reviewed journals.

[unreadable] DESCRIPTION (provided by applicant): Fluid reasoning, or the capacity to think logically and solve problems in novel situations, is central to human cognition. The acquisition of fluid reasoning ability during childhood is thought to serve as a scaffold that supports learning in other cognitive domains, including reading and arithmetic. A fundamental question concerns the brain mechanisms that underlie the development of fluid reasoning over childhood and adolescence. The proposed research examines the typical developmental changes in brain structure and function associated with improvements in fluid reasoning between the ages of 5 and 17. An accelerated longitudinal design will be used, enabling the assessment of within-person changes over 1-3 years, with two measurement occasions per participant. Changes in brain structure will be assessed with structural magnetic resonance imaging and diffusion tensor imaging. Additionally, changes in brain function will be assessed with functional magnetic resonance imaging during the performance of two reasoning tasks. Finally, a battery of cognitive measures will be used to assess changes in reasoning ability, as well as processing speed, short-term memory, working memory, and executive function. Dynamical systems modeling will be used to examine the interrelations between brain structure, function, and performance from childhood to adolescence. These analyses will be used to evaluate hypotheses about the neural mechanisms underlying developmental changes in reasoning ability. This combined developmental, cognitive neuroscientific, and quantitative approach is novel, and should yield important advances on several fronts. First, the measurement of brain activation associated with fluid reasoning in individuals of varying age and ability level will provide fresh insights into the neural mechanisms underlying the changes in an important higher-level cognitive function about which relatively little is known. Second, up to now, the few published longitudinal studies on brain development have focused on changes in brain structure. As such, this longitudinal dataset will be invaluable in terms of characterizing typical developmental changes over a large part of childhood and adolescence in terms of both brain structure and function. Finally, this research may provide insights into the nature of reasoning deficits in a number of neurological disorders affecting children and/or adults, including Traumatic Brain Injury, autism, schizophrenia, and frontotemporal dementia. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Episodic memory, or the ability to consciously remember past events, is central to the human experience. In a number of mental health disorders, this form of memory is among the most severely impaired cognitive functions. In the case of schizophrenia, episodic memory dysfunction precedes the onset of the full-blown disorder and predicts long-term functional outcomes. In typically developing children, episodic memory improves rapidly during childhood, and then improves more slowly during adolescence. The brain mechanisms supporting these improvements are not yet understood. Neuroscientific research has shown that the hippocampus plays a fundamental role in episodic memory, supporting the formation and retrieval of representations that bind the different aspects of an event. By contrast, lateral prefrontal cortex is thought to play a supportive role in episodic memory, controlling the strategic encoding and retrieval of relevant memories through long-range projections to the hippocampus. It has long been assumed that the hippocampus-dependent binding mechanism is already in place by early childhood, and that the large changes in episodic memory observed during middle childhood and beyond result from the protracted development of the prefrontal cortex. Challenging this view, the proposed research will investigate whether and how changes in the hippocampus - as well as changes in specific tracts that project to the hippocampus - contribute to the development of episodic memory. The proposed research will examine the within-individual changes in brain structure and brain function that underlie changes in episodic memory performance from age 8 to 14 years. To this end, a sample of 180 typically-developing children will be tested three times over the course of 5 years. As compared with cross- sectional research, which is the norm in developmental cognitive neuroscience, this longitudinal approach will enable the identification of the antecedents and consequences of changes in brain structure, brain function, and episodic memory. Relevance to Public Health: The proposed research will lay the foundation for future research on such mental health disorders as schizophrenia, for which atypical hippocampal development may be an early indicator of disease onset.

Abstract
Collaborative Research: The Role of Brain Connectivity in Reasoning Development

Understanding the patterns of communication between brain regions, and how they develop across childhood, is critical for understanding the development of the neural mechanisms that implement complex cognitive operations such as reasoning. Functional connectivity, or correlations in patterns of brain activation (measured via fMRI), is thought to reflect this inter-regional communication. But communication between brain regions ultimately depends on structural connectivity: the white matter tracts that, either directly or indirectly, connect them. This proposal is aimed at resolving two open questions: 1) What are the dynamic relationships between structural and functional connectivity, for the key networks known to be involved in reasoning and other higher cognitive processes, as these develop together across childhood?, and 2) How do these dynamic relationships affect developmental improvements in reasoning ability? The answers that we obtain will provide both fundamental insight into the development of brain connectivity and mechanistic insight into the development of reasoning ability. This knowledge could impact future research both on educational and training programs designed to teach reasoning ability, and on interventions or medical programs designed to correct problems in reasoning.

