Investigating Mediodorsal Thalamus Representations Underlying Human Cognitive Flexibility

Kai Hwang

Status: Not yet enrolling

Conditions: Attention Deficit Disorder With Hyperactivity (ADHD); Schizophrenia

Treatments: Other: High-resolution fMRI during working memory, cognitive control, and decision-making tasks

Study type: Interventional

Funder types: Other

Identifiers

NCT07217652

202412272

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 100 estimated patients

Sex: All

Ages: 18 to 35 years old

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

• No history of any neurological, psychiatric, or medical condition that could affect cognition
• No use of benzodiazepines, long-acting opioids, or other psychotropic drugs that could alter cognitive performance
• Normal or corrected-to-normal vision (visual acuity)
• Normal color perception (Farnsworth-Munsell 100 Hue Test)
• Fluent in English
• No metal implants (including aneurysm clip, cardiac pacemaker, ICD, IUD, neurostimulation system, spinal cord stimulator, internal electrodes or wires, bone stimulator, ear implant, insulin or other infusion pump or device, prosthesis, artificial or prosthetic limb, shunt, vascular access port or catheter, thermodilution catheter, medication patch, radiation seeds or implants, wire mesh implant, tissue expander, surgical staples or clips or sutures, joint replacement, joint/bone pin/screw/nail/wire/plate, dentures, or non-removable hearing aid)
• No exposure to shrapnel or other-related MR contraindications
• No non-removable body piercing jewelry
• No non-removable makeup
• No history of claustrophobia
• No history of breathing problems
• Not currently pregnant or trying to get pregnant (this will be determined via self report and no records will be kept).

Exclusion criteria

• Has a history of any neurological, psychiatric, or medical condition that could affect cognition
• Use of benzodiazepines, long-acting opioids, or other psychotropic drugs that could alter cognitive performance
• Not fluent in English
• Known metal implants (including aneurysm clip, cardiac pacemaker, ICD, IUD, neurostimulation system, spinal cord stimulator, internal electrodes or wires, bone stimulator, ear implant, insulin or other infusion pump or device, prosthesis, artificial or prosthetic limb, shunt, vascular access port or catheter, thermodilution catheter, medication patch, radiation seeds or implants, wire mesh implant, tissue expander, surgical staples or clips or sutures, joint replacement, joint/bone pin/screw/nail/wire/plate, dentures, or non-removable hearing aid)
• History of claustrophobia
• Currently pregnant or trying to get pregnant (this will be determined via self report and no records will be kept).

Trial design

Primary purpose: Basic Science

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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100 participants in 1 patient group

Within subject manipulation of working memory, cognitive control, and decision making

Experimental group

Description:

Participants will complete a series of cognitive tasks designed to engage working memory, cognitive control, and decision-making. During these tasks, participants will view stimuli and make rule-based or value-based choices that require updating and applying context to guide behavior. Brain activity will be measured using high-resolution 7-Tesla functional MRI to assess how the mediodorsal thalamus and prefrontal cortex represent and update contextual information. Computational models will link behavior and neural activity to test how thalamic signals support flexible cognition and adaptive decision-making.

Treatment:

Other: High-resolution fMRI during working memory, cognitive control, and decision-making tasks