J Head Trauma Rehabil

Vol. 28, No. 4, pp. 241–249

c 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
Copyright 

Exercise Treatment for Postconcussion

Syndrome: A Pilot Study of Changes
in Functional Magnetic Resonance
Imaging Activation, Physiology,
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and Symptoms
John J. Leddy, MD, FACSM, FACP; Jennifer L. Cox, PhD; John G. Baker, PhD;
David S. Wack, PhD; David R. Pendergast, EdD; Robert Zivadinov, MD, PhD;
Barry Willer, PhD

Purpose: To compare functional magnetic resonance imaging (fMRI) activation patterns during a cognitive task,
exercise capacity, and symptoms in postconcussion syndrome (PCS) patients who received exercise treatment (n =
4) with a PCS placebo stretching group (n = 4) and a healthy control group (n = 4). Methods: Subjects completed
a math processing task during fMRI and an exercise treadmill test before (time 1) and after approximately 12 weeks
(time 2). Exercise subjects performed aerobic exercise at 80% of the heart rate (HR) attained on the treadmill test,
20 minutes per day with an HR monitor at home, 6 days per week. The program was modified as the HR for
symptom exacerbation increased. Results: At time 1, there was no difference in fMRI activation between the 2 PCS
groups but healthy controls had significantly greater activation in the posterior cingulate gyrus, lingual gyrus, and
cerebellum versus all PCS subjects (P < .05, corrected for multiple comparisons). At time 2, exercise PCS did not
differ from healthy controls whereas placebo stretching PCS had significantly less activity in the cerebellum (P < .05
corrected) and in the anterior cingulate gyrus and thalamus (P < .001, uncorrected) versus healthy controls. At time
2, exercise PCS achieved a significantly greater exercise HR (P < .001) and had fewer symptoms (P < .0004) than
placebo stretching PCS. Cognitive performance did not differ by group or time. Conclusions: Controlled aerobic
exercise rehabilitation may help restore normal cerebral blood flow regulation, as indicated by fMRI activation, in
PCS patients. The PCS symptoms may be related to abnormal cerebral blood flow regulation. Key words: exercise,
fMRI, physiology, postconcussion syndrome

R ECENT developments have supported the use of

standardized exercise testing and controlled aero-
Author Affiliations: Department of Orthopaedics and University Sports
Medicine (Drs Leddy and Baker), Buffalo Neuroimaging Analysis Center,
Department of Neurology (Drs Cox and Zivadinov), Department of
Nuclear Medicine (Drs Baker and Wack), Department of Physiology and
Biophysics (Dr Pendergast), and the Department of Psychiatry (Dr Willer),
State University of New York at Buffalo, Buffalo.
The authors acknowledge the assistance of the Buffalo Neuroimaging Analysis
Center (BNAC), located in the Jacobs Neurological Institute (JNI) at the
Buffalo General Hospital, for performing the fMRI studies for this project.
Dr Leddy received funding from the University at Buffalo Interdisciplinary
Research Development Fund. Drs Willer and Leddy received funding from the
Robert Rich Family Foundation and the Buffalo Sabres Foundation.
The authors declare no conflicts of interest.
Corresponding Author: John J. Leddy, MD, FACSM, FACP, Uni-
versity Sports Medicine, 160 Farber Hall—SUNY, Buffalo, NY 14214
(leddy@buffalo.edu).
DOI: 10.1097/HTR.0b013e31826da964
bic exercise treatment as an approach to treating post-
concussion syndrome (PCS).1 This diagnostic and treat-
ment approach proposes that one fundamental cause
of refractory PCS is persistent physiologic dysfunction.2
Physiologic dysfunction may include altered autonomic
function and impaired autoregulation and distribution
of cerebral blood flow (CBF).2 Recent studies have re-
ported about the efficacy, safety, and reliability of ex-
ercise assessment of concussion and for a program of
controlled and progressive subsymptom threshold ex-
ercise rehabilitation in ameliorating PCS.1,3 Exercise
assessment and aerobic exercise training may reduce
concussion-related physiological dysfunction by restor-
ing autonomic balance and by improving autoregulation
of cerebral blood flow.4–8
Functional magnetic resonance imaging (fMRI) mea-
sures differences in the magnetic properties of oxy-
genated versus deoxygenated blood, which is called
241

