Clinical history and multidisciplinary assessment was consistent with the diagnosis of coexisting sports-related concussion and migraine with brainstem aura. The authors discuss the pearls and pitfalls of managing patients who develop migraine headache with visual aura after sports-related head injury and the value of a comprehensive multidisciplinary approach to this unique patient population. Related Topics. Assessment of individual needs, communication with the health care team, and genuine concern are necessary.
One successful approach to the group process is "The Family Huddle", a technique which has enjoyed positive results at one institution. How does Europe PMC derive its citations network? Protein Interactions. Protein Families. Nucleotide Sequences. Functional Genomics Experiments. Impairments in CO2 reactivity have also been demonstrated in the context of repetitive subconcussive trauma.
In one TCD study, professional boxers exhibited substantial alterations in 31 CO2 reactivity when compared to controls that were negatively correlated with number of rounds fought Impairments in CO2 reactivity have been reported in high school American football players compared to non-contact sport controls during the first half of the season, but resolved by end-of-season Female high school soccer players exhibited CO2 reactivity impairments that were associated with cumulative impact exposure and persisted for up to months post-season It is evident that sport-related head trauma induces alterations in cerebrovascular sensitivity to CO2; however, much less is known regarding the effects on other mechanisms controlling CBF, including cerebral autoregulation and neurovascular coupling.
Coined static cerebral autoregulation CA , this observation indicates reflexive adjustments in cerebrovascular resistance to changes in blood pressure. As perfusion pressure falls there is a consequent vasodilation and reduction in cerebrovascular resistance to support CBF; the reverse occurs in response to elevations in perfusion pressure. It is accepted that CA acts to adjust resistance at the level of the cerebral arterioles and pial vessels , though animal data exists to support 32 potential contributions from large intracranial and extracranial arteries Furthermore, the slope of the pressure-passive regions of the CA curve differs in hypertensive versus hypotensive ranges, suggesting a greater buffering capacity against surges in pressure relative to reductions in pressure While classical definitions of CA were derived from evaluations of the pressure-flow relationship during steady-state conditions static CA , research has increasingly focused on the influence of dynamic changes in MAP — for example, during changes in posture — on CBF dynamic CA.
The advent of TCD allowed for improved temporal resolution, indexing CBF in major intracranial blood vessels on a beat-by-beat basis. Following rapid transient hypotension induced by the release of inflated thigh occlusion cuffs, the earliest study of dynamic CA demonstrated a similar drop between MAP and CBFv, but a quicker recovery of the CBFv, suggesting relative rather than absolute buffering The frequency-dependent behaviour of CA is known to involve autonomic and myogenic contributions, which appear to operate at different frequencies Characterization of dynamic CA has provided valuable clinical information, allowing differentiation of cerebrovascular responses to fluctuations in blood pressure occurring at different durations and amplitudes observed during everyday life , Disruptions in CA are predictive of outcome in acquired brain injury populations: in severe TBI, acutely compromised CA is a significant predictor or poor outcome , ; in patients with Fabry disease, impaired CA is thought to increase risk of stroke ; following subarachnoid haemorrhage, CA dysfunction is among the primary factors predisposing patients to delayed cerebral ischemia and vasospasm at an individual level ; impaired CA is also an established independent risk factor for stroke However, evidence for CA impairments in cases of mild head trauma is not as robust.
In one small study, a subset of hospitalized mTBI patients — eight of 29, the majority of whom also exhibited structural damage on CT — demonstrated impaired CA In the only study evaluating CA in the context of sport-related head trauma, Bailey and colleagues reported impairments in an index of 34 CA relative to control subjects in a cohort of professional boxers that correlated with combat volume Apart from this study, very little is known to what extent the dynamic, frequency-dependent relationship between BP and CBF is affected by sport-related concussion and repetitive subconcussive trauma As such, Chapter 3: and Chapter 4: of this thesis entail the first prospective evaluations of CA function via driven MAP oscillations and a widely-used technique known as transfer function analysis TFA , recently suggested as a gold-standard for evaluating the cerebral pressure-flow relationship This is pertinent to the evaluation of CA, as the pressure-flow relationship is frequency dependent described in Section 1.
