Research Shows Promising Results for Parkinson’s Disease Treatment

Researchers from Carnegie Mellon University have found a way to make deep brain stimulation (DBS) more precise, resulting in therapeutic effects that outlast what is currently available. The work, led by Aryn Gittis and colleagues in CMU’s Gittis Lab and published in Science, will significantly advance the study of Parkinson’s disease. 

DBS allows researchers and doctors to use thin electrodes implanted in the brain to send electrical signals to the part of the brain that controls movement. It is a proven way to help control unwanted movement in the body, but patients must receive continuous electrical stimulation to get relief from their symptoms. If the stimulator is turned off, the symptoms return immediately.

Gittis, an associate professor of biological sciences in the Mellon College of Science and faculty in the Neuroscience Institute, said that the new research could change that.

“By finding a way to intervene that has long-lasting effects, our hope is to greatly reduce stimulation time, therefore minimizing side effects and prolonging battery life of implants.”

Gittis set the foundation for this therapeutic approach in 2017, when her lab identified specific classes of neurons within the brain’s motor circuitry that could be targeted to provide long-lasting relief of motor symptoms in Parkinson’s models. In that work, the lab used optogenetics, a technique that uses light to control genetically modified neurons. Optogenetics, however, cannot currently be used on humans.

Since then, she has been trying to find a strategy that is more readily translated to patients suffering from Parkinson’s disease. Her team found success in mice with a new DBS protocol that uses short bursts of electrical stimulation.

“This is a big advance over other existing treatments,” Gittis said. “In other DBS protocols, as soon as you turn the stimulation off, the symptoms come back. This seems to provide longer lasting benefits — at least four times longer than conventional DBS.”

In the new protocol, the researchers target specific neuronal subpopulations in the globus pallidus, an area of the brain in the basal ganglia, with short bursts of electrical stimulation. Gittis said that researchers have been trying for years to find ways to deliver stimulation in such a cell-type specific manner.

“That concept is not new. We used a ‘bottom up’ approach to drive cell type specificity. We studied the biology of these cells and identified the inputs that drive them. We found a sweet spot that allowed us to utilize the underlying biology,” she said. 

Teresa Spix, the first author of the paper, said that while there are many strong theories, scientists do not yet fully understand why DBS works.

“We’re sort of playing with the black box. We don’t yet understand every single piece of what’s going on in there, but our short burst approach seems to provide greater symptom relief. The change in pattern lets us differentially affect the cell types,” she said.

Spix, who defended her Ph.D. in July, is excited about the direct connection this research has to clinical studies.

“A lot of times those of us that work in basic science research labs don’t necessarily have a lot of contact with actual patients. This research started with very basic circuitry questions but led to something that could help patients in the near future,” Spix said.

Next, neurosurgeons at Pittsburgh’s Allegheny Health Network (AHN) will use Gittis’ research in a safety and tolerability study in humans. Nestor Tomycz, a neurological surgeon at AHN, said that researchers will soon begin a randomized, double blind crossover study of patients with idiopathic Parkinson’s disease. The patients will be followed for 12 months to assess improvements in their Parkinson’s disease motor symptoms and frequency of adverse events.

“Aryn Gittis continues to do spectacular research which is elucidating our understanding of basal ganglia pathology in movement disorders. We are excited that her research on burst stimulation shows a potential to improve upon DBS which is already a well-established and effective therapy for Parkinson’s disease,” Tomycz said.

Donald Whiting, the chief medical officer at AHN and one of the nation’s foremost experts in the use of DBS, said the new protocol could open doors for experimental treatments.

“Aryn is helping us highlight in the animal model things that are going to change the future of what we do for our patients. She’s actually helping evolve the care treatment of Parkinson’s patients for decades to come with her research,” Whiting said.

Tomycz agreed. “This work is really going to help design the future technology that we’re using in the brain and will help us to get better outcomes for these patients.”

Treating Severe Depression with On-Demand Brain Stimulation

UCSF Health physicians have successfully treated a patient with severe depression by tapping into the specific brain circuit involved in depressive brain patterns and resetting them using the equivalent of a pacemaker for the brain.

The study, which appears in Nature Medicine, represents a landmark success in the years-long effort to apply advances in neuroscience to the treatment of psychiatric disorders.

“This study points the way to a new paradigm that is desperately needed in psychiatry,” said Andrew Krystal, PhD, professor of psychiatry and member of the UCSF Weill Institute for Neurosciences. “We’ve developed a precision-medicine approach that has successfully managed our patient’s treatment-resistant depression by identifying and modulating the circuit in her brain that’s uniquely associated with her symptoms.”

