Brain Markers Predicting Reading Recovery After Stroke

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.

Study Overview

• Status: Completed
• Conditions: Left-Hemisphere Stroke
• Intervention / Treatment: Diagnostic test: Perfusion functional Magnetic Resonance Imaging (perfusion fMRI)

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.

• Study Type: Observational
• Enrollment (Actual): 26

Contacts and Locations

Study Locations

• United States
  • New Jersey
    • West Orange, New Jersey, United States, 07052
      • Kessler Foundation

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

34 participants with first-ever left-brain stroke

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Subacute Stroke Sample; 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); 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.
Chronic Stroke Sample; 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); 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.

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

Collaborators and Investigators

• Sponsor: Kessler Foundation
• Collaborators: Rutgers University; National Center for Medical Rehabilitation Research (NCMRR)

Study record dates

Study Major Dates

• Study Start (Actual): April 4, 2018
• Primary Completion (Actual): July 1, 2021
• Study Completion (Actual): July 1, 2021

Study Registration Dates

• First Submitted: February 15, 2019
• First Submitted That Met QC Criteria: February 15, 2019
• First Posted (Actual): February 19, 2019

Study Record Updates

• Last Update Posted (Actual): August 31, 2021
• Last Update Submitted That Met QC Criteria: August 30, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Keywords: stroke; recovery; subacute; fMRI; chronic; perfusion; BOLD; reading; activation
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Stroke
• Other Study ID Numbers: R-784-13

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Data generated in this project may be shared in accordance with the NIH and Kessler Foundation policies, as well as the Notice of Privacy of Practices signed by each participant in the study. In case data is shared, it will be de-identified, such that no link can be made to the individual participant. Data may be shared upon request after the acceptance for publication of the main findings of the study. Publication of findings will occur during the project, if appropriate, or at the conclusion of the project, consistently with the typical scientific process.

Access to methodology and software tools generated in the course of the project will be granted for educational, research, and non-profit purposes. Sharing of such study resources will be provided via web-based applications (e.g., GitHub), as appropriate.

• IPD Sharing Time Frame: The data will be available 1 year after study completion (3/31/2021 - anticipated). The data will be available indefinitely
• IPD Sharing Access Criteria: The data will be made available upon request

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No