The capsule, which is about the size of a multivitamin, uses an accelerometer to measure the patient’s breathing rate and heart rate. In addition to diagnosing sleep apnea, the device could also be useful for detecting opioid overdoses in people at high risk, the researchers say.

“It’s an exciting intervention to help people be diagnosed and then receive the appropriate treatment if they suffer from obstructive sleep apnea,” says Giovanni Traverso, an associate professor of mechanical engineering at MIT and a gastroenterologist at Brigham and Women’s Hospital. “The device also has the potential for early detection of changes in respiratory status, whether it’s a result of opiates or other conditions that could be monitored, like asthma or chronic obstructive pulmonary disease (COPD).”

In a study of 10 human volunteers, the researchers showed that the capsule can be used to monitor vital signs and to detect sleep apnea episodes, which occur when the patient repeatedly stops and starts breathing during sleep. The patients did not show any adverse effects from the capsule, which passed harmlessly through the digestive tract.

Traverso is one of the senior authors of the study, along with Robert Langer, an MIT Institute Professor and member of MIT’s Koch Institute for Integrative Cancer Research; Victor Finomore, director of the Human Performance and Applied Neuroscience Research Center at the West Virginia University School of Medicine; and Ali Rezai, director of the Rockefeller Neuroscience Institute at the West Virginia University School of Medicine. The paper appears today in the journal Device.

Vital sign measurements

Over the past decade, Traverso and Langer have developed a range of ingestible sensors that could be used to monitor vital signs and diagnose disorders of the GI tract, such as gastrointestinal slowdown and inflammatory bowel diseases.

This new study focused on measuring vital signs, using a capsule developed by Celero Systems that includes an accelerometer that detects slight movements generated by the beating of the heart and the expansion of the lungs. The capsule also contains two small batteries and a wireless antenna that transmits data to an external device such as a laptop.

In tests in an animal model, the researchers found that this capsule could accurately measure breathing rate and heart rate. In one experiment, they showed that the sensor could detect the depression of breathing rate that resulted from a large dose of fentanyl, an opioid drug.

Building on those results, the researchers decided to further test the capsule in a clinical trial at the West Virginia University Rockefeller Neuroscience Institute. Ten patients who enrolled in the study were monitored using the ingestible capsule, and these patients were also connected to the sensors typically used to monitor sleep, so the researchers could compare measurements from both types of sensors.

The researchers found that their ingestible sensor was able to accurately measure both breathing rate and heart rate, and it also detected a sleep apnea episode that one of the patients experienced.

“What we were able to show is that using the capsule, we could capture data that matched what the traditional transdermal sensors would capture,” Traverso says. “We also observed that the capsule could detect apnea, and that was confirmed with standard monitoring systems that are available in the sleep lab.”

In this study, the researchers monitored signals emitted by the capsule while it was in the stomach, but in a previous study, they showed that vital signs can also be measured from other parts of the GI tract.

“The stomach generally offers some of the best signals, mainly because it’s close to the heart and the lungs, but we know that we can also sense them elsewhere,” Traverso says.

None of the patients reported any discomfort or harm from the capsule. Radiographic imaging performed 14 days after the capsules were ingested revealed that all of them had passed through the patients’ bodies. The research team’s previous work has shown that objects of similar size usually move through the digestive tract in a little more than a day.

Close monitoring

The researchers envision that this kind of sensor could be used to diagnose sleep apnea in a less intrusive way than the skin-based sensors that are now used. It could also be used to monitor patients when they begin treatment for apnea, to make sure that the treatments are effective.

Celero Systems, a company founded by Traverso, Langer, Jeremy Ruskin, a professor of medicine at Harvard Medical School, and Benjamin Pless, now CEO of the company, is now working on sensors that could be used to detect sleep apnea or opioid overdose.

“We know that people who have had an overdose are at higher risk of recurrence, so those individuals could be monitored more closely so that in the event of another overdose, someone could help them,” Traverso says.

In future work, the researchers hope to incorporate an overdose reversal agent such as nalmefene into the device, so that drug release would be triggered when the person’s breathing rate slowed or stopped. They are also working on strategies to lengthen the amount of time that the capsules could remain in the stomach.

The research was funded by the Karl van Tassel Career Professorship, MIT’s Department of Mechanical Engineering, and Celero Systems.

Authors of the paper also include Pless, James Mahoney, Justin Kupec, Robert Stansbury, Daniel Bacher, Shannon Schuetz, and Alison Hayward.

