Suk-tak Chan1, Cora Ordway1, Ronald J Calvanio2, Ferdinando S Buonanno2, and Kenneth K Kwong1
1Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, MA, United States, 2Neurology, Massachusetts General Hospital, Boston, MA, United States
Synopsis
We used fMRI to map BOLD
responses to breath-by-breath O2-CO2 exchange ratio (bER)
under breath hold protocol for patients with persistent symptoms from mild
traumatic brain injury (mTBI). Comparing to controls, reduced cerebrovascular
reactivity (CVR) to bER was reported for patients in insula, anterior
cingulate, nucleus accumbens and ventral tegmental area, basically regions which
overlapped with the dopamine pathway.
The mean resting bER decreased with increased symptom severity indicated
by burden scores. Our findings are
consistent with impaired dopamine pathway reported for TBI patients and show
the success of using bER to evaluate CVR to breath hold.
Introduction
The brain of patients with mild traumatic brain injury (mTBI) can often
appear normal on conventional clinical imaging including computed tomography
(CT) and magnetic resonance imaging (MRI).
There is still an unmet need of an imaging strategy with increased
sensitivity to characterize the injury as well as the post-concussion symptoms
(PCS) after the injury. Instead of using
exogenous CO2 challenge which is often used to evaluate cerebrovascular
reactivity (CVR) in patients, in this study, we used the changes of endogenous
gases during breath holding to evaluate the cerebrovascular responses in
patients with mTBI. Disturbances in
respiratory functions after TBI are often accompanied by hypoxia1 which can lead to disturbances in brain gas
exchange and disorders of the cerebral acid-base balance due to increased
anaerobic metabolism.2, 3 Chronic hypoxemia
and metabolic acidosis have been suggested to play an important role in the
pathophysiological pathways that underlies the development of permanent brain
damage. In a separate study on healthy
subjects under breath hold challenge, our team has shown a strong dynamic
coupling between cerebrovascular responses and breath-by-breath ratio of
changes of partial pressures of O2 (PO2) to CO2 (PCO2),
in short, breath-by-breath O2-CO2 exchange ratio
(bER). In this study, we measured the blood
oxygenation level dependent (BOLD) signal changes to bER in patients with mTBI
under breath hold challenge. The
successful application of bER in evaluating CVR under breath hold challenge would offer an
alternative technique to exogenous CO2 challenge for patients with
acute injuries.Subjects and Methods
Participants: A total of 21
subjects aged from 20 to 49 years were included in this study. Ten of them were patients with mild TBI (no
loss of consciousness or loss of consciousness of <30 minutes’ duration, and
the Glasgow Coma Scale (GCS) score was >=13). The remaining 11 subjects were healthy controls
without brain injury. Methods: MRI scanning was
performed on a 3-Tesla scanner (Siemens Medical Germany) in the Athinoula A.
Martinos Center for Biomedical Imaging at the Massachusetts General
Hospital. All the experimental procedures were explained to the subjects,
and signed informed consent was obtained prior to participation in the
study. Whole brain MRI datasets were acquired for each subject: 1)
T1-weighted 3D-MEMPRAGE; 2) BOLD-fMRI images (TR=1450ms, TE=30ms, flip
angle=90º, FOV=220×220mm, matrix=64×64, slice thickness=5mm, slice gap=1mm) acquired when the
subject were under breath hold challenge. The paradigm consisted of 2
consecutive phases (resting and breath holding) repeated 6 times. The resting
phase lasted no less than 60 seconds, while the breath holding phase lasted 30
seconds. The challenge lasted 10 minutes. Before MRI acquisition when the
subjects were at rest and during MRI acquisition when the subjects were under
breath hold challenge, physiological changes including PCO2, PO2
and respiration were measured by calibrated gas analyzers and respiratory bellow. Symptom burden was assessed using Rivermead
Post Concussion Questionnaire (RPQ). Data
analysis: During resting state and under breath hold
challenge, time series of bER were derived as the ratio of the change in PO2
(ΔPO2 = inspired PO2 –
expired PO2) to the change in PCO2 (ΔPCO2
= expired PCO2 – inspired PCO2) measured between end
inspiration and end expiration in each respiratory cycle. All the BOLD-fMRI data were imported into the
software AFNI4 for time-shift
correction, motion correction, normalization and detrending. CVR in each voxel
was derived by regressing ΔBOLD on bER acquired
under breath hold challenge. Individual subject
maps of CVR with ΔBOLD per unit change of
bER were derived. Maps of ΔBOLD/bER from mTBI and
control groups were compared using unpaired t-tests. All the statistical
parametric maps will be cluster-corrected using a threshold estimated with
Monte Carlo simulation algorithm. The
time series of bER acquired during resting state was averaged to correlate with
the RPQ scores.Results
Comparing with controls without brain injury, reduced CVR was observed
in insula, anterior cingulate, nucleus accumbens, ventral tegmental area in
patients with mTBI (Fig1). Most of the
brain regions overlapped with the regions of dopamine pathway.5 The mean
resting bER decreased with increased symptom severity indicated by RPQ scores
(Fig2).Discussion
While the physiological mechanisms underlying the strong correlation
between bER and ΔBOLD under breath
hold challenge are not completely understood, our team
found in another study on healthy subjects that bER and ΔPO2 are
superior to ΔPCO2 to map the cerebrovascular responses to the brief
breath hold challenge. Our finding
of inverse relationship between resting bER and RPQ scores in 10 patients with
mTBI is consistent with some extent of respiratory decline reported in previous
studies.1-3 Reduced CVR found in the brain regions overlapping
with those on the dopamine pathway in mTBI patients may explain the persistence of symptoms. Conclusion
Our fMRI findings are consistent with the impaired dopamine pathway
reported in the literature on TBI patients.
It also shows the success of using bER to evaluate CVR in patients with
mTBI under breath hold challenge which has the potential to serve as an alternative
approach to study CVR for patients with acute injuries.Acknowledgements
This
research was carried out in whole at the Athinoula A. Martinos Center for
Biomedical Imaging at the Massachusetts General Hospital, using resources
provided by the Center for Functional Neuroimaging Technologies, P41EB015896, a
P41 Biotechnology Resource Grant supported by the National Institute of
Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health,
as well as the Shared Instrumentation Grant S10RR023043.References
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