Investigating Mediodorsal Thalamus Representations Underlying Human Cognitive Flexibility

Attention Deficit Disorder With Hyperactivity (ADHD), Schizophrenia

Cognitive control, working memory, decision making

The goal of this basic experimental research study is to examine how the human thalamus supports flexible thinking and behavior. Specifically, the research aims to elucidate how the mediodorsal (MD) thalamus encodes and updates "context"-the mental framework that determines which rules or actions are relevant in a given situation. This work may contribute to understanding why certain psychiatric conditions, such as schizophrenia and ADHD, involve difficulties with cognitive flexibility and control. The primary research questions are: Does the MD thalamus represent the context that organizes how working memory guides task selection? Does the MD thalamus signal when context needs to be updated after a change in task demands? Do these thalamic representations support generalization to new situations or rules? Participants will complete cognitive tasks while undergoing high-resolution brain imaging using 7-Tesla MRI. The investigators will combine behavioral data, computational modeling, and advanced neuroimaging analyses to examine how the thalamus interacts with the cortex during flexible decision-making.

The human brain's ability to learn and execute behaviors tailored to environmental contingencies is crucial for adaptive cognition. Central to this capacity are neural representations of context, which organize the associations between sensory features and behavioral utility. Despite their significance, the neural mechanisms underlying the encoding and updating of context representations remain poorly understood. This gap in knowledge is particularly relevant for understanding cognitive deficits in psychiatric disorders such as schizophrenia and ADHD. This research study proposes to test the hypothesis that the human mediodorsal (MD) thalamus is critical for encoding, updating, and generalizing context representations. Previous studies have shown that damage to the MD thalamus impairs task switching and working memory in humans, consistent with findings from non-human animal models. Additionally, single-unit recordings in animals reveal that MD neurons rapidly encode task context, a process dependent on the convergence of prefrontal afferents. Preliminary fMRI data indicate that the human MD thalamus tracks task context and its updates following switches. However, a critical gap exists in interpreting these results due to the lack of quantitative models and advanced neuroimaging approaches to delineate the specific representations and computations carried out by the human MD. To address this gap, the investigators will use a computational cognitive neuroscience approach, integrating computational models with high-resolution 7T MRI and advanced neuroimaging analyses. This study has three specific aims: Aim 1: Determine whether the MD thalamus encodes context representations that organize how working memory guides task selection. Aim 2: Investigate whether the MD thalamus encodes context prediction errors that flexibly switch prefrontal task representations. Aim 3: Assess whether MD context representations enable generalization to novel stimulus-response contingencies during decision-making. For all aims, the investigators will develop computational models that specify both cognitive processes and neural implementations to predict behavior and guide neuroimaging data analyses. This study aims to establish a new conceptual and empirical framework for understanding thalamic computation in humans, with significant implications for theories of cognitive control, adaptive human behavior, and cognitive dysfunction.

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United States