Alexander D Wright

Myelin Water Fraction Is Transiently Reduced after a Single Mild Traumatic Brain Injury – A Prospective Cohort Study in Collegiate Hockey Players

Impact-related mild traumatic brain injuries (mTBI) are a major public health concern, and remain as one of the most poorly understood injuries in the field of neuroscience. Currently, the diagnosis and management of such injuries are based largely on patient-reported symptoms. An improved understanding of the underlying pathophysiology of mTBI is urgently needed in order to develop better diagnostic and management protocols. Specifically, dynamic post-injury changes to the myelin sheath in the human brain have not been examined, despite ‘compromised white matter integrity’ often being described as a consequence of mTBI. In this preliminary cohort study, myelin water imaging was used to prospectively evaluate changes in myelin water fraction, derived from the T2 decay signal, in two varsity hockey teams (45 players) over one season of athletic competition. 11 players sustained a concussion during competition, and were scanned at 72 hours, 2 weeks, and 2 months post-injury. Results demonstrated a reduction in myelin water fraction at 2 weeks post-injury in several brain areas relative to preseason scans, including the splenium of the corpus callosum, right posterior thalamic radiation, left superior corona radiata, left superior longitudinal fasciculus, and left posterior limb of the internal capsule. Myelin water fraction recovered to pre-season values by 2 months post-injury. These results may indicate transient myelin disruption following a single mTBI, with subsequent remyelination of affected neurons. Myelin disruption was not apparent in the athletes who did not experience a concussion, despite exposure to repetitive subconcussive trauma over a season of collegiate hockey. These findings may help to explain many of the metabolic and neurological deficits observed clinically following mTBI.

Where's Waldo? The utility of a complicated visual search paradigm for transcranial Doppler-based assessments of neurovascular coupling.

BACKGROUND The concept of neurovascular coupling has been postulated since the late 1800s and has been demonstrated most commonly in humans using visual stimuli (e.g. reading, checkerboards). These traditional paradigms evoke only a moderate cerebral blood flow response due to the relative simplicity of the visual stimuli. NEW METHOD Forty subjects completed three visual paradigms each challenging the visual processing areas to a different extent: reading text, complicated visual searching (new method: Wheres Waldo) and viewing coloured dots. Posterior and middle cerebral artery (PCA, MCA) velocities were recorded using transcranial Doppler ultrasound during each visual paradigm. RESULTS Prior to the presentation of the visual stimuli there were no differences in mean arterial pressure, or PCA or MCA velocities for the three paradigms. All three paradigms led to an elevation in PCA and MCA velocities after a delay (∼1.1s). Whereas velocity elevation was consistent across the three paradigms in the MCA, it was markedly larger during the Wheres Waldo task in the PCA. Thus, although the onset of the neurovascular coupling response was similar across the three visual paradigms, its overall magnitude was stimulus-dependent. COMPARISON WITH EXISTING METHODS Given that PCA velocity can be affected by blood pressure or carbon dioxide alterations, traditional neurovascular coupling paradigms (e.g. reading, checkerboards) appear to have a lower signal-to-noise ratio than that observed in complicated visual search tasks such as Wheres Waldo. CONCLUSIONS We recommend complicated visual search paradigms such as Wheres Waldo be considered for future transcranial Doppler-based neurovascular coupling studies.

Differential Systolic and Diastolic Regulation of the Cerebral Pressure-Flow Relationship During Squat-Stand Manoeuvres

OBJECTIVE Cerebral pressure-flow dynamics are typically reported between mean arterial pressure and mean cerebral blood velocity. However, by reporting only mean responses, potential differential regulatory properties associated with systole and diastole may have been overlooked. MATERIALS AND METHODS Twenty young adults (16 male, age: 26.7 ± 6.6 years, BMI: 24.9 ± 3.0 kg/m2) were recruited for this study. Middle cerebral artery velocity was indexed via transcranial Doppler. Cerebral pressure-flow dynamics were assessed using transfer function analysis at both 0.05 and 0.10 Hz using squat-stand manoeuvres. This method provides robust and reliable measures for coherence (correlation index), phase (timing buffer) and gain (amplitude buffer) metrics. RESULTS There were main effects for both cardiac cycle and frequency for phase and gain metrics (p < 0.001). The systolic phase (mean ± SD) was elevated at 0.05 (1.07 ± 0.51 radians) and 0.10 Hz (0.70 ± 0.46 radians) compared to the diastolic phase (0.05 Hz: 0.59 ± 0.14 radians; 0.10 Hz: 0.33 ± 0.11 radians). Conversely, the systolic normalized gain was reduced (0.05 Hz: 0.49 ± 0.12%/%; 0.10 Hz: 0.66 ± 0.20%/%) compared to the diastolic normalized gain (0.05 Hz: 1.46 ± 0.43%/%; 0.10 Hz: 1.97 ± 0.48%/%). CONCLUSIONS These findings indicate there are differential systolic and diastolic aspects of the cerebral pressure-flow relationship. The oscillations associated with systole are extensively buffered within the cerebrovasculature, whereas diastolic oscillations are relatively unaltered. This indicates that the brain is adapted to protect itself against large increases in systolic blood pressure, likely as a mechanism to prevent cerebral haemorrhages.