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242 JOURNAL OF HEAD TRAUMA REHABILITATION/JULY–AUGUST 2013
blood oxygenation level dependent (BOLD) imaging.
Functional MRI is thus an indirect indicator of changes
in local CBF to areas of increased neural activity. A num-
ber of studies have examined patterns of fMRI hemo-
dynamic BOLD response related to PCS using working
memory tasks. Several early studies reported abnormal
activations during working memory tasks after mild trau-
matic brain injury.9,10 Chen et al11 found that 13 of
15 symptomatic athletes had a more widely distributed
fMRI activation pattern relative to healthy controls dur-
ing a working memory task even though their perfor-
mances were similar. In a separate study, Chen et al12
divided athletes with PCS into low and moderate symp-
tom groups. The moderate symptom group showed re-
duced performance on a computerized cognitive mea-
sure whereas both PCS groups showed atypical fMRI
activations during a working memory task when com-
pared with controls.
Lovell et al13 compared fMRI (using the N-back test),
a computerized battery of cognitive tests, and symp-
tom reports of 28 concussed athletes with 13 healthy
controls. They found that athletes with increased acti-
vation on initial fMRI had a delayed recovery versus
athletes without increased activation. Initial changes in
brain activation were associated with changes in self-
reported symptoms and computerized cognitive test per-
formance. Chen et al14 used fMRI at 2 time points with 4
athletes who recovered from PCS, 5 athletes with ongo-
ing PCS, and 6 healthy controls. At time 1, athletes with
PCS showed decreased activation in a region where nor-
mal controls showed increased activation during a work-
ing memory task. The athletes with PCS also showed
increased activations at time 1 in other areas not seen
among the normal controls. At time 2, the athletes who
had recovered were similar to controls whereas PCS ath-
letes showed activations similar to their time 1 patterns.
To our knowledge, there is no study that has used
fMRI to assess activation changes before and after a spe-
cific treatment program for PCS. Reduction in symp-
toms with controlled exercise treatment may be associ-
ated with normalization of autoregulation of CBF as
reflected by normalization of hemodynamic changes
during a working memory task. In this study, consistent
with Chen et al,11 we interpret changes in fMRI BOLD
signals to reflect changes in cognitive task-related neu-
ral activations that serve as an indirect measure of local
CBF. The purpose of this study was to compare fMRI
brain activation patterns in PCS patients who were given
exercise treatment versus a placebo stretching treatment
versus healthy controls. Prior to treatment, we expected
different patterns during a working memory task for indi-
viduals with PCS when compared with healthy controls.
After exercise treatment, we expected no difference be-
tween the exercise-treated PCS group and the healthy
control group.
Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
METHODS
Participants
Study participants included 10 consecutive patients
(5 females; age range, 17–52 years) from a University
Concussion Clinic with PCS and 5 healthy controls (4
females; age range, 18-34 years), who were recruited from
the community. Patients were eligible for the study if (1)
a clinical interview confirmed that the patient’s symp-
