In the dark room of the scanner, a person watches for rare flashes on a screen. An infrared camera records their pupil a thousand times per second, while an MRI scanner simultaneously logs which brain areas light up. In this way, 89 volunteers aged 19 to 78 helped scientists see how the pupil becomes a display on which the brain outputs two different signals.
The first signal is rapid pupil changes. When a person notices an unexpected stimulus, the pupil suddenly dilates and immediately returns to baseline. These spikes coincide with activity in extensive areas of the cortex, cerebellum, and brainstem, where there are especially many terminals that release noradrenaline. Noradrenaline is a substance the brain uses as an "attention!" button: it makes neurons respond faster and helps you focus.
The second signal is pupil size at rest, after rapid changes have been removed. It turned out to be linked to brain regions with many opioid and cannabinoid receptors. These systems act as a background regulator: they don't spike with every stimulus but slowly set the overall level of arousal, much like a speaker's volume doesn't change with each note but determines how loud the whole piece of music sounds.
With age, the link between rapid pupil changes and the brain weakens. In older participants, fewer brain regions synchronized with the pupil, and the match with the noradrenaline map decreased. However, the link between pupil size and opioid and cannabinoid receptors remained unchanged from 19 to 78 years. This means the pupil's display doesn't break down entirely: one part dims while the other keeps glowing steadily.
Previously, it was unclear whether the pupil reflects the activity of this specific region or of several chemical systems at once, and whether this link persists with age. Now it's clear that rapid pupil changes are a fingerprint of the noradrenaline system, while absolute size is a fingerprint of the opioid and cannabinoid systems. The trick is simple: compare spatial maps of correlation between pupil and brain activity with maps of receptor density obtained using PET.
The practical benefit is obvious. Pupillometry, measuring the pupil with a camera, costs pennies compared to tomography. If the weakening link between pupil and brain truly indicates a decline in the noradrenaline system, such a test could become an early warning of Alzheimer's risk. But for now it's only a first step: long-term observations of the same people are needed to check whether a dimming pupil signal really heralds memory problems. For the time being, the pupil remains a window through which we can see the brain age, but that window is only just beginning to be wiped clean.
The locus coeruleus occupies on average just 5 voxels at 2 mm resolution, making it one of the smallest objects that can be studied with fMRI.
Not published on arXiv. Here are its page, the PDF and the formalization: you can check it yourself, not only read our account.