Objective Concussion Assessment Using MRI and Metabolomics

November 20, 2023 updated by: Michael Noseworthy PhD, St. Joseph's Healthcare Hamilton

Correlating Advanced MRI Techniques With Neuropsychological Analysis and Immunosensing Assays for Assessment of Sport-related Mild Traumatic Brain Injuries (mTBI)

Mild traumatic brain injury (mTBI), also referred to as concussions, affect millions of people around the world and can cause harmful long term effects. Unfortunately, concussions can be hard to diagnose and many people have lasting post-concussion symptoms such as headaches, difficulty concentrating, and light sensitivity. Recent studies have shown that advanced magnetic resonance imaging (MRI) techniques can identify subtle brain changes caused by a concussion. This study aims to track concussions over time measuring MRI brain scans and post-concussion symptoms to gain a better understand how the brain is affected in comparison to symptoms.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Mild traumatic brain injuries (mTBI) are a major health concern due to the risk of short and long-term complications. In order to understand the effects of an TBI (also referred to as a concussion), studies have examined the physiological and cognitive impact of concussions on the brains of youth and collegiate athletes. Based on athletic-exposure (AE), the most concussions in the National Collegiate Athletics Association (NCAA) occur in Men's wrestling, Men's and Women's ice hockey, Men's football, and Women's soccer (Zuckerman et al. 2015). It has been estimated that 300 000 sport-related concussions (SRC) occur annually in the United States among youth and collegiate athletes (Coronado et al. 2015; Gessel et al. 2007; Langlois et al. 2006; Thurman et al. 1998). However, a SRC estimate would likely be grossly underestimated due to underreporting and failure to seek medical treatment (Karlin 2011; Kaut et al. 2003; Kerr et al. 2016; McCrea et al. 2004; Roozenbeek et al. 2013). In reality, the number of annual SRC could be as high as 1.6 to 3.8 million occurrences (Langlois et al. 2006).

Brain injuries are classified as mild, moderate or severe based on patient reported symptoms, cognitive impairment and structural damage visualized using medical imaging (Bodin et al. 2012; DeCuypere and Kilmo 2012; DeMatteo et al. 2010; Roozenbeek et al. 2013). A major challenge facing mTBI diagnosis has been standardizing assessment, predicting prognosis, and clearing people to return to work or sport. In order to more accurately diagnose and treat patients, healthcare providers require a better understanding of how to brain is affected acutely, and the timeline for when it returns to a pre-concussion state. Recent technological innovations show promise to supplement the current behavioural and psychological assessments. Current concussion and mTBI diagnosis are often based on tests that assess a patient's sensory feedback, mental cognition, motor control, and post-concussion symptoms (Bodin et al. 2012; DeCuypere and Klimo 2012).

To supplement symptom tracking, magnetic resonance imaging (MRI) has been shown in research to be an invaluable concussion tool. The health of brain white matter can be predicted based on the relativistic shape of the myelin surrounding axons and the diffusivity of water along the length of the axons by using a MRI technique called diffusion tensor imaging (DTI)(Asken et al. 2018; Jonkman et al. 2015). In addition, the function of brain grey matter can be assessed using functional magnetic resonance imaging (fMRI) by measuring the paramagnetic differences between oxygenated and deoxygenated blood, based on the Blood-Oxygen Level Dependent (BOLD) signal (Horn et al. 2014; Liu et al. 2018; Ogawa et al. 1990). Activated brain regions have a greater BOLD signal due to magnetic field inhomogeneities caused by changes in blood volume, blood flow, and local metabolism (Ogawa et al. 1990). An fMRI can be used to analyze brain resting state activation patterns, a primary connective system is the Default Mode Network (DMN)(Mak et al. 2017). The DMN has been shown to have decreased activity following a mTBI (Bonnelle et al. 2011; Zhou et al. 2012).