The squared Coherence function is estimated as: 35 Equation 1. Gain provides a ratio of output amplitude to input amplitude. In the setting of intact CA, higher Phase indicates more rapid adjustment of cerebrovascular resistance to changing MAP. Low gain indicates low magnitudes of MAP oscillation transferred to the cerebrovasculature i. No published studies to date have used TFA to evaluate the influence of sport-related head trauma on CA function.
For over years, it has been appreciated that local neural and metabolic activity within the cortex are tightly coupled with regional perfusion , though the exact mechanisms underlying this relationship in humans are still debated.
The coupling between cortical activity and CBF is a characteristic of the neurovascular unit, a term describing the functional and anatomical relationship between neurons, supporting glial cells astrocytes, pericytes, oligodendroglia , vascular smooth muscle cells, and endothelial cells Figure Multiple pathways have been proposed to contribute to the NVC response, including local accumulation of vasoactive metabolic by-products e. CO2, nitric oxide NO , adenosine, arachidonic acid metabolites , direct neural control of the cerebrovasculature, pericyte-mediated changes in capillary tone, and astrocyte-mediated vasosignaling reviewed in: , Ultimately, gap junctions between adjacent vascular smooth muscle cells are thought to facilitate intramural propagation of vascular signals to yield vasoactivity in remote pial arterioles up-stream of the signal origin Schematic illustration of the components of the neurovascular unit from the level of capillaries to pial arterioles.
At the capillary level Level 1 , the neurovascular unit is comprised of endothelial cells, pericytes, astrocytes and neurons. At the parenchymal arteriole level Level 2 , the neurovascular unit consists of a single layer of vascular smooth muscle cells, pericytes not illustrated astrocytic end-feet, and neuron processes. At the pial arteriole level Level 3 , the endothelium is surrounded by multiple layers of smooth muscle, astrocyte processes, and perivascular nerve endings originating from peripheral ganglia.
Image reproduced with permission from Elsevier. The entire cerebrovascular tree is innervated with sympathetic and parasympathetic fibres and growing evidence supports a role for autonomic activity in modulating CBF via its effects on cerebrovascular resistance ,, Indeed, the fast initial rise in CBF following cortical activation is thought to result from sympathetic activation within the cortex ,, Furthermore, increased extracellular glutamate activates N-methyl-D-aspartate NMDA receptors to stimulate neuronal NO synthase and the subsequent release of NO onto nearby parenchymal arterioles When ATP levels are low in neurons, adenosine is also released locally to exert a vasodilatory effect Glutamate has been shown to induce dilation, whereas norepinephrine induces constriction of pericytes in brain slice preparations Astrocytes form a critical component of the neurovascular unit, acting as a bridge between neurons and cerebral blood vessels with end-feet that envelope penetrating arterioles.
Excitatory and inhibitory neurons synapse on both astrocytes and GABAergic interneurons that are closely associated with astrocytic end-feet. Glutamate released from active neurons triggers metabotropic receptor-mediated calcium uptake into neighbouring astrocytes reviewed in: The resulting change in calcium concentration initiates a signaling cascade leading to the release of arachidonic acid vasoconstrictory and its metabolic derivatives including epoxyeicosatrienoic acid EET and prostaglandins vasodilatory onto arteriolar smooth muscle cells and vascular endothelial cells Inhibitory interneurons communicating with neurons, astrocytes, and microvessels play a role in integrating local signals and releasing vasoactive substances e.
Interestingly, recent work has suggested reciprocal communication from blood vessels to astrocytes to neurons — a so-called vasculo-neuronal coupling Although our understanding of exact mechanisms governing neurovascular coupling — and certainly vasculo-neuronal coupling — remains incomplete, it is clear that multiple overlapping pathways exist to ensure CBF is appropriately altered in response to changes in local neural activity Flow 40 velocity in the PCA then tends to plateau for the duration of visual stimulation, reflecting a matching of CBF to metabolic demand.