toms met the World Health Organization International
Classification of Diseases, Tenth Revision, criteria for PCS15 ;
(2) they had an identifiable threshold (heart rate [HR]
and systolic blood pressure) for exacerbation of symp-
toms on a progressive exercise test1 ; and (3) they were
symptomatic for 6 weeks or more but 12 months or less
postinjury. Patients were otherwise “apparently healthy,”
which was defined as absence of signs and symptoms of
and low risk for cardiopulmonary disease according to
the American College of Sports Medicine.16 Athlete was
defined as someone involved in competitive scholas-
tic/collegiate athletics or a competitive recreational ath-
lete training on a regular basis. All participants gave
informed consent in accordance with the University’s
Health Sciences Institutional Review Board.
Of the 10 patients with PCS, 2 were dropped from
the study after the initial MRI examination because of
concomitant/other diagnoses that could confound the
fMRI results (posttraumatic stress disorder and malinger-
ing). One healthy control dropped out of the study after
the first fMRI examination due to a scheduling conflict.
Healthy controls (n = 4) were free from previous head
injury. Some subjects had a history of prior concussions
but we did not examine the effects of these because the
sample was too small. See Table 1 for demographic and
clinical summary of the study participants. The stretch-
ing group had 2 athletes (1 high school and 1 collegiate),
the exercise group had 2 athletes (both college athletes),
and the control group had 2 athletes (1 high school and
1 collegiate). Participants in the controlled aerobic exer-
cise treatment group (n = 4) and the stretching (placebo)
treatment group (n = 4) were blind to the expected ef-
fectiveness of their treatment condition. Participants in
the placebo treatment group were subsequently offered
exercise treatment.
Design
The first 5 participants eligible for treatment were
assigned to controlled aerobic exercise treatment. The
second 5 participants with PCS were assigned to the
placebo stretching group. This choice for assignment
was based on the fact that interaction among partic-
ipants was probable and we wanted participants to
share a view of their assigned treatment as likely to be
 TABLE 1 Demographics, time intervals, heart rate and symptoms for the PCS exercise, PCS stretching, and healthy control
groups at time 1 and time 2
HR in bpm HR in bpm
Time after achieved on achieved on
Time after first Time exercise test exercise test
concussion evaluation between time 1 (% time 2 (% Number of Number of
to first to first fMRI maximum maximum symptoms symptoms
Age, y Sex Athlete (no.) fMRI, d fMRI, d scans, d predicted HR) predicted HR) (time 1) (time 2)
Individual data: PCS exercise group
1 26 F YES 62 22 67 147 (76) 180 (93) 20 3
2 18 F YES 65 25 60 150 (74) 190 (94) 18 2
3 33 F NO 75 37 57 130 (70) 179 (96) 16 3
4 26 M NO 59 31 83 151 (78) 190 (98) 16 0
Mean data 24 2 65.25 28.75 67 145 (75) 185 (95)a 17.5 2b
Individual data: PCS stretching group
1 19 M YES 270 16 137 135 (67) 140 (70) 18 18
2 27 M NO 110 13 103 148 (77) 158 (82) 22 20
3 17 M YES 33 26 30 161 (79) 148 (73) 13 3
4 30 F NO 270 10 134 172 (90) 162 (85) 22 18
Mean data 21 2 170.75 16.25 101 154 (78) 152 (78) 19 15
Individual data: healthy control group
1 29 F NO NA NA 71 NA NA NA NA
2 18 F YES NA NA 88 NA NA NA NA
3 19 F YES NA NA 102 NA NA NA NA
4 18 F NO NA NA 103 NA NA NA NA
Mean data 21 2 91

