Changes in brain structure and function in a multisport cohort of retired female and male athletes, many years after suffering a concussion.

Abstract

Mild traumatic brain injury is widely regarded as a misnomer: it is globally a major cause of disability and is hypothesized as a potential causal factor in subsequent neurodegeneration. Commonly arising in sport, mounting evidence of varying degrees of cognitive impairment in retired athletes exposed to repeated concussions motivates close examination of its cumulative effects on the brain. Studying a cohort of 125 retired athletes with a mean of 11 reported concussions and 36 matched controls with none, here we evaluated whole-brain volumetric and subcortical morphological effects with Bayesian regression models and functional connectivity effects with network-based statistics. Estimates of potential cognitive impact were derived from meta-analytic functional mapping based on 13,459 imaging studies. Across the array of brain structural and functional effects identified, regions significantly lower in volume in the concussed group included, in order of greatest effect size, the middle frontal gyrus, hippocampus, supramarginal gyrus, temporal pole, and inferior frontal gyrus. Conversely, brain regions significantly larger within the athlete group included, in order of greatest effect size, the hippocampal and collateral sulcus, middle occipital gyrus, medial orbital gyrus, caudate nucleus, lateral orbital gyrus, and medial segment to the postcentral gyrus (all significant with 95% Bayesian credible interval). Subcortical morphology analysis corroborated these findings, revealing a significant, age-independent relationship between inward deformation of the hippocampus and the number of concussions sustained (corrected- p<0.0001). Functional connectivity analyses revealed a distinct brain network with significantly increased edge strength in the athlete cohort comprising 150 nodes and 400 edges (corrected-p=0.02), with the highest degree nodes including the pre-central and post-central gyri and right insula. The functional communities of the greatest eigenvector centralities corresponded to motor domains. Numerous edges of this network strengthened in athletes were significantly weakened with increasing bouts of concussion, which included disengagement of the frontal pole, superior frontal, and middle frontal gyri (p=0.04). Aligned to meta-analytic neuroimaging data, the observed changes suggest possible functional enhancement within the motor, sensory, coordination, balance, and visual processing domains in athletes, attenuated by concussive head injury with a negative impact on memory and language. That such changes are observed many years after retirement from impact sport suggests strong repetition effects and/or underpinning genetic selection factors. These findings suggest that engagement in sport may benefit the brain across numerous domains, but also highlights the potentially damaging effects of concussive head injury.

Competing Interest Statement

Michael Turner is employed as CEO and Medical Director of the International Concussion and Head Injury Research Foundation (ICHIRF) and was formerly employed as the Chief Medical Adviser to the British Horseracing Authority (BHA) and the Lawn Tennis Association (LTA). He is Honorary Medical Adviser to the Jockeys Insurance Scheme (PRIS) for which he receives a discretionary honorarium. ICHIRF is a not-for-profit organisation. He undertakes no clinical duties but has been reimbursed for travel and accommodation at conferences, symposia, and scientific meetings by the organisers. He does not hold any shares in any company related to concussion or brain injury assessment or technology. Antonio Belli is a founding member, consultant, and shareholder of Marker Diagnostics, a spinout company of the University of Birmingham. He is a Director of ICHIRF. James Ruffle provided statistical analysis with funding from the Racing Foundation, the Concussion Foundation and ICHIRF Rudolph J. Castellani, M.D., is subcontracted to the Lieber Institute for Brain Development and the Neurobiobank at the University of Maryland to assist with brain examinations. He has received research funding from the Chuck Knoll Foundation for Brain Injury Research. A small percentage of his practice involves forensic neuropathology and medico-legal testimony, some of which involve former contact sport athletes. Dr Castellani does not receive research funding or any form of financial support from any sport organization or players association. Paul McCrory is a co-investigator on grants relating to mild TBI funded by several governmental and other organizations. He is funded under a Fellowship awarded by the National Health & Medical Research Council of Australia. He has a clinical consulting practice in neurology, including medico-legal work. He has been reimbursed by the government, scientific bodies, and commercial organizations for discussing or presenting research relating to mild traumatic brain injury and sport-related concussion at meetings, scientific conferences, and symposiums. He does not hold any individual shares in or receive monies from any company related to concussion or brain injury assessment or technology. He acknowledges unrestricted philanthropic support from CogState Inc. (2001-16). He is the Specialist Consultant to the Scientific Committees of the International Concussion and Head Injury Research Foundation in London and the Sports Surgery Clinic in Dublin. Dr. McCrory did not receive any form of financial support directly related to this manuscript.

Funding Statement

The ICHIRF project is currently funded by a combination of grant funding (EU Erasmus - Galway-Mayo Institute of Technology SCAT Project); commercial funding (Marker AG); and philanthropically funding (Godolphin Racing, the Injured Jockeys Fund (UK), the Irish Injured Jockeys Fund, British Association of Sports and Exercise Medicine, the National Football League (US), the Footballers Association, the Racing Foundation, and private donors) as well as charitable donations. Reimbursement for travel expenses is available to participants however they are not paid for their involvement in the study.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Staged ethical approval was obtained from St Mary's University, Twickenham, Waldgrave Road, London TW1 4SX, UK initially on 1st June 2015 (no reference number was provided by the University Ethics Committee). Study approved. 27th October 2015, as above, Reference SMEC.2015.16.53. Approved 12th June 2017, as above, Reference SMEC.2016.17.115. Approved 26th January 2018, as above, Reference SMEC.2017.18.051. Approved In preparation for BREXIT, and before screening in Ireland, the whole study was re-submitted for ethical approval to the Beacon Hospital Research Ethics Committee (BHREC), The Beacon Hospital, Sandyford, Dublin D18 AK68, Ireland, and approved on 10th October 2019. Reference BEA0130. An International, multicentre study into the long-term effects of concussion. The International Concussion and Head Injury Research Foundation (ICHIRF) Study. Fully Approved. All participants provided informed consent in writing. The trial is registered as ISRCTN 11312093.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

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I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

Yes

Data Availability

All data will be made available to suitably qualified researchers once the study as been completed.

AbbreviationsfMRIfunctional Magnetic Resonance ImagingNBSNetwork-Based StatisticsTBITraumatic Brain Injury

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