For patients with Parkinson’s disease, deep-brain stimulation (DBS) offers relief from physical symptoms. This surgical procedure involves implanting ultrathin wire electrodes into a specific area of the brain. To treat Parkinson’s, surgeons target a brain structure called the subthalamic nucleus, near the center of the brain. Electrodes, sometimes referred to collectively as a “brain pacemaker,” deliver high-frequency electrical pulses that interfere with neuronal activity in the targeted brain tissue.
To date, more than 100,000 Parkinson’s patients have been treated in with this technique. The procedure can effectively control symptoms such as tremor and rigidity—but, like all treatments, it has unwanted side effects. For reasons that are still unclear, it can cause binge eating in a small minority of patients.
That observation led a group of neurosurgeons at Yale University School of Medicine to explore further. Now the team has found a neural pathway in the mouse brain that triggers binge eating when stimulated. Their findings, published May 25 in Science, provide clues about how the brain controls eating behavior, and could help to explain why DBS sometimes causes binge eating in Parkinson’s patients. If a similar neural switch can be found in humans, it could eventually lead to new therapies for this eating disorder.
In their study, Xiaobing Zhang and Anthony N. van den Pol used a widely adopted method called optogenetics that enables a particular brain circuit to be turned on or off. The researchers injected genetically engineered viruses into a group of cells in a part of the subthalamic nucleus called the zona incerta, which synthesizes a brain-signaling molecule called GABA that ratchets down neural activity. The virus carried a gene into these cells that began to express a variant of a fungal protein called channelrhodopsin. This made the cells sensitive to light, enabling the researchers to activate them with great precision, using laser pulses delivered into the brain by optical fibers.
They found activating these neurons immediately caused binge eating, making the mice eat more than one third of their daily food rations in just 10 minutes, and increasing their preference for high-fat foods. Weak stimulation, delivered for 10 minutes and repeated four times at 30-minute intervals, worsened overeating and the desire for fatty foods, causing the mice to consume nearly three quarters of their daily food intake, and to gain weight. Untreated “control” animals, by contrast, ate less than one quarter of their daily rations over the same period of time.
The researchers also found these same cells became more active when the mice were deprived of food for a day as well as in response to ghrelin, known as the so-called “hunger hormone.” On the other hand, destroying the neurons by injecting them with a virus-carrying gene that caused the death of the cells decreased the animals’ overall food intake and reduced their weight gain by more than 50 percent over a period of eight weeks.
Zhang and van den Pol engineered their viruses in such a way that the channelrhodopsin gene was fused to another gene encoding a red fluorescent protein, enabling them to “label” the GABA neurons and trace the route of the long fibers, or axons, extending from the main body of the cells, confirming the cells project these fibers to cells in a brain region called the paraventricular thalamus. Silencing or killing these cells had the same effect as activating the GABA neurons—increasing the animals’ food intake—whereas activating them stopped their eating. “I think our findings give us some insight into the parts of the brain that might be involved in binge eating,” van den Pol says. “But it’s difficult to know at this point whether the zona incerta is generally responsible for binge eating in humans.”
Valerie Voon, a cognitive and behavioral neuroscientist at the University of Cambridge, who was not involved with the study, called the findings “intriguing observations that potentially address several poorly understood observations in the clinical literature.” For example, she says they may help explain “why stimulation of the subthalamic nucleus in patient’s with Parkinson’s disease can worsen eating behaviors and weight gain.” Voon adds that the findings point to effects of stimulation on neurons in the zona incerta that might explain the behaviors.
Should the results of this study be applicable to people, they could help surgeons minimize the risk of binge eating as a side effect in Parkinson’s patients treated with DBS. They may also be useful for the development of drug treatments for the behavior. “Binge eating is found in only a small percent of people undergoing DBS, but the placement of electrodes may be a critical factor,” van den Pol explains, “and if we could find a safe drug that selectively inhibited GABA cells of the zona incerta, that might be beneficial as a treatment.”
Van den Pol says he and his colleagues want to learn more about the role of these cells, and their anatomy. “We hope to continue trying to understand the role of the GABA zona incerta neurons, where else they project to, what parts of the brain signal the zona incerta and what other functions they may contribute to.”