Abbreviations: bpm, beats per minute; fMRI, functional magnetic resonance imaging; HR, heart rate; NA, not applicable; PCS, postconcussion syndrome.
a Significant at P < .001 versus PCS stretching group.
b Significant at P < .0004 versus PCS stretching group.
Exercise Treatment for Postconcussion Syndrome

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243
244 JOURNAL OF HEAD TRAUMA REHABILITATION/JULY–AUGUST 2013
effective. Healthy controls were recruited to match the
PCS group on the basis of age, sex, and athletic status.
There were no preenrollment interventions in this
study. The PCS aerobic exercise group participants were
instructed to perform a controlled and progressive aer-
obic exercise program at 80% of the HR attained on a
treadmill test.1 The treadmill test was performed in our
clinic. Participants exercised for 20 minutes per day with
a Polar heart rate monitor (Kempele, Finland), 6 days
per week, at home or in a gym. This program was mod-
ified as the HR for symptom exacerbation increased.1
Subjects were considered ready for the second fMRI
scan when they were able to exercise up to age-predicted
maximum HR without exacerbation of symptoms.1 The
PCS stretching group participants were provided with
a booklet that explained (in written and figure format)
a standardized and gradually progressive 12-week low-
impact breathing and stretching program developed at
the University. The PCS controls were instructed not
to exceed a low target HR (40%-50% of age predicted
max) so as not to affect cardiovascular fitness. Exam-
ples of stretches included quadriceps, double or single
knee to chest, sitting hamstring, and so forth. Partici-
pants stretched with an HR monitor for 20 minutes per
day, 6 days per week. All participants had an fMRI ex-
amination at baseline and again after approximately 12
weeks (Table 1). The healthy control participants also
completed 2 fMRI scans with approximately the same
time interval between the scans.
Treadmill test and symptom reports
The PCS subjects exercised on a treadmill at time 1
and time 2 following a Balke treadmill protocol to as-
sess for symptom exacerbation as per previous studies.1,3
Heart rate, blood pressure, symptoms, and perceived ex-
ertion were recorded every 2 minutes until either symp-
tom exacerbation or exhaustion.1 Resting concussion
symptoms were recorded at time 1 and time 2, prior to
exercise testing, using the Postconcussion Scale (PCS), a
validated assessment instrument that includes 22 symp-
toms of concussion (headache, dizziness, photophobia,
etc) with sound psychometric properties and normative
data for men and women.17
fMRI conditions
Participants completed an fMRI math task that was
modeled after the math task from Automated Neuropsy-
chological Assessment Metrics (ANAM). This comput-
erized cognitive test is widely used for baseline and
postinjury assessment of concussion and had been used
in previous behavioral studies in our group.18 The con-
struct validity of the ANAM Math Processing subtest
as a measure of processing speed and working memory
has received support from confirmatory factor analyses
Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
with traditional neuropsychological measures.19 Partic-
ipants saw simple math problems that were displayed
in white 50-point font on one line centered on a black
background. The math problem consisted of the addi-
tion and subtraction of 3 numbers. Participants were
asked to press a button under their right index finger if
the answer was less than 5 and to press a button under
their right middle finger if the answer was greater than 5.
Participants were asked to respond as quickly and as ac-
curately as possible. Seventy-two trials were completed
during the 5-minute run. The accuracy (percent cor-
rect) and speed (mean reaction time) were recorded for
each participant. Subjects heard instructions over head-
phones just prior to the task. Stimuli were presented
with Resonance Technology headphones, goggles, and
a button response system (Resonance Technology Inc,
Northridge, California; www.mrivideo.com).
fMRI acquisition
Functional and structural MRI data were acquired
using a 3T GE Signa LX Excite 12.0 scanner (Buffalo
Niagara MRI Center, Buffalo, NY) with an 8-channel
head coil. Functional images were acquired using gradi-
ent echo T2∗ Echo Planar Imaging, which generated 33,
5-mm thick slices with no gap between slices (repetition
time = 2500 msec, 144 repetitions for math task, echo
time = 35 msec, voxel size = 1 × 1 × 5 mm3 , matrix
size = 64 × 64, field of view = 24 mm2 , flip angle =
90◦ ). Image slices were aligned with the AC-PC plane.
Functional images were overlaid on a high-resolution
structural fast spoiled gradient scan (repetition time =
9.2 msec, echo time = 4.1 msec, voxel size = 1 × 1 × 1
mm3 , flip angle = 20◦ ).
fMRI analysis
Statistical Parametric Mapping 5 was used to analyze
all fMRI experiments (Wellcome Department of Cog-
nitive Neuroscience, London, England). Oblique axial
images were realigned, coregistered, and normalized. Im-
ages were smoothed using a full-width half maximum 8-
mm Gaussian smoothing kernel. A height threshold of
P < .001 was selected for initial comparisons. Regions
were considered significant that survived false discovery
rate threshold of P < .05, which corrects for multiple
comparisons. Given the few subjects in each group in
our pilot study, we also report potential findings of in-
terest at P < .001, uncorrected. The resting condition
was subtracted from the math task condition. At time 1
and time 2, group comparisons included exercise PCS
compared with controls, stretching PCS compared with
controls, exercise and stretching PCS groups combined
compared with controls, and exercise PCS compared
with stretching PCS.
 Exercise Treatment for Postconcussion Syndrome 245