Whereas this phenomenon is maintained at rest ,,, , during moderate exercise , and throughout healthy human aging , , impairments in NVC have been revealed across a variety of clinical conditions. It has been proposed that neuronal damage and astrocytic scar formation precludes normal NVC responses in severe TBI patients, with some of these individuals exhibiting inverse NVC responses , Mechanistically, biophysical models of TBI have estimated increased heterogeneity in CBF transit time across capillaries — secondary to capillary compression by astrocytic end-feet — to cause relevant reductions in oxygen availability However, effects of mild sport-related head trauma on NVC dynamics are currently unknown.
Insights may be gleaned from the various functional MRI studies that have been conducted, though the interpretation of results is not straightforward.
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Typically, increases in cortical activation in mTBI patients relative to healthy controls have been reported across multiple brain regions reviewed in 67 and may be related to symptom severity, often despite no differences in task 41 performance between groups However, other fMRI studies have concluded concussions cause hypoactivation, particularly in individuals with persistent symptoms, though task performance was not always equal between groups A recent prospective study demonstrated global hyperactivation that gradually declined in extent during the recovery process, with BOLD responses measured at 3-days, 2-weeks, and 2-months post-injury One study has suggested an association between the degree of hyperactivation and prolonged recovery Only one study has considered the potential for mTBI to alter the dynamics of hemodynamic responses, and reported greater activation in the visual cortex of mTBI patients presenting to the emergency department relative to controls, particularly in the second window after stimulus onset, suggesting a shorter time-to-peak response Although inconsistency across fMRI studies may be partly attributed to methodological differences and injury heterogeneity across samples , a recent meta-analysis of fMRI findings in mTBI observed hyperactivation during continuous tasks and hypoactivation during tasks requiring discrete periods of working memory It remains unclear if multiple concussions in combination with repetitive subconcussive trauma are detrimental to NVC over the course of a career.
Multiple recent task-based fMRI studies in high-school American football athletes have demonstrated changes in hemodynamic response 42 patterns to cortical activation as a function of head impact exposure across a single season 20,22,69,76, During in-season assessments, athletes performing abnormally on tests of cognition showed reduced temporal and occipital cortex BOLD responses and experienced higher numbers of impacts to the top-front of the head relative to subjects performing normally Relative to preseason scans, within-subject visual BOLD responses were much more variable during periods of the season with high contact volume, although these deficits tended to normalize with cessation of contact Whereas a history of multiple concussions may not detrimentally affect hemodynamic responses to cortical activation in otherwise healthy young adult athletes , , multiple concussions have been shown to negatively affect cortical recruitment patterns in the relational memory network of former professional football players Thus, multiple studies have reported changes in BOLD responses following repetitive subconcussive trauma.
However, the extent to which NVC dynamics are affected by sport-related head trauma may be better estimated by obtaining pre-injury data using techniques providing better temporal resolution, such as TCD. Vascular tone in pial arterioles is sensitive to neurotransmitters including norepinephrine, whereas parenchymal 43 arterioles do not respond as effectively Rather, in vitro work suggests signaling from intrinsic neurons causes a release of vasoactive mediators that exert constrictory or dilatory effects on local endothelial cells, astrocytes, and upstream vascular smooth muscle reviewed in: , However, determining the functional role of intrinsic cerebrovascular innervation in humans has proved challenging Extrinsic postganglionic autonomic fibres arise from three sources, including the sphenopalatine ganglion, superior cervical ganglion, and the trigeminal ganglion , A role for sympathetic modulation of CBF is directly supported by observations in of increases in CBF following cervical ganglionectomy and following pharmacological blockade of cervical ganglion Indeed, it is thought that sympathetic activity plays a protective role in preventing cerebral hyper-perfusion by increasing vessel tone, particularly during changes in perfusion pressure , The influence of parasympathetic activity is more poorly understood, though it is thought to counteract sympathetically-mediated vasoconstriction through activation of the trigeminal nerves While the precise role of autonomic innervation in the regulation of CBF remains controversial , it is clear that the autonomic nervous system has the capacity to modulate cerebral hemodynamics.
