A sweet spot in the deep brain with direct lines of communication to motor regions far out on the cerebral cortex might hold a key to halting the progression of early-stage Parkinson’s disease.
A new analysis of data collected 15 years ago from research participants with early-stage Parkinson’s links their responses to deep brain stimulation, or DBS, with electrode placements that bear certain long-range network connections in the brain. Reported in the Annals of Neurology, the study led by researchers at Vanderbilt University Medical Center and Charité-Berlin University of Medicine suggests an optimal target for implanting electrodes in these patients.
Remarkably, in the 24-month VUMC pilot some patients randomized to DBS experienced a halting of underlying disease progression as measured by motor symptoms. Neurosurgeon Peter Konrad, MD, PhD, now at West Virginia University in Morgantown and a co-author of the new study, targeted permanent electrode implants on a small deep brain neuronal cluster, the dorsolateral subthalamic nucleus, or STN. In the new report, electrode placements in positive responses to DBS are shown to converge on an STN address whose 3D coordinates are given in tenths of a millimeter.
The software toolbox used to find this sweet spot is called Lead-DBS. It’s designed to reconstruct DBS electrode placements from preoperative and postoperative brain images. Developed in Germany, the toolbox was not available when the pilot was conducted.
Neurologist David Charles, MD, launched the pilot with Konrad in 2006, and it remains the only DBS trial in early-stage patients, and the only DBS trial ever to use therapy washouts to examine underlying disease progression. Thirty patients randomized to Parkinson’s medications or to medication plus DBS undertook periodic weeklong admissions to VUMC’s clinical research unit for washouts of all therapy. Video recordings made during these periods enabled blinded scoring of motor symptom progression.
The pilot was designed to test the safety of DBS in early-stage Parkinson’s and was not sized to demonstrate efficacy or influence clinical practice. Of the 15 patients randomized to DBS, five had exceptional responses — no progression of their motor symptoms after two years.
“A core research question that we had was, can early deep brain stimulation impact or change the underlying progression of Parkinson’s? In this study, we were able to look at associations between where each patient was being stimulated, and by how much, and how their motor symptoms progressed over the two-year clinical trial,” said Mallory Hacker, PhD, assistant professor of Neurology and lead author of the study.
Hacker spent a month in Berlin learning how to use Lead-DBS at the lab of one of its developers, Andreas Horn, MD, PhD, who joins Charles as co-senior author of the new study. (Horn is now at Harvard University in Cambridge, Massachusetts.)
“We’d been searching for a shared patient characteristic that might explain these exceptional responses to DBS, and we’d never really been able to find one,” said Charles, professor and vice-chair of Neurology. “All of a sudden, Dr. Hacker goes over to Berlin to collaborate with Dr. Horn’s laboratory and, lo and behold, electrode placements in these exceptional responders localized to a very specific location in the subthalamic nucleus, where they were found to modulate a distinct set of network connections, and were shown to stay clear of interaction with another set of network connections.” It turned out that patients with electrodes nearer the sweet spot were able to manage symptoms with less drugs and with lower stimulation settings on their implants.
Compared to sweet spot studies in typical DBS patients, the location emerging in the new analysis, Charles said, “is similar, but it’s distinct, a little more ventral and a little more lateral.”
In patients with positive responses, the report highlights long-range connections originating from the supplementary motor area and the primary motor cortex, running through the sweet spot and subject there to modulation by DBS electrodes. Hacker stressed that, while these same positive network connections show up in studies in more advanced Parkinson’s patients, this is the only study to have looked at the underlying progression of motor symptoms.
Another long-range connection picked up in the analysis, from the pre-supplemental motor area, is correlated with poorer responses from participants, running by electrode placements more distant from what is now considered a likely sweet spot.
“Avoiding the pre-supplemental motor area is potentially integral to slowing motor progression,” Charles said.
For cross-validation, patient responses were removed from the DBS pilot set one at a time, leaving them to be predicted based on the network connections obtained in all electrode placements across the cohort.
“Those numerous cross-validations,” Charles said, “suggest that this isn’t a spurious, random finding. There are strong correlations between these different network connections and how much patients’ underlying motor symptoms progressed.”
Echoing a point stressed by Charles, Hacker said, “We consider the results of this study hypothesis-generating. We can’t take this result as indication that we should change clinical practice or change the way DBS is done today, but it does provide us with a great foundation to further explore if DBS applied in early-stage Parkinson’s may slow motor progression.”
When Charles started this work, studies of DBS for Parkinson’s had tracked symptoms, but effects on disease progression had never been measured. In 1997 the Food and Drug Administration had approved DBS for certain symptoms of advanced Parkinson’s, and in 2002 had expanded this approval for additional symptoms. Patients are implanted with wire-thin electrodes, positioned through two surgical openings in the cranium to deliver a constant electric current to small clusters of neurons located deep within the brain on both sides. (As with pacemakers, the battery for DBS is typically implanted just below the collarbone.) There are no physical pain sensors in the brain, so this is typically an awake procedure, with the surgical team trying various stimulation settings and various electrode placements in the STN, discussing what works best with the immobilized (and alert) patient.
After the pilot, the FDA approved VUMC to lead a yet-to-be-funded, full-scale multisite trial of DBS versus standard care in early-stage Parkinson’s. In 2016, DBS was approved for mid-stage Parkinson’s patients, those at least four years from onset, but with no full-scale early-stage trial yet begun, that’s as far as FDA approvals have gone. Charles and Hacker say they remain committed to leading the FDA-approved trial investigating whether DBS slows Parkinson’s progression in early-stage patients.
The sole remaining VUMC researcher on the new study is Thomas Davis, MD. Apart from Konrad, all other authors are associated with Horn’s lab. The pilot was supported by the National Institutes of Health (TR000445).
