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Cerebrovascular reactivity assessed by transcranial Doppler ultrasound in sport-related concussion: A systematic review

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Traumatic brain injury influences regulation of cerebral blood flow in animal models and in human studies. We reviewed the use of transcranial Doppler ultrasound (US) to monitor cerebrovascular reactivity following sport-related concussion. A narrative and systematic review of articles published in the English language, from December 1982 to October 2013. Articles were retrieved via numerous databases using relevant key terms. Observational, cohort, correlational, cross-sectional and longitudinal studies were included. Three publications met the criteria for inclusion; these provided data from 42 athletes and 33 controls. All three studies reported reductions in cerebrovascular reactivity via transcranial Doppler US. These initial results support the use of cerebrovascular reactivity as a research tool for identifying altered neurophysiology and monitoring recovery in adult athletes. Larger cross-sectional, prospective and longitudinal studies are required to understand the sensitivity and prognostic value of cerebrovascular reactivity in sport-related concussion. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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Cerebrovascular reactivity assessed by transcranial
Doppler ultrasound in sport-related concussion:
a systematic review
Andrew J Gardner,
1
Can Ozan Tan,
2,3
Philip N Ainslie,
4,5
Paul van Donkelaar,
6
Peter Stanwell,
7
Christopher R Levi,
8
Grant L Iverson
9
For numbered afliations see
end of article.
Correspondence to
Dr Andrew J Gardner, Centre
for Translational Neuroscience
and Mental Health, University
of Newcastle, Level 5, McAuley
Building, Calvary Mater
Hospital, Waratah, NSW 2298,
Australia;
andrew.gardner@neurogard.
com.au
Accepted 9 November 2014
To cite: Gardner AJ,
Tan CO, Ainslie PN, et al.Br
J Sports Med Published
Online First: [please include
Day Month Year]
doi:10.1136/bjsports-2014-
093901
ABSTRACT
Background Traumatic brain injury inuences
regulation of cerebral blood ow in animal models and
in human studies. We reviewed the use of transcranial
Doppler ultrasound (US) to monitor cerebrovascular
reactivity following sport-related concussion.
Review method A narrative and systematic review of
articles published in the English language, from
December 1982 to October 2013.
Data sources Articles were retrieved via numerous
databases using relevant key terms. Observational,
cohort, correlational, cross-sectional and longitudinal
studies were included.
Results Three publications met the criteria for
inclusion; these provided data from 42 athletes and 33
controls. All three studies reported reductions in
cerebrovascular reactivity via transcranial Doppler US.
Conclusions These initial results support the use of
cerebrovascular reactivity as a research tool for
identifying altered neurophysiology and monitoring
recovery in adult athletes. Larger cross-sectional,
prospective and longitudinal studies are required to
understand the sensitivity and prognostic value of
cerebrovascular reactivity in sport-related concussion.
INTRODUCTION
Most major guidelines for management of
sport-related concussion call for physical rest
acutely after injury, with graded return to exertion
and exercise after concussion symptoms resolve,
although the evidence behind this recommendation
is limited.
13
Most athletes appear to recover symp-
tomatically from a concussion between 2 and
28 days (with the large majority of cases recovering
in 510 days) following injury,
46
although a small
percentage experience persisting symptoms.
78
Even if overt symptoms are gone at rest and with
light exertion, strenuous effort (such as return to
sports) may induce symptoms.
9
Clinically, this is
often observed as exertion-induced headache, con-
fusion or dizziness and it presents a major obstacle
to full return to sport.
At present, the mechanisms that may underlie
the link between sports-induced concussion, strenu-
ous activity and postconcussion symptoms are not
well understood. Impaired responsiveness of cere-
brovasculature to changes in arterial carbon dioxide
(CO
2
; ie, impairment in cerebrovascular reactivity)
may play a role. The pathophysiology of impaired
cerebrovascular reactivity in the setting of concus-
sion is not understood. We reviewed data on the
link between sports-related concussion,
cerebrovascular reactivity and postconcussion
symptoms (initial or exertion-induced).
Cerebral vasoreactivity and traumatic
brain injury
The ability of the cerebral vasculature to maintain
steady supply of oxygenated blood in the face of
changing arterial CO
2
, that is, cerebral vasoreactiv-
ity, is critical to neurophysiological health. Cerebral
blood ow is strongly inuenced by alterations in
arterial CO
2
concentrations. Cerebral vessels dilate
in response to increased arterial CO
2
(ie, in
response to hypercapnia) and constrict in response
to reduced arterial CO
2
(ie, in response to hypo-
capnia). These responses are rapid, occurring with
approximately 6 s delay,
10
and are vital to regulate
and maintain central pH.
There is some evidence linking traumatic brain
injury (TBI) impaired cerebral vasoreactivity and
outcomes. For example, impaired cerebral vasoreac-
tivity in the initial days following severe injury pre-
dicts poor outcomes.
11 12
Moreover, a disruption
in cerebrovascular reactivity occurs in the days
immediately after a mild cortical impact injury in
animals,
13
and shortly after sports-related concus-
sion.
14
Anecdotal evidence suggests that symptoms
similar to those associated with concussion (specif-
ically, headache) can arise, at least in part, as a
result of derangement in cerebral vasoreactivity. For
example, individuals with migraine demonstrate
excessive increases and decreases in cerebral blood
ow in response to hypercapnia and to hypocapnia
that might be associated with the development and/
or persistence of headaches.
15
A long-lasting
impairment in cerebral vasoreactivity could relate
to exertion-induced postconcussive symptoms.
Mild to moderate exertion is associated with a
small increase in arterial CO
2
(ie, hypercapnia) that
increases cerebral blood ow.
16
However, with
increasing intensity of exercise, ventilation increases
exponentially with work rate, resulting in a reduc-
tion in arterial CO
2
(ie, hypocapnia). Thus, intense
exercise is accompanied by decreases in cerebral
blood ow; this ultimately interferes with adequate
oxygenation of the brain,
17
especially if cerebral
vasoreactivity is impaired (gure 1).
Physiology and pathophysiology of
cerebrovascular reactivity: implications for
sports-related concussion
The specics of the physiology that underlies cere-
bral vasoreactivity are largely unknown, but avail-
able data suggest that the endothelial nitric oxide
Gardner AJ, et al.Br J Sports Med 2014;0:17. doi:10.1136/bjsports-2014-093901 1
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(NO) system has a necessary role in the normal cerebrovascular
response to carbon dioxide changes, and animal and in vitro
studies of brain injury have shown that NO is among the
biochemical mediators in the post-traumatic phase.
18
NO is
involved in the pathogenesis of neuronal damage after experi-
mental brain trauma. NO synthase is induced by experimental
contusions in animals.