Generally, parasympathetic activation slows heart rate and increases heart rate variability, whereas sympathetic activation yields opposite effects. Reduced heart rate variability is thought to reflect an impaired ability of the autonomic nervous system to respond dynamically to the environment, and has been associated with poorer outcome in a variety of clinical scenarios; for example, decreased variance in R-R intervals as well as decreased power in the very low and low frequency ranges have been found to be independently predictive of mortality in myocardial infarction patients Some groups have suggested that central autonomic dysregulation may at least partly explain the observed increase in long-term mortality in persons with a history of mTBI Associations reported in recent studies from Sung and colleagues suggest altered cardiac autonomic function may contribute to enduring emotional dysfunction following mTBI, particularly in female patients , Given the extensive autonomic innervation of the cerebrovasculature , alterations in autonomic drive could contribute to altered cerebral hemodynamics following sport-related head trauma, though no evidence currently exists to support this idea.
Secondary objectives were to evaluate relationships between changes in cerebrovascular function and biomechanical metrics of head impact exposure. The results of this work will be incorporated within a broader investigation of the physiological effects of head trauma in sport, towards an evidence base that will aid in the development of objective tools to be used to prevent, identify, and manage dangerous levels of exposure to sport-related head trauma.
Hypothesis 1a: Brain myelin content will be reduced following a concussion. Hypothesis 1b: Brain myelin content will be reduced following a season of exposure to repetitive subconcussive head trauma. Hypothesis 2a: Dynamic cerebral autoregulation will be temporarily impaired following acute concussion. Hypothesis 2b: The dynamic cerebral pressure-flow relationship will be impaired in otherwise healthy athletes with a history of three or more concussions relative to those with no 46 history of concussion. Hypothesis 2c: Greater impairment in CA will correlate with higher symptom severity scores, as well as with degree of impairment in neurocognitive function.
Hypothesis 3a: Dynamic cerebral autoregulation will be impaired following one season of participation in contact sports. Hypothesis 3b: The dynamic cerebral pressure-flow relationship will be unaffected following one season of competition in elite athletes who experience little-to-no head trauma i. Hypothesis 3c: Higher degrees of head impact exposure will be associated with higher degrees of impairment in cerebral autoregulation.
Hypothesis 4a: NVC dynamics will be temporarily altered following a single sport-related concussion. Hypothesis 4b: NVC dynamics will be altered in otherwise healthy athletes with a history of three or more concussions relative to those with no history of concussions. Hypothesis 4c: Larger alterations in NVC dynamics will be related to higher symptom severity scores, as well as the degree of impairment in neurocognitive function post-injury.
Hypothesis 5a: NVC dynamics will be altered following one season of participation in contact sports. Hypothesis 5b: NVC dynamics will be unaffected following one season of competition in elite athletes who experience little-to-no head trauma i. Hypothesis 5c: Higher degrees of head impact exposure will be associated with larger alterations in NVC dynamics.
Following this overview chapter, Chapter 2: entails an original research study into the effects of sport-related head trauma on the integrity of the myelin sheath using a novel MRI-based imaging technique. The fraction of total water content in the brain attributable to myelin was evaluated at preseason in collegiate ice hockey athletes, with repeat evaluations occurring at three post-concussion time-points as well as after completion of the competitive season.
In a similar longitudinal design, Chapter 3: assessed the effects of acute and multiple prior concussions on indices of dynamic CA using a hemodynamic challenge commonly experienced in everyday life — shifts in posture from squatting to standing. Chapter 4: extends from the findings in Chapter 3 but with a focus on the effects of exposure to repetitive subconcussive head trauma through comparison of pre- and post-season CA function in contact and non-contact sport athletes.
