Clayton E. Curtis - US grants

A series of event-=related functional magnetic resonance imaging (fMRI) studies are proposed to investigate the functional neuroanatomy of working memory, with special emphasis on inhibitory control as an executive function. This new technology, along with careful and precise manipulations of task parameters that are known to interfere with working memory performance will be used to accomplish several objectives that include: 1) identify regions of the prefrontal cortex (PFC) that are responsible for the protection of information in working memory from cortex (PFC) that are responsible for the protection of information in working memory from internal (i.e., stemming from mnemonic representations) and external (i.e., stemming from non-mnemonic, perceptual distraction) sources of interference; 2) characterize the material-specific (i.e., verbal, object, spatial) effects of proactive interference; and 3) characterize the differential effects of having distractors that are of the same or different material type as the information being maintained (e.g., verbal maintenance and verbal distraction vs. verbal maintenance and spatial distraction). The overall goal of this project is to precisely characterize the neural and cognitive processes mediated by the PFC that support the ability to suppress inappropriate or irrelevant information that can interfere with working memory.

[unreadable] DESCRIPTION (provided by applicant): The prefrontal cortex (PFC) is critical for adaptive higher-order cognitive behaviors that are compromised by a wide variety of mental health disorders including schizophrenia, (ADHD), substance abuse disorders, Alzheimer's and Parkinson's Disease, and AIDS-related dementia. A better understanding of basic neural mechanisms will lead to improved diagnostic, prognostic, and therapeutic procedures. Although the PFC is critical for the planning, maintenance, selection, and execution of willed behavior, we know very little about the mechanisms by which it accomplishes these goals. Barriers to our progress in this regard include 1) a poor understanding of how the crucial animal work on PFC functions translates to the human species we are trying to understand, and 2) a lack of understanding of how the PFC influences ongoing behavior through its functional interactions with other brain areas. Here we propose a divide-and-conquer strategy for better understanding the functions of the PFC. In AIM 1, we will localize a key portion of the PFC, the human homolog of the monkey frontal eye field (FEF) and treat it as a model system for detailed study of PFC functions. We strategically chose the FEF as our model because 1) unlike other PFC areas, we have methods for localizing it in humans, 2) data from monkey FEF, as compared to other PFC areas, offer testable predictions about the functional homologies between the species, and most importantly 3) the FEF is implicated in many of the same high-level cognitive behaviors that the PFC in general is implicated. We will study the mechanisms that the human FEF uses for planning, attention, memory, and selection. Working within a better-defined and constrained system like the oculomotor system may quickly lead to mechanistic accounts of these functions that may be less tenable in a more complicated and less understood system like the PFC as a whole. Although the PFC is thought to influence ongoing behavior through its functional interactions with other brain areas, there is a dearth of evidence to support this theory. In AIM 2, we will use fMRI to measure functional interactions between the PFC and other brain areas that together may form networks supporting the critical behaviors. Together, the two AIMS embrace both functional specialization at the local level and distributed processing at the network level and will allow us to test critical hypotheses about how the PFC supports intention, attention, and working memory. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Neural activity persists during the maintenance of working memory (WM) representations and is thought to integrate perception and action over time and across brain areas through the coordination of multiple neural systems. Yet, there is a fundamental gap in understanding the neural mechanisms by which WM coordinates large-scale brain networks. This gap in knowledge is a critical problem because a host of psychiatric and neurologic symptoms stem from a primary WM dysfunction. The long-term goal of this work is to understand the mechanisms by which high-level cognition emerges through the temporal integration of sensory and motor functions across the cortex. The proposal's objective is to test new models of how the synchronization of neuronal oscillations may provide a neural mechanism for structuring recurrent interactions between different nodes in neural networks that support cognition. The central aim of the project is to test several critical predictions from recet theories of the role of neural oscillations and synchrony in high-level cognition using intracrania electroencephalography (iEEG) recordings from the prefrontal and posterior parietal cortices of human patients with pharmacologically intractable epilepsy. The rationale for the proposed research is that, as we better understand the mechanisms by which nodes in large-scale networks interact to give rise to high-level cognition, we will then be able to devise strategies fr understanding the basis, treatment, and prevention of mental disease. The objective will be to test, refine, and possibly refute, tenets of neural synchronization theories and will be accomplished by pursuing three specific aims: 1) Identify the frequencies at which neural oscillations persist during WM maintenance; 2) Test if WM maintenance enhances oscillatory frontal-parietal coupling; and 3) Determine how neural oscillations in different frequency bands interact. Strong preliminary data based on neural activity recorded from subdural electrodes on the surface of the frontal and parietal cortices of patients performing a memory guided saccade task demonstrate the feasibility of project aims in the applicant's hands. Under aim 1, gamma and alpha band oscillations were delay period (i.e., WM related) as well as spatially selective (i.e., contralateralized). Under aim 2, neural oscillations in frontal and parietal cortex synchronized during WM maintenance. Under aim 3, the phase of low frequency oscillations modulated the power of high frequency oscillations during WM maintenance. The approach is innovative because it capitalizes on an extremely rare population of patients with subdural electrodes over frontal and parietal cortex and relies on iEEG recording of neural signals that have the requisite sensitivity and temporal resolution to directly test recent theories of neural synchronization. The proposed research is significant because it is expected to test critical models of how neural oscillations structure computation and communication in the human brain thereby providing a thorough theoretical framework within which clinical researchers can develop strategies for the diagnosis and treatment of psychiatric and neurologic disorders.

