Key Points
- Researchers investigated whether modulating a deep brain region called the zona incerta (ZI) could alleviate persistent tremor in patients with Parkinson’s disease.
- Results showed that targeting the ZI holds distinct promise for relieving both postural and rest tremors.
The results from a focused ultrasound neuromodulation clinical research study (NCT06259708) at the University of British Columbia in Vancouver, Canada, were recently published in Brain Stimulation. The study, which was seeking to improve tremor control in patients with tremor-dominant Parkinson’s disease (TDPD), compared the effectiveness of targeting the zona incerta (ZI) versus the ventral intermediate (VIM) nucleus of the thalamus.
Although significant tremor control may be achieved after focused ultrasound VIM thalamotomy in patients with essential tremor (ET) and TDPD, Parkinsonian tremor differs from ET in both pathophysiology and presentation. While Parkinsonian tremor presents more at rest, ET is characterized by postural tremor. The team therefore hypothesized that the ZI may be a more suitable target for Parkinsonian tremor.
“My motivation for designing this study stemmed from observing the limitations in achieving sustainable tremor control after focused ultrasound VIM thalamotomy in patients with TDPD,” said Hongchae ‘Iris’ Baek, PhD, a program manager at the Foundation and co-author of the publication who conceptualized the project. “Unlike the highly durable outcomes observed in patients with essential tremor, a significant portion of TDPD patients experience early tremor relapse. This discrepancy suggests that conventional VIM targeting does not fully engage the complex disease circuitry involved in Parkinson’s disease. Supported by retrospective clinical data indicating that extended lesion into the posterior subthalamic area (which includes the ZI) improves the durability of tremor control, the team hypothesized that a lack of ZI involvement might lead tremors to return.”
Furthermore, because resting tremor is a classic hallmark sign of Parkinson’s disease, the team set out to directly evaluate treatment effects on both resting and postural tremors. Anatomically, the ZI functions as a critical hub within the Parkinson’s disease tremor circuit, making it an ideal candidate for tremor modulation.
Martin J. McKeown, MD, head of the Division of Neurology at the University of British Columbia, led the clinical study. The study enrolled 19 participants who completed a within-subject, crossover protocol that used the NeuroFUS neuromodulation device with Brainsight neuronavigation. A collimator with degassed water was attached to the transducer, and participants’ hair was covered with ultrasound gel to reduce interference.
All participants received both VIM and ZI stimulation in two separate sessions on the same day. Half received VIM targeting first and the other half ZI targeting first. Both groups were given a 4-hour washout period between treatments. The team analyzed tremor severity and resting-state functional MRI (rs-fMRI) changes before and after each stimulation session.
The study revealed the ultrasound modulation to be target- and tremor-specific. VIM targeting was more effective at reducing postural tremor, whereas ZI targeting was effective at improving both postural and rest tremor. The team also discovered that individual changes in resting state functional connectivity of the ZI, as well as changes in the fractional amplitude of low-frequency fluctuations, predicted treatment success. They concluded that targeting the ZI was a promising target for treating TDPD.
“Another interesting finding was that we observed a network priming effect, which revealed that the sequence of the stimulation matters when conducting multi-target crossover protocols,” said Dr. Baek.
“Although tremor amplitude returned to baseline following the 4-hour washout period, the neurophysiological evaluation suggested that the brain had not fully reverted to its pre-stimulation state,” stated Dr. McKeown. “This highlights a critical consideration for the methodological design of future multi-target crossover trials utilizing focused ultrasound neuromodulation.”
Dr. Baek added, “The results from this proof-of-concept study are highly encouraging. We are now working to launch a follow-on study using the thermal effects of focused ultrasound to validate the zona incerta as a safe, feasible, and effective therapeutic target for permanent lesioning.”
This research study was funded by the Focused Ultrasound Foundation.
See Brain Stimulation (Open Access)
Related Stories
Parkinson’s Disease Neuromodulation Study Begins at the University of British Columbia February 2025