Chapter 5: presents an evaluation of the within-subject effects of sport-related concussion on dynamics of the NVC response in the PCA using a visual stimulation paradigm. Finally, Chapter 7: summarizes 48 the five studies in this thesis, provides an interpretation of their collective conclusions, and identifies important avenues for future research.
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. 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. 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 50 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 inform many of the metabolic and neurological deficits observed clinically following mTBI.
The Centers for Disease Control and Prevention estimate that approximately 1. Symptoms of concussion, a form of mTBI, are thought to result from mild diffuse axonal injury DAI that is not detectable on conventional computed tomography or magnetic resonance imaging MRI. Currently, the diagnosis and management of this broadly defined and poorly understood injury are based on clinical observation and patient-reported symptoms, despite numerous recent efforts towards the development of objective tools to link functional deficits with quantifiable structural changes.
Furthermore, emerging evidence has suggested a possible link between clinically manifest concussions, as well as repetitive sub-clinical head impacts, and the development of long-term neurodegenerative changes, termed chronic traumatic encephalopathy The long-lasting effects of single and repetitive mTBI may include serious cognitive and behavioural deficits, such as problems with affect regulation, attention, memory, and depression Given these concerns, it is imperative that techniques be developed to 51 provide a more thorough understanding of precisely how mild traumatic brain injuries affect the brain.
Myelin is thought to be an important player in the pathophysiology of TBI, though its role is poorly understood 82,83 ; increasingly, evidence implicates that damage to either myelin or the axon can lead to subsequent damage to the other 84, In the case of sport-related head trauma, biomechanical forces imparted on the head cause linear and rotational acceleration-deceleration of the brain within the rigid cranium, which creates diffuse shear strains in the brain tissue.
Due to the viscoelastic nature of this tissue, the rate at which such strains are applied is an important factor towards the resultant tissue damage. While primary axotomy is generally observed following high magnitude impacts associated with more severe traumatic brain injuries, it is thought that the axonal pathology observed in mTBI develops over days to weeks following the initial insult 78,80, Current theories describe a post-traumatic neurometabolic cascade involving ionic flux and indiscriminate glutamate release, leading to mitochondrial dysfunction and calcium sequestration, and a subsequent energy crisis with cytoskeletal damage 78, Intracellular calcium overload has been recognized as a significant cause of damage to both myelin and oligodendrocytes Impaired axonal transport leads to swellings within the axon containing organelles and other transport materials, creating the potential for a sequence of secondary axonal disconnection and Wallerian degeneration 78, Prolonged global and regional reductions in cerebral blood flow have also been reported following concussion, and were related to recovery duration 2,43 ; experimental work has demonstrated that accumulative oxidative stress in the context prolonged cerebral hypoperfusion suppresses both the differentiation of oligodendrocyte precursor cells to oligodendrocytes as well as myelin staining 52 Thus, loss of oligodendrocytes and corresponding demyelination of affected axons is anticipated 83,84, Histopathologically, this has been observed as axonal bulbs, irregular tortuous axonal varicosities and small globoids of degraded myelin sheath 82,90, While various reports have implicated that myelin fragmentation and degradation occurs following axonal injury 82,90,95, , dynamic in vivo myelin changes have not been directly observed in the human brain.
Whether the result of direct, multifocal primary traumatic axonal injury or secondary axotomy, subsequent axonal degeneration is a possible outcome of mild DAI, but axon damage and myelin disruption may be reversible 82, Our current understanding of the pathophysiology of mTBI is derived primarily from post-mortem studies and animal models. While post-mortem studies are useful for exploring histopathological changes in the brain following mTBI, by definition they are unable to provide information on the dynamic post-injury changes explained using animal models.
However, it is recognized that the substantial mass and inertia of the human brain play an important role in the development of diffuse axonal injury 78 , highlighting an inherent challenge in the development of valid rodent models of mTBI A non-invasive method for objective, in-vivo evaluation of the pathophysiological changes associated with concussion is currently one of the primary goals in mTBI research. Specifically, the dynamic effects of acute mTBI on myelin in the human brain represent a major gap in our understanding of these injuries.