DESCRIPTION (provided by applicant): Despite the widespread appreciation that the prefrontal and posterior parietal cortices (PFC/PPC) are necessary for flexible action and efficient perception, there is a fundamental gap in understanding the control mechanisms by which they accomplish these goals. This gap in knowledge is a critical problem because a host of psychiatric and neurologic disorders stem from a primary dysfunction of executive control. The long-term goal is to understand the mechanisms by which the PFC and PPC exert control over motor and sensory systems. The objective of the current proposal is to test a new model of how activity in the PFC and PPC form maps of prioritized space that tag salient and relevant locations in the visual field, which can then be used as the basis of executive control signals. The mechanisms of bias are likely to involve mechanisms used for saccade planning. The central aim of the project is to test the extent to which the patterns of neural activity in the human PFC and PPC are consistent with predictions from the priority map theory, including the functional organization of priority maps, the nature of what is prioritized, and the representation of competing priorities. The rationale for the proposed research is that a better understanding of how control is exerted will lead to a strong theoretical framework within which strategies for the understanding of mental disease will develop. The objective will be to test, refine, and possibly refute, tenets of the priority map theory which will be accomplished by pursuing three specific aims: 1) test the hypothesis that the activity in priority maps is agnostic about what led to prioritization; 2) test the hypothesis that the activity in priority maps encodes the incentives associated with multiple prioritized items; and 3) test the hypothesis that the activity in priorit maps encodes the cue probabilities associated with multiple prioritized items. Strong preliminary data demonstrate the feasibility of aims in the applicant's hands. Several candidate priority maps were identified in frontoparietal cortex using novel topographical mapping approaches. Under Aim 1, both delay period activity and multivariate patterns of brain activity in candidate priority maps were remarkably similar, if not interchangeable, across a variety of spatial cognition tasks (e.g., memory, attention, planning). Under Aim 2, behavioral measures and spatially specific activity in frontal and parietal cortex scaled with the incentive driven priorites of locations maintained in working memory. Under aim 3, working memory performance scaled with the likelihood that maintained locations would be later probed. The approach is innovative because it is highly programmatic; uses novel approaches to combat individual differences in the functional neuroanatomy of the PFC and PPC; sidesteps past inferential weaknesses with novel analyses; and uses powerful methods to rigorously test key hypotheses. The proposed research is significant because it is expected to test an important new model of executive control and will provide a detailed understanding of the mechanisms by which the human brain exerts control, such that models of dysfunction of these mechanisms can be targeted as causes of and potential treatments for neuropathology.