Previous clinical trials have shown limited success for treating depression with traditional deep brain stimulation (DBS), in part because most devices can only deliver constant electrical stimulation, usually only in one area of the brain. A major challenge for the field is that depression may involve different brain areas in different people.

What made this proof-of-principle trial successful was the discovery of a neural biomarker – a specific pattern of brain activity that indicates the onset of symptoms – and the team’s ability to customize a new DBS device to respond only when it recognizes that pattern. The device then stimulates a different area of the brain circuit, creating on-demand, immediate therapy that is unique to both the patient’s brain and the neural circuit causing her illness.

This customized approach alleviated the patient’s depression symptoms almost immediately, Krystal said, in contrast to the four- to eight-week delay of standard treatment models and has lasted over the 15 months she has had the implanted device. For patients with long-term, treatment-resistant depression, that result could be transformative.

“I was at the end of the line,” said the patient, who asked to be known by her first name, Sarah. “I was severely depressed. I could not see myself continuing if this was all I’d be able to do, if I could never move beyond this. It was not a life worth living.”

Applying Proven Advances in Neuroscience to Mental Health

The path to this project at UC San Francisco began with a large, multicenter effort sponsored under President Obama’s BRAIN (Brain Research through Advancing Innovative Neurotechnologies) Initiative in 2014.

Through that initiative, UCSF neurosurgeon Edward Chang, MD, and colleagues conducted studies to understand depression and anxiety in patients undergoing surgical treatment for epilepsy, for whom mood disorders are also common. The research team discovered patterns of electrical brain activity that correlated with mood statesandidentified new brain regions that could be stimulated to relieve depressed mood. 

With results from the previous research as a guide, Chang, Krystal, and first author Katherine Scangos, MD, PhD, all members of the Weill Institute, developed a strategy relying on two steps that had never been used in psychiatric research: mapping a patient’s depression circuit and characterizing her neural biomarker.

“This new study puts nearly all the critical findings of our previous research together into one complete treatment aimed at alleviating depression,” said Chang, who is co-senior author with Krystal on the paper and the Joan and Sanford Weill Chair of Neurological Surgery.

The team evaluated the new approach in June 2020 under an FDA investigational device exemption, when Chang implanted a responsive neurostimulation device that he has successfully used in treating epilepsy.

“We were able to deliver this customized treatment to a patient with depression, and it alleviated her symptoms,” said Scangos. “We haven’t been able to do this the kind of personalized therapy previously in psychiatry.”

To personalize the therapy, Chang put one of the device’s electrode leads in the brain area where the team had found the biomarker and the other lead in the region of Sarah’s depression circuit where stimulation best relieved her mood symptoms. The first lead constantly monitored activity; when it detected the biomarker, the device signaled the other lead to deliver a tiny (1mA) dose of electricity for 6 seconds, which caused the neural activity to change.

“The effectiveness of this therapy showed that not only did we identify the correct brain circuit and biomarker, but we were able to replicate it at an entirely different, later phase in the trial using the implanted device,” said Scangos. “This success in itself is an incredible advancement in our knowledge of the brain function that underlies mental illness.”

Translating Neural Circuits into New Insights

For Sarah, the past year has offered an opportunity for real progress after years of failed therapies.

“In the early few months, the lessening of the depression was so abrupt, and I wasn’t sure if it would last,” she said. “But it has lasted. And I’ve come to realize that the device really augments the therapy and self-care I’ve learned while being a patient here at UCSF.”

The combination has given her perspective on emotional triggers and irrational thoughts on which she used to obsess. “Now,” she said, “those thoughts still come up, but it’s just…poof…the cycle stops.”

While the approach appears promising, the team cautions that this is just the first patient in the first trial.

“There’s still a lot of work to do,” said Scangos, who has enrolled two other patients in the trial and hopes to add nine more. “We need to look at how these circuits vary across patients and repeat this work multiple times. And we need to see whether an individual’s biomarker or brain circuit changes over time as the treatment continues.”

FDA approval for this treatment is still far down the road, but the study points toward new paths for treating severe depression. Krystal said that understanding the brain circuits underlying depression is likely to guide future non-invasive treatments that can modulate those circuits.

Added Scangos, “The idea that we can treat symptoms in the moment, as they arise, is a whole new way of addressing the most difficult-to-treat cases of depression.”