Think back to hearing a favorite song, seeing an old friend or eating a favorite meal. When we have these positive experiences, the brain releases a chemical called dopamine. Sometimes, when we’re hungry, we want to have that favorite meal because we know it’ll be good. That’s normal. We also know there can be too much of a good thing. And we know when to stop…most of the time.
Casey Halpern, MD
In some people, the part of the brain that regulates dopamine is dysregulated. Think of it like a traffic signal that’s stuck on yellow and can’t turn red when it should. This pursuit of the feel-good sensation leads to craving, and then, when the traffic signal is broken, it leads to compulsion.
This is the case with people suffering from binge eating disorder. This mental health illness is most common eating disorder and is associated with people frequently losing control over their eating. But it’s not hunger that drives them; it’s the craving. And, similar to other compulsions, they can’t stop.
A Penn Medicine study made national headlines recently, showing early promise that what the brain can’t self-regulate in loss of control while eating, smart deep brain stimulation (DBS) can.
“The DBS is smart,” said Casey Halpern, MD, an associate professor of Neurosurgery at the Perelman School of Medicine and director of Stereotactic and Functional Neurosurgery at Pennsylvania Hospital. “It senses the craving and upcoming loss of control and then delivers the stimulation at those most vulnerable times.”
The study, led by Halpern, has shown that this smart DBS approach might be the key to unlocking the obsessed brain and restoring the stop signal that patients need.
How Halpern Began to Study Cravings in the Brain
Throughout high school and college, Halpern had a growing interest in the brain. As a result, his unplanned meeting with neurologist Murray Grossman, MD, on the University of Pennsylvania campus as a first-year student was serendipitous. Grossman, who had been Halpern’s soccer coach in high school, is director of the Penn FTD (frontotemporal dementia) Center. When they met on Locust Walk that day, he asked Halpern if he’d like to do research in his lab, which focused on neurologic disorders such as Alzheimer’s and Parkinson’s disease.
Halpern jumped at the opportunity and throughout his Penn education—as an undergrad, a student at the Perelman School of Medicine and then as a neurosurgical resident at the Hospital of the University of Pennsylvania — his work in the lab and Grossman’s mentorship helped him zero in on his future career.
His decision to focus on image-guided neurosurgery stems from the first deep brain stimulation (DBS) he saw, which eliminated the tremors in a patient with Parkinson’s disease. In DBS — which Halpern describes to a “pacemaker for the brain” — electrodes are implanted in specific regions of the brain where the uncontrolled behavior is located. In this case, the electrodes disrupted the tremor-related signal. As neurosurgeon Gordon Baltuch, MD, performed the procedure, Halpern watched the stimulator turn on and the tremor “just disappeared” as he recalled.
“The patient did so well I never wanted to do anything else,” Halpern said, adding that Baltuch went on to become his mentor, as well.
Halpern knew early on that he wanted to apply DBS to diseases beyond Parkinson’s and other neurologic disorders. Obesity and related disorders became his focus. He said one of his mentors, Alan Rosenquist, PhD, now an emeritus professor of Neuroscience, advised him to broaden his research to look at the reward mechanisms of obesity, not just obesity. “If you do that,” he told Halpern, “you’ll not only help patients with obesity but also people with addiction and other psychiatric disorders.”
“I decided to spend the rest of my career looking for craving cells,” Halpern recalled.
Moving Toward to FDA Approval for a Clinical Study
There wasn’t yet enough preclinical evidence to justify doing these kinds of studies in human trials back in 2007. However, Halpern discovered a research lab on the Penn campus, led by Tracy Bale, PhD, formerly at Penn, that was using mouse models to study binge eating behavior and reached out to work with her.
The mouse studies showed that DBS could stop the bingeing brought on by cravings but more important, it showed the specific part of the mouse’s brain that controlled them: the nucleus accumbens, one of the main regions of the brain that receives dopamine.
“The nucleus accumbens is one of or the only region in the human brain that shares strong evolutionary development with the mouse brain,” Halpern said. “Every other part of the human brain has evolved differently. We targeted a structure we could expand to a human.”
After completing his residency in 2014, Halpern continued his mouse studies at Stanford University. Five years later, based on the data collected from the mouse studies as well as in-depth imaging studies on humans, Halpern received FDA approval to proceed with the first clinical trial on humans using DBS to control loss of control eating. The surgery took place at the start of 2020. Both study participants had suffered with this binge eating disorder for much of their lives and each had undergone gastric bypass surgery but, unfortunately, had regained most, if not all, of the weight.
To induce cravings during the surgery — in which the patients were awake — each was shown a picture showing a food they would typically binge on. When the patients saw the picture of the food, “we had instant results,” Halpern said.
The implanted electrodes sensed signals that predicted a binge; neutral pictures got no reaction. The electrodes then stimulated the lit-up areas in the nucleus accumbens, disrupting the craving-related signals. “That gave us the confidence that we were in the part of the brain we wanted to modulate…and that led to success in this early clinical trial.”
Thanks to the surgery, neither of these first two trial participants now meets the criteria for binge eating disorder, after having it for more than 20 to 30 years.
“Their relationship with food has substantially improved,” Halpern said. “They don’t binge anymore.”
Halpern, who returned to Penn in 2021, will begin a second clinical trial in the next few months, this time with six patients. This trial will continue for about a year.
Expanding the Scope
Halpern is extremely grateful to the many mentors who helped him throughout his career. “I really believe in mentorships,” he stressed, and he pays this forward in his own labs through numerous post-doctoral students, grad students, residents and medical students.
He hopes to expand his research beyond obesity disorders, to other forms of compulsive behavior that occur in the nucleus accumbens. “The dysregulation of the dopamine system seen in obsessive compulsive disorder [OCD] and in addiction also converge in that region of the brain.”
He is also working with researchers from neurology, psychiatry and engineering to develop noninvasive strategies to control these behaviors. They have been able to detect the same signal predicting a craving on the scalp, which may help develop methods that don’t require brain surgery to intervene. One such possibility may be to use transcranial magnetic stimulation, which has already been approved for depression and OCD.
“I’m a neurosurgeon focusing on mental health. Neurosurgery is the answer for some of those patients but not the majority,” Halpern said. “I’m going to focus on both.”