Sport-Related Concussion Alters Indices of Dynamic Cerebral Autoregulation

Sport-related concussion is known to affect a variety of brain functions. However, the impact of this brain injury on cerebral autoregulation (CA) is poorly understood. Thus, the goal of the current study was to determine the acute and cumulative effects of sport-related concussion on indices of dynamic CA. Toward this end, 179 elite, junior-level (age 19.6 ± 1.5 years) contact sport (ice hockey, American football) athletes were recruited for preseason testing, 42 with zero prior concussions and 31 with three or more previous concussions. Eighteen athletes sustained a concussion during that competitive season and completed follow-up testing at 72 h, 2 weeks, and 1 month post injury. Beat-by-beat arterial blood pressure (BP) and middle cerebral artery blood velocity (MCAv) were recorded using finger photoplethysmography and transcranial Doppler ultrasound, respectively. Five minutes of repetitive squat–stand maneuvers induced BP oscillations at 0.05 and 0.10 Hz (20- and 10-s cycles, respectively). The BP–MCAv relationship was quantified using transfer function analysis to estimate Coherence (correlation), Gain (amplitude ratio), and Phase (timing offset). At a group level, repeated-measures ANOVA indicated that 0.10 Hz Phase was significantly reduced following an acute concussion, compared to preseason, by 23% (−0.136 ± 0.033 rads) at 72 h and by 18% (−0.105 ± 0.029 rads) at 2 weeks post injury, indicating impaired autoregulatory functioning; recovery to preseason values occurred by 1 month. Athletes were cleared to return to competition after a median of 14 days (range 7–35), implying that physiologic dysfunction persisted beyond clinical recovery in many cases. When comparing dynamic pressure buffering between athletes with zero prior concussions and those with three or more, no differences were observed. Sustaining an acute sport-related concussion induces transient impairments in the capabilities of the cerebrovascular pressure-buffering system that may persist beyond 2 weeks and may be due to a period of autonomic dysregulation. Athletes with a history of three or more concussions did not exhibit impairments relative to those with zero prior concussions, suggesting recovery of function over time. Findings from this study support the potential need to consider physiological recovery in deciding when patients should return to play following a concussion.

Acute sport-related concussion induces transient impairment in dynamic cerebral auto regulation that is related to scat3 performance

Objective Examine how the frequency-dependent relationship between blood pressure (BP) and cerebral blood velocity (CBV) is affected by acute sport-related concussion. Design Prospective Cohort. Setting Laboratory. Participants: 136 male contact-sport athletes (19.1±1.4 years) recruited, subset of 14 sustained concussions (19±1.4 years). Intervention Participants completed baseline (T0) and post-injury testing at 72-hours (T1), 2-weeks (T2), and 1-month (T3). BP was monitored via finger photoplethysmography, and transcranial Doppler ultrasound indexed CBV in the middle cerebral artery. Squat-stand manoeuvers were performed at 0.05 and 0.10Hz to enhance BP variation. RM-ANOVA independent variables included time (4) and frequency (2). Outcome measures Transfer function analysis point estimates quantified coherence (correlation), phase (synchronisation) and gain (amplitude buffer) metrics between BP and CBV waveforms. Results Significant frequency-time interactions for phase (p=0.007) and gain (p=0.049). Simple effects analysis revealed time effects for phase at 0.10 Hz, indicating reductions at T1 (95% CI: 0.033 – 0.24 rads, p=0.008) and T2 (95% CI: 0.014–0.196 rads, p=0.02) compared to T0. On average, return-to-play occurred at T2 (median 14 days). Phase reductions at T1 were correlated with Standardised Assessment of Concussion performance (r=0.659, p=0.02). Conclusions These results reveal transient post-concussion impairments in the capacity of the cerebrovasculature to buffer BP oscillations, which exceeded clinical recovery duration. Phase reductions at 0.10Hz suggest the presence of a cerebrovascular autonomic dysregulation, which could leave the brain less protected to BP surges. This key finding may help explain why the brain is more vulnerable to additional trauma during the post-injury recovery period. Competing interests None.