Despite that many failures of high-level cognition are due to the limited resources that support working memory (WM), we know almost nothing about the neural mechanisms underlying these WM limitations, nor the strategies employed to mitigate the limits of our memory. This gap in our knowledge is a critical problem because a host of psychiatric and neurologic disorders stems from a primary WM dysfunction. Our long-term goal is to understand the mechanisms by which WM representations are limited and how these limitations can be mitigated and remediated. Utilizing Bayesian theory, our overall hypothesis is that noisy population dynamics encode a probability distribution over WM stimulus dimensions, where a greater width in this distribution leads to less certainty about a remembered stimulus. The central aim of the project is to understand the role of uncertainty in the neural encoding of WM representations, including how neural uncertainty limits WM precision, how strategic use of prioritization improves the quality of WM, and how population activity in frontoparietal and visual cortex differentially impact the quality of WM. The rationale for the proposed research is that, as we better understand the neural mechanisms of WM, a strong theoretical framework will emerge within which strategies for understanding and treating cognitive dysfunction will emerge. We test our central hypothesis by pursuing three: With three specific aims, we will test the hypotheses that 1) neural populations encode behaviorally relevant representations of WM uncertainty; 2) sculpting population activity within topographic maps to favor prioritized locations improves the quality of WM representations; and 3) control signals in association cortex, in the form of persistent activity, affect the quality of spatial WM representations in visual cortex. Strong preliminary data demonstrate the feasibility of proposed work as well as initial support for the hypotheses. Under Aim 1, behavioral and modeling data demonstrated that humans use representations of uncertainty and patterns of fMRI activity in retinotopic areas in visual cortex were used to construct generative models of spatial WM that allowed for the estimation of memory uncertainty in neural populations. Under Aim 2, WM resource limitations were overcome by prioritizing some memories, which improved WM by reducing error and uncertainty in the population activities in visual maps where these representations are stored. Under Aim 3, the strength of neural activity during retention intervals in prefrontal and parietal cortex predicted the quality of neural representations of memorized locations decoded in early visual cortex. Overall, the proposed work will generate data needed to test how neural populations encode representations of WM. The approach is innovative because it combines neural and computational modeling to directly test WM theories within a test bed of well-defined topographically organized populations. The proposed research is significant because it is expected to provide new insights into the mechanisms that support WM, in addition to providing new targets for cognitive remediation in psychiatric, neurologic, and geriatric populations.

Despite that many failures of high-level cognition are due to the limited resources that support working memory (WM), we know almost nothing about the neural mechanisms underlying these WM limitations, nor the strategies employed to mitigate the limits of our memory. This gap in our knowledge is critical because a host of neuropsychiatric disorders suffer from WM dysfunction. Our long-term goal is to understand the mechanisms by which WM representations are limited and how these limitations can be mitigated. Our overall hypothesis is two-fold. 1) A network of cortical areas support WM, where the population dynamics within distinct nodes encode and maintain stimulus features and mnemonic strategies. 2) The amount of available WM resources is proportional to some properties of the node?s population (e.g., size) within which these dynamics reside. The central aim of the project is to dissect the cortical network that supports WM, causally linking canonical WM mechanisms to visual field maps in frontal, parietal, and occipital cortex, and identifying the underlying mechanisms that limit WM. The rationale for the proposed research is that, as we better understand the neural mechanisms of WM, a strong theoretical framework will emerge within which strategies for understanding individual differences and treating cognitive dysfunction will emerge. Using functional brain imaging, transcranial magnetic stimulation (TMS), and computational modeling, we test our central hypothesis by pursuing three specific aims. 1) The structure of the neural populations that encode WM representations constrain the precision, capacity, and resilience of WM; 2) Prefrontal and parietal cortex make critical but distinct contributions to WM; and 3) Early visual cortex is necessary for the maintenance of visual WM. Strong preliminary data demonstrate the feasibility of proposed work as well as initial support for the hypotheses. Under Aim 1, the size of retinotopically-defined frontal and parietal visual field maps predicts both individual differences in the precision of WM and the degree to which TMS affects WM. Under Aim 2, TMS to parietal cortex impacts memory precision, while perturbation of frontal cortex affected the strategic allocation of WM resources. Under Aim 3, TMS to primary visual cortex causes a loss of precision for remembered items encoded in the perturbed portion of the visual field, supporting a model by which visual cortex acts as a workspace for top-down feedback signals during WM. Overall, the proposed work will generate data needed to dissect the cortical network that supports WM, causally linking canonical WM mechanisms to visual field maps in frontal, parietal, and occipital cortex, and identifying the underlying mechanisms that limit WM. The approach is innovative because it combines computational neuroimaging, modeling, and causal techniques to directly test WM theories within a test bed of well-defined topographically organized populations. The proposed research is significant because it is expected to provide key insights into the causes of WM limits in humans, in addition to providing new targets for cognitive remediation in psychiatric, neurologic, and geriatric populations.