The long-term goal of our research program is to develop new treatments for improving behavioral deficits post-stroke based on a formal theory of brain function and organization. However, the immediate goal of this competitive renewal is to identify patterns of disrupted structural and functional connectivity that are related to stroke-induced deficits, determine how they change during recovery, and see if they predict outcome. Computational theories have proposed that lesions to the brain will have different effects based on the underlying network architecture. Mechanisms controlling recovery of function may similarly depend on network architecture.
Specific Aim 1 measures changes in whole brain functional connectivity (FC) after damage to peripheral networks that are mainly connected within the network vs. central networks that communicate more broadly with other brain networks. We measure separately the effect of cortical vs. white matter pathway damage. We predict that peripheral lesions (either to gray or white matter) will produce FC changes that are mainly limited to the affected network, while central lesions (either gray or white matter) will produce multi- network FC changes. Peripheral networks are connected to input/output pathways and mediate predominantly sensory or motor functions. Central networks are connected through association pathways and mediate predominantly attention and memory functions.
Specific Aim 2 uses a machine learning ridge regression method to test the idea that sensory-motor deficits and their recovery are more dependent on structural damage and anatomical disconnection, whereas cognitive impairments are better captured by multi-network functional connectivity dysfunction. An important clinical goal of the project is to determine whether advanced neuroimaging techniques, such as structural imaging, DTI, and fMRI can provide useful clinical information on an individual patient's recovery and outcome, over and above that provided by measures of acute behavior, demographic variables, and amount of treatment.
In Specific Aim 3 we enter neuroimaging data into a classifier to predict outcome in individual patients, as well as to predict the effect of rehabilitation interventions. Finally, in Specific Aim 4 we move from correlation and prediction to mechanism. Our basic hypothesis is that changes in functional connectivity after focal injury reflect alterations in brain dynamics, specifically a decrease in the variability of inter-regional phase differences. This hypothesis is tested empirically by phase measurements, but also computationally, using a biophysically based model that can simulate the FC changes observed in patients. Importantly, the model also estimates the information capacity of the damaged brain, which we will correlate with the patient's empirically measured degree of modularity and profile of behavioral deficits.

Public Health Relevance

The goal of this project is to use advanced neuroimaging techniques to understand how a stroke changes the large-scale physiology of the brain, and how those changes in turn relate to the behavioral problems caused by the stroke. We use techniques that allow us to measure how a stroke damages the connectivity of the brain, both by damaging the fiber bundles that transmit information between brain regions, but also by changing the functional communication across many brain regions. We test hypotheses concerning: 1) how damage to different parts of the brain affect these measures of connectivity; 2) how measures of connectivity can help us to predict the outcome of individual stroke patients; and, 3) whether computational modeling of connectivity can help us understand the behavioral deficits caused by a stroke.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS095741-01
Application #
9064398
Study Section
Special Emphasis Panel (ZRG1-IFCN-Q (02))
Program Officer
Babcock, Debra J
Project Start
2015-09-30
Project End
2020-06-30
Budget Start
2015-09-30
Budget End
2016-06-30
Support Year
1
Fiscal Year
2015
Total Cost
$558,553
Indirect Cost
$147,618
Name
Washington University
Department
Neurology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Astafiev, Serguei V; Zinn, Kristina L; Shulman, Gordon L et al. (2016) Exploring the physiological correlates of chronic mild traumatic brain injury symptoms. Neuroimage Clin 11:10-9
Astafiev, Serguei V; Shulman, Gordon L; Metcalf, Nicholas V et al. (2015) Abnormal White Matter Blood-Oxygen-Level-Dependent Signals in Chronic Mild Traumatic Brain Injury. J Neurotrauma 32:1254-71
Diwakar, Mithun; Harrington, Deborah L; Maruta, Jun et al. (2015) Filling in the gaps: Anticipatory control of eye movements in chronic mild traumatic brain injury. Neuroimage Clin 8:210-23
Siegel, Joshua S; Snyder, Abraham Z; Ramsey, Lenny et al. (2015) The effects of hemodynamic lag on functional connectivity and behavior after stroke. J Cereb Blood Flow Metab :