During the third day of Building Bridges ’26, in a talk titled ‘Where does fatigue come from?’, Anna Kuppuswamy began with a paradox: everyone experiences fatigue, but it resists definition. To study it, we need to define it, yet it is subjective and has no quantity to measure or track. Fatigue is something reported.
She tested whether fatigue fits existing categories. It is felt in the body, so it might be a sensation—but all sensations have a receptor or pathway, and fatigue has none. It can change behaviour, so it might be an emotion—but emotions have an object, such as fear tied to a threat. Neither box fits.
Research on chronic fatigue has lagged behind, and many conditions overlap with it. Motivational disorders are one example: apathy and fatigue cannot be differentiated from the outside, only through reporting. Arousal is another: sleepiness is relieved by sleep; fatigue is not. Pain shares interoceptive machinery, but fatigue can occur without pain. Mood is also entangled: fatigue is a criterion for depression, yet it appears without depression, and antidepressants lift mood but not fatigue.
These conditions do not share a single pathology. One might look to the body, the mind, or the brain. Each is reasonable, Kuppuswamy suggested, and each is wrong. Fatigue is not a readout of a bodily quantity, and diseases do not predict it either. A more sophisticated account is metacognitive—not purely so, but something of that kind. Pain faced a similar argument fifty years ago. Today, no one thinks the absence of tissue damage makes pain purely psychological; nociplastic pain is a useful precedent.
‘In every condition where fatigue occurs, resting brain activity is abnormal’
So Kuppuswamy turned to the brain. In every condition where fatigue occurs, resting brain activity is abnormal. But the abnormalities are not identical. Four patterns keep appearing. They are diffuse: distributed rather than focal, and more distributed as samples grow. They are non-specific: the same networks appear in diseases with nothing in common. They are direction-inconsistent: hyper- and hypo-connectivity can appear in the same network, often within the same study. And they are entangled with arousal: inseparable from wakefulness, usually treated as contamination.
Fatigue, then, is everywhere, in everyone, in both directions at once, and inseparable from being awake. It is not a place, Kuppuswamy proposed; it is a setting. Like gain in a system, or interest rates, the gain setting changes with fatigue. The stimulus remains unclear. Diffuse patterns can be explained by gain, as can non-specific and direction-inconsistent findings, and gain is entangled with arousal.
But one setting is not enough. Kuppuswamy invoked Spearman’s problem in a new domain: all cognitive tests correlate positively, which led to a two-factor model—one general number plus a profile. She proposed the same structure for fatigue: a gain, plus a residual for each channel, including bodily signals, external senses, and effort.
The talk offered no simple source for fatigue. Instead, it reframed the question. Fatigue may not be a thing located in one system, but a global setting that shapes how signals, senses, and effort are processed—reported by the person who feels it, and visible in the brain only as a diffuse, shifting configuration.
More from the conference:
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