Systolic and Diastolic Regulation of the Cerebral Pressure-Flow Relationship Differentially Affected by Acute Sport-Related Concussion

OBJECTIVE To determine whether acute sports-related concussion (SRC) exerts differential effects on cerebral autoregulatory properties during systole versus diastole. MATERIALS AND METHODS One hundred and thirty-six contact-sport athletes tested preseason; 14 sustained a concussion and completed follow-up testing at 72 hours, 2 weeks, and 1 month post-injury. Five minutes of repetitive squat-stand maneuvers induced blood pressure (BP) oscillations at both 0.05 and 0.10 Hz. Beat-by-beat peak-systolic and end-diastolic BP (sysBP/ diasBP) and middle cerebral artery blood velocity (sysMCAv/diasMCAv) were recorded using finger photoplethysmography and transcranial Doppler ultrasound, respectively. Relationships between sysBP-sysMCAv and diasBP-diasMCAv were quantified using transfer function analysis to estimate coherence (correlation), gain (response magnitude), and phase (response latency). RESULTS Significant main effects of the cardiac cycle were observed across all outcome metrics. A significant main effect of SRC was observed for 0.10 Hz phase: systolic and diastolic phases were reduced at 72 h (21.8 ± 5.2%) and 2 weeks (22.7 ± 7.1%) compared to preseason but recovered by 1 month. Concussion significantly impaired diastolic, but not systolic, gain: 0.10 Hz diastolic gain was increased (27.2 ± 7.7%) at 2 weeks, recovering by 1 month. CONCLUSIONS Impairments in autoregulatory capacity, observed for a transient period following SRC that persist beyond symptom resolution and clinical recovery, appear to be differentially affected across the cardiac cycle. Similar patterns of impairment were observed for systolic and diastolic phases (response latency); however, normalized gain (response magnitude) impairments were identified only in diastole. These findings may explain the increased cerebral vulnerability as well as exercise-induced symptom exacerbation observed post-SRC.

Anticipatory postural adjustments as a function of response complexity in simple reaction time tasks

The central nervous system preplans postural responses to successfully perform complex multi-joint movements. These responses have been termed anticipatory postural adjustments (APAs), and they constitute a general type of response to stabilize posture prior to movement initiation. APA sequences are elicited with shorter latency when a startling acoustic stimulus is applied, demonstrating their preplanned nature. Increasing task complexity using a simple reaction time (RT) paradigm has been shown to delay limb movement RT as a result of additional planning or sequencing requirements; however, the effect of task complexity on APA dynamics is unclear. The purpose of the present study was to investigate if task complexity modulates APA onset in a manner analogous to that observed in the primary effector. 13 participants completed 150 trials of simple (1-target) and complex (2- or 3-target) arm movements while standing on a force plate. Results indicated participants had significantly faster arm movement RTs in the simple versus the most complex condition. Similar to the primary effector, APA RTs were longer in the most complex (3-target) movement compared to both the 1-target and 2-target movements. Furthermore, APA excursion velocities were scaled to the complexity of the upcoming movement: the rate of APAs increased from simplest to most complex movements. These findings clearly demonstrate APAs are sensitive to task complexity, further elucidating their preplanned role in stabilizing posture which enables the successful completion of intended movements.