A serious issue surrounding head injuries is the need for a method to diagnose athletes immediately following the injury. The growing interest in using metabolomics for the discovery of clinically relevant biomarkers associated with mild traumatic brain injury (mTBI) could be a solution. However, most studies to date have relied exclusively on blood specimens and/or targeted metabolite panels involving small cohorts of patients without adequate replication, and validation of aberrant metabolic changes in circulation to independent MRI-based brain imaging (Fiandaca et al. 2018; Orešič et al. 2016). We propose to include an analysis of fasting saliva and urine specimens from mTBI patients for comprehensive metabolite profiling using high throughput multi-segment injection-capillary electrophoresis-mass spectrometry technology (DiBattista et al. 2019; Yamamoto et al. 2019), which allows for rapid non-targeted analysis of polar/hydrophilic metabolites, as well as non-polar/ionic lipids with stringent quality control (Azab et al. 2019).

This study aims to track concussion recovery over 6-months using clinical standards of concussion symptoms and objective MRI and metabolomics metrics. Concussion participants will complete three study visits: acutely within 2-weeks of a concussion, 3-month follow-up and 6-month follow-up. Participants will be recruited from St. Joseph's Healthcare Hamilton and local athletic organizations. The study protocol will be identical for all three study visits. Participants will complete the Post-Concussion Symptom Scale (PCSS) and Depression Anxiety Stress Scale (DASS-42) to measure the presence and self-reported severity of common post-concussion symptoms. The MRI data will be used to measure brain function (resting state fMRI) and microstructural properties (diffusion tenor imaging), while the metabolomics will measure if metabolites have abnormal presence or concentration post-concussion based on urine and saliva samples. These quantitative methods will be compared to the subjective concussion symptom scores to identify if brain and physiological abnormalities persist past symptom resolution, and if certain brain regions are more frequently affected by concussion. It is hypothesized that across all three time points that brain function will have decreased BOLD signal fractal complexity and network connectivity (representative of concussion-related injuries), and white matter damage will be present based on the primary DTI metric of fractional anisotropy. It is also hypothesized that post-concussion symptoms will be self-reported as resolved or almost resolved by the 3-month follow-up study visit.

Study Type

Observational

Enrollment (Estimated)

100

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

  • Name: Michael D Noseworthy, PhD, PEng
  • Phone Number: 23727 905.525.9140
  • Email: nosewor@mcmaster.ca

Study Locations

  • Canada
    • Ontario
      • Hamilton, Ontario, Canada, L8N 4A6
        • Recruiting
        • Imaging Research Center at St. Joseph's Healthcare Hamilton
        • Contact:
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult

Accepts Healthy Volunteers

Yes

Sampling Method

Non-Probability Sample

Study Population

Participants for this prospective observational cohort will include 50 individuals who have recently sustained a concussion within the last 2 weeks. Participants will primarily be recruited based on their involvement in collision or contact sport, causing sport-related concussions. Fifty healthy control participants will be recruited with the intention to have age, sex and athletic status matching to the concussion participants.

Description

Inclusion Criteria:

  • Aged between 9-50
  • Recently sustained a concussion (within the last 2 weeks)

Exclusion Criteria:

  • Aged 8 and younger or 51 and older
  • Unable to provide consent (e.g., poor English language skills, etc.)
  • History of liver or kidney disease

  • MRI contraindications:

    • Pacemaker
    • Stent
    • Joint prothesis
    • Implanted devices
    • Claustrophobia
    • Pregnant
    • Permanent piercings
  • Chronic/abusive use of alcohol and/or illicit drugs
  • Previous stroke or moderate/severe traumatic brain injury, subarachnoid hemorrhage, or intracranial hemorrhage
  • Healthy control participants must not have a concussion history or recently sustained a concussion