1921
However, the exact role of elevated
NO after injury remains controversial. Inhibition of NO syn-
thase has been shown to increase mortality
22
and also reduce
neurological decits
23
after experimental contusion in rats. It is
possible that different isoforms of NO synthase may have differ-
ent roles. For example, it appears that NO produced by endo-
thelial NO synthase may be protective, whereas NO produced
by neuronal NO synthase causes cellular damage in traumatised
brain tissue.
21
Consistent with a neuroprotective role, there is
enhanced expression of endothelial NO synthase in the micro-
vasculature surrounding the area of impact after moderate trau-
matic injury in rats.
20
Regardless of its possible neuroprotective
role, overproduction of NO in the cerebrovasculature in patho-
logical states (including TBI) may lead to excessive vasodilation
and abnormal vascular permeability.
24
Therefore, it is possible that overproduction of endothelial
NO after sports-induced concussion may lead to increased
blood ow and impaired cerebral vasoreactivity. As mentioned
above, excessive increases and decreases in cerebral blood ow
in response to hypercapnia and to hypocapnia might be asso-
ciated with the development and/or persistence of headaches.
15
Figure 1 Exercise intensity effects for cerebrovascular reactivity (CVR).
Figure 2 PRISM ow diagram. CVR, cerebrovascular reactivity.
2 Gardner AJ, et al.Br J Sports Med 2014;0:17. doi:10.1136/bjsports-2014-093901
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Thus, and given that exertion and physical activity is associated
with alterations in arterial CO
2
, it is conceivable that altered
cerebral vasoreactivity due to dysregulation of the endothelial
NO system might partially underlie initial and exertion-induced
symptoms after sports-related concussion. If true, this link
opens up new venues for treatment and recovery. To further
explore this link, we examined studies that have assessed cere-
bral vasoreactivity following sport-related concussion by system-
atically reviewing available observational (ie, no intervention
was applied), cohort, correlational, cross-sectional and longitu-
dinal studies.
METHODS
We reviewed the literature in three stages. First, articles were
retrieved via online database searching, hand-searching reference
lists and cited reference searches (gure 2). The search was
limited to those that were published in English-language journals
from December 1982 (when the use of transcranial Doppler to
monitor cerebrovascular regulation was rst described
25
)to
October 2013. Key articles retrieved via online databases and
hand-searching reference lists were also used for further cited ref-
erence search, and the results of cited reference searches were
further narrowed using relevant key words (gure 2). The review
of the references acquired from the database search results was
carried out by two of the authors (AJG and PS) independently. If
there was a disagreement between reviewers, a third reviewer was
to be sought to make the nal decision; however, this was not
required for the current review. Next, we reviewed the titles and
abstracts of articles to assess eligibility for inclusion in this review.
Articles were regarded as relevant and warranting inclusion if
they were experimental studies examining cerebral vasoreactivity
via transcranial Doppler in concussed athletic samples. Papers
describing moderate to severe TBI were excluded. Studies were
included whether they were conducted acutely or postacutely (ie,
there were no restrictions placed on time since injury) and
whether or not they also used other outcome measures (eg, neu-
roimaging, symptom checklists, balance testing or neuropsycho-
logical testing). If there was uncertainty about whether a study
should be included based on the review of the title and abstract,
the full article was retrieved. Lastly, all retrieved articles were
independently assessed for quality using a standardised quality
assessment checklist selected for its generic comprehensiveness
and currency (table 1), as previously described.
2629
RESULTS
A total of 2504 articles were identied using this search strat-
egy. Of the identied citations, 2498 were retrieved and
screened for eligibility. Eleven citations were excluded because
cerebral vasoreactivity was not used as a research method and
2303 were excluded on the basis that the human participants
were not athletes (ie, not sport-related concussion cases). Of
the remaining 181 excluded articles, 72 were excluded because
they were not research studies (eg, conference presentation,
abstract only, commentary) and 109 were excluded on the basis
that the study was conducted with animals. We were surprised
to nd that there were only three articles on the possible rela-
tion between sports-related concussion and cerebral vasoreac-
tivity in humans.
Subsequently, we extracted from the identied studies the
data that pertain to (1) participant demographics (athletes and
control subjects), (2) characteristics of participants (sport, expos-
ure to concussion, concussive history), (3) methodological
details (technique and data collection), (4) time lapsed (immedi-
ate (minutes to hours), acute (114 days), subacute stage (24
weeks), prolonged and chronic stages (greater than 4 weeks))
and (5) results of the study (see tables 2 and 3for a summary of
results).
Overall, a total of 42 athletes and 33 healthy athlete, neuro-
logically intactcontrol volunteers participated across the three
studies. One study examined the effects of repetitive blows to
the head from a career in boxing by using active non-concussed
boxers (ie, had not been diagnosed with a concussion recently)
who had recently (within the past 72 h) completed a sparring
session and compared these results with physical-tness
matched non-boxing control athletes (ie, controls who had not
engaged in any form of contact sport that may have resulted in
head trauma and had not sustained a concussion).
30
The other
two studies were primarily comprised of hockey players
(85%
31
and 90%
14
). Among the two, one study did not
compare results with a control group,
31
while the other
recruited non-concussed athletes from the same university as
the concussed athletes were recruited.
14
Although the control
athletes in this latter study had not suffered a concussion in
the previous 2 months, there were no further details provided
on their concussion history.
Bailey et al
30
reported that boxers performed more poorly
on cognitive tests measuring attention, working memory, pro-
cessing speed, memory and executive function (eg, inhibitory
Table 1 Quality assessment rating results
Quality assessment rating criteria questions Bailey et al
30
Len et al
31
Len et al
14
1. Was the research question clearly stated? Yes Yes Yes
2. Was the selection of study participants/patients free from bias? Yes Yes Yes
3. Were study groups comparable? Yes No Yes
4. Was method of handling withdrawals described? N/A No N/A
5. Was blinding used to prevent introduction of bias? Yes No No
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s)
described in detail? Were intervening factors described?
Yes Yes Yes
7. Were outcomes clearly defined and the measurements valid and reliable? Yes Yes Yes
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes Yes Yes
9. Were conclusions supported by results with biases and limitations taken into consideration? Yes Yes Yes
10. Is bias due to studys funding or sponsorship unlikely? Yes Yes Yes
Overall quality rating Positive Neutral Positive
N/A, not applicable.
Gardner AJ, et al.Br J Sports Med 2014;0:17. doi:10.1136/bjsports-2014-093901 3
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control). This coincided with marked orthostatic hypotension,
cerebral hypoperfusion and corresponding cortical
de-oxygenation during orthostatic stress. Under normal circum-
stances, cerebral autoregulation (another component of cere-
brovascular regulation) can buffer against reductions in blood
pressure. However, it is possible that autoregulation may not
completely mitigate the impact of relatively large changes in
pressure consequent to orthostatic hypotension (due to impair-
ments in peripheral vascular control) on cerebral blood ow,
and this may partly explain the poor cognitive performance of
the boxers. Nonetheless, compared to controls, the boxers also
had marked differences on cerebral vasoreactivity, and there
was a signicant negative correlation between the number of
rounds fought and reductions in cerebral vasoreactivity.