To address these questions, we will combine fMRI, DTI, and behavioral data from three longitudinal developmental datasets, collected at UC Berkeley, UC Davis, and Vanderbilt University. By combining datasets, we are able to examine longitudinal data from 400 children and young adults between the ages of 6 and 22. Our primary measures of interest include a) intrinsic functional connectivity between specific regions of interest; b) structural connectivity, measured via fractional anisotropy along tracts that connect these regions; and c) reasoning ability, measured via standard cognitive tests. Our main analyses will focus on connectivity within and between two brain networks, the fronto-parietal network and cingulo-opercular network, which are most closely associated with reasoning and other higher cognitive functions. Mixed-model regression analyses will be employed to examine concurrent relationships among structural and functional connectivity in these networks and reasoning ability. Multivariate latent difference score models will be employed to examine lead-lag relationships. The outcome of this research will be a model of interacting structural and functional connectivity development across childhood, and of how the co-development of these two indicators of neural communication relates to developmental improvements in reasoning ability.

The ability to reason about the relations between sets of concepts?relational reasoning?gives rise to abstract thought, and has fueled some of humanity?s greatest achievements in science and technology. Although prior research has identified where in the brain relational reasoning takes place, this project pushes the research field by addressing how the brain represents abstract relations. Specifically, the project aims to address three key questions: (1) Can the brain represent an abstract idea independently of the concrete entities that comprise the content of the idea? (2) Do people represent concepts in an abstract manner only when explicitly required to do so, or are abstract relations also retrieved spontaneously? (3) What neural markers reliably predict differences in reasoning capacity between individuals? That is, do individuals whose brains represent abstract relations more readily also tend to have stronger reasoning skills, and/or to perceive meaningful connections that others miss? This project will identify the computational basis for abstract thought and reasoning, thereby creating an opportunity to refine artificial intelligence systems by providing them with more efficient learning mechanisms. This work will inform future research examining how children, and adults as lifelong learners, form representations of abstract concepts.

This project integrates recent advances in multivariate fMRI, computational modeling, and behavioral methodology to discover the neurocognitive mechanisms underlying the representation of abstract relations. Research will systematically examine the neural bases of this representation, as well as the influence of task context and individual differences. First, behavioral priming and neural similarity measures, alongside metrics from a computational model of relational reasoning, will characterize the overlap in representation between pairs of concepts that are only abstractly related. Second, manipulation of task demands will determine whether the magnitude, location, and stability of neural representations vary with explicit cognitive instructions. Finally, development of a novel 'neural score' metric will determine neural markers of individual differences in relational reasoning.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

PROJECT SUMMARY A distinctive feature of the human brain is the many folds (sulci) in the cortex. Estimates are that 60-70% of the cortex is hidden in sulcal depths. Sulci appear at different time periods in the womb: those that appear early (primary) are hypothesized to be under tighter genetic control, and therefore more similar in location and shape across people, than those that develop later (tertiary). Although modern cognitive neuroscience has largely overlooked these later-developing sulci, for historical and methodological reasons, patterns of tertiary sulci are theorized to have functional significance (Sanides, 1964). Elaborating on this idea, we theorize that sulcal deepening during development pulls cortical regions closer together, which minimizes wiring length and increases the efficiency of local neural signals, which in turn could contribute to improved cognitive functioning. The central hypothesis of this R21 proposal is that the development of tertiary sulci in association cortices has consequences for the development of functional brain architecture and high-level cognition. We propose to test this hypothesis for the first time, focusing on the long overlooked tertiary sulci in lateral prefrontal cortex (latPFC), a brain region implicated in higher-level cognitive capacities such as reasoning. To explore the functional significance of these latPFC sulci, we propose to characterize the relationships between sulcal anatomy, reasoning ability, and functional brain architecture in individual participants. To this end, we will leverage an existing multimodal, longitudinal dataset of 148 participants ages 6-20 that includes anatomical and functional MRI and behavioral measures. In Aim 1a, all latPFC tertiary sulci in both hemispheres of the brain in each individual will be manually defined, as modern automated methods to identify sulci do not include tertiary sulci. Aim 1b is to develop an automated approach to identify all latPFC tertiary sulci that we will share freely with the field. Once the lengthy process of sulcal definition is complete, we will examine whether features of latPFC tertiary sulci develop with age (Aim 2a). We will then test whether individual differences in these features helps to explain and/or predict differences in reasoning ability, measured as a latent factor based on three standardized assessments (Aim 2b). Finally, to relate brain anatomy with brain function, we will test whether individual latPFC tertiary sulci serve as landmarks identifying functional regions during a reasoning task, and whether sulcal- functional relationships are stable or change over development (Aim 3). Theoretically, our proposal advances theories linking the development of neuroanatomical and functional features of latPFC to cognitive development and tests a classic hypothesis. Methodologically, it should yield automated tools to define latPFC tertiary sulci, which could also be applied to other cortical locations in the future. Translationally, as previous studies reported latPFC sulcal anomalies in ADHD, schizophrenia, and bipolar disorder, but did not consider tertiary sulci or examine developmental trajectories, the proposed research will serve as a foundation for future studies of the role of sulcal anatomy in neurodevelopmental disorders.