Hypoxia alters posterior cingulate cortex metabolism during a memory task: A 1H fMRS study.

Environmental hypoxia (fraction of inspired oxygen (FIO2) ∼ 0.120) is known to trigger a global increase in cerebral blood flow (CBF). However, regionally, a heterogeneous response is reported, particularly within the posterior cingulate cortex (PCC) where decreased CBF is found after two hours of hypoxic exposure. Furthermore, hypoxia reverses task-evoked BOLD signals within the PCC, and other regions of the default mode network, suggesting a reversal of neurovascular coupling. An alternative explanation is that the neural architecture supporting cognitive tasks is reorganised. Therefore, to confirm if this previous result is neural or vascular in origin, a measure of neural activity that is not haemodynamic-dependant is required. To achieve this, we utilised functional magnetic resonance spectroscopy to probe the glutamate response to memory recall in the PCC during normoxia (FIO2 = 0.209) and after two hours of poikilocapnic hypoxia (FIO2 = 0.120). We also acquired ASL-based measures of CBF to confirm previous findings of reduced CBF within the PCC in hypoxia. Consistent with previous findings, hypoxia induced a reduction in CBF within the PCC and other regions of the default mode network. Under normoxic conditions, memory recall was associated with an 8% increase in PCC glutamate compared to rest (P = 0.019); a change which was not observed during hypoxia. However, exploratory analysis of other neurometabolites showed that PCC glucose was reduced during hypoxia compared to normoxia both at rest (P = 0.039) and during the task (P = 0.046). We conclude that hypoxia alters the activity-induced increase in glutamate, which may reflect a reduction in oxidative metabolism within the PCC. The reduction in glucose in hypoxia reflects continued metabolism, presumably by non-oxidative means, without replacement of glucose due to reduced CBF.

Dietary nitrate supplementation effect on dynamic cerebral autoregulation in normoxia and acute hypoxia.

We tested the hypothesis that increasing the nitric oxide (NO) bioavailability by dietary nitrate would recover the hypoxia-induced reduction in dynamic cerebral autoregulation (CA). Twelve healthy males (age 21 ± 2 years) completed four days of dietary supplementation with a placebo or inorganic nitrate drink (140-ml beetroot juice per day) followed by 60-min of normoxia or hypoxia (fraction of inspired oxygen [FiO2] = 13%). Duplex ultrasonography was used to perform volumetric change-based assessment of dynamic CA in the internal carotid artery (ICA). Dynamic CA was assessed by rate of regulation (RoR) of vascular conductance using the thigh-cuff method. Four days of beetroot supplementation increased circulating nitrate by 208 [171,245] µM (mean difference [95% confidence interval]) compared with placebo. Dynamic CA was lower in hypoxia than normoxia (RoR Δ-0.085 [-0.116, -0.054]). Compared with placebo, nitrate did not alter dynamic CA in normoxia (RoR Δ-0.022 [-0.060, 0.016]) or hypoxia (RoR Δ0.017 [-0.019, 0.053]). Further, nitrate did not affect ICA vessel diameter, blood velocity or flow in either normoxia or hypoxia. Increased bioavailability of NO through dietary nitrate supplementation did not recover the hypoxia-induced reduction in dynamic CA. This suggests the mechanism of hypoxia-induced reduction in dynamic CA does not relate to the availability of NO.

Reversal of neurovascular coupling in the default mode network: Evidence from hypoxia.

Local changes in cerebral blood flow are thought to match changes in neuronal activity, a phenomenon termed neurovascular coupling. Hypoxia increases global resting cerebral blood flow, but regional cerebral blood flow (rCBF) changes are non-uniform. Hypoxia decreases baseline rCBF to the default mode network (DMN), which could reflect either decreased neuronal activity or altered neurovascular coupling. To distinguish between these hypotheses, we characterized the effects of hypoxia on baseline rCBF, task performance, and the hemodynamic (BOLD) response to task activity. During hypoxia, baseline CBF increased across most of the brain, but decreased in DMN regions. Performance on memory recall and motion detection tasks was not diminished, suggesting task-relevant neuronal activity was unaffected. Hypoxia reversed both positive and negative task-evoked BOLD responses in the DMN, suggesting hypoxia reverses neurovascular coupling in the DMN of healthy adults. The reversal of the BOLD response was specific to the DMN. Hypoxia produced modest increases in activations in the visual attention network (VAN) during the motion detection task, and had no effect on activations in the visual cortex during visual stimulation. This regional specificity may be particularly pertinent to clinical populations characterized by hypoxemia and may enhance understanding of regional specificity in neurodegenerative disease pathology.