1. Medicine
  2. Neuroscience

Multi-tract multi-symptom relationships in pediatric concussion

  1. Guido I Guberman  Is a corresponding author
  2. Sonja Stojanovski
  3. Eman Nishat
  4. Alain Ptito
  5. Danilo Bzdok
  6. Anne L Wheeler
  7. Maxime Descoteaux
  1. McGill University, Canada
  2. University of Toronto, Canada
  3. Université de Sherbrooke, Canada
https://doi.org/10.7554/eLife.70450
Share this article
Cite this article
  1. Guido I Guberman
  2. Sonja Stojanovski
  3. Eman Nishat
  4. Alain Ptito
  5. Danilo Bzdok
  6. Anne L Wheeler
  7. Maxime Descoteaux
(2022)
Multi-tract multi-symptom relationships in pediatric concussion
eLife 11:e70450.
https://doi.org/10.7554/eLife.70450
  2. Download BibTeX
  3. Download .RIS

Abstract

Background: The heterogeneity of white matter damage and symptoms in concussion has been identified as a major obstacle to therapeutic innovation. In contrast, most diffusion MRI (dMRI) studies on concussion have traditionally relied on group-comparison approaches that average out heterogeneity. To leverage, rather than average out, concussion heterogeneity, we combined dMRI and multivariate statistics to characterize multi-tract multi-symptom relationships.

Methods: Using cross-sectional data from 306 previously-concussed children aged 9-10 from the Adolescent Brain Cognitive Development Study, we built connectomes weighted by classical and emerging diffusion measures. These measures were combined into two informative indices, the first representing microstructural complexity, the second representing axonal density. We deployed pattern-learning algorithms to jointly decompose these connectivity features and 19 symptom measures.

Results: Early multi-tract multi-symptom pairs explained the most covariance and represented broad symptom categories, such as a general problems pair, or a pair representing all cognitive symptoms, and implicated more distributed networks of white matter tracts. Further pairs represented more specific symptom combinations, such as a pair representing attention problems exclusively, and were associated with more localized white matter abnormalities. Symptom representation was not systematically related to tract representation across pairs. Sleep problems were implicated across most pairs, but were related to different connections across these pairs. Expression of multi-tract features was not driven by sociodemographic and injury-related variables, as well as by clinical subgroups defined by the presence of ADHD. Analyses performed on a replication dataset showed consistent results.

Conclusions: Using a double-multivariate approach, we identified clinically-informative, cross-demographic multi-tract multi-symptom relationships. These results suggest that rather than clear one-to-one symptom-connectivity disturbances, concussions may be characterized by subtypes of symptom/connectivity relationships. The symptom/connectivity relationships identified in multi-tract multi-symptom pairs were not apparent in single-tract/single-symptom analyses. Future studies aiming to better understand connectivity/symptom relationships should take into account multi-tract multi-symptom heterogeneity.

Funding: financial support for this work from a Vanier Canada Graduate Scholarship from the Canadian Institutes of Health Research (GIG), an Ontario Graduate Scholarship (SS), a Restracomp Research Fellowship provided by the Hospital for Sick Children (SS), an Institutional Research Chair in Neuroinformatics (MD), as well as a Natural Sciences and Engineering Research Council CREATE grant (MD).

Data availability

All data used in this project were obtained from the Adolescent Brain Cognitive Development Study. This dataset is administered by the National Institutes of Mental Health Data Archive and is freely available to all qualified researchers upon submission of an access request. All relevant instructions to obtain the data can be found in https://nda.nih.gov/abcd/request-access. The Institutional Review Board of the McGill University Faculty of Medicine and Health Sciences reviewed the application and confirmed that no further ethics approvals were required.

The following previously published data sets were used

Article and author information

Author details

  1. Guido I Guberman

    Department of Neurology and Neurosurgery, McGill University, Montreal, Canada
    For correspondence
    guido.guberman@mail.mcgill.ca
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4422-2225

  2. Sonja Stojanovski

    Department of Physiology, University of Toronto, Toronto, Canada
    Competing interests
    No competing interests declared.

  3. Eman Nishat

    Department of Physiology, University of Toronto, Toronto, Canada
    Competing interests
    No competing interests declared.

  4. Alain Ptito

    Department of Neurology and Neurosurgery, McGill University, Montreal, Canada
    Competing interests
    No competing interests declared.

  5. Danilo Bzdok

    Montreal Neurological Institute (MNI), McGill University, Montreal, Canada
    Competing interests
    No competing interests declared.

  6. Anne L Wheeler

    Department of Physiology, University of Toronto, Toronto, Canada
    Competing interests
    No competing interests declared.

  7. Maxime Descoteaux

    Department of Computer Science, Université de Sherbrooke, Sherbrooke, Canada
    Competing interests
    Maxime Descoteaux, works as Chief Scientific Officer for IMEKA. He holds the following patents: DETERMINATION OF WHITE-MATTER NEURODEGENERATIVE DISEASE BIOMARKERS (Patent Application No.: 63/222,914), PROCESSING OF TRACTOGRAPHY RESULTS USING AN AUTOENCODER (Patent Application No.: 17/337,413). No other authors have any financial or other conflicts of interest..

Funding

Canadian Institutes of Health Research (Vanier Canada Graduate Scholarship)

  • Guido I Guberman

Government of Ontario (Ontario Graduate Scholarship)

  • Sonja Stojanovski

Hospital for Sick Children (Restracomp Research Fellowship)

  • Sonja Stojanovski

Université de Sherbrooke (Institutional Research Chair)

  • Maxime Descoteaux

Natural Sciences and Engineering Research Council of Canada (CREATE Grant)

  • Maxime Descoteaux

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: The data used in this study were obtained from the Adolescent Brain Cognitive Development Study. All aspects related to ethical standards were managed by the ABCD Study team. The Institutional Review Board of the McGill University Faculty of Medicine and Health Sciences reviewed the application and confirmed that no further ethics approvals were required.

