RHI Interval Effects on Brain Health

Official title

Defining the Role of Repetitive Head Impact Time Intervals in Mitigating Subconcussive Neural Injury

Overview

Military service members frequently experience repetitive insults or impacts to the head (RHIs). The purpose of the proposed randomized controlled trial is to understand how time intervals affect neurological responses to repetitive subconcussive head impacts.

Detailed description

This study will address whether, and to what extent, the interval of time between repetitive head impact (RHI) clusters (short, 24 hours; long, 72 hours) influences neuronal cellular, physiological, and functional integrity. We will leverage a human laboratory model of RHI to standardize and isolate the effects of RHI in the context of direction, magnitude, and frequency of head impact.

There are three aims that navigate this study:

Aim 1: To determine the effect of the interval of time between RHI clusters on neural cellular and molecular integrities through expression profiles of biofluid proteomic and transcriptomic biomarkers.

Hypotheses: Significant elevations in proteomic biomarkers will be observed acutely after experiencing RHI, and there will be cumulative increase in these biomarkers after 4 weeks of consistent exposure to RHI. The shorter interval of RHI clusters will yield greater degrees of biomarker changes as compared to the longer interval.

Aim 2: To examine the effect of the interval of time between RHI clusters on retinal and ocular-motor health, as assessed by retinal changes on optical coherence tomography (OCT), convergence, and pupillometry.

Hypotheses: A shorter interval of RHI clusters will result in altered retinal coherence and declines in convergence and choice reaction time compared to a longer interval. After 4 weeks of recurring exposure to RHI, declines in retinal and ocular-motor health will persist for 2-week post RHI exposure in the shorter-interval group, but the longer-interval group will normalize by the 2-week post-RHI follow-up.

Aim 3: To determine the influence of the interval of time between RHI clusters in neuronal network as assessed by quantitative EEG and choice reaction time.

Hypotheses: A shorter interval of RHI clusters will induce greater changes in EEG output acutely and chronically after RHI exposure, compared to the longer interval. Changes in EEG signals will persist for 2-week post RHI exposure in the shorter interval, but the changes will be normalized in the longer-interval group.

Interventions

• Other Short Interval
  A standardized and reliable soccer heading protocol will be used for the experiment. Participants perform 16 headers or kicking with 1 header per 30 seconds. The sessions (twice per week for 4 weeks) will be separated by 24 hours.
• Other Long Interval
  A standardized and reliable soccer heading protocol will be used for the experiment. Participants perform 16 headers or kicking with 1 header per 30 seconds. The sessions (twice per week for 4 weeks) will be separated by 72 hours.
• Device BrainScope qEEG
  An Investigational version of the BrainScope FDA-cleared qEEG acquisition device will be used in this study. The investigational nature of the device is simply based on the code which does not produce a diagnostic result for the blinded researcher. Electrodes will be placed around the participant's forehead and scalp to acquire electrical readings of brain activity.

Primary outcome measures

• Blood Biomarkers - NfL [Time frame: Baseline, 24 hours following the final heading session, 14 days following the final heading session]
• Blood Biomarkers - GFAP [Time frame: Baseline, 24 hours following the final heading session, 14 days following the final heading session]
• Blood Biomarkers - pTau [Time frame: Baseline, 24 hours following the final heading session, 14 days following the final heading session]
• Optical Coherence Tomography/Angiography (OCT/A) 1 [Time frame: Baseline, 24 hours following the final heading session, 14 days following the final heading session]
• Optical Coherence Tomography/Angiography (OCT/A) 2 [Time frame: Baseline, 24 hours following the final heading session, 14 days following the final heading session]
• Optical Coherence Tomography/Angiography (OCT/A) 3 [Time frame: Baseline, 24 hours following the final heading session, 14 days following the final heading session]
• Quantitative Electroencephalography (qEEG) [Time frame: Baseline, 24 hours following the final heading session, 14 days following the final heading session]

Secondary outcome measures (9)