It has previously been identified that decomposing the T2 decay signal results in three components. As such, the fraction of total brain water attributable to myelin can be estimated, and is termed the myelin water fraction MWF. Recent advances in myelin water imaging have enabled rapid exploration of myelin damage across the whole brain Previous work has demonstrated a good quantitative relationship between MWF, as derived from MR images, and histological staining for myelin in tissue from both the central nervous system and peripheral nervous system Being the only technique that has been validated by histopathology, T2-relaxation based myelin water imaging has provided novel insights in demyelinating diseases, such as multiple sclerosis research , but has never been used in the context of mTBI to evaluate post-injury myelin dynamics.
In this prospective study, we followed a group of individuals at high risk of sustaining a concussion, comprised of two varsity hockey teams, for one athletic season. This is the first study to directly evaluate myelin changes following mTBI in the in vivo human brain, assessing myelin water fraction in the context of sport-related head trauma. Accordingly, our objectives in the current study were to observe changes in myelin water fraction, relative to baseline, at acute, sub-acute, and chronic post-mTBI time points in a group of individuals at high-risk of sustaining a mTBI.
We hypothesized that a reduction in myelin water fraction would be observed following concussion, with recovery to near-baseline values by 54 two months post-injury. Players who were diagnosed with a concussion by an independent physician, based on criteria outlined in the 3rd Consensus Statement on Concussion in Sport 39 , underwent additional scans and testing at hours, 2-weeks, and 2-months after injury. End of season scans were also completed for the non-concussed cohort.
The sample size for this preliminary study was determined from previous cross-sectional literature reports on expected incidence of concussions. Cross-sectional imaging studies have found effects of concussion with less than 15 subjects each The rationale was then to work with two varsity ice hockey teams where one could expect eight to 12 concussions within a season, sufficient for a preliminary prospective study with pre-injury data from the same brains. Exclusion criteria included a history of severe cognitive impairment, psychiatric or other central neurological disorder, pacemaker use, previous eye surgery, or having worked in an environment likely to expose the participants to the risk of metal fragments being embedded in their eyes.
No participants were excluded from this study on these grounds. All participants provided written informed consent prior to participation in the study, which was approved by the University of British Columbia Clinical Research Ethics Board H The T2 decay was decomposed using a non-negative least squares fit with an extended phase graph algorithm and flip angle optimization MWF was calculated as T2 signal from ms divided by the total T2 signal.
Total data acquisition time was 48 minutes. Results from the conventional scans are reported elsewhere Impact-related mTBI is a very heterogeneous injury However, in the current preliminary study, the intent was to prospectively investigate myelin dynamics after mTBI without making any clinical predictions on an individual basis, let alone correlate clinical measures with imaging measures.
All subjects' FA data were then aligned into a common space using the nonlinear registration tool FNIRT, which uses a b-spline representation of the registration warp field. Next, the mean FA image was created and thinned to create a mean white matter skeleton that represents the centres of all tracts common to the group.
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Voxelwise statistics were carried out using the randomise tool in FSL for permutations with threshold-free cluster enhancement to assess differences in myelin water fraction at each post-injury time point compared to baseline, while controlling for, as explanatory variables, age, gender, SCAT2 results, and whether scans were acquired before or after an upgrade to the scanner's gradient system occurred.
These methods were chosen explicitly to examine diffuse changes in brain structure, without a priori assumptions as to where such changes would occur, while compensating for multiple comparisons. This approach effectively restricts analysis to areas that are injured in the majority of subjects, and follows the myelin signal in these brain areas.
Analysis of the data was performed by non-supervised algorithms. The study had a conventional imaging component as well, which required the reading of MRI data by radiologists.
These data will be reported elsewhere. When comparing baseline scans between concussed and non-concussed athletes, voxelwise TBSS revealed no significant differences in myelin water fraction.