Reviewing Editor

  1. Alexander Shackman, University of Maryland, United States

Publication history

  1. Preprint posted: April 7, 2021 (view preprint)
  2. Received: May 17, 2021
  3. Accepted: April 26, 2022
  4. Accepted Manuscript published: May 17, 2022 (version 1)
  5. Version of Record published: May 25, 2022 (version 2)

Copyright

© 2022, Guberman et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 805
    Page views
  • 158
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Guido I Guberman
  2. Sonja Stojanovski
  3. Eman Nishat
  4. Alain Ptito
  5. Danilo Bzdok
  6. Anne L Wheeler
  7. Maxime Descoteaux
(2022)
Multi-tract multi-symptom relationships in pediatric concussion
eLife 11:e70450.
https://doi.org/10.7554/eLife.70450

Categories and tags

Research organism

Further reading

    1. Medicine
    2. Physics of Living Systems

    High spatial resolution analysis using automated indentation mapping differentiates biomechanical properties of normal vs. degenerated articular cartilage in mice

    Anand O Masson, Bryce Besler ... Roman J Krawetz
    Research Article

    Characterizing the biomechanical properties of articular cartilage is crucial to understanding processes of tissue homeostasis vs. degeneration. In mouse models, however, limitations are imposed by their small joint size and thin cartilage surfaces. Here we present a 3D automated surface mapping system and methodology that allows for mechanical characterization of mouse cartilage with high spatial resolution. We performed repeated indentation mappings, followed by cartilage thickness measurement via needle probing, at 31 predefined positions distributed over the medial and lateral femoral condyles of healthy mice. High-resolution 3D x-ray microscopy (XRM) imaging was used to validate tissue thickness measurements. The automated indentation mapping was reproducible, and needle probing yielded cartilage thicknesses comparable to XRM imaging. When comparing healthy vs. degenerated cartilage, topographical variations in biomechanics were identified, with altered thickness and stiffness (instantaneous modulus) across condyles and within anteroposterior sub-regions. This quantitative technique comprehensively characterized cartilage function in mice femoral condyle cartilage. Hence, it has the potential to improve our understanding of tissue structure-function interplay in mouse models of repair and disease.

    1. Cancer Biology
    2. Medicine

    Non-coding RNAs in drug and radiation resistance of bone and soft-tissue sarcoma: a systematic review

    Huan-Huan Chen, Tie-Ning Zhang ... Tao Zhang
    Research Article Updated

    Background:

    Sarcomas comprise approximately 1% of all human malignancies; treatment resistance is one of the major reasons for the poor prognosis of sarcomas. Accumulating evidence suggests that non-coding RNAs (ncRNAs), including miRNAs, long ncRNAs, and circular RNAs, are important molecules involved in the crosstalk between resistance to chemotherapy, targeted therapy, and radiotherapy via various pathways.

    Methods:

    We searched the PubMed (MEDLINE) database for articles regarding sarcoma-associated ncRNAs from inception to August 17, 2022. Studies investigating the roles of host-derived miRNAs, long ncRNAs, and circular RNAs in sarcoma were included. Data relating to the roles of ncRNAs in therapeutic regulation and their applicability as biomarkers for predicting the therapeutic response of sarcomas were extracted. Two independent researchers assessed the quality of the studies using the Würzburg Methodological Quality Score (W-MeQS).

    Results:

    Observational studies revealed the ectopic expression of ncRNAs in sarcoma patients who had different responses to antitumor treatments. Experimental studies have confirmed crosstalk between cellular pathways pertinent to chemotherapy, targeted therapy, and radiotherapy resistance. Of the included studies, W-MeQS scores ranged from 3 to 10 (average score = 5.42). Of the 12 articles that investigated ncRNAs as biomarkers, none included a validation cohort. Selective reporting of the sensitivity, specificity, and receiver operating curves was common.

    Conclusions:

    Although ncRNAs appear to be good candidates as biomarkers for predicting treatment response and therapeutics for sarcoma, their differential expression across tissues complicates their application. Further research regarding their potential for inhibiting or activating these regulatory molecules to reverse treatment resistance may be useful.

    Funding:

    This study’s literature retrieval was supported financially by the 345 Talent Project of Shengjing Hospital of China Medical University (M0949 to Tao Zhang).

    1. Medicine

    Retinopathy of prematurity: Metabolic risk factors

    Zhongjie Fu, Anders K Nilsson ... Lois EH Smith
    Review Article

    At preterm birth, the retina is incompletely vascularized. Retinopathy of prematurity (ROP) is initiated by the postnatal suppression of physiological retinal vascular development that would normally occur in utero. As the neural retina slowly matures, increasing metabolic demand including in the peripheral avascular retina, leads to signals for compensatory but pathological neovascularization. Currently, only late neovascular ROP is treated. ROP could be prevented by promoting normal vascular growth. Early perinatal metabolic dysregulation is a strong but understudied risk factor for ROP and other long-term sequelae of preterm birth. We will discuss the metabolic and oxygen needs of retina, current treatments, and potential interventions to promote normal vessel growth including control of postnatal hyperglycemia, dyslipidemia and hyperoxia-induced retinal metabolic alterations. Early supplementation of missing nutrients and growth factors and control of supplemental oxygen promotes physiological retinal development. We will discuss the current knowledge gap in retinal metabolism after preterm birth.