Is the locus coeruleus the brain’s gain control?
A prominent idea in neuroscience is that the locus coeruleus acts as a gain control for the cortex — adjusting how strongly networks respond to signals rather than carrying specific information itself. The “adaptive gain” theory formalises this: phasic and tonic modes of locus-coeruleus firing tune performance (Aston-Jones and Cohen (2005)).
Two threads make that relevant to ME/CFS.
Cortical gain. Norepinephrine modulates cortical excitation-inhibition balance and signal-to-noise: in mice, manipulating adrenergic signalling shifted these, and atomoxetine flattened the cortical signal-to-noise curve (Medina-Coss Y Leon et al. (2025)). If locus-coeruleus output is dysregulated, the responsiveness of cortical networks changes.
Barrier immunity. Separately, norepinephrine can act on the vasculature to reduce tight-junction molecules and permit immune-cell entry — the “gateway reflex” (Matsuyama et al. (2021)). A dysregulated gain signal could touch both cortical processing and brain-barrier surveillance.
The speculative payoff. A gain-control failure would give a single mechanism for two otherwise-separate experiences: ordinary sensory or bodily signals being felt as disproportionately intense, and altered neuroimmune access to the brain. That is more far-reaching than “norepinephrine is low” — though it is also less directly evidenced.
The caveats. Both arms are mouse/review evidence; neither has been measured against a noradrenergic index in ME/CFS. The idea is testable — an arousal index should correlate with sensory-gating and with a barrier marker — but it is not yet tested.