Autumn 2021

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Volume 31 – Autumn 2021

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Michael A. McCrea, PhD, ABPP

Medical College of Wisconsin, Milwaukee, WI

Kevin M. Koch, PhD

Medical College of Wisconsin, Milwaukee, WI

SPOTLIGHT

Neuroimaging of acute sport-related concussion: advancing science and clinical practice

by Michael A. McCrea, PhD, ABPP, Professor and Vice Chair of Research in the Department of Neurosurgery, the Shekar N. Kurpad, MD, PhD Chair in Neurosurgery and Co-Director, Center for Neurotrauma Research (CNTR), and Kevin M. Koch, PhD, Professor of Radiology & Biomedical Engineering; Director, Center for Imaging Research (CIR), Division of Imaging Sciences, Medical College of Wisconsin, Milwaukee, WI

Sport-related concussion (SRC) is among the most common injuries in contact and collision sports, affecting millions of athletes internationally per year. Based on its overall incidence, acute effects and concerns about potential long-term effects on neurologic health, SRC is now recognized as a major public health problem and has the focus and attention of sports medicine professionals, the scientific community, sportgoverning bodies and athletes themselves^1,2. Clinically, due to the highly heterogenous nature of brain injury, SRC is often considered among the most complex injuries to assess and manage in a sports-medicine setting.

Over the past two decades, applied research has drastically improved our understanding of the pathophysiology and natural history of SRC. These scientific advances have had a direct translational impact on international consensus guidelines and contemporary approaches to the diagnosis, assessment and management of SRC at all competitive levels around the world. Advanced neuroimaging has played a central role in advancing the science of SRC and informing modern-day approaches to concussion assessment, management and return-to-play decisions.

Preclinical and human studies have demonstrated that mild traumatic brain injury (mTBI), including SRC, produces a complex sequence of pathophysiological changes in the brain, commonly referred to as the "neurometabolic cascade." The effects of this cascade on brain structure and function manifest as commonly identified clinical signs, symptoms and impairments of injury^3,4.

At the Medical College of Wisconsin, much of our research on mTBI has been conducted on our Discovery™ MR750 3.0T system. Funding has been provided by GE Healthcare, the National Collegiate Athletic Association (NCAA) and the US Department of Defense. We have since migrated protocols and current research activities to the SIGNA™ Premier, GE’s most advanced 3.0T MR system.

Michael A. McCrea, PhD, ABPP

Medical College of Wisconsin, Milwaukee, WI

Kevin M. Koch, PhD

Medical College of Wisconsin, Milwaukee, WI

Understanding neurobiological recovery after SRC

Objectively determining when an athlete achieves physiological recovery after SRC remains an important priority, both scientifically and clinically. Advanced quantitative neuroimaging capable of evaluating functional and/or microstructural disturbances is a central component of this ongoing work^5,6. Through the employment of advanced neuroimaging, several studies over the past decade have informed our understanding of the time course and trajectory of neurobiological recovery after concussion.

MR imaging has been widely used to study the acute effects of SRC on brain structure and function, as well as neurobiological recovery and return to play after SRC⁵. A growing number of studies employing advanced quantitative MR imaging (qMRI) have demonstrated acute alterations in measures of white matter microstructural integrity, cerebral blood flow and brain functional connectivity after SRC that are not visualized using conventional CT or routine MR. Specifically, following acute SRC, advanced qMRI studies of injured athletes have identified changes in cerebral blood flow^7-9, white matter microstructure^10-12 and functional brain connectivity^13-15.

During the earliest acute post-injury window, recent studies using qMRI have revealed subtle evidence of microstructural changes, primarily in deeper tissue regions. These recent observations have leveraged advanced qMRI methods such as diffusion tensor imaging (DTI), diffusion kurtosis imaging (DKI), and quantitative susceptibility mapping (QSM)‡.

Studies using DTI and DKI metrics to characterize white matter changes after acute SRC have shown that concussed athletes exhibit a widespread decrease in mean diffusivity (MD), increased axial kurtosis and, to a lesser extent, decreased axial and radial diffusivities compared to non-concussed control athletes (Figure 1)¹⁶. Further, even more widespread differences in diffusion metrics have been detected in the concussed athletes one week or longer post injury, despite improvement of symptoms and cognitive performance. These MR findings suggest that the athletes might not have reached full physiological recovery a week after the injury, which has important implications for the management of SRC because allowing an athlete to return to play before the brain has fully recovered from injury may have negative consequences.

A — 24 HOURS

B — 8 DAYS

Figure 1. Athletes with acute SRC show increased mean diffusivity (red-yellow voxels) relative to non-concussed controls at (A) 24 hours and (B) eight days post injury¹⁶.

QSM has also shown promise as a biomarker for SRC^17-19. As a quantitative extension of routinely applied susceptibility-weighted (SWI) sequences, QSM can utilize raw MR signal information extracted from the SWI MR acquisitions to estimate an isotropic magnetic susceptibility tensor for each tissue voxel. Physiological changes to biological tissues impart subtle changes in magnetism that can often be detected with QSM measurements.

SWI is well established as a useful diagnostic tool and is a key component of many routine neurological MR protocols. Within existing TBI MR examination protocols, SWI and Fluid-Attenuated Inversion Recovery (FLAIR) are arguably the most utilized and relevant image contrasts. Unlike other advanced MR metrics, which require additional (sometimes time-consuming) data acquisition windows, QSM can be derived from data acquired within existing SWI sequences in TBI MR protocols.

Along with conventional SWI, QSM has been used to identify regions of focal tissue damage in complicated mTBI on a cohort of military personnel¹⁷. In addition, a preliminary group of studies of mTBI¹⁸ and SRC¹⁹ have shown group magnetism changes in gray and white matter regions. Specifically, in concussed subjects reductions in susceptibility have been identified within the deep gray matter while increases of susceptibility have been identified in the deep white matter tracts.

