PROJECT SUMMARY Cognitive control is an umbrella term that describes processes that regulate cognitive, perceptual, and motor functions needed to perform adaptive, goal-directed behaviors. Patients with neurological and psychiatric disorders, for example schizophrenia, attention-deficit hyperactivity disorder (ADHD), traumatic brain injury and stroke, suffer from impairments in cognitive control. Although the function of frontoparietal and striatal circuits in cognitive control have been extensively studied, increasing evidence suggests a role for the thalamus. Thalamic nuclei have reciprocal and non-reciprocal connections with multiple cortical regions, integrate modulatory inputs from other subcortical structures, and innervate both excitatory and inhibitory cortical neurons. Despite this prominent connectivity profile, the role of the human thalamus in cognitive control and effects of its dysfunction are not well understood. The objective of the proposed research is to determine the cognitive control functions of the human thalamus. Our central hypothesis, based on our extensive preliminary data and anatomical properties of thalamocortical circuits in animal models, is that thalamic nuclei support cognitive control by modulating cortical activities that include evoked responses, cortical network interactions, and neural oscillations. These cortical activities instantiate neurocognitive processes that select or maintain task-relevant information, and they can be selectively amplified through targeted increases in thalamocortical interactions. Consequently, thalamocortical dysfunction can lead to cognitive rigidity, increased distraction, and poor planning. To test our hypothesis, we propose a novel approach that integrates cognitive behavioral tasks that specifically manipulate processes that select and maintain task-relevant information (for example, working memory and set switching), multimodal neuroimaging (fMRI and EEG), and human thalamic lesions studies. We will first determine the functional organization (topography) of thalamocortical functional connectivity for cognitive control (Aim 1), which has not yet been systematically mapped in humans. We will then determine how thalamocortical interactions select and maintain task-relevant information by examining its relationship with, and modulatory effects on, task- related cortical activities (Aims 2 and 3). For all studies, we will recruit healthy individuals, patients with focal thalamic lesions, and control patients from a lesion comparison group. By collecting multimodal neuroimaging data from patients with focal thalamic lesions, we will determine how the disruption of thalamocortical interactions affects task-related cortical neural activities and behavior. Results from our proposed research will establish how the distribution of thalamocortical connectivity enables thalamic nuclei to participate in multiple cognitive control functions, and specify the cognitive and neural repercussions of thalamocortical dysfunction observed in patients with thalamic stroke, as well as other disorders such as ADHD and schizophrenia.

PROJECT NARATIVE The proposed research is relevant to public health because it will advance our understanding of how the human thalamus contributes to goal-directed behaviors (cognitive control). Many psychiatric and neurological disorders, such as schizophrenia, attention-deficit hyperactivity disorder (ADHD), stroke and traumatic brain injury, affect thalamic function and have significant impairments in cognitive control. The proposed research is relevant to NIH's mission because it can provide insights into the diagnosis and treatment of clinical disorders inflicted by dysfunctional cognitive control.