A History of Concussion Does Not Lead to an Increase in Ocular Near Point of Convergence

Ocular near point of convergence (NPC) has been shown to be sensitive to the effects of concussion and subconcussive impacts. To determine if NPC is also sensitive to a previous history of concussion, male contact-sport athletes either with (n=26) or without (n=16) a history of at least one previous concussion had their NPC assessed. The results showed that participants with a history of concussion displayed NPC values (9.4±1.6 cm) indistinguishable from those with no history of concussion (8.4±2.1 cm, t-test, p=0.09). This was the case regardless of whether 1, 2, or 3 or more concussions had occurred and despite the fact participants with concussion (mean time since last concussion: 1136 days) suffered from an increased number and severity of symptoms as assessed with the SCAT 3 (3.6±2.2 vs. 2.13±1.89 symptoms, 6.1±4.1 vs. 3.19±2.99 severity, t-test, p<0.05). Taken together, these results imply that NPC may not be a suitable tool to assess the potential long-term effects of one or more concussions over a longer time frame.: Future research using larger sample sizes is warranted to evaluate the potential dose-response relationship between number of prior concussions and NPC.

Sub-concussive trauma, acute concussion, and history of multiple concussions: Effects on quiet stance postural control stability

Although balance control has been studied extensively following acute concussion, little is known regarding repetitive sub-concussive head impacts or chronic exposure to multiple concussive events. Quiet stance postural control was characterized in contact sport athletes at pre-season (n = 135) and post-season (n = 48) to evaluate the effects of subconcussive trauma to the head. To determine the impact of acute concussion on postural control, athletes diagnosed with a concussion during the season (n = 12) were tested at 72-h, 2-weeks, and 1-month post-injury. Because only 4 of the concussed athletes completed baseline testing, control athletes (n = 12) matched for sport, age, body mass index (BMI), and previous concussion history served as a comparison group. Finally, the effects of previous concussion history on quiet stance postural control were determined by comparing pre-season data in contact sport athletes with either zero (Hx0, n = 50) or three or more (Hx3+, n = 25) previous concussions. A force plate was used to compare changes in centre-of-pressure root-mean-square displacement (RMSdisp) and mean-velocity (COPvel) in the anterior/posterior (AP) and medial/lateral (ML) directions. One-minute trials were performed with feet hip-width apart, hands-on-hips, and A) eyes-open and B) eyes-closed. Biomechanical head-impact exposure (impacts over 10 g) was indexed over the season using mastoid-fixed impact sensors. In acutely injured athletes, repeated-measures ANOVA revealed a significant effect of time for RMSdisp AP with increased displacement at 2 weeks compared to 72 h (p = 0.008, 95% CI: -0.180, -0.310 cm). No other COP variables were affected by acute concussion. Moreover, there was no effect of concussion history or repeated sub-concussive impacts on any quiet stance metric. Additionally, head-impact exposure metrics were not correlated with COP metrics. Taken together, the data suggests alterations in COP sway during quiet stance persist in the acute 2-week period after injury. These findings were not present with either a history of multiple concussions or exposure to sub-concussive head impacts indicating acute concussion does not have appear to have long term effects for these measures.

Cerebral Autoregulation Is Disrupted Following a Season of Contact Sports Participation

Repetitive subconcussive head impacts across a season of contact sports participation are associated with a number of deficits in brain function. To date, no research has investigated the effect of such head impact exposure on dynamic cerebral autoregulation (dCA). To address this issue, 179 elite, junior-level (age 19.6 ± 1.5 years) contact sport (ice hockey, American football) athletes were recruited for pre-season testing. Fifty-two non-concussed athletes returned for post-season testing. Fifteen non-contact sport athletes (age 20.4 ± 2.2) also completed pre- and postseason testing. dCA was assessed via recordings of beat-by-beat mean arterial pressure (MAP) and middle cerebral artery blood velocity (MCAv) using finger photoplethysmography and transcranial Doppler ultrasound, respectively, during repetitive squat-stand maneuvers at 0.05 and 0.10 Hz. Transfer function analysis was used to determine Coherence (correlation), Gain (response amplitude), and Phase (response latency) of the MAP-MCAv relationship. Results showed that in contact sport athletes, Phase was reduced (p = 0.027) and Gain increased (p < 0.001) at post-season compared to pre-season during the 0.10 Hz squat-stand maneuvers, indicating cerebral autoregulatory impairment in both the latency and magnitude of the response. Changes in Phase were greater in athletes experiencing higher numbers and severity of head impacts. By contrast, no changes in dCA were observed in non-contact sport controls. Taken together, these results demonstrate that repetitive subconcussive head impacts occurring across a season of contact sports participation are associated with exposure-dependent impairments in the cerebrovascular pressure-buffering system capacity. It is unknown how long these deficits persist or if they accumulate year-over-year.