General anaesthetics transformed surgery by allowing consciousness to be switched off temporarily, but scientists still do not fully understand how the drugs produce that state. The question reaches beyond operating rooms because anaesthesia is offering clues about the brain and the nature of consciousness itself.

In 1797, British naval commander Admiral Horatio Nelson had his right arm amputated in an operation that saved his life. According to legend, the only anaesthetic offered to him was a swig of rum.

For most of human history, even limb removal was performed while patients remained fully awake. The introduction of general anaesthetics in 1846 changed surgery by making it possible to suspend consciousness and then restore it.

More than 350 million operations are now performed under general anaesthesia each year. Yet researchers still cannot fully explain how these medicines make a patient unconscious, even as the drugs provide an unusual way to investigate consciousness.

Anaesthetics fall into several categories, with some directly blocking pain and others making patients sleepy and relaxed. General anaesthetics go further by eliminating awareness of what is happening.

Many substances can induce unconsciousness, ranging from xenon, a gas rarely used in practice, to propofol, the most widely used general anaesthetic. Although their chemical structures can differ considerably, they all interfere with communication among nerve cells in the brain.

Magnetic resonance imaging scans show a global reduction in brain activity under general anaesthesia. What remains uncertain is whether unconsciousness requires the entire brain to shut down or whether certain regions trigger the broader collapse in activity.

Nick Franks, professor of biophysics and anaesthetics at Imperial College London, points to brain regions that appear particularly sensitive to anaesthesia. These areas shut down first, raising the possibility that they help initiate the wider loss of activity.

The thalamus, a structure deep within the brain, appears to power down early after a general anaesthetic is administered. Because the thalamus acts as a hub between brain regions and plays a crucial role in initiating and maintaining sleep, researchers are examining whether anaesthetics exploit natural sleep circuitry.

“If you anaesthetise an animal and then stimulate a very selective part of the thalamus, you can wake the animal up,” says Franks. He also notes that thalamic stimulation has awakened some people in a coma, although more research is needed to determine whether this explains anaesthetic unconsciousness.

Other scientists consider the cerebral cortex, the brain’s wrinkled outer layer, the main home of consciousness. The frontal and parietal lobes have also been implicated because they support critical thinking and sensory processing, including touch.

Research also suggests the brain may enter a third state that is neither fully conscious nor fully unconscious. Accidental awareness, in which patients remember aspects of surgery after waking, is estimated to affect one in 15,000 patients undergoing an operation.

Jaideep Pandit, a consultant anaesthetist at the Oxford University Hospitals, tested this possibility by giving patients an anaesthetic and muscle relaxant while using a tourniquet to keep one forearm from becoming paralysed. One third squeezed an experimenter’s fingers on command despite showing no signs of wakefulness or pain during surgery.

General anaesthesia also lets scientists study what changes when consciousness disappears. Andrea Luppi, a neuroscientist at the University of Cambridge, used functional MRI scans to examine blood flow and functional connectivity, which measures how effectively different brain regions communicate and coordinate their activity.

Luppi and colleagues found that anaesthetised brains became less individually distinctive and more similar to one another. They also became less distinguishable from the brains of other primates, suggesting that the human brain regions most affected by anaesthesia are among the most evolutionarily recent.

During wakefulness, brain regions can interact even without direct connections, but such communication is rare under anaesthesia. Luppi’s findings support the idea that consciousness emerges through coordination among different brain hubs rather than activity within one specific region.

Anaesthetics may also help researchers compare different altered states of consciousness. While anaesthetics dampen communication between brain regions, psychedelics such as LSD and psilocybin appear to open new lines of communication, leaving scientists with much more to learn about where consciousness resides.