The overlap between long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) continues to yield surprising insights—especially when we stop looking only in the blood and start paying attention to the brain itself.
A recent study examining cerebrospinal fluid (CSF) immune signatures in ME/CFS has opened a fascinating window into what may be the neurological heart of these illnesses. In this study, researchers identified a subgroup of patients whose CSF revealed elevated levels of cytokines and matrix metalloproteinases—markers of neuroinflammation. Notably, these changes were not seen in their blood. The inflammation, it appears, was confined to the brain.
Where exactly in the brain is this happening?
To answer that, we need to revisit the choroid plexus, the small but mighty structure that produces CSF. Located in the lateral, third, and fourth ventricles of the brain, the choroid plexus serves as an immune interface—regulating what enters the brain and how it responds. And while all ventricles matter, it’s the fourth ventricle, nestled in the brainstem, that commands particular attention.
The brainstem is the hub for autonomic regulation—controlling heart rate, blood pressure, respiration, and sleep. It’s also intimately involved in attention, fatigue, and the brain's internal sense of balance. The CSF drawn for immune analysis primarily reflects activity in this region, and the presence of inflammatory markers here directly implicates brainstem circuits as drivers of the symptoms we see in both ME/CFS and long COVID: fatigue, POTS, brain fog, and sleep-wake disruption.
But this inflammation doesn’t appear to be new. It seems more likely that long COVID unmasks a pre-existing vulnerability—a simmering neuroinflammatory state that becomes clinically visible when SARS-CoV-2 disrupts immune regulation. Think of it like a wound that never fully healed, flaring up with renewed intensity when challenged.
The implication? Long COVID, at least in part, may not be a new disease—but a revelation of who was already at risk. And recovery will depend on understanding and resetting the neuroimmune landscape, particularly in and around the fourth ventricle.
This is a call to shift our focus inward—toward the brainstem, toward the choroid plexus, and toward the quiet currents of cerebrospinal fluid that may hold the key to unravelling the chronic fatigue puzzle.
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