RESULTS TABLE 3 Math-Rest, time 1: regions

Table 1 presents the demographics, maximum HR more active in control subjects than in
achieved during the exercise treadmill test, and number concussed patients (exercise and stretching
of symptoms (as recorded on the Postconcussion Scale) PCS groups combined)a
reported at rest at time 1 and time 2 for each subject. A
paired Student t test (2-tailed) comparing the increase in Region BA xb yb zb T-Value
HR from time 1 to time 2 for the PCS exercise group was
significant at P < .001. For the PCS stretching group, Left posterior 30 −9 −66 9 8.01
cingulate
it was nonsignificant (P < .75). A paired Student t test
Right cuneus 31 2 −62 6 6.76
(2-tailed) comparing the number of symptoms at time 1 Left cerebellum – −10 −41 −18 7.6
to time 2 for the PCS exercise group was significant at Right cerebellum – 10 −41 −18 6.9
P < .0004. For the PCS stretching group, it was non-
significant (P < .16).
Abbreviations: BA, Brodmann area; PCS, postconcussion syn-
Table 2 presents the average accuracy and the average drome.
mean reaction times during the math processing task a All P < .05, false discovery rate, corrected.

for the exercise, stretching, and healthy control groups. b x, y, and z are Talairach coordinates.

Paired Student t tests (2-tailed) revealed that there were

no significant differences among all 3 groups at time 1
or at time 2.
fMRI time 1 results
At time 1 there were no significant differences be-
tween the symptomatic exercise and stretching PCS
groups; similarly, there were no differences between the
exercise PCS group itself versus healthy controls and
the stretching PCS group itself versus healthy controls.
Table 3 and Figure 1 show that, at time 1, when com-
pared with the 2 combined PCS groups, the healthy con-
trol group showed increased activation in the posterior
cingulate gyrus, lingual gyrus, and cerebellum during the
ANAM Math Processing subtest.
fMRI time 2 results
At time 2, there were no significant differences be-
tween the PCS exercise treatment group and the healthy
control group. Table 4 and Figure 2 show that, at time
2, the PCS stretching group had less activity in the cere-
bellum, cingulate gyrus, and thalamus versus healthy
controls. There were no regions showing increased ac-
tivity for PCS stretching versus healthy controls at time
2. Although there were no clusters that survived our
threshold for significance (P < .05, false discovery rate),
the PCS exercise group had a small cluster (7 voxels)
of increased activity in the cingulate gyrus (0, 17.52,
39.66 mm, Talairach coordinates) at time 2 when com-
pared with the PCS stretching group (P = .055, cluster-
wise, family-wise error). There was no region where the
stretching PCS group had significantly increased activa-
tion versus the exercise PCS group.
DISCUSSION
This is the first study to provide support for the hy-
pothesis that a specific treatment program of controlled

TABLE 2 Average accuracy and mean

reaction times for the PCS exercise, PCS
stretching, and healthy control groups at
time 1 and time 2a
Time 1 Time 2
Average accuracy, % correct
Exercise 90 85
Stretching 82 88
Control 86 93
Average reaction time, ms
Exercise 2690 2291
Stretching 2622 2474
Control 2317 2112
Figure 1. Math-Rest, time 1: Posterior cingulate and cerebel-
lum activation greater in normal controls than all postconcus-
Abbreviation: PCS, postconcussion syndrome. sion syndrome subjects. Peak voxels are significant at P < .05,
a Comparisons are nonsignificant. false discovery rate; Image threshold = P < .001, uncorrected.
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246 JOURNAL OF HEAD TRAUMA REHABILITATION/JULY–AUGUST 2013