Consistent with Bailey et al,
30
Len et al
14
reported that while
there was no middle cerebral artery blood velocity difference
between injured athletes and controls at rest, under physio-
logical stress (ie hypocapnia (hyperventilation) and hypercapnia
(breath holding)), the concussed athlete group demonstrated
impairment in cerebral vasoreactivity (as assessed via repetitive
breath holding) compared to the controls. Lastly, in a second
study, Len et al
31
found that the reduction in the cerebral
vasoreactivity (assessed via repetitive breath holding) following
concussion tended to resolve over the rst 5 days postinjury.
Therefore, while limited in number, available studies show
impairment in cerebral vasoreactivity after sports-related
concussion.
CONCLUSIONS
Available animal and in vitro studies suggest a link between
neurotrauma and impaired cerebral vasoreactivity.
Overproduction of endothelial NO after neurotrauma may
lead to impaired cerebral vasoreactivity; this might partially
underlie initial and exertion-induced symptoms after sports-
related concussion. Only three studies in humans explored
this link. The ndings of these studies were reasonably con-
sistent with the animal and in vitro data. We highlight that
there are important population and methodological differ-
ences among the three studies. Two of the three studies exam-
ined athletes who had recently been diagnosed with a
sports-related concussion, and only two used control groups
(physical-tness matched non-boxing control athletes, and
non-concussed adolescent and young adult contact sport ath-
letes). Moreover, two of the studies in sports-related concus-
sion
14 31
assessed cerebral vasoreactivity via repetitive 20 s
breath-holding. Breath holding provokes not only changes in
arterial carbon dioxide tension, but it also may change sympa-
thetic nerve activity, intrathoracic (thus, arterial blood) pres-
sure and cardiac output. Thus, it remains possible that the
reported impairments in cerebral vasoreactivity following
sports-related concussion may reect mechanisms other than
cerebrovascular reactivity to elevations in CO
2
, such as cere-
bral autoregulation of neurovascular coupling that allow cere-
brovasculature to meet oxygen and glucose requirements of
the brain despite changes in blood pressure or metabolic
demand. Despite their limitations, these three studies provide
preliminary support for the possibility that cerebrovascular
responses to changes in arterial gases (ie, cerebral vasoreactiv-
ity) may be disrupted after sport-related concussion. The
pathophysiological mechanisms that underlie this disruption
are not yet clear. Although there are data suggesting that the
sympathetic nervous system restrains cerebrovascular
responses to CO
2
,
32
neither agonists nor antagonists of the
sympathetic system demonstrate any direct effect on
Table 2 Study characteristics
N Sex Time postinjury
References Athletes Controls M F Mean age (SD) Mean SD Symptoms Concussion definition Concussion history Level of play Sports Follow-up period (If any)
Bailey
et al
30
12 12 24 0 SRC: 27 (4.0)
Controls: 28
(4.0)
72 h
postsparring
NR Chronic Brain
Injury scale
scores; 8 mild,
4 moderate
NR (only bout and sparring
exposure)
Individual bout
history reported
P boxing (super
featherweight,
and light
heavyweight)
N/A
Len et al
31
20 0 16 4 19.7 (3.3) 2 days NR SCAT-2 symptom
score
A blow to the head causing
an alteration in mental
status and one or more of
the following symptoms:
headache, nausea,
vomiting, dizziness/balance
problems, fatigue, trouble
sleeping, drowsiness,
sensitivity to light or noise,
blurred vision, difficulty
remembering or difficulty
concentrating
Previous mTBIs
reported
A hockey,
snowboarding,
basketball, fight
2, 4 and 8 days
Len et al
14
10 21 28 3 21.4 (1.7) 4.5 1.1 SCAT-2 (all
asymptomatic)
NR Indication of a
history of concussion
but history NR
A hockey,
basketball
N/A
A, amateur; F, female; M, male; mTBIs, mild traumatic brain injuries; N/A, not applicable; NR, not reported; P, professional; SCAT-2, Sport Concussion Assessment Tool 2 SRC, sport-related concussed participants.
4 Gardner AJ, et al.Br J Sports Med 2014;0:17. doi:10.1136/bjsports-2014-093901
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vasoreactivity.
33 34
The role of myogenic mechanisms is also
unclear. In animals, calcium channel antagonists blunt the
vasoconstrictive effects of hyperventilation
3537
and the vaso-
dilatory effects of hypercapnia.
38 39
In humans, however,
calcium channel antagonists have been reported to decrease
40
or have no effect on
41 42
vasoreactivity. Conversely, the cere-
bral vasoreactivity is decreased with pharmacological inhib-
ition of NO
43
and in populations with apparent endothelial
dysfunction.
44 45
For example, in healthy participants, NO
synthase inhibition via L-NMMA blunts the cerebral blood
ow response to hypercapnia and this can be reversed by
L-arginine.
43
Vasoreactivity is improved with acute L-arginine
administration in those with impaired vasoreactivity but not
in those with normal vasoreactivity.
44
Thus, the primary
physiological mechanism that underlies cerebral vasoreactivity
appears to be dependent on an intact endothelial NO system
(gure 1). Given that NO appears to be among the primary
biochemical mediators of vascular responses during the post-
traumatic phase (see Introduction section), these data further
reinforce the possible link between disruption in cerebral
vasoreactivity and sports-induced concussion.
We emphasise two important limitations. First, all three
studies reviewed above included adult volunteers. Yet, the
impact of concussion on cerebral vasoreactivity may differ
across the lifespan.
46
For example, Becelewski and Pierzchala
47
reported decreased vasoreactivity in younger but not in older
individuals following TBI. Thus, further research in paediatric
and adolescent populations is necessary. Second, deconditioning
during the rest period after initial injury, rather than (or in add-
ition to) the injury per se may impact mechanisms that underlie
cerebral vasoreactivity. In young healthy athletes, exercise train-
ing may not have appreciable effects on cerebrovascular control,
as a cerebrovascular function is at or near its peak capacity.
However, detraining can result in signicant decits in cerebral
regulatory control. This may be relevant to some athletes who
have sustained concussions because prolonged physical rest may
lead to serious deconditioning and resultant declines in cerebro-
vascular control (including vasoreactivity).
48
Thus, independent
of, or in addition to the primary cerebrovascular dysfunction
due to head trauma, prolonged rest after concussion leads to
deconditioning that may induce physiological changes in cere-
brovascular control.
Table 3 Cerebrovascular reactivity study characteristics
Study
CVR specifications, data acquisition and
analysis Other assessment methods used Study findings
Bailey et al
30
2 MHz-pulsed transcranial Doppler ultrasound
system (Multi-Dop X4; DWL Elektroniche
Systeme).
