Experimental hypoxia to probe neuro-metabolic and vascular dysregulation in ME/CFS: a multimodal proof-of-concept MRI study

Background Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a poorly understood, debilitating multisystem condition. Converging evidence implicates impaired cellular bioenergetics, neuroinflammation and defective neurovascular coupling that may manifest as "virtual hypoxia" only under physiological stress. Methods We performed a single-session multimodal 3T MRI study combining brain volumetry, arterial spin labelling (ASL) and multivoxel proton magnetic resonance spectroscopy under normoxia and two controlled hypoxic challenges (oxygen saturation 87 {+/-} 3%) in 26 ME/CFS patients and 27 age- and sex-matched healthy controls. Results After intracranial-volume normalization, patients showed a reduced brainstem volume (1.46 0.14 vs. 1.55 {+/-} 0.18 % of eTIV; p = 0.013, FDR-p = 0.039), whereas deep grey matter and whole-brain parenchymal fraction did not differ between groups. Whole-brain cerebral blood flow (CBF) rose under hypoxia in both groups (controls +4.8 {+/-} 13.0%, patients +3.7 {+/-} 11.7%), with greater initial inter-individual variability in patients (patient-to-control variance ratio up to 6.94; FDR-p = 0.001). Thalamic lactate-to-creatine (Lac/tCr) ratios increased with hypoxia in controls (FDR-p = 0.028) but were already elevated at normoxia in patients (0.171 vs. 0.135; FDR-p = 0.021) and did not rise further (FDR-p = 0.38). In exploratory analyses, patients showed exaggerated inverse coupling between thalamic total N-acetylaspartate (tNAA/tCr) and white-matter CBF. Conclusions These findings provide in vivo evidence of impaired neuro-metabolic and vascular adaptive capacity in ME/CFS, supporting the virtual hypoxia hypothesis and highlighting candidate imaging markers for stratification that warrant validation.