TABLE 4 Math-Rest, time 2: regions more Prior to treatment, each PCS participant had a unique
pattern of increased or decreased activation that dif-
active in control subjects than the fered from other individual participants. Individuals in
stretching PCS group the healthy control group did not show this somewhat
random, individually unique pattern of increased or de-
Region BA xa ya za T-Value creased activation. These findings are consistent with
Left – −23 −64 −17 18.51b previous studies that used different working memory
cerebellum tasks and found that each individual PCS subject had
Left 31, −13 −21 42 11.8c a unique activation pattern versus controls.11–14 These
cingulate 32,
findings have been interpreted to reflect a compensatory
gyrus 24
Left – −16 −10 10 9.65c mechanism whereby the brain allocates additional pro-
thalamus cessing resources to accomplish a task that has become
Right – 17 −36 5 8.6c more difficult than before injury. Although performance
thalamus may remain average for a period of time, it is likely
that compensatory mechanisms lead to fatigue over an
Abbreviations: BA, Brodmann area; PCS, postconcussion syn- extended period of cognitive activity. Consistent with
drome. this, our PCS participants reported a greater number of
a x, y, and z are Talairach coordinates.
symptoms at rest at time 1, including fatigue, when com-
b P < .05, false discovery rate corrected.
c P < .001, uncorrected.
pared with normative data for noninjured individuals.17
We hypothesize that fatigue, a common complaint of
aerobic exercise may restore patterns of hemodynamic PCS patients,17,20 and perhaps specifically fatigue af-
response on BOLD fMRI to normal control levels in ter working memory challenges,21 as well as other PCS
PCS patients during a cognitive task to a greater degree symptoms, may be related to the increased activation
than a placebo stretching program. For the Math-Rest seen on fMRI during cognitive tasks in symptomatic pa-
condition, the combined exercise and stretching groups tients. We hypothesize that controlled aerobic exercise
of 8 PCS participants showed different activation pat- treatment may help to alleviate PCS symptoms by restor-
terns in several brain regions at time 1 when compared ing normal CBF regulation and that this change may be
with the 4 participants in the healthy control group. At associated with restoration of a normal hemodynamic
time 2, after treatment, the exercise PCS group had fMRI response to working memory tasks.
activation patterns that did not differ from the control The combined PCS groups in this study experienced
group whereas the stretching PCS group differed from an exacerbation of symptoms before they reached their
controls. maximum HR during a structured exercise assessment
Interestingly, the PCS group performed similarly to at time 1. At time 2, however, the PCS exercise group
the healthy control group for accuracy and speed on the could reach maximum exercise capacity whereas the
working memory task at the pretreatment time point PCS stretching group could not. A recent study of pe-
(time 1). The mean scores for our control group were at diatric sport concussion reported significant alterations
or below normative values for the ANAM Math Process- in global CBF within 72 hours of injury in concussed
ing subtest; thus, it is unlikely that a ceiling effect would athletes versus controls that persisted beyond 30 days
explain the lack of a difference between the groups. Pre- in some subjects.22 One interpretation of our findings
treatment performance in the PCS participants, how- is that the controlled exercise treatment helped to re-
ever, was associated with the “cost” of altered CBF dis- store normal autoregulation of CBF. It is conceivable
tribution as measured by fMRI hemodynamic response. that problems with control of CBF may be associated

Figure 2. Math-Rest, time 2: (A) Left cerebellum (P < .05, false discovery rate, corrected); (B) Left cingulate; and (C) thalamic
(P < .001, uncorrected) activation in normal controls greater than stretching postconcussion syndrome subjects.

Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
 Exercise Treatment for Postconcussion Syndrome
with changes in fMRI hemodynamic response during a
working memory task, a hypothesis that warrants further
study. In contrast to the exercise group, altered hemo-
dynamic fMRI response persisted at time 2 for the PCS
stretching placebo group versus healthy controls. This
could be consistent with the different exercise capacities
observed between the 2 PCS groups at time 2 as well as
the difference in symptom reports at rest between the
two groups at time 2. We hypothesize that the exer-
cise and rest symptoms reported by PCS patients reflect
abnormal patterns of hemodynamic response brought
on by physiological and cognitive stressors. Controlled
progressive aerobic exercise treatment may help to re-
store normal CBF regulation by conditioning the brain
to gradually adapt to repetitive mild elevations of sys-
tolic blood pressure.23 There might be an association be-
tween this treatment effect and normalization of hemo-
dynamic responses seen in this study. This hypothesis
could be tested in future studies that measure actual
global CBF autoregulation during exercise as well as
global CBF and fMRI activation patterns during a cog-
nitive task.
Chen et al14 found no initial differences between their
3 groups of concussed subjects (recovered, did not re-
cover, and normal control) in behavioral performance
using a working memory task different than ours. The
groups with PCS showed decreased activation in the left
dorsolateral prefrontal cortex (Brodmann area 9/46), a
region where normal controls showed increased activa-
tion. The groups with PCS also showed activations in
other areas not used by normal controls in perform-
ing the task. As noted earlier, the authors interpreted
this as compensatory recruitment of other brain regions
to carry out the task.14 The participants in our study
showed variable changes in activation without a con-
sistent increase or decrease in the left dorsolateral pre-
frontal cortex. This discrepancy may reflect the different
working memory task used by Chen et al14 versus the
ANAM Math Processing task used in this study. Because
the ANAM Math Processing task is widely used clini-
cally to determine recovery from concussion,18 and is
used in return to play decisions for athletes, the changes
in activation seen during this task and the corresponding
changes in self-reported symptoms and exercise capacity
are especially interesting.
We studied the response to a specific treatment pro-
gram rather than the post hoc spontaneous recovery in
PCS studied by Chen et al.14 Nonetheless, there are sim-
ilarities in the results. Consistent with our results, Chen
et al14 found that athletes who spontaneously recov-
ered showed hemodynamic response patterns that were
similar to controls whereas athletes who did not recover
had patterns similar to their own time 1 patterns. In both
studies, healthy controls showed similar time 1 and time
2 activations, indicating effective CBF regulation as well
Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
247
as good retest reliability for the fMRI hemodynamic
response during the working memory tasks. Self-report
of symptoms reflected the changes over time in fMRI
activations in both studies.
Lovell et al13 also found that initial PCS versus healthy
control differences in fMRI brain activation patterns
were associated with self-reported symptoms. In addi-
tion, they found decreased computerized cognitive test
performance. In their study, though, there was increased
activation in particular regions on initial fMRI associ-
ated with greater symptoms, decreased cognitive per-
formance, and prolonged recovery. In our study, both
PCS groups showed reduced activation when compared
with healthy controls, which is similar to the findings of
Chen et al.14
In interpreting the results of the group comparisons, a
number of caveats need to be considered. Previous stud-
ies have shown that compensatory activations during
working memory tasks in PCS patients vary among in-
dividuals. Thus, our findings may represent coincidental
individual differences in recruitment of additional pro-
cessing resources to accomplish a working memory task.
An additional consideration is the possibility of a type
II error due to the relatively small sample size. For ex-
ample, there was not a significant difference for the PCS
exercise group versus the healthy control group at time
2. Nonetheless, even considering the possibility of a
type II error, greater differences were found between the
PCS stretching and the healthy control groups at time 2
than between the PCS exercise and the healthy control
groups. The time between concussion and first MRI was
much greater for the exercise versus the stretching group
(171 vs 65 days), which conceivably could have led to
findings related to inherent group differences rather than
a treatment effect. The exercise-treated group, however,
recovered despite greater symptom duration whereas the
placebo group did not.
The specific regions of fMRI activation that were dif-
ferent across groups can be interpreted cautiously with
reference to previous studies. At time 1, there was de-
creased activation in the left posterior cingulate gyrus
and in the right and left cerebellum for the 2 PCS groups
when compared with the healthy control group. The
posterior cingulate region has shown decreased activa-
tion in previous functional imaging studies among pa-
tients with mild memory problems related to Alzheimer
disease.24,25 Support for involvement of the cerebellum
in cognition, including verbal working memory and ex-
ecutive functioning, has also been reported.26,27
At time 2, the PCS stretching group showed decreased
activation in the left cerebellum, left anterior cingulate,
and the thalamus when compared with the healthy con-
trol group. In addition to the support for the cerebel-
lum’s role in cognition noted earlier, an fMRI study re-
ported increased activity in the anterior cingulate cortex
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248 JOURNAL OF HEAD TRAUMA REHABILITATION/JULY–AUGUST 2013
and prefrontal cortex during complex working memory
tasks.28 This result was interpreted to reflect engaging
attention control and selection processes that support
active maintenance in working memory. There is also
support for a role for the thalamus in contributing to
the control of visual attention and awareness.29
In summary, a specific treatment program of con-
trolled aerobic exercise treatment restored fMRI hemo-
dynamic response during a cognitive task to normal
control levels in PCS patients to a greater degree than
a placebo stretching program. Hemodynamic response
during the math cognitive task showed the expected dif-
ferences between the groups. Before exercise treatment,
the 2 PCS groups combined were different from healthy
controls but not from each other. After treatment, the
exercise group was not different from healthy controls
whereas the placebo group showed several regional dif-
ferences from healthy controls and also showed a small
regional difference approaching significance when com-
pared with the exercise group. Controlled exercise treat-
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