CO
2
measurement was performed in the supine
position with each participants head elevated to
30°. PETCO
2
was sampled from a leak-free mask
and analysed via capnography (ML 206;
ADInstruments). Following 10 min of breathing
room air, the inspirate was rapidly changed to
5% CO
2
with 21% O
2
and balanced nitrogen for
3 min. Following a 5 min recovery breathing
room air, participants hyperventilated at 15 bpm
for 3 min. From this, vasoreactivity was
calculated as the % increase/decrease in MCAv
from baseline per 1 mm Hg increase/decrease in
PETCO
2
recorded during the final 30 s (average
taken) of the hypercapneic/hypocapneic challenge
when steady-state was achieved
NP testing dCA (tight-cuff technique and transfer
function analysis) orthostatic tolerance (supine and
standing) mean arterial blood pressure (finger
photoplethysmography).
End-tidal CO
2
(capnography).Near-IR spectroscopy
(cortical oxyhaemoglobin concentration)
Vasoreactivity was reduced, resulting in a
lower range of blood flow responses.
Vasoreactivity was most marked in boxers
with the highest chronic traumatic brain injury
scores and correlated to the volume and
intensity of sparring during training.
These impairments coincided with more
marked cerebral hypoperfusion and
corresponding cortical de-oxygenation during
orthostatic stress
Len et al
31
A 2 MHz Doppler probe (Nicolet Companion III,
VIASYS Healthcare, Burlington, ON, Canada) was
placed over the right temporal window.
An electronic metronome was used during the
respiratory protocol to maintain proper cadence
during hyperventilation. Analysis of PETCO
2
was
conducted using a breath-by-breath expired gas
analysing system (Sensormedics vMax 2200,
VIASYS Healthcare), which was calibrated before
and after each test with primary standard gases
(16% O
2
,4%CO
2
, balance N
2
; 26% O
2
, balance
N
2
) and a 3.0 L factory calibrated syringe for
ventilation calibration
SCAT-2 Altered cerebral vasoreactivity following
concussion that resolves over approximately
the first 5 days of recovery.
Following a concussion:
Vasoreactivity is impaired in response to
respiratory stress;
The impairment may be resolved as early as
4 days post-injury
Len et al
14
A 1.6 MHz Doppler probe (Nicolet Companion III;
VIASYS Healthcare, Burlington, ON, Canada) was
placed over the right temporal window.
Breath-by-breath analysis of PETCO
2
was
conducted using an automated expired gas
analysing system (SensorMedics Vmax 2200;
VIASYS Healthcare)
SCAT-2 Normal cerebrovascular responses may be
impaired in the days immediately after
occurrence of concussion
5% carbon dioxide and controlled hyperventilation; CVR, cerebrovascular reactivity; CVRCO
2
, cerebrovascular reactivity to changes in carbon dioxide: dCA, dynamic cerebral
autoregulation; MCA, middle cerebral artery; MCAv, middle cerebral artery blow flow velocity; N
2
, nitrogen; NP, neuropsychological; O
2
, oxygen; PETCO2, end-tidal carbon dioxide;
SCAT-2, Sport Concussion Assessment Tool 2; vMCA, mean cerebral blow flow velocity.
Gardner AJ, et al.Br J Sports Med 2014;0:17. doi:10.1136/bjsports-2014-093901 5
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What are the new ndings?
Although assessment of cerebrovascular responses to
changes in arterial gases (ie, cerebral vasoreactivity) after
neurotrauma is not a new concept; our review highlights
that this concept has been underexplored in athletes
suffering from sport-related concussion.
Three studies to date provide preliminary support for the
possibility that cerebral vasoreactivity may be impaired after
sport-related concussion.
Although the ndings of human studies appear to be
consistent with the animal and in vitro data, the limited
number and scope of studies in humans highlight the urgent
need for more research.
Author afliations
1
Centre for Translational Neuroscience and Mental Health, School of Medicine and
Public Health, University of Newcastle, Callaghan, New South Wales, Australia
2
Cardiovascular Research Laboratory, Spaulding Rehabilitation Hospital, Boston,
Massachusetts, USA
3
Department of Physical Medicine and Rehabilitation, Harvard Medical School,
Boston, Massachusetts, USA
4
Faculty of Health and Social Development, School of Health and Exercise Sciences,
Centre for Heart, Lung, and Vascular Health, Vancouver, British Columbia, Canada
5
University of British ColumbiaOkanagan Campus, Vancouver, British Columbia,
Canada
6
Faculty of Health and Social Development, School of Health and Exercise Sciences,
University of British ColumbiaOkanagan Campus, Vancouver, British Columbia,
Canada
7
Faculty of Health, Centre for Translation Neuroscience and Mental Health, School of
Health Sciences, University of Newcastle, Callaghan, New South Wales, Australia
8
Centre for Translational Neuroscience and Mental Health, School of Medicine and
Public Health, University of Newcastle, Callaghan, New South Wales, Australia
9
Department of Physical Medicine and Rehabilitation, Harvard Medical School;
Spaulding Rehabilitation Hospital, MassGeneral Hospital for Children Sports
Concussion Program, & Red Sox Foundation and Massachusetts General Hospital
Home Base Program, Boston, Massachusetts, USA
Contributors AJG developed the concept, methodology, conducted the literature
search, established and reviewed the eligibility criteria of articles acquired from the
database search, and structured the review. He authored the initial drafts of the
manuscript, gures and tables. COT authored the background information pertaining
to the physiology and pathophysiology of cerebrovascular reactivity in animal models
as well as human studies. PNA and PvD also provided editing and comments on the
entire manuscript with particular focus on the background content regarding the
physiology and pathophysiology of cerebrovascular reactivity. PS reviewed the
eligibility of references acquired from the database search in addition to providing
expert input to the nal draft of the manuscript. CRL provided expert input to the
nal draft of the manuscript. GLI assisted with the development of the concept and
methodology. He also provided considerable editing and comments on all sections,
the gures and tables to nalise the manuscript.
Competing interests AJG has a clinical practice in neuropsychology involving
individuals who have sustained sports-related concussion (including current and
former athletes). He has received travel funding from the Australian Football League
(AFL) to present at the Concussion in Football Conference in 2013. Previous grant
funding includes the NSW Sporting Injuries Committee, the Brain Foundation and
the Hunter Medical Research Institute, supported by Jennie Thomas. GI has been
reimbursed by the government, professional scientic bodies and commercial
organisations for discussing or presenting research relating to mild TBI and
sport-related concussion at meetings, scientic conferences and symposiums. He has
a clinical and consulting practice in forensic neuropsychology involving individuals
who have sustained mild TBIs. He has received research funding from several test
publishing companies, including ImPACT Applications, Inc, CNS Vital Signs and
Psychological Assessment Resources (PAR, Inc). He is a co-investigator, collaborator,
or consultant on grants relating to mild TBI funded by several organisations,
including, but not limited to, the Canadian Institute of Health Research, Alcohol
Beverage Medical Research Council, Rehabilitation Research and Development
(RR&D) Service of the US Department of Veterans Affairs, Vancouver Coastal Health
Research Institute and Roche Diagnostics Canada.