The study in mice, published in Neuron, is the first to show how hunger hormones can directly impact activity of the brain’s hippocampus when an animal is considering food.

Lead author Dr Andrew MacAskill (UCL Neuroscience, Physiology & Pharmacology) said: “We all know our decisions can be deeply influenced by our hunger, as food has a different meaning depending on whether we are hungry or full. Just think of how much you might buy when grocery shopping on an empty stomach. But what may seem like a simple concept is actually very complicated in reality; it requires the ability to use what’s called ‘contextual learning’.

“We found that a part of the brain that is crucial for decision-making is surprisingly sensitive to the levels of hunger hormones produced in our gut, which we believe is helping our brains to contextualise our eating choices.”

For the study, the researchers put mice in an arena that had some food, and looked at how the mice acted when they were hungry or full, while imaging their brains in real time to investigate neural activity. All of the mice spent time investigating the food, but only the hungry animals would then begin eating.

The researchers were focusing on brain activity in the ventral hippocampus (the underside of the hippocampus), a decision-making part of the brain which is understood to help us form and use memories to guide our behaviour.

The scientists found that activity in a subset of brain cells in the ventral hippocampus increased when animals approached food, and this activity inhibited the animal from eating.

But if the mouse was hungry, there was less neural activity in this area, so the hippocampus no longer stopped the animal from eating. The researchers found this corresponded to high levels of the hunger hormone ghrelin circulating in the blood.

Adding further clarity, the UCL researchers were able to experimentally make mice behave as if they were full, by activating these ventral hippocampal neurons, leading animals to stop eating even if they were hungry. The scientists achieved this result again by removing the receptors for the hunger hormone ghrelin from these neurons.

Prior studies have shown that the hippocampus of animals, including non-human primates, has receptors for ghrelin, but there was scant evidence for how these receptors work.

This finding has demonstrated how ghrelin receptors in the brain are put to use, showing the hunger hormone can cross the blood-brain barrier (which strictly restricts many substances in the blood from reaching the brain) and directly impact the brain to drive activity, controlling a circuit in the brain that is likely to be the same or similar in humans.

Dr MacAskill added: “It appears that the hippocampus puts the brakes on an animal’s instinct to eat when it encounters food, to ensure that the animal does not overeat — but if the animal is indeed hungry, hormones will direct the brain to switch off the brakes, so the animal goes ahead and begins eating.”

The scientists are continuing their research by investigating whether hunger can impact learning or memory, by seeing if mice perform non-food-specific tasks differently depending on how hungry they are. They say additional research might also shed light on whether there are similar mechanisms at play for stress or thirst.

The researchers hope their findings could contribute to research into the mechanisms of eating disorders, to see if ghrelin receptors in the hippocampus might be implicated, as well as with other links between diet and other health outcomes such as risk of mental illnesses.

First author Dr Ryan Wee (UCL Neuroscience, Physiology & Pharmacology) said: “Being able to make decisions based on how hungry we are is very important. If this goes wrong it can lead to serious health problems. We hope that by improving our understanding of how this works in the brain, we might be able to aid in the prevention and treatment of eating disorders.”

“Depression affects millions of individuals worldwide, necessitating more effective treatments. Conventional methods, such as drug therapy with delayed onset of action and psychotherapy, have limitations in yielding satisfactory results for many patients. A pioneering advancement in treatment is urgently needed,” said Professor He Jufang, Wong Chun Hong Chair Professor in Translational Neuroscience at CityU.

Previous research found that stress leads to neural plasticity changes in brain’s valence-coding systems (“valence” refers to the degree to which something is pleasurable or aversive), which are strongly associated with depression, post-traumatic stress disorders and anxiety disorders. Also, some studies revealed that depression is correlated with the hyperactivated amygdala. “However, the neural mechanism that mediates depression in amygdala is still poorly understood,” said Professor He.

Over the years, Professor He’s research group has focused on memory formation and encoding studies. Previously, they discovered that cholecystokinin (CCK), a key neuromodulator, is crucial for inducing long-term potentiation (LTP) — a lasting increase in communication strength between neurons — to enable memory formation. They also found that the CCK and CCK-B receptors (CCKBR is one of three known types of CCK receptors in the central nervous system) mediate neuroplasticity, as well as visual and sound associative memory formation, in the auditory cortex, and trace fear memory formation in the amygdala. Other studies have found that CCKBR antagonist (which blocks the binding of the CCK and CCK-B receptors, thus inhibiting the effect of the binding) exhibited an anti-depressant effect in mice.

