My research program focuses on three primary areas of interest:
Tinnitus and the role of the basal ganglia in auditory perception
I am collaborating with Dr. Steven Cheung in the Department of Otolaryngology on studies related to the role of the basal ganglia in auditory perception. We published our first paper on this work in Neuroscience, which describes the use of acute deep brain stimulation (DBS) of the caudate in a cohort of movement disorders patients with comorbid tinnitus undergoing DBS surgery. In it, we describe a specific area of the caudate (area LC) that modulates tinnitus when stimulated. These experiments provided evidence for the first time that the caudate may play a role in tinnitus and auditory perception.
We subsequently published a second patient cohort that describes the triggering of phantom sounds in patients without tinnitus by acutely stimulating area LC. This publication includes a proposed new model for the basal ganglia to account for these findings and explain the natural history of tinnitus. We were granted an IDE from the FDA in 2012 and received a U01 grant from the NIH/NIDCD in 2013 for a first-in-human clinical trial to investigate the use of DBS in patients with medically refractory tinnitus. This trial is currently enrolling subjects, and is gathering extensive intraoperative recordings as well as functional imaging with fMRI and MEG (under the direction of Dr. Nagarajan) to better understand the pathophysiology and functional connectivity of this disorder.
Gene therapy for Parkinson’s disease
I have been extensively involved in four gene therapy trials for Parkinson’s disease: (1) AAV-AADC phase I, completed 2008 with UCSF as the only site; (2) AAV-neurturin phase I, completed 2006 with UCSF as the primary site; (3) AAV-neurturin phase II, completed 2007 with UCSF as the highest enrolling site in a multicenter trial; (4) AAV-neurturin phase IIb, completed 2013 with UCSF again as the lead site. By virtue of our involvement in these trials, we have become the most experienced center in gene therapy for Parkinson’s disease in the world. One major shortcoming in these trials has been the inability to monitor the infusions during the procedure to ensure adequate coverage of the intended target. This was demonstrated in post-mortem examinations from two of the subjects in the neurturin trials, where the average putaminal coverage was only 14%.
In 2012, our group was awarded a grant from the Michael J. Fox Foundation to perform a phase Ib AAV-AADC gene transfer clinical trial in humans using the ClearPoint iMRI system (see next section). This allows us to perform convection-enhanced delivery of viral vector mixed with gadoteridol to visualize the infusions in the putamen using real-time MRI imaging.
The study has now been expanded and is also being funded by Voyager Therapeutics. I am the clinical PI on the study with Co-PI Dr. Chad Christine (Department of Neurology), and Dr. Krystof Bankiewicz (Department of Neurological Surgery) who performed all of the pre-clinical studies.
Interventional MRI (iMRI) guided DBS implantation
This is a completely novel method for implanting DBS electrodes that was first developed by our group at UCSF in 2003. Traditional surgical methods for DBS implantation require an awake patient and involve physiologic mapping of the brain, which results in multiple brain penetrations, longer procedures times and discomfort for some patients. Our group has devised a technique to place DBS electrodes using real-time MRI imaging. We developed a new surgical methodology and partnered with private industry to develop surgical instruments specifically designed for this procedure. A series of phantom tests were performed to validate the technique, and an IRB approved trial was started in human Parkinson’s subjects in 2004. The entire procedure is performed within the bore of a 1.5T MRI scanner and has several advantages over traditional DBS implantation. No physiologic mapping is required, so implantation may be performed under general anesthesia with a single penetration of the brain. The procedure time is reduced by about 50%, and real-time imaging during surgery allows for immediate detection of complications and accounts for brain shift.
We have collaborated with our current funding partner, MRI Interventions, to develop a second-generation system (ClearPoint). The system consists of a skull mounted stereotactic platform and a software environment that allows iMRI DBS to be performed in any MRI scanner, and was approved by the FDA in late 2010. This technique is now being used in over 30 centers in the US and Europe, however we remain the most experienced center in iMRI guided functional neurosurgery in the world by a large margin. Our program has expanded to include 3T MRI programs at the VA and the new UCSF Children’s Hospital. We are also using ClearPoint for drug infusions such as gene therapy (see above) and laser ablations for epilepsy and neoplastic disease with other surgeons on our faculty (Drs. Chang, Aghi and Auguste). This body of work has been continuously funded since 2003. My primary collaborators in this effort are Dr. Philip Starr (Department of Neurological Surgery) and Dr. Alastair Martin (Department of Radiology), and our core surgical movement disorders neurology team (Drs. Ostrem, Galifianakis, San Luciano and Katz).