Provenance and peer review Not commissioned; externally peer reviewed.
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Gardner AJ, et al.Br J Sports Med 2014;0:17. doi:10.1136/bjsports-2014-093901 7
Review
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review
sport-related concussion: a systematic
transcranial Doppler ultrasound in
Cerebrovascular reactivity assessed by
Peter Stanwell, Christopher R Levi and Grant L Iverson
Andrew J Gardner, Can Ozan Tan, Philip N Ainslie, Paul van Donkelaar,
published online December 1, 2014Br J Sports Med
http://bjsm.bmj.com/content/early/2014/12/01/bjsports-2014-093901
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... Vascular remodeling changes after TBI include a reduction in the overall volume of cerebral blood vessels suggesting that TBI may result in chronic brain hypoperfusion 8 . Post-TBI cerebrovascular alterations including CBF changes are also observed in pre-clinical TBI animal models [9][10][11][12][13] . Collectively, these data support the hypothesis that TBI results in acute cerebrovascular damage that can evolve into a chronic condition that includes abnormal CBF. ...
Preprint
Background. Previous clinical work suggested that altered cerebral blood flow (CBF) in severe traumatic brain injury (sTBI) correlates with poor executive function and clinical outcome. However, the molecular consequences of altered CBF on endothelial cells (ECs) and their blood flow-sensor organelle called cilia are not known. Methods. We performed laser speckle contrast imaging, single cell isolation, and single cell RNA sequencing (scRNAseq) after sTBI in a closed skull, linear impact mouse model. Validation of select ciliary target protein changes was performed using flow cytometry. Additionally, in vitro experiments modeled the post-injury hypoxic environment to evaluate the effect on cilia protein ARL13B in human brain microvascular ECs. Results. We detected immediate reductions in CBF that were sustained for at least 100 minutes in both impacted and non-impacted sides of the brain. Our scRNAseq data detected heterogeneity in the brain cortex-derived EC cluster and demonstrated that two of five unique EC sub-clusters changed their relative proportions post-sTBI. Consistent with flow changes, we identified multiple genes associated with the fluid shear stress pathway that were significantly differentially expressed in brain ECs post-injury. Also, ECs displayed activation of ischemic pathway as early as day 1 post-injury, and enrichment of hypoxia pathway at day 7 and 28 post-injury. Arl13b ciliary gene expression was lost on day 1 in ECs cluster and remained lost for the entire course of the injury. We validated the loss of cilia protein ARL13B specifically from brain ECs as early as day 1 post-injury and detected the protein in the peripheral blood of the injured mice. We also determined that hypoxia could induce loss of ARL13B protein from cultured ECs. Conclusions. In severe TBI, blood flow is disrupted in both impacted and non-impacted regions of the brain, creating a hypoxic environment that may influence ciliary gene and protein expression on ECs.
... Numerous neuroimaging modalities have been used during both hypercapnia and hypocapnic assessments including transcranial Doppler ultrasound (TCD) (Gardner et al. 2015), functional near-infrared spectroscopy (Mathieu et al. 2020), functional magnetic resonance imaging (Fisher et al. 2018), arterial spin labelling (Smeeing et al. 2016), among others. These results have commonly shown a unit increase of ~ 3-6% per Torr change in the partial pressure end-tidal value of CO 2 (P ET CO 2 ) during hypercapnia, and a ~ 1-3% change per Torr in P ET CO 2 during hypocapnia (Willie et al. 2014). ...
Article
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Introduction Cerebrovascular reactivity (CVR) describes the vasculature’s response to vasoactive stimuli, where prior investigations relied solely on mean data, rather than exploring cardiac cycle differences. Methods Seventy-one participants (46 females and 25 males) from two locations underwent TCD measurements within the middle or posterior cerebral arteries (MCA, PCA). Females were tested in the early-follicular phase. The hypercapnia response was assessed using a rebreathing protocol (93% oxygen and 7% carbon dioxide) or dynamic end-tidal forcing as a cerebral blood velocity (CBv) change from 40 to 55-Torr. The hypocapnia response was quantified using a hyperventilation protocol as a CBv change from 40 to 25-Torr. Absolute and relative CVR slopes were compared across cardiac cycle phases, vessels, and biological sexes using analysis of covariance with Tukey post-hoc comparisons. Results No differences were found between hypercapnia methods used (p > 0.050). Absolute hypercapnic slopes were highest in systole (p < 0.001), with no cardiac cycle differences for absolute hypocapnia (p > 0.050). Relative slopes were largest in diastole and smallest in systole for both hypercapnia and hypocapnia (p < 0.001). Females exhibited greater absolute CVR responses (p < 0.050), while only the relative systolic hypercapnic response was different between sexes (p = 0.001). Absolute differences were present between the MCA and PCA (p < 0.001), which vanished when normalizing data to baseline values (p > 0.050). Conclusion Cardiac cycle variations impact CVR responses, with females displaying greater absolute CVR in some cardiac phases during the follicular window. These findings are likely due to sex differences in endothelial receptors/signalling pathways. Future CVR studies should employ assessments across the cardiac cycle.
... The participants will be encouraged to eat a small meal at least 2 h before testing and asked to void their bladder within 30 min of arrival. Participants will be attached to the following equipment: bilateral transcranial Doppler to measure blood flow velocity of the brain [19,38], Functional near infrared spectroscopy (fNIRS) -fNIRS to measure oxygenation of the brain [13], and a Finapres Nova to record electrocardiogram and blood pressure continuously via finger photoplethysmography. The Finapres has a 5-lead ECG to record heart rate and the electrocardiogram [36,39], a mouth-piece connected to a gas analyzed to collect expired carbon dioxide and oxygen [40], and a seismocardiograph to record cardiac cycle timing intervals and contractile parameters [12,41]. ...
Article
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Background Cannabinoids such as cannabidiol (CBD) exhibit anti-inflammatory properties and have the potential to act as a therapeutic following mild traumatic brain injury. There is limited evidence available on the pharmacological, physiological and psychological effects of escalating CBD dosages in a healthy, male, university athlete population. Furthermore, no dosing regimen for CBD is available with implications of improving physiological function. This study will develop an optimal CBD dose based on the pharmacokinetic data in contact-sport athletes. The physiological and psychological data will be correlated to the pharmacokinetic data to understand the mechanism(s) associated with an escalating CBD dose. Methods/design Forty participants will receive escalating doses of CBD ranging from 5 mg CBD/kg/day to 30 mg CBD/kg/day. The CBD dose is escalated every two weeks in increments of 5 mg CBD/kg/day. Participants will provide blood for pharmacological assessments at each of the 10 visits. Participants will complete a physiological assessment at each of the visits, including assessments of cerebral hemodynamics, blood pressure, electrocardiogram, seismocardiogram, transcranial magnetic stimulation, and salivary analysis for genomic sequencing. Finally, participants will complete a psychological assessment consisting of sleep, anxiety, and pain-related questionnaires. Discussion This study will develop of an optimal CBD dose based on pharmacological, physiological, and psychological properties for future use during contact sport seasons to understand if CBD can help to reduce the frequency of mild traumatic injuries and enhance recovery. Trial registration Clinicaltrials.gov: NCT06204003.