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Concussion
Individuals who have recently sustained a concussion within the past 2-weeks.
Diagnostic test: Magnetic resonance imaging (MRI)
All participants will have 3 MRI scanning sessions to track brain health over time following the same protocol each time. The MRI sessions will occur acutely (<2 weeks post-concussion), 3-months and 6-months post-concussion. A series of MRI scans will be acquired including T1, T2, T2-FLAIR, SWI, ASL, rsfMRI, and DTI scans to characterize structural, microstructural, functional and tissue perfusion changes within the brain over time.
Diagnostic test: Urine and saliva samples
At each study visit all participants will be asked to provide small urine and saliva samples for a metabolomic analysis using a high throughput multi-segment injection-capillary electrophoresis-mass spectrometry technology. This will allow for rapid non-targeted analysis of polar/hydrophilic metabolites, as well as non-polar/ionic lipids with stringent quality control.
Behavioral: Questionnaires
The Post-Concussion Symptom Scale (PCSS) and the Depression Anxiety Stress Scale (DASS-42) will be used to assess the self-reported presence and severity of known concussion-related symptoms.
Healthy Control
Individuals who have limited to no concussion history, and have not recently sustained a concussion.
Diagnostic test: Magnetic resonance imaging (MRI)
All participants will have 3 MRI scanning sessions to track brain health over time following the same protocol each time. The MRI sessions will occur acutely (<2 weeks post-concussion), 3-months and 6-months post-concussion. A series of MRI scans will be acquired including T1, T2, T2-FLAIR, SWI, ASL, rsfMRI, and DTI scans to characterize structural, microstructural, functional and tissue perfusion changes within the brain over time.
Diagnostic test: Urine and saliva samples
At each study visit all participants will be asked to provide small urine and saliva samples for a metabolomic analysis using a high throughput multi-segment injection-capillary electrophoresis-mass spectrometry technology. This will allow for rapid non-targeted analysis of polar/hydrophilic metabolites, as well as non-polar/ionic lipids with stringent quality control.
Behavioral: Questionnaires
The Post-Concussion Symptom Scale (PCSS) and the Depression Anxiety Stress Scale (DASS-42) will be used to assess the self-reported presence and severity of known concussion-related symptoms.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Functional brain characteristics
Time Frame: 45-minute MRI sessions acutely, 3-months and 6-months post-concussion
Brain function will be examined based on the network connectivity and fractal complexity of the rsfMRI BOLD signal. This will be measured across known brain networks (e.g., Default Mode Network) and specific regions-of-interest (e.g., insula).
45-minute MRI sessions acutely, 3-months and 6-months post-concussion
Microstructural brain characteristics
Time Frame: 45-minute MRI sessions acutely, 3-months and 6-months post-concussion
Microstructural brain changes will be examined based on diffusion tensor imaging (DTI) metrics of fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity. This will be measured within specific regions-of-interest (e.g., insula).
45-minute MRI sessions acutely, 3-months and 6-months post-concussion
Post-concussion symptoms
Time Frame: Acutely, 3-months and 6-months post-concussion
Tracking of self-reported post-concussion symptoms using PCSS and DASS-42 questionnaires
Acutely, 3-months and 6-months post-concussion

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Metabolomics
Time Frame: Acutely, 3-months and 6-months post-concussion
High throughput multi-segment injection-capillary electrophoresis-mass spectrometry technology will be used to analyze the urine and saliva samples to identify if any polar or non-polar metabolites are abnormal post-concussion, and that may indicate physiological markers for future assessment and treatment options.
Acutely, 3-months and 6-months post-concussion

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

St. Joseph's Healthcare Hamilton

Collaborators

McMaster University

Investigators

  • Principal Investigator: Dinesh Kumbhare, MD, PhD, University Health Network, Toronto
  • Principal Investigator: Michael D Noseworthy, PhD, PEng, McMaster University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 11, 2023

Primary Completion (Estimated)

December 15, 2025

Study Completion (Estimated)

December 15, 2025

Study Registration Dates

First Submitted

August 12, 2023

First Submitted That Met QC Criteria

August 12, 2023

First Posted (Actual)

August 15, 2023

Study Record Updates

Last Update Posted (Estimated)

November 22, 2023

Last Update Submitted That Met QC Criteria

November 20, 2023

Last Verified

November 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Concussion MRI & recovery

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

IPD Plan Description

Study data may be shared upon request to the research team.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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