Felipe Barreto1,2, Nicholas Evanoff3, Donald Dengel3, Petr Bednarik1,4,5, Ivan Tkac1, Lynn Eberly6, Carlos Salmon2, and Silvia Mangia1
1CMRR, Department of Radiology, University of Minnesota, Minneapolis, MN, United States, 2Department of Physics, University of Sao Paulo, Ribeirao Preto, Brazil, 3School of Kinesiology, University of Minnesota, Minneapolis, MN, United States, 4Central European Institute of Technology, Masaryk University, Brno, Czech Republic, 5Department of Medicine, University of Minnesota, Minneapolis, MN, United States, 6Division of Biostatistics, University of Minnesota, Minneapolis, MN, United States
Synopsis
Previous
fMRI studies have demonstrated reduced evoked vascular responses during mild hypoxia,
which might indicate smaller neuronal recruitment during activation. Here we
used fMRS at 7T to quantify the effects of mild hypoxia on stimulus-induced
metabolic changes during visual stimulation. Our preliminary findings obtained
on 6 healthy volunteers show that mild hypoxia does not result in detectable differences
of functional metabolic changes as compared to normoxia, consistent with similar
functional energy demands in both conditions. Together with previous fMRI
findings, our results suggest that mild hypoxia alters the neurovascular coupling,
but does not result in smaller neuronal recruitment during activation.Purpose
Tight
coupling between oxygen consumption and oxygen delivery through the vascular
system is essential to proper brain function. Previous studies have shown mild
hypoxia, defined as the physiological state on which arterial blood oxygen
saturation (Y) ranges between 80-85%, causes a reduced extension of BOLD,
cerebral blood flow (CBF) and cerebral blood volume (CBV) activated areas
during a visual stimulation.
1-6 The amplitude of BOLD signal is
also reduced, however the amplitude of CBF and CBV evoked responses in the
active areas is unaltered. Overall, it remains unclear if smaller neuronal
populations are recruited during hypoxia, in which case the energetic cost of
activation is expected to be also reduced, or whether mild-hypoxia mainly
results in a different neurovascular coupling, in which case the functional energy
demands should remain unchanged. The present study aims at quantifying the
effect of mild hypoxia on functional energy metabolism as measured by stimulus-induced
changes in metabolite levels using functional spectroscopy (fMRS) at 7T.
Methods
Data
from 6 subjects (males, 26±6 years) were acquired using a 7T/90cm Agilent
magnet interfaced to Siemens console. End-tidal CO
2 (PetCO
2)
and O
2 (PetO
2) were controlled using a prospective
feed-forward gas delivery system (RespirAct, Thornhill Inc). Subjects were
fitted with a special breathing mask and individual “baseline” PetCO
2
was measured. Two gas conditions were defined based on the targeted PetO
2:
normoxia (100 mmHg) and hypoxia (45 mmHg). During both study conditions PetCO
2
was held constant to each individual’s initial baseline value. Subject’s heart
rate (HR) and Y were monitored using a pulse oximeter. Subject’s targeted
respiratory rate was 10 bpm, cued by an auditory metronome. Spectra were
acquired with semi-LASER (TR=5 s, TE=26 ms, 32 scans/spectra) from a 2x2x2 cm
3
voxel positioned in the occipital cortex during a 10 min-long fMRS paradigm (REST-STIM),
repeated for each gas condition. The stimulus consisted of radial red and black
checkerboards flickering at 8 Hz, whereas the rest condition was a black screen.
In order to minimize possible quantification bias induced by linewidth changes,
spectra linewidths were matched to the broadest linewidth corresponding to hypoxia
REST by using the linewidth measured on creatine peak at 3 ppm.
7 The
resulting line-matched spectra were quantified with LCModel. In order to estimate
the BOLD effect, unsuppressed water signals were also acquired from the voxel during
a brief 1-min stimulation paradigm in both gas conditions. Statistical
significance of changes was inferred by two-tailed paired t-test.
Results and discussion
The
mean difference of PetCO
2 in between normoxia and hypoxia was 0.8±2.4%
from the normoxia value, which demonstrates the excellent PetCO
2
control achieved during both gas conditions. HR and Y changed from 67±6 bpm and
98.5±0.7% during normoxia to 81±8 bpm to 82.2±1.1% during hypoxia, respectively.
The functional water peaks revealed a smaller BOLD effect during hypoxia in
comparison to normoxia (0.19±0.24 Hz vs 0.48±0.37 Hz, p=0.01, Fig. 1), in
agreement with previous MRI
findings.
1-6 Spectra were artifact-free during the entire experiment,
while the linewidth of creatine increased significantly in hypoxia as compared to
normoxia (11.2±0.7 to 12.5±0.6 Hz, Fig. 2). Typical functional changes in metabolite
concentrations
7 were observed for both gas conditions. In
particular, glutamate (Glu) and lactate (Lac) levels increased during stimulation
as compared to rest, whereas aspartate (Asp) and glucose (Glc) decreased (Fig.
3). Within the limited number of participants studied so far, concentration
changes during stimulation vs. rest in normoxia were not different from changes during
hypoxia. This finding, if confirmed in a larger cohort of subjects, would suggest
similar functional energetic demands, and therefore similar neuronal population
recruitment, during normoxia and mild hypoxia.
Conclusion
Our preliminary fMRS
findings suggest that the reduced oxygen availability during mild hypoxia does
not affect the energetic demands of the activated cortex. Together with
findings from MRI studies
1-6, this observation suggests that mild
hypoxia induces an altered neurovascular coupling, but does not result in
smaller neuronal recruitment during visual activation. We are currently
acquiring data on a larger cohort of subjects to confirm the findings of this
pilot study.
Acknowledgements
NIH grants: P41 EB015894 and P30 NS076408; Pilot grant (TTR) from CTSI U of Minnesota.
Supported by CAPES and CNPq.References
[1] Barreto et al.
ISMRM 2015. [2] Tuunanen and Kauppinen, Neuroimage. 2006; 30: 102-9. [3] Tuunanen
et al. MRM. 2006; 24:993-9. [4] Tuunanen et al. JCBFM. 2006;263-73. [5] Ho et
al. Neuroimage. 2008. 2008; 41: 179-88. [6] Mintun et al. 2001. PNAS; 98:
6859-64. [7] Bednarik et al. JCBFM. 2015; 1-10.