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Within the non-concussed cohort, no significant differences were identified between pre-season and post-seasons scans. Eight out of 11 concussed subjects were able to complete scanning at 72 hours post-injury, 10 out of 11 athletes were scanned at 2 weeks, and nine out of 11 were scanned at 2 months post-injury Figure Myelin water fraction maps from a concussed athlete at baseline left and two weeks post-injury right. Myelin water fraction is measured as the T2 signal from ms divided by the total T2 signal. A region of the corpus callosum with a visible reduction in MWF post-injury is highlighted by the red arrow.
Fig 1 from Within the concussed cohort, TBSS showed clusters of voxels with significantly reduced myelin water fraction at two weeks post-injury, relative to baseline Figure Across all significant voxels, this represented a 5. No significant MWF changes were observed between baseline and 2 months post-injury. Relative myelin water fraction change post-injury.
Change scores for myelin water fraction, relative to baseline, plotted against time for each subject with a mild traumatic brain injury in all significant voxels A across the whole brain; B in the splenium of the corpus callosum a structure most commonly affected in mild TBI.
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Note: time zero refers to baseline. Fig 2 in These voxel clusters were located in 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 as shown in Figure Brain areas with significantly reduced myelin water fraction.
Areas of significantly reduced myelin water fraction in athletes with concussion at two weeks post-injury, superimposed on a standard brain. These areas include 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. Fig 3 from In contrast, tract-based spatial statistics of post-season MWF maps demonstrated no differences from pre-season scans in athletes who did not sustain a concussion.
Myelin water fraction, derived from the T2 decay signal, is a direct marker of myelin content in the brain. These data may indicate a process of transient myelin disruption following mTBI in areas of the brain 62 previously shown to exhibit diffusivity changes reviewed in Furthermore, MWF recovered to near-baseline values by 2 months post-injury. That no differences were seen between pre- and post-season for non-concussed athletes is encouraging, given recent concern over the effect of exposure to repetitive sub-clinical trauma The exact time course of myelin alterations following sport-related concussion cannot be determined from this exploratory study.
As the subjects were acutely concussed and enduring the worst phase of their symptoms, only eight of the 11 subjects were able to complete the 72 hour scan; it is possible that the reduced sample size at this time point may have obviated statistical significance from being achieved. Previous work has demonstrated that peak concentrations of myelin basic protein in the cerebrospinal fluid CSF occur at hours following severe TBI, where primary axotomy likely occurred In milder forms of TBI such as concussion, where primary axotomy does not occur, myelin degradation as a downstream effect of the post-injury neurometabolic cascade and subsequent neuroinflammation may take longer to occur, which may also explain the why the MWF reduction at 72 hours post-injury did not achieve statistical significance.
It is important to point out that, although we observed a significant reduction in MWF at 2 weeks post-injury, peak reductions in myelin content may have occurred earlier or later. Indeed, significant loss of myelin for up to 21 days following injury has been reported following fluid percussion injury in rats 93 , although this injury model is recognized to be of greater severity than sport-related concussion.
Maxwell and colleagues demonstrated that optic nerve fibre degeneration may be initiated days to weeks after a mechanical stretch injury Similarly, true recovery of MWF to baseline values may have occurred earlier or later than two months following injury. Myelin debris is known to stimulate neuroinflammatory processes 82, In the context of Wallerian degeneration, myelin debris has been reported to remain for several months before full clearance by macrophages , while previous work has shown myelin fragments contained within activated microglia for up to 4 weeks after fluid percussion injury Remyelination of multiple sclerosis lesions has also been observed within 2 months The exact time course of myelination dynamics following mTBI in humans is not currently known.
Nevertheless, the authors of the current preliminary article postulate that myelin fragmentation and degeneration led to the observed reductions in MWF, with the recovery of MWF by two months post-injury likely due to remyelination of the affected axons by oligodendrocytes. We are inferring that changes in myelin water fraction are indicative of true changes in myelination within the brain.
T2 relaxation-based MWI provides insight into tissue characteristics that are not observed using standard MR imaging techniques.