By Deborah Borfitz

July 19, 2023 | Researchers at the Laureate Institute for Brain Research (Tulsa, Oklahoma) are repurposing a vibrating capsule that is FDA-cleared for treating chronic constipation to study how people sense the hidden signals originating in their gastrointestinal (GI) system. As a tool for assessing the “visceral acuity” of individuals with abnormal gut sensations, the tiny swallowable device could prove useful in identifying when the problem is due to a disorder of the gut-brain interaction rather than the GI tract, according to psychiatrist and neuroscientist Sahib Khalsa, M.D., Ph.D. 

The traditional way of studying gut-brain interactions is using mechanical or electrical forms of stimulation, he says, and the investigators are usually gastroenterologists who might inflate a balloon they have rectally inserted into patients or had them swallow. “As a psychiatrist, that’s not my area of expertise and certainly it would not be something that clinically you would expect to be a regular part of mental health care, but we understand that abnormal heart sensations, breath sensations, and even gut sensations are a part of different psychiatric disorders.” 

In the case of the gut, Khalsa is talking about people with eating disorders such as anorexia nervosa who might feel abnormal fullness after eating small amounts of food or be experiencing a lot of general stomach or abdominal discomfort as well as constipation. “As it turns out, when you don’t put a lot of food in the gut you can impact bowel function, and [until now] we didn’t have a way in mental health to assess these gastrointestinal sensations.” 

This gets to why he was intrigued to learn about the drug-free vibrating capsule, developed by Vibrant Limited, and the possibility of using it to measure visceral acuity much like an ophthalmologist uses an eye chart to measure visual acuity. To accommodate the new intended use, Vibrant agreed to change both the rate and amount of vibration that the device would generate when it reached the stomach. 

As reported in a study that published recently in Nature Communications (DOI: 10.1038/s41467-023-39058-4), the capsule induced “gastric evoked potentials” in the brain, showing that increases in amplitude correlated well with the perceptual accuracy of healthy male and female participants ages 18-40. A signal detection algorithm was used that allowed researchers to measure the degree of sensitivity to the capsules when they were vibrating at different times and strengths.  

Gastric evoked potential is a term coined by the researchers to reflect the fact that the voltage in the brain is stimulated in the stomach. It seems to trigger electroencephalogram signals in different areas of the brain than has been seen with heartbeat-evoked potential, Khalsa says. 

Gut-Brain Communication

Khalsa has been actively studying the brain-body connection over the past 15 years, notably a process known as “interoception” by which the nervous system senses, interprets, and integrates signals that originate from inside the body. These include heart-brain communication, whereby people sense their heartbeat, lung-brain communication, making them aware that they are breathing, and others. 

Signals originating in the GI system are different in that they tend to be neither visual nor auditory and are therefore relatively hard to measure. The gut comprises a long tube about 24 feet in length and is stimulated when food and water are consumed, says Khalsa, but it is difficult to know how signals coming from within the gut are impacting human brain function in real time.  

He has done many heart-brain communication studies using intravenous drugs to mimic the effect of adrenaline, to learn how the brain responds when heart signals are manipulated. The use of the vibrating capsule to study gut-brain communication is an analogous approach.  

A common clinical scenario is when patients visit a gastroenterologist with bothersome gut sensations and receive the “good news” that they have no identifiable abnormalities in their gut such as an ulcer or cancer, says Khalsa. But since they still have symptoms, they may get referred to someone specializing in mental health—ideally, a psychiatrist with the tools to identify what is going on symptomatically as well as what aspect of their nervous system is off.  

He says that the vibrating capsule, a little larger than a multivitamin, appears to be a step toward better understanding gut feelings and gut-brain interactions in both healthy and clinical populations. The capsule acts as a wireless probe, which gets activated when put in a base unit prior to ingestion. “It is preprogrammed to deliver vibrations according to a particular sequence,” Khalsa explains.     

Programmable Pills

During the study, participants sat in a chair with a handheld device and were told to press a button on it whenever they felt a sensation they thought was coming from the capsule and release it as soon as the feeling stopped, says Khalsa. The capsule would vibrate in three-second increments. “We could tell when the vibrations had occurred, so if [individuals] pressed the button during the vibration window then we assumed they were correctly sensing a change in their gut.” 

Sensations were assessed under a range of stimulations, from normal to enhanced, with the expectation that visceral acuity would improve in parallel. This was assessed by their greater accuracy and quicker reaction time in pushing the button, he says. 

Researchers employed event-related averaging to gauge what was happening in the brain of study participants. The onset of the capsule vibration was “time zero” and every event was averaged to the start of the vibration, explains Khalsa. 

Electrical signals were measured with a scalp EEG and thus relatively weak. Averaging together a lot of these stimulations allowed the research team to detect gastric evoked potential changes in the brain, he says.  

The capsules were all pre-programmed to start vibrating within a few minutes of being swallowed, to ensure stomach sensations were being measured. To stimulate contractions to improve constipation, Vibrant instead programs the capsules to start vibrating after about eight hours to give them time to migrate to the large intestine, says Khalsa. 

For the mental health application, researchers used abdominal X-ray imaging in a subset of people to verify that the capsule was vibrating either in the stomach or a small segment of the small intestine called the duodenum, both of which contain sensory receptors that are sensitive to mechanical stimulation, he adds. 

Clinical Need

The imagined clinical utility of the vibrating capsule is “substantial” in the world of psychiatry, where many patients present with abnormal gut sensations without a way to assess them or evaluate the effects of treatment, says Khalsa. The device could also help improve diagnostic testing and treatment monitoring of GI disorders such as irritable bowel syndrome and functional dyspepsia where patients may likewise experience strange stomach sensations (e.g., heartburn, bloating, pain with defecation) that aren’t detectable using standard tests. 

In fact, a subset of patients with these functional GI disorders may respond well to cognitive behavioral therapy that is focused on learning how to ignore or at least live with the gut sensations, Khalsa continues. “Even in that scenario, the therapy practitioner doesn’t have clear evidence that the person actually has abnormal gut-brain interaction or an abnormal gut sensation.” Getting the all-clear from a gastroenterologist when symptoms persist is like saying “everything on the ground is perfectly normal in town when you’re flying 20,000 feet up.” 

The longer-term possibility for the vibrating capsule is that it could be utilized to develop treatments to, for example, train patients how to better feel and attend to gut sensations, he says. “That alone could potentially help resolve some of these symptomatic issues.”  

Among the required next steps would be clinical trials to evaluate the device as a diagnostic marker in various populations experiencing an abnormality of gut-brain interaction, including individuals with eating disorders and functional GI disorders, says Khalsa. The capsule’s ability to predict responses to current treatments would also have to be tested, and some form of feedback training with the capsule would be needed to evaluate whether improvement in patients’ sensitivity to their gut-brain interactions provides symptom relief. 

Thanks to a Research Project Grant from the National Institutes of Health, Khalsa and his team are currently evaluating capsule-induced sensations in patients with anorexia nervosa to learn not only whether patients show abnormal sensations, as they expect, but also the degree of sensation and if that predicts how well patients do after they leave the hospital. If so, it might serve as a prognostic marker of visceral acuity so treating psychiatrists know if additional therapy and monitoring is needed to prevent relapse. 

Anorexia nervosa is a common eating disorder with one of the highest mortality rates—up to 20%—of all psychiatric diseases, he notes. Relapse affects upwards of one out of every two patients over the first one to two years after inpatient discharge. “It can be a very deadly and chronic relapsing condition, and so anything that would give us a more objective indicator of illness severity and recalcitrance of the illness would be very helpful.”