So Professor He’s group hypothesized that CCK might facilitate aversive memory formation by enabling LTP in the basolateral amygdala (BLA) — a brain region involved in processing emotional memories and thought to be dysregulated in depression, thus enhancing the development of depression.

In their latest study, they tested this hypothesis using various experimental methods, including in vitro electrophysiological recording, optogenetic manipulation, drug manipulation and behavioural analysis of mice, to examine the critical role of CCK and CCKBR in depression. They found that a CCKBR antagonist called YM022 had an anti-depressant-like effect by blocking neuroplasticity-caused aversive memory formation in mice.

The results of the in-vitro recording in the BLA showed that the YM022 significantly suppressed neuroplasticity. The neuroplasticity induction rate reached 72.3% in the control group; but it was only 10.2% in the drug-treated group.

Moreover, the team underwent a series of behavioural tests to determine the antagonist’s efficacy. The results showed that depressive behaviours in mice treated with a CCKBR antagonist was reduced.

“Remarkably, the YM022 shows anxiolytic effects with a dose of 3.0 ug/kg, which is 3,000 times lower than the required dosage of current antidepressants,” said Professor He. “These results indicate that CCKBR is a potential target for depression treatment, and that the selected antagonist, YM022, may be a good anti-depressant candidate due to its extremely small effective dose. This paves the way for targeted drug development that specifically addresses the abnormalities observed in the basolateral amygdala.” Next, the research team will focus on the precise mechanisms and potential side effects of CCKBR antagonists to set the stage for future clinical trials involving human subjects.

The research was supported by Hong Kong Research Grants Council, the Innovation and Technology Fund, the Health and Medical Research Fund, and the following charitable foundations: the Wong Chun Hong Endowed Chair Professorship, the Charlie Lee Charitable Foundation, and the Fong Shu Fook Tong Foundation.

Traditionally, cisplatin-based chemotherapy has been the standard treatment for bladder cancer patients who are able to tolerate this drug. However, responses have been limited, and durable outcomes rare. Over the past years, two phase-3 clinical trials studied the effects of combining immunotherapy with either chemotherapy or a new drug, enfortumab vedotin, to treat bladder cancer (more exact: urothelial carcinoma). With success, both studies show a significant increase in both overall survival as well as progression-free survival.

Medical oncologist Michiel van der Heijden from the Netherlands Cancer Institute (NKI) explains: “these results mark a milestone in bladder cancer research, providing the first evidence of a survival benefit of combination therapy involving immune checkpoint inhibitors over chemotherapy. This is an exciting development in our field, as these findings will thoroughly change the treatment landscape for advanced bladder cancer. It is a testament to the collaborative efforts of researchers, and most importantly, the resilience of all patients who participated in this study.”

Combining therapies

The CheckMate 901 trial investigated a new combination of the drugs nivolumab and gemcitabine-cisplatin and compared this to treatment with only chemotherapy. The results demonstrated that patients treated with both drugs showed a 22% reduction in the risk of death compared to patients only treated with chemotherapy. The findings also showed that the combination of nivolumab and chemotherapy led to a significant improvement in progression-free survival vs chemotherapy alone.

The results will be published in the New England Journal of Medicine at the same time as the presentation at ESMO.

During this ESMO presidential session, the results of another phase-3 in the same treatment line will be presented, featuring a novel combination of an antibody-drug conjugate with immune checkpoint inhibition, using Enfortumab Vedotin + pembrolizumab. This study found a statistically significant and clinically meaningful improvement in overall survival and progression-free survival as well. These results will be published in a scientific journal at a later time.

Both treatments are yet to be registered and approved in the Netherlands for health insurance coverage, meaning that they will not yet be readily available. In the US, the Enfortumab Vedotin + pembrolizumab is already available for a subgroup of bladder cancer patients, based on a phase 2 study.

Unique

Michiel van der Heijden is involved in both these trials, making it a special occasion for the NKI to have such a leading role in two large studies that can change clinical practice. “It is very special to give a presidential lecture during ESMO. I have not had this honor before and it may very well not happen again anytime soon. Last year was a very special occasion as well, as two NKI researchers, Myriam Chalabi and John Haanen, both presented their findings in the presidential session. Not many researchers have received this honor, making this a really unique moment for the NKI once again.”