Metabolic changes in the activated human visual cortex during mild hypoxia
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 CO2 (PetCO2) and O2 (PetO2) were controlled using a prospective feed-forward gas delivery system (RespirAct, Thornhill Inc). Subjects were fitted with a special breathing mask and individual “baseline” PetCO2 ¬≠was measured. Two gas conditions were defined based on the targeted PetO2: normoxia (100 mmHg) and hypoxia (45 mmHg). During both study conditions PetCO2 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 cm3 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 PetCO2 in between normoxia and hypoxia was 0.8±2.4% from the normoxia value, which demonstrates the excellent PetCO2 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 concentrations7 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 studies1-6, 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.

Figures

Figure 1. Example of average water peaks from a single subject during different gas and stimulus conditions.

Figure 2. Example of NMR spectra from a single subject during rest (32 averages) in normoxia (black) and hypoxia (red).

Figure 3. Average metabolic concentrations during fMRS paradigm averaged over subjects. (Paired two-tailed t-test). Error bars represent the SD.



Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)
3341