Brain Markers Predicting Reading Recovery After Stroke

Study Overview
=================
Brief Summary
-----------------
For millions of stroke survivors acquired reading deficits represent a significant handicap preventing them from returning to work or continuing their education. The goal of the proposed research is to investigate what brain mechanisms enable recovery of impaired reading. To achieve this goal, the project will directly measure changes in brain perfusion (blood flow) and activation among recovering stroke survivors using a neuroimaging technique called perfusion fMRI (functional Magnetic Resonance Imaging). The project will test if re-perfusion (return of circulation) and re-appearance of reading-related brain activity in the left-brain network for reading is associated with recovery. The ability to predict recovery from neuroimaging has tremendous value in rehabilitation for generating prognoses. It may also dramatically improve the quality of research evaluation for novel, targeted interventions such as noninvasive brain stimulation or pharmacologic therapies.

Detailed Description
-----------------
There is a fundamental gap in understanding the neuro-behavioral time-course of reading recovery following stroke. It is not known whether recovery of reading is associated with improved blood circulation and neural activity of the peri-infarct area, or whether circulation in the unaffected, contralateral brain areas contributes to functional recovery. Continued existence of this gap represents an important problem because, until it is filled, knowledge about optimal timing and targets for restorative therapies to improve reading will remain out of reach. The long-term goal is to develop clinical prognostic and therapeutic tools to improve reading limitations. The overall objective of this project is to characterize the neural mechanisms of recovery from stroke-induced reading impairments. The central hypothesis of this study is that subacute-to-chronic recovery of reading ability is potentiated by reperfusion (improved blood flow) of the left reading network. Reperfusion promotes the return of neural activity and supports behavioral recovery. In contrast, increased perfusion of the right brain areas represents a maladaptive response and is associated with worse chronic reading ability. This hypothesis has been formulated on the basis of preliminary data. The rationale for the proposed research is that once the neural recovery from stroke-induced reading impairments is characterized, clinicians will be able to predict individual recovery potential and select appropriate rehabilitation goals. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) Determine whether post-stroke changes in cerebral blood flow predict recovery of reading ability; and 2) Determine whether increased baseline perfusion of the left reading network is paralleled by greater reading-related neural activation. Under the first aim, perfusion in the peri-infarct tissue, left reading network, and homologous right brain areas will be examined among left stroke patients with reading impairments. A non-invasive measure of perfusion (Arterial Spin Labeling, ASL MRI) will be applied longitudinally: <4 weeks post-stroke (sub-acute) and >3 months post-stroke (chronic) to test if increased perfusion of the left reading network is coupled with an improvement of reading accuracy. Under the second aim, reading-induced brain activity will be recorded in the same group of patients using perfusion-based functional MRI. The effect of task-related neural activity on recovery will be separated from the effect of cerebral blood flow by statistically controlling for baseline circulation and by modeling independent contributions of perfusion and BOLD (Blood Oxygen Level Dependent) signals in order to estimate cerebral oxygen consumption rate, which is directly related to neural activity. The conceptual innovation of this study is that it offers the opportunity to examine reading recovery as distinct from other functions. The methodological innovation is in using simultaneously-acquired perfusion and BOLD signals, helping to measure longitudinal changes in circulation and neural activity with unprecedented precision. The proposed research is significant because it can help greatly improve the effectiveness of post-stroke rehabilitation.

Official Title
-----------------
Brain Markers Predicting Reading Recovery After Stroke

Conditions
-----------------
Left-Hemisphere Stroke

Intervention / Treatment
-----------------
* Diagnostic Test: Perfusion functional Magnetic Resonance Imaging (perfusion fMRI)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: age >18 years right-handed fluent and literate in English prior to stroke no prior neurological disorders or clinical stroke event <4 weeks post-stroke ability to undergo an MRI and complete study tasks presence of reading deficits Exclusion Criteria: participants with severe aphasia resulting in severe language deficits and inability to consent participants with very large lesions resulting in severe cognitive deficits and inability to consent

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Subacute Stroke Sample<br>Participants with first-ever left-brain stroke, < 4 weeks post stroke, age >18 years, right-handed, fluent and literate in English prior to stroke, no prior neurological disorders or clinical stroke event, <4 weeks post-stroke; able to undergo an MRI and complete study tasks, and presence of reading deficits. | Diagnostic Test: Perfusion functional Magnetic Resonance Imaging (perfusion fMRI)<br>* The goal of this test is to measure brain activity during subacute and chronic post-stroke period using a widely available non-invasive neuroimaging tool - functional Magnetic Resonance Imaging (fMRI). Because fMRI relies in part on cerebral blood flow, which is altered in stroke, measuring longitudinal changes in neural activity with fMRI requires that we control for concomitant changes in blood circulation. To do this, we will employ a novel dual-echo perfusion fMRI sequence, which will allow us to separately estimate neural and vascular contributions to fMRI.<br>|
| Chronic Stroke Sample<br>The same group of participants examined in the chronic post-stroke period (>3 months post-stroke) | Diagnostic Test: Perfusion functional Magnetic Resonance Imaging (perfusion fMRI)<br>* The goal of this test is to measure brain activity during subacute and chronic post-stroke period using a widely available non-invasive neuroimaging tool - functional Magnetic Resonance Imaging (fMRI). Because fMRI relies in part on cerebral blood flow, which is altered in stroke, measuring longitudinal changes in neural activity with fMRI requires that we control for concomitant changes in blood circulation. To do this, we will employ a novel dual-echo perfusion fMRI sequence, which will allow us to separately estimate neural and vascular contributions to fMRI.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reading Aloud Accuracy - subacute | Percent correct of single words read aloud | within 1 week of study enrollment | 
| Reading Aloud Accuracy - chronic | Percent correct of single words read aloud | 3 months after study enrollment | 
| Phonology Task Accuracy - subacute | 2-alternative forced choice task of pseudoword rhyming | within 1 week of enrollment | 
| Phonology Task Accuracy - chronic | 2-alternative forced choice task of pseudoword rhyming | 3 months after study enrollment | 
| Semantics Task Accuracy - subacute | 2-alternative forced choice task of picture matching | within 1 week of enrollment | 
| Semantics Task Accuracy - chronic | 2-alternative forced choice task of picture matching | 3 months after study enrollment | 
| Orthography Task Accuracy - subacute | 2 alternative forced choice between a correctly spelled word and a phonological foil | within 1 week of enrollment | 
| Orthography Task Accuracy - chronic | 2 alternative forced choice between a correctly spelled word and a phonological foil | 3 months after study enrollment | 
| Perfusion MRI - subacute | Subacute cerebral blood flow (CBF) in peri-infarct tissue, left reading network, and right homologous areas | within 1 week of enrollment | 
| Perfusion MRI - chronic | Subacute-to-chronic change of CBF in peri-infarct tissue, left reading network, and right homologous areas | 3 months after enrollment | 
| Functional MRI - subacute | Brain activation for reading words and nonwords; task-induced change in oxygen consumption | within 1 week of enrollment | 
| Functional MRI - chronic | Subacute-to-chronic change of brain activation for reading words and pseudowords; longitudinal and task-induced change in oxygen consumption | 3 months after enrollment | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
stroke, reading, fMRI, perfusion, activation, BOLD, recovery, subacute, chronic