Science’s understanding of a mysterious and rare disorder known as Alice in Wonderland syndrome just got a little bit better thanks to a study that mapped a brain circuit that seems to be involved in the condition. The research, which has been posted as a preprint and is yet to be peer-reviewed, identified a network encompassing two distinct brain regions: one involved in body perception, and one in processing size and scale.

In Lewis Carroll’s Alice’s Adventures in Wonderland, our eponymous heroine follows a frantic white rabbit down his hole and into the topsy-turvy world of Wonderland. She meets a cast of iconic characters, from the Cheshire Cat to the decapitation-happy Queen of Hearts – but before any of that, she’s faced with a questionable bottle of liquid labeled “Drink Me”. With an almost admirable lack of self-preservation instinct, she does so, and promptly finds herself shrinking down to a minute size.

It’s these events from the book that give Alice in Wonderland syndrome (AIWS) its name. It’s a rare phenomenon, with only around 170 cases having been described in the medical literature according to the authors of the recent preprint. 

Most often, people with AIWS report episodes in which they perceive their own body parts, others’ bodies, or objects as being too large or too small. In recent years, there have been calls from some researchers to broaden the umbrella of AIWS to cover other disorders of perception, such as tachysensia, in which people feel that time is moving faster than it should.

With symptoms so unusual, and so few well-documented cases, it’s been a struggle to determine the cause of AIWS, as the authors of the preprint explain: “AIWS has variably been classified as a hallucination, an illusory misperception, or a disorder of multisensory integration related to body representation.” The most common trigger is migraine, but brain damage and tumors have also been implicated in some cases. 

Brain damage resulting in AIWS has been reported in various different brain regions. To make sense of this, the authors of the study performed a technique called lesion network mapping on brain scans from 37 people with AIWS, all cases previously documented in the medical literature.

The team compared the scans with data from 1,000 healthy people and 1,073 lesions associated with 25 different neuropsychiatric disorders. They discovered that while the individual AIWS brain lesions varied in their locations, over 85 percent of them were connected to two specific hubs: the right extrastriate body area (EBA) and the left inferior parietal lobe (IPL). 

The right EBA is part of the brain’s larger visual processing area, and is activated when we are observing a body or its parts. Meanwhile, the left IPL is activated when we’re trying to determine something’s size. Putting two and two together, it starts to make sense that these two regions would be involved in a disorder that makes people’s body parts appear abnormally small or large.

“This connectivity pattern was specific to AIWS when compared to lesions causing other neuropsychiatric disorders and aligned with neuroimaging findings in patients with AIWS from other etiologies,” the authors explain in their paper. 

Speaking to New Scientist, neuropsychologist Joel Frank (who was not directly involved in the study) pointed out that the sample size was small, but the methods used are promising. “By identifying the correlated regions in the brain, more precise diagnostic tools can be developed,” Frank said.

The study, should it be validated in peer review, opens up the prospect of more accurate diagnosis and maybe even treatments for AIWS in the future. While the authors highlight that theirs is the “largest study of AIWS lesion locations to date,” they do accept the limitations of the small sample size and the need for more data to be collected. 

But it’s a good first step, and as Alice herself lamented in the book when waiting for the Mock Turtle to recount his autobiography, “I don’t see how he can ever finish, if he doesn’t begin.”

The preprint, which has not been subject to external peer review, is posted to medRxiv.