Adaptive Deep-Brain Stimulation Promising for Parkinson's

Damian McNamara

June 12, 2018

A closed-loop deep-brain stimulation (DBS) system that automatically adjusts energy output based on neural feedback could spare dyskinesia in patients with Parkinson's disease, as well as other side effects of current open-loop DBS devices, a new feasibility study suggests.

"Open-loop deep-brain stimulation works well for many people with Parkinson's disease, but it doesn't respond to changing needs based on a patient's medication cycle," study investigator Philip Starr, MD, from the Department of Neurosurgery at the University of California San Francisco, told Medscape Medical News.

"Adaptive stimulation will be useful for patients with fluctuating stimulation needs," he added.

The study was published online May 9 in the Journal of Neural Engineering,  

"Brittle Fluctuators"

The adaptive approach holds particular promise for about 10% of people with Parkinson's disease known as "brittle fluctuators." These patients often quickly alternate between extreme states of dyskinesia and bradykinesia.

Other researchers have demonstrated that this population often experiences painful and severe stimulation-induced dyskinesia (PloS One. 2014;9:e94856).

"It can be difficult to program these people with traditional DBS, where a little amount of stimulation can send them from frozen to dyskinetic," Starr said. In addition, "sometimes you might hit the right spot in the office but their needs will fluctuate with medication later in the day."

Patients with Parkinson's disease who develop hypophonia or difficulty articulating their speech could also benefit from a responsive DBS system, he added.  "Adaptive stimulation might help them talk normally during times when they do not need stimulation."

This new study builds on earlier findings by Starr and colleagues in which they identified several neural signatures that reflect simulation-induced adverse effects (J Neurosci. 2016;36:6445-6458).  

For example, narrowband gamma oscillations of 60 to 90 Hz detected in the motor cortex corresponded to dyskinesia; because these signals are in a predictable frequency range and are not altered by voluntary movement, it represents a promising control signal for adaptive DBS, the researcher noted.

Starr and colleagues developed an adaptive DBS algorithm by first testing a prototype on an externalized control system. Then they tested a totally embedded system in development (Activa PC + S, Medtronic) in two patients.

This implantable pulse generator allows long-term recording and stimulation and is connected to a subdural paddle lead placed over the ipsilateral motor cortex during surgery. This lead senses changes in the narrowband gamma signal and adjusts the stimulation output in the subthalamic nucleus (STN) lead accordingly.

When the signal was high, suggesting dyskinesia was likely, stimulation in the ipsilateral STN was reduced; in contrast, when the system senses a low signal, the stimulation was increased.

Less Stimulation Needed

The two men in the study were 61 years and 65 years old. They had been diagnosed with Parkinson's disease 7 to 8 years previously and were not  brittle fluctuators  or hyophonic.

One had open-loop DBS implanted 3 years before study entry, the other at 23 months before entry. At surgery, their baseline Unified Parkinson's Disease Rating Scale scores on and off medication were 14 and 30 (patient 1) and 14 and 29 (patient 2), respectively. Patient 2 was implanted with unilateral DBS.

"Our approach to feedback — sensing from a cortical electrode —  is quite easy to place with the same surgical exposure. It's placed posterior to cover the motor cortex," Starr said.

A neurologist blinded to DBS assignment reviewed video recordings to compare clinical efficacy. The neurologist observed no overt clinical differences between adaptive and open-loop DBS.

The adaptive DBS was associated with less total energy use compared with open-loop DBS. For example, during dyskinesia, sessions using adaptive DBS saved 38% to 45% of total energy.

Energy saving, Starr said, is not just about extending battery life. "If you can decrease the overall energy use, it means less stimulation is needed overall."

The algorithm performed well, the researchers noted, with transitions above and below the stimulation threshold appropriately triggered by alterations in the gamma power.

User Friendly

Some people are adept at manually adjusting their DBS systems to avoid dyskinesia. "I have some young Parkinson's disease patients who are sophisticated with adjusting their stimulator with a hand-held device," he said.

However, this new adaptive technology could make it automatic, thereby expanding the benefit to more patients. With this new technology, "you don't have to be tech savvy to do it."

In addition, the system could benefit patients with Parkinson's disease who have cognitive impairment, the researchers noted.

Adaptive DBS using neural control embedded within a completely implantable device has shown promise in other movement disorders. Other research focused on people with Tourette's syndrome (Neuroimage Clin. 2016;12:165-172) and essential tremor (IEEE Trans Neural Syst Rehabil Eng. 2017;25:2180-2187). 

"We feel like other indications for DBS, like major depression, could benefit from a closed-loop system," Starr said.

"Parkinson's disease is the best understood condition we treat with DBS, and we see this [technology] as part of a platform for wider applications in the future," he added.

"We have demonstrated the feasibility of adaptive DBS in PD using a fully implantable device, with feedback control provided by a cortical gamma band oscillation related to the emergence of dyskinesia, a common adverse effect of levodopa therapy and of STN DBS," the researchers note.

"While the total energy delivered by adaptive stimulation was substantially less than that of open-loop stimulation, blinded clinical ratings confirmed similar efficacy for both approaches," they add.

Starr and colleagues are planning a trial to evaluate the closed-loop DBS system in the patients with Parkinson's disease who might benefit the most, including brittle fluctuators.

Participants will receive 1 month of treatment with standard DBS and 1 month with closed-loop DBS, assigned in a randomized and blinded fashion. In terms of safety, patients will have a button on their controller to go into open-loop stimulation if needed.

Early Days

"These are early days," but the technology looks promising, Michael S. Okun, MD, medical director of the Parkinson's Foundation and professor and chair of neurology at the Fixel Center for Neurological Diseases at the University of Florida in Gainesville, told Medscape Medical News

"The idea of capturing signals in the brain — what people call 'electrical biomarkers' — to sense and deliver stimulation to the brain is pretty exciting."

Okun agreed that the side effect profile would likely be better with adaptive DBS than with traditional devices because it avoids the need for continuous stimulation.

"This group is using a novel technology that they pioneered — cortical sensing with a strip. The advantage is they can see what is going on in the [neural] network," he added.  "Where this really impacts patients is where you can take individual symptoms and assign them to changes in the network."

National Institutes of Health grants and funding from the University of California Postdoctoral Fellowship program, the National Science Foundation, and the National Defense Science and Engineering Graduate Fellowship program supported the study. Starr is a coinventor listed on the preliminary patent filed by the University of California San Francisco. Okun has disclosed no relevant financial relationships.

J Neural Eng. Published online May 9, 2018. Abstract

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