Neurovascular and synaptic milieu of brain-resident cells in cognitive dysfunction of myalgic encephalomyelitis/chronic fatigue syndrome.

backgroundCognitive dysfunction (“brain fog”), encompassing impairments in attention, processing speed, memory, and executive function, is a prevalent and disabling feature of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). While systemic immune abnormalities are well documented, the central nervous system processes linking peripheral immune disturbance to cognitive impairment remain poorly defined, limiting mechanism-based stratification and therapeutic development. MAIN BODY: This review synthesizes evidence from neuroimaging, neuroimmunology, neurovascular biology, and cellular metabolism to propose a brain-centered, cell-resolved framework for ME/CFS-associated cognitive dysfunction. Distinct from prior neuroimmune or neurovascular syntheses that emphasize systemic inflammation or vascular dysfunction in isolation, this review adopts a brain-centered perspective. Existing findings are organized around interactions among brain-resident cellular populations within the neurovascular and synaptic microenvironment. Across studies, human evidence is largely derived from cross-sectional imaging, biomarker, and physiological assessments, supplemented by mechanistic insights from experimental models. The strength and consistency of evidence vary across proposed mechanisms: neurovascular and glial alterations are supported by relatively convergent imaging and biomarker data, whereas neuronal network imbalance, oligodendrocyte involvement, and extracellular vesicle–mediated signaling remain more heterogeneous and hypothesis-generating. Accordingly, microglial priming, astrocytic dysfunction, excitation–inhibition imbalance, and neurovascular unit alterations are interpreted as associative and context-dependent processes rather than established causal drivers of cognitive impairment.

conclusionsTaken together, primarily cross-sectional human studies complemented by experimental data support a model in which cognitive dysfunction in ME/CFS reflects persistent but potentially modifiable neuroimmune and neurometabolic dysregulation, rather than fixed structural neurodegeneration. The translational value of this framework lies in its capacity to hierarchize mechanistic pathways by evidential strength and cellular context, thereby informing hypothesis-driven patient stratification and prioritization of glial-, vascular-, or metabolism-targeted interventions for future testing. Longitudinal and interventional studies will be essential to determine causal relationships and to evaluate whether targeting specific brain-resident cellular processes can meaningfully improve cognitive outcomes in ME/CFS.