Most recently, our group published analyses of acute postinjury (within 48 hours) QSM data collected on a cohort of 75 concussed football athletes and 75 matched controls²⁰. This study reproduced the group effects observed within our previous smaller cohort study¹⁹. Additionally, we performed initial individualized analyses of acute QSM markers as a function of injury symptom presentation. This analysis found that acute QSM values within deep gray and deep white matter tissue compartments statistically correlated with self-reported symptom durations in concussed athletes. Within this study, we also performed prognostic modeling using the acute QSM metrics to predict more severe injuries. In this analysis, combined QSM metrics yielded an area-under the-curve (AUC) model validation performance of 0.77 in receiver-operatorcharacteristic (ROC) analysis when predicting post-injury symptom durations greater than two weeks. Figure 2 provides maps demonstrating bulk tissue compartment offsets within an individual subject from this study cohort. The displayed subject had a long duration of self-reported symptoms (34 days) and showed proportionally shifted QSM levels in the white and deep gray matter analysis compartments.

Figure 2. QSM maps reflecting differences of a severely concussed athlete with self-reported symptom durations of 34 days relative to the control group mean QSM map. Clear positive shifts in the white matter (increase/red) and deep gray matter (decrease/blue) compartments are visualized. Tissue compartments were derived from stability analysis using an independent control group with a coefficient of variation threshold of 0.6 used to define regions of QSM stability¹⁹.

Alteration in blood flow is among the common pathophysiological mechanisms of TBI. Our studies have deployed arterial spin labeling (ASL) MR to evaluate cerebral blood flow (CBF) changes in acute SRC. A study by Wang et al.⁸ compared CBF maps in American football players with acute concussion to non-concussed football players at 24 hours and eight days after SRC. While the control group did not show any changes in CBF between the two time points, concussed athletes demonstrated a significant decrease in CBF at eight days relative to 24 hours (Figure 3). These data support the hypothesis that physiological changes persist beyond the point of clinical recovery after SRC. Our results also indicate that advanced ASL methods might be useful for detecting and tracking the longitudinal course of underlying neurophysiological recovery from concussion.

Figure 3. Longitudinal analysis on ASL data found a significant group by time interaction. Both between- and within-group comparisons showed that SRC had low regional CBF within 24 hours (24h) after the concussion that further decreased at eight days (8d) post-injury and gradually recovered to the control group level at six months (6m) after injury⁸. (Note: p value: * < 0.05, ** <0.01; *** <0.001.)

SRC has also been associated with changes in functional brain connectivity during the acute and subacute phase. A recent study by Kaushal and colleagues¹³ utilized resting state functional MR imaging (rs-fMRI) to evaluate changes in rs-functional connectivity (rs-FC) of the whole-brain network at several time points after SRC, while also exploring the relationship between rs-FC and clinical outcome. Concussed athletes had a global increase in connectivity at eight days postconcussion relative to controls, with no differences at the 48-hour, 15-day or 45-day visits. Further, the group effect at the eight-day visit was driven by the large minority of concussed athletes still symptomatic at eight days post injury, while symptomatic concussed athletes did not differ from controls in rs-FC (Figure 4). Collectively, these findings point toward a lag in whole-brain rs-FC alterations following SRC, which correlates with self-reported clinical symptoms over the course of post-injury recovery.

Figure 4. Network-based statistic results: (top) whole group analysis, (bottom) sub-group analysis. Shown are the nodes (i.e., regions of interest) and edges (connections) of networks in which concussed athletes had significantly greater connectivity than controls at the eight-day visit. Edges are colored based on t-stat values. Nodes and edges are projected onto the MNI standard template brain using BrainNet Viewer. Nodes are displayed via a sphere at the center of mass for each ROI. L = left; R = right. Reprinted with permission, Resting-state functional connectivity after concussion is associated with clinical recovery, Michael A. McCrea, Human Brain Mapping, Volume 40, Copyright 2018, Timothy B. Meier as specified in Human Brain Mapping, Wiley.

Studies have also demonstrated the potential prognostic utility^13-15 of qMRI in predicting time to recovery and return to play after SRC. As previously discussed within our QSM analysis, alterations on qMRI can correlate with clinical measures of injury severity (i.e., symptom endorsement or deficits on objective measures of function). In addition, resolution of acute qMRI alterations trends towards a course of improvement that generally parallels other clinical recovery metrics (i.e., duration of symptom endorsement and return to activity).

While the clinical effects of SRC (e.g., symptoms and functional impairments) typically resolve within several days, evidence increasingly suggests persistent neurophysiological abnormalities beyond the point of clinical recovery. Although the trajectory of alterations on qMRI trend towards an equilibrium recovered state over time, multiple studies have reported persistent changes in some qMRI metrics that extend beyond clinical recovery and return-to-play milestones. Collectively, these findings fuel the theory that the "tail" of neurobiological recovery may extend beyond the time point of clinical recovery (e.g., symptom resolution, return-to-normal function). This theory has potential implications for clinical management if we are to base return-to-activity decisions on both the athlete’s observed clinical recovery and what the science tells us about how long it typically takes for the brain to recover after SRC.

In summary, these recent developments and cohort analyses have demonstrated that qMRI is critical to advancing our fundamental understanding of TBI and concussion. Observations made using qMRI have provided vital answers to critical questions related to SRC, including acute post-injury microstructural effects, recovery trajectories and return-to-play status. This work collectively benefits clinicians around the world who are ultimately tasked with the care of athletes affected by SRC at all levels of competitive sport.