• Near Point of Convergence (NPC) [Time frame: Baseline, 24 hours following the final heading session, 14 days following the final heading session]
• Pupillary Size Measurement and Reactivity 1 [Time frame: Baseline, 24 hours following the final heading session, 14 days following the final heading session]
• Pupillary Size Measurement and Reactivity 2 [Time frame: Baseline, 24 hours following the final heading session, 14 days following the final heading session]
• Pupillary Size Measurement and Reactivity 3 [Time frame: Baseline, 24 hours following the final heading session, 14 days following the final heading session]
• Pupillary Size Measurement and Reactivity 4 [Time frame: Baseline, 24 hours following the final heading session, 14 days following the final heading session]
• Pupillary Size Measurement and Reactivity 5 [Time frame: Baseline, 24 hours following the final heading session, 14 days following the final heading session]
• Pupillary Size Measurement and Reactivity 6 [Time frame: Baseline, 24 hours following the final heading session, 14 days following the final heading session]
• Pupillary Size Measurement and Reactivity7 [Time frame: Baseline, 24 hours following the final heading session, 14 days following the final heading session]
• Choice Reaction Time (CRT) [Time frame: Baseline, 24 hours following the final heading session, 14 days following the final heading session]

Eligibility criteria

Inclusion criteria

• Current soccer player (intercollegiate, club, intramural, recreational).
• At least 5 years of soccer heading experience (justification below).
• Ability to provide informed consent without a legally authorized representative (LAR).

Exclusion criteria

• Any head, neck, or face injury within the 6 months prior to enrollment, including concussions, that precludes participation in contact sports.
• Participants with eye conditions or diseases that could impact the blood vessels in the eye -such as but not limited to: glaucoma, macular degeneration, diabetic retinopathy.
• Determination that the participant is unsuitable for study entry or potentially unable to complete all aspects of the study based on the judgement of the Investigator.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Prevention

Study locations

United States · 1 center

• Indiana University School of Public Health — Bloomington

Publications

• Marchi N, Bazarian JJ, Puvenna V, Janigro M, Ghosh C, Zhong J, Zhu T, Blackman E, Stewart D, Ellis J, Butler R, Janigro D. Consequences of repeated blood-brain barrier disruption in football players. PLoS One. 2013;8(3):e56805. doi: 10.1371/journal.pone.0056805. Epub 2013 Mar 6. PMID 23483891
• Kawata K, Rubin LH, Takahagi M, Lee JH, Sim T, Szwanki V, Bellamy A, Tierney R, Langford D. Subconcussive Impact-Dependent Increase in Plasma S100beta Levels in Collegiate Football Players. J Neurotrauma. 2017 Jul 15;34(14):2254-2260. doi: 10.1089/neu.2016.4786. Epub 2017 Apr 27. PMID 28181857
• Puvenna V, Brennan C, Shaw G, Yang C, Marchi N, Bazarian JJ, Merchant-Borna K, Janigro D. Significance of ubiquitin carboxy-terminal hydrolase L1 elevations in athletes after sub-concussive head hits. PLoS One. 2014 May 7;9(5):e96296. doi: 10.1371/journal.pone.0096296. eCollection 2014. PMID 24806476
• Oliver JM, Jones MT, Kirk KM, Gable DA, Repshas JT, Johnson TA, Andreasson U, Norgren N, Blennow K, Zetterberg H. Serum Neurofilament Light in American Football Athletes over the Course of a Season. J Neurotrauma. 2016 Oct 1;33(19):1784-1789. doi: 10.1089/neu.2015.4295. Epub 2016 Mar 16. PMID 26700106
• Oliver JM, Anzalone AJ, Stone JD, Turner SM, Blueitt D, Garrison JC, Askow AT, Luedke JA, Jagim AR. Fluctuations in blood biomarkers of head trauma in NCAA football athletes over the course of a season. J Neurosurg. 2018 May 29;130(5):1655-1662. doi: 10.3171/2017.12.JNS172035. Print 2019 May 1. PMID 29807487
• Shahim P, Zetterberg H, Tegner Y, Blennow K. Serum neurofilament light as a biomarker for mild traumatic brain injury in contact sports. Neurology. 2017 May 9;88(19):1788-1794. doi: 10.1212/WNL.0000000000003912. Epub 2017 Apr 12. PMID 28404801
• Joseph JR, Swallow JS, Willsey K, Lapointe AP, Khalatbari S, Korley FK, Oppenlander ME, Park P, Szerlip NJ, Broglio SP. Elevated markers of brain injury as a result of clinically asymptomatic high-acceleration head impacts in high-school football athletes. J Neurosurg. 2018 Jul 3;130(5):1642-1648. doi: 10.3171/2017.12.JNS172386. Print 2019 May 1. PMID 29966462
• Tierney GJ, Higgins B. The incidence and mechanism of heading in European professional football players over three seasons. Scand J Med Sci Sports. 2021 Apr;31(4):875-883. doi: 10.1111/sms.13900. Epub 2021 Jan 18. PMID 33280186

Identifiers

NCT: NCT07010887 · 24461

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