In this application, I propose a program of technology development and validation that will allow to safely image the brain of patients with deep brain stimulation (DBS) implants using magnetic resonance imaging (MRI). This new technology, which builds on my previous work on parallel transmit (pTx) pulse design and specific absorption rate (SAR) monitoring, will allow the vast array of MRI anatomical and functional sequences to be deployed for the first time in DBS patients. Although DBS is a common therapy of severe motion disorders such a dystonia and Parkinson disease and has shown promise for the treatment of some psychiatric disorders such as depression, its mechanisms of action are not understood. Moreover, anatomical targets of the DBS electrode are not yet established in the case of psychiatric disorders. MRI is an ideal modality to quantify the changes in the functional networks of the brain that occur during the DBS treatment. The program of technology development and validation proposed in this grant would leverage the unmatched potential of MRI for neuroimaging to DBS patients. To solve the safety problem of MRI in the presence of a DBS implant, I propose to design radio-frequency (RF) pulses using multiple transmit channels as opposed to only one as is done with the ubiquitous birdcage coil. I will study two cases in particular: A birdcage coil driven independently on its two quadrature ports (2 independent transmit channels) and an 8 channels pTx coil. As my preliminary results show (see Research Strategy section), the additional degrees-of-freedom of these two coils allow the pulse designer to sculpt the 3D electric field distribution so as to minimize it at the location f the implant. As a result, induced currents and SAR are minimized. There are also tremendous degrees-of-freedom in the RF pulse itself, which needs to be designed while explicitly constraining SAR at the implant location. To apply these tools in humans, I propose a comprehensive safety testing program combining electromagnetic simulations and temperature mapping in realistic 3D-printed head phantoms. I will collaborate closely with the FDA and Medtronics (manufacturer of the only FDA-approved DBS implants) on the safety evaluation of these RF approaches. In my final Aim, I propose to perform a pilot study in a few DBS patients in order to verify that the quality of the data obtained such low- SAR MRI protocols is adequate (image quality metrics detailed in the Research Strategy). This research proposal fits exactly my research background and interests and will allow me to reach my short term goal of becoming an independent investigator. A K99/R00 award would help me jumpstart a bioengineering career focused on solving clinically important problems using innovative imaging approaches. After the R00 phase, I will submit an R01 building on the work performed in this grant. This R01 application will use the technology developed in Aims 1 and 2 and will leverage the preliminary human data obtained in Aim 3. My ultimate goal is to use MRI to explain the mechanisms of action and guide the development of emerging DBS strategies such as close-loop DBS and DBS arrays with multiple electrodes. To facilitate my progression to a position of independence, I have designed with my mentors a training program involving coursework, specialized seminars and clinical shadowing that will provide me with basic knowledge in neuroscience and the clinical practice of DBS as well as skills in neuroimaging data analysis. This training is crucial or me to reach a position of independence. Indeed, it will allow to design and conduct (after the K99/R00 period) my own MRI experiment. Moreover, although I do not intent to become neuroscientist myself, basic training in neuroscience is needed for me to efficiently collaborate with colleagues in this field. During the K99 phase of the award, I will be mentored by world-leading experts in MRI safety (Dr. Wald), DBS design and evaluation (Dr. Bonmassar) and neuroimaging evaluation of DBS patients (Dr. Dougherty) as well as consultants from MGH, the FDA and Medtronics. This research will be performed at the A. A. Martinos Center for Biomedical Imaging, a world-leading institution for functional neuroimaging and the study of brain changes in health and disease. The project will greatly benefit from the unique resources of the Martinos Center, including large computer clusters for electromagnetic simulations and data analysis as well as a 3 T MRI Siemens Skyra scanner with parallel transmit capability. I will also use the unique resources of the MGH Division for Neurotherapeutics, including rooms for psychometric evaluation, DBS programming devices and a large DBS patient pool. This project will also take advantage of an MGH-lead $35 Million grant funded by DARPA and aiming at designing the next generation of closed-loop DBS electrodes. The goals of this K99 application and the DARPA grant are different but highly complementary (the DARPA effort focuses on the development of new DBS implant technology and contains no imaging of DBS patients). This collaboration framework will help me foster collaborations with world-class DBS researchers and will likely increase the impact and visibility of my own work.
Deep rain stimulation (DBS) is an established treatment of motor disorders such as Parkinson disease and has shown promise for the treatment of psychiatric illnesses however its mechanisms of action are not known and its clinical efficacy in psychiatric disorders is not established. Magnetic resonance imaging is an ideal modality to quantify the changes occurring in the functional networks of the brain during the DBS treatment; unfortunately MRI is currently contraindicated in the presence of DBS implants. In collaboration with FDA and