... The breath-holding maneuver is a useful and well-tolerated screening method for CVR and was validated in numerous per reviewed publications. [125][126][127][128][129][130] While numerous studies have focused on the acute period of brain parenchymal, behavioral, and vascular changes associated with mTBI, few have followed these changes over a more prolonged, chronic course of injury, or have attempted to correlate these changes with any enduring morbidity, like post-traumatic stress disorder. On the vascular front, there were significant contributions to the understanding of the brain's microvascular response to injury, illustrating that in the early hours post-injury the cerebral microcirculation shows impaired vascular reactivity to known vasodilator challenges. ...
Article
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Neurologists, neurosurgeons, and neurointensivists, including military, have a large armamentarium of diagnostic and monitoring devices available to detect primary and secondary brain injury and guide therapy in patients with acute traumatic brain injury (TBI) to avoid cerebral ischemia due to the posttraumatic vasospasm (PTV) and intracranial hypertension (ICH). This review summarizes the advantages and the specific roles of transcranial Doppler (TCD) ultrasonography for patients with acute and longterm effects of TBI. In critical care setting numerous publications showed that TCD is predictive of angiographic PTV and onset of ICH. The post TBI status of cerebrovascular reactivity and cerebral hemodynamics also has important implications with regard to the treatment of long-term effects of mild TBI (mTBI). Today it is abundant evidence that TCD is an important tool for monitoring the natural course of acute moderate and severe TBI, for evaluating the effect of medical treatment or intervention, for forecasting, and for identifying high-risk patients for onset of cerebral ischemia after TBI. TCD makes good clinical and economic sense as it is a reliable, quantitative, non-invasive and non-expensive “biomarker” to the acute clinical manifestations of TBI. TCD clinical utilization holds promise for better detection, characterization, and monitoring of objective cerebral hemodynamics changes in symptomatic patients with TBI not readily apparent by standard CT or conventional MRI techniques. TCD utilization will improve the sensitivity of neuroimaging to subtle brain perturbations and combining these objective measures with careful clinical characterization of patients may facilitate better understanding of the neural bases and treatment of the signs and symptoms of TBI. This review summarizes the advantages and the specific roles of TCD ultrasonography for patients with acute and long-term effects of TBI.
Article
Sport-related concussion (SRC) can impair the cerebrovasculature both acutely and chronically. Transcranial Doppler (TCD) ultrasound assessment has the potential to illuminate the mechanisms of impairment and provide an objective evaluation of SRC. The current systematic review investigated studies employing TCD ultrasound assessment of intracranial arteries across three broad categories of cerebrovascular regulation: neurovascular coupling (NVC), cerebrovascular reactivity (CVR), and dynamic cerebral autoregulation (dCA). The current review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) database (CRD42021275627). The search strategy was applied to PubMed, as this database indexes all biomedical journals. Original articles on TCD for athletes with medically diagnosed SRC were included. Title/abstract and full-text screening were completed by three authors. Two authors completed data extraction and risk of bias using the Methodological Index for Non-Randomized Studies and Scottish Intercollegiate Guideline Network checklists. Of the 141 articles identified, 14 met the eligibility criteria. One article used an NVC challenge, eight assessed CVR, and six investigated dCA. Methodologies varied widely among studies, and results were heterogeneous. There was evidence of cerebrovascular impairment in all three domains roughly 2 days post-SRC, but the magnitude and recovery of these impairments were not clear. There was evidence that clinical symptom resolution occurred before cerebrovascular function, indicating that physiological deficits may persist despite clinical recovery and return to play. Collectively, this emphasizes an opportunity for the use of TCD to illuminate the cerebrovascular deficits caused by SRC. It also highlights that there is need for consistent methodological rigor when employing TCD in a SRC population.
Article
Emerging evidence suggests that advanced neuroimaging modalities such as arterial spin labelling (ASL) might have prognostic utility for pediatric concussion. This study aimed to: 1) examine group differences in global and regional brain perfusion in youth with concussion or orthopedic injury (OI) at 72 h and 4 weeks post-injury; 2) examine patterns of abnormal brain perfusion within both groups and their recovery; 3) investigate the association between perfusion and symptom burden within concussed and OI youths at both time-points; and 4) explore perfusion between symptomatic and asymptomatic concussed and OI youths. Youths ages 10.00-17.99 years presenting to the emergency department with an acute concussion or OI were enrolled. ASL-magnetic resonance imaging scans were conducted at 72 h and 4 weeks post-injury to measure brain perfusion, along with completion of the Health Behavior Inventory (HBI) to measure symptoms. Abnormal perfusion clusters were identified using voxel-based z-score analysis at each visit. First, mixed analyses of covariance (ANCOVAs) investigated the Group*Time interaction on global and regional perfusion. Post hoc region of interest (ROI) analyses were performed on significant regions. Second, within-group generalized estimating equations investigated the recovery of abnormal perfusion at an individual level. Third, multiple regressions at each time-point examined the association between HBI and regional perfusion, and between HBI and abnormal perfusion volumes within the concussion group. Fourth, whole-brain one-way ANCOVAs explored differences in regional and abnormal perfusion based on symptomatic status (symptomatic vs. asymptomatic) and OIs at each time-point. A total of 70 youths with a concussion [median age (interquartile range; IQR) = 12.70 (11.67-14.35), 47.1% female] and 29 with an OI [median age (IQR) = 12.05 (11.18-13.89), 41.4% female] were included. Although no Group effect was found in global perfusion, the concussion group showed greater adjusted perfusion within the anterior cingulate cortex/middle frontal gyrus (MFG) and right MFG compared with the OI group across time-points (ps ≤ 0.004). The concussion group showed lower perfusion within the right superior temporal gyrus at both time-points and bilateral occipital gyrus at 4 weeks, (ps ≤ 0.006). The number of hypoperfused clusters was increased at 72 h compared with 4 weeks in the concussion youths (p < 0.001), but not in the OIs. Moreover, Group moderated the HBI-perfusion association within the left precuneus and superior frontal gyrus at both time-points, (ps ≤ 0.001). No association was found between HBI and abnormal perfusion volume within the concussion group at any visits. At 4 weeks, the symptomatic sub-group (n = 10) showed lower adjusted perfusion within the right cerebellum and lingual gyrus, while the asymptomatic sub-group (n = 59) showed lower adjusted perfusion within the left calcarine, but greater perfusion within the left medial orbitofrontal cortex, right middle frontal gyrus, and bilateral caudate compared with OIs. Yet, no group differences were observed in the number of abnormal perfusion clusters or volumes at any visit. The present study suggests that symptoms may be associated with changes in regional perfusion, but not abnormal perfusion levels.
Article
Background: Evidence suggests that mild TBI injuries, which comprise >75% of all TBIs, can cause chronic post-concussive symptoms, especially when experienced repetitively (rTBI). rTBI is a major cause of cognitive deficit in athletes and military personnel and is associated with neurovascular changes. Current methods to monitor neurovascular changes in detail are prohibitively expensive and invasive for patients with mild injuries. New method: We evaluated the potential of multispectral optoacoustic tomography (MSOT) to monitor neurovascular changes and assess therapeutic strategies in a mouse model of rTBI. Mice were subjected to rTBI or sham via controlled cortical impact and administered pioglitazone (PG) or vehicle. Oxygenated and deoxygenated hemoglobin were monitored using MSOT. Indocyanine green clearance was imaged via MSOT to evaluate blood-brain barrier (BBB) integrity. Results: Mice subjected to rTBI show a transient increase in oxygenated/total hemoglobin ratio which can be mitigated by PG administration. rTBI mice also show BBB disruption shortly after injury and reduction of oxygenated/total hemoglobin in the chronic stage, neither of which were affected by PG intervention. Comparison with existing methods: MSOT imaging has the potential as a noninvasive in vivo imaging method to monitor neurovascular changes and assess therapeutics in mouse models of rTBI. In comparison to standard methods of tracking inflammation and BBB disruption, MSOT can be used multiple times throughout the course of injury without the need for surgery. Thus, MSOT is especially useful in research of rTBI models for screening therapeutics, and with further technological improvements may be extended for use in rTBI patients.
Article
Sports-related concussion is now in public awareness more than ever before. Investigations into underlying pathophysiology and methods of assessment have correspondingly increased at an exponential rate. In this review, we aim to highlight some of the evidence supporting emerging techniques in the fields of neurophysiology, neuroimaging, vestibular, oculomotor, autonomics, head sensor, and accelerometer technology in the setting of the current standard: clinical diagnosis and management. In summary, the evidence we reviewed suggests that (1) head impact sensors and accelerometers may detect possible concussions that would not otherwise receive evaluation; (2) clinical diagnosis may be aided by sideline vestibular, oculomotor, and portable EEG techniques; (3) clinical decisions on return-to-play eligibility are currently not sensitive at capturing the neurometabolic, cerebrovascular, neurophysiologic, and microstructural changes that biomarkers have consistently detected days and weeks after clinical clearance. Such biomarkers include heart rate variability, quantitative electroencephalography, as well as functional, metabolic, and microstructural neuroimaging. The current challenge is overcoming the lack of consistency and replicability of any one particular technique to reach consensus.
Article
Full-text available
Concussion remains one of the inherent risks of participation in rugby league. While other injuries incurred by rugby league players have been well studied, less focus and attention has been directed towards concussion. The current review examined all articles published in English from 1900 up to June 2013 pertaining to concussion in rugby league players. Publications were retrieved via six databases using the key search terms: rugby league, league, football; in combination with injury terms: athletic injuries, concussion, sports concussion, sports-related concussion, brain concussion, brain injury, brain injuries, mild traumatic brain injury, mTBI, traumatic brain injury, TBI, craniocerebral trauma, head injury and brain damage. Observational, cohort, correlational, cross-sectional and longitudinal studies were all included. 199 rugby league injury publications were identified. 39 (20%) were related in some way to concussion. Of the 39 identified articles, 6 (15%) had the main aim of evaluating concussion, while the other 33 reported on concussion incidence as part of overall injury data analyses. Rugby league concussion incidence rates vary widely from 0.0 to 40.0/1000 playing hours, depending on the definition of injury (time loss vs no time loss). The incidence rates vary across match play versus training session, seasons (winter vs summer) and playing position (forwards vs backs). The ball carrier has been found to be at greater risk for injury than tacklers. Concussion accounts for 29% of all injuries associated with illegal play, but only 9% of injuries sustained in legal play. In comparison with other collision sports, research evaluating concussion in rugby league is limited. With such limited published rugby league data, there are many aspects of concussion that require attention, and future research may be directed towards these unanswered questions.
Article
OBJECTIVE Nitric oxide (NO) is a universal mediator of biological effects in the brain. It has been implicated in the pathophysiological processes of traumatic brain injury. Understanding its pathophysiological role in vivo requires an understanding of the cellular sources and tissue compartments of the differentially regulated NO synthase (NOS) isoforms. This study was undertaken to investigate the cellular sources and tissue compartments of NO produced after experimental brain contusions in rats, by analysis of the early expression of the three isoforms of NOS, i.e., the inducible, endothelial, and neuronal isoforms. METHODS Focal brain contusions were produced in 24 rats using a weight-drop model. The animals were killed 6, 12, 24, 36, or 48 hours after trauma. Sections were analyzed by immunohistochemical and immunofluorescence analyses. Double staining assays were used to define which cells produced the different NOS isoforms. RESULTS Increases in endothelial NOS-, inducible NOS (iNOS)-, and neuronal NOS-positive cells were detectable by 6 hours after trauma. Endothelial NOS and iNOS levels peaked at 6 and 12 hours, respectively. Expression of neuronal NOS initially increased to a peak at 12 hours but then decreased to a level lower than that in control samples at 36 hours. Endothelial NOS was expressed exclusively in endothelial cells, whereas iNOS was expressed in neutrophils and macrophages. Neuronal NOS was predominantly detected in neurons but was also unexpectedly detected in polymorphonuclear cells. CONCLUSION In this model, the most striking finding regarding NO-producing enzymes was the expression of iNOS in polymorphonuclear cells and macrophages, cells that invade injured brain tissue. iNOS is thus implicated as a therapeutic target in contusional injuries. This pattern of NOS expression cannot be generalized to all types of brain injuries. The different compartments and cells that can produce NO are differentially regulated; therefore, compartmentalization can explain why NO is beneficial or detrimental, depending on the circumstances. A knowledge of different potential sites and sources of NO is required for any attempts to interfere with the pathophysiological properties of NO. (46;177;2000)
Article
Background: Rugby Union, a popular full-contact sport played throughout the world, has one of the highest rates of concussion of all full-contact sports. Objective: The aim of the current review was to systematically evaluate the available evidence on concussion in Rugby Union and to conduct a meta-analysis of findings regarding the incidence of concussion. Methods: Articles were retrieved via a number of online databases. The current review examined all articles published in English up to May 2014 pertaining to concussion in Rugby Union players. The key search terms included 'Rugby Union', 'rugby', 'union', and 'football', in combination with the injury terms 'athletic injuries', 'concussion', 'sports concussion', 'sports-related concussion', 'brain concussion', 'brain injury', 'brain injuries', 'mild traumatic brain injury', 'mTBI', 'traumatic brain injury', 'TBI', 'craniocerebral trauma', 'head injury', and 'brain damage'. Results: The final search outcome following the eligibility screening process resulted in the inclusion of 96 articles for this review. The meta-analysis included a total of 37 studies. The results of the meta-analysis revealed an overall incidence of match-play concussion in men's rugby-15s of 4.73 per 1,000 player match hours. The incidence of concussion during training was 0.07 per 1,000 practice hours. The incidence of concussion in women's rugby-15s was 0.55 per 1,000 player match hours. In men's rugby-7s match-play, concussion incidence was 3.01 per 1,000 player match hours. The incidence of concussion varied considerably between levels of play, with elite level play recording a rate of 0.40 concussions per 1,000 player match hours, schoolboy level 0.62 concussions per 1,000 player match hours, and the community or sub-elite level recording a rate of 2.08 concussions per 1,000 player match hours. The incidence of concussion in men's rugby-15s as a function of playing position (forwards vs. backs) was 4.02 and 4.85 concussions per 1,000 player match hours, respectively. Conclusions: Concussion is a common injury sustained and reported in match play and to a lesser extent during practice by Rugby Union players. Based on the available published data, there appears to be a variation in risk of concussion across level of play, with the sub-elite level having the greatest incidence of injury. Future research focused on studying the acute consequences and best management strategies in current players, and the potential longer term outcomes of concussion in retired players, is needed. A focus on the areas of prevention, injury identification, and medical management, and risk for long-term outcomes will be of benefit to current athletes.
Data
54 ▸ Additional material is published online only. To view these files please visit the journal online (http://dx.doi. org/10.1136/bjsports-2013-092313). To cite: McCrory P, Meeuwisse WH, Aubry M, et al. Br J Sports Med 2013;47:250–258. PREAMBLE This paper is a revision and update of the recommen-dations developed following the 1st (Vienna 2001), 2nd (Prague 2004) and 3rd (Zurich 2008) International Consensus Conferences on Concussion in Sport and is based on the deliberations at the 4th International Conference on Concussion in Sport held in Zurich, November 2012. 1–3 The new 2012 Zurich Consensus statement is designed to build on the principles outlined in the previous documents and to develop further concep-tual understanding of this problem using a formal consensus-based approach. A detailed description of the consensus process is outlined at the end of this document under the Background section. This document is developed primarily for use by physi-cians and healthcare professionals who are involved in the care of injured athletes, whether at the recre-ational, elite or professional level. While agreement exists pertaining to principal messages conveyed within this document, the authors acknowledge that the science of concussion is evolving, and therefore management and return to play (RTP) decisions remain in the realm of clinical judgement on an individualised basis. Readers are encouraged to copy and distribute freely the Zurich Consensus document, the Concussion Recognition Tool (CRT), the Sports Concussion Assessment Tool V.3 (SCAT3) and/or the Child SCAT3 card and none are subject to any restrictions, provided they are not altered in any way or con-verted to a digital format. The authors request that the document and/or the accompanying tools be dis-tributed in their full and complete format. This consensus paper is broken into a number of sections 1. A summary of concussion and its management, with updates from the previous meetings; 2. Background information about the consensus meeting process; 3. A summary of the specific consensus ques-tions discussed at this meeting; 4. The Consensus paper should be read in conjunc-tion with the SCAT3 assessment tool, the Child SCAT3 and the CRT (designed for lay use).
Article
Traditional structural neuroimaging techniques are normal in athletes who sustain sports-related concussions and are only considered to be clinically helpful in ruling out a more serious brain injury. There is a clinical need for more sophisticated, non-invasive imaging techniques capable of detecting changes in neurophysiology following injury. Concussion is associated with neurometabolic changes including neuronal depolarization, release of excitatory neurotransmitters, ionic shifts, changes in glucose metabolism, altered cerebral blood flow, and impaired axonal function. Proton magnetic resonance spectroscopy (1H-MRS, or simply MRS) is capable of measuring brain biochemistry and has the potential to identify and quantify physiologic changes following concussion. The focus of the current review is to provide an overview of research findings using MRS in sport-related concussion. A systematic review of articles published in the English language, up to February 2013, was conducted. Articles were retrieved via the databases: PsychINFO, Medline, Embase, SportDiscus, Scopus, Web of Science, and Informit using key terms: magnetic resonance spectroscopy, nuclear magnetic resonance spectroscopy, neurospectroscopy, spectroscopy, two-dimensional nuclear magnetic resonance spectroscopy, correlation spectroscopy, J-spectroscopy, exchange spectroscopy, nuclear overhauser effect spectroscopy, NMR, MRS, COSY, EXSY, NOESY, 2D NMR, craniocerebral trauma, mild traumatic brain injury, mTBI, traumatic brain injury, brain concussion, concussion, brain damage, sport, athletic, and athlete. Observational, cohort, correlational, cross-sectional, and longitudinal studies were all included in the current review. The review identified 11 publications that met criteria for inclusion, comprised of data on 200 athletes and 116 controls. Nine of 11 studies reported a MRS abnormality consistent with an alteration in neurochemistry. The results support the use of MRS as a research tool for identifying altered neurophysiology and monitoring recovery in adult athletes, even beyond the resolution of post-concussive symptoms and other investigation techniques returning to normative levels. Larger cross-sectional, prospective, and longitudinal studies are required to understand the sensitivity and prognostic value of MRS within the field of sport-related concussion.
Article
Objective: To update the 1997 American Academy of Neurology (AAN) practice parameter regarding sports concussion, focusing on 4 questions: 1) What factors increase/decrease concussion risk? 2) What diagnostic tools identify those with concussion and those at increased risk for severe/prolonged early impairments, neurologic catastrophe, or chronic neurobehavioral impairment? 3) What clinical factors identify those at increased risk for severe/prolonged early postconcussion impairments, neurologic catastrophe, recurrent concussions, or chronic neurobehavioral impairment? 4) What interventions enhance recovery, reduce recurrent concussion risk, or diminish long-term sequelae? The complete guideline on which this summary is based is available as an online data supplement to this article. Methods: We systematically reviewed the literature from 1955 to June 2012 for pertinent evidence. We assessed evidence for quality and synthesized into conclusions using a modified Grading of Recommendations Assessment, Development and Evaluation process. We used a modified Delphi process to develop recommendations. Results: Specific risk factors can increase or decrease concussion risk. Diagnostic tools to help identify individuals with concussion include graded symptom checklists, the Standardized Assessment of Concussion, neuropsychological assessments, and the Balance Error Scoring System. Ongoing clinical symptoms, concussion history, and younger age identify those at risk for postconcussion impairments. Risk factors for recurrent concussion include history of multiple concussions, particularly within 10 days after initial concussion. Risk factors for chronic neurobehavioral impairment include concussion exposure and APOE ε4 genotype. Data are insufficient to show that any intervention enhances recovery or diminishes long-term sequelae postconcussion. Practice recommendations are presented for preparticipation counseling, management of suspected concussion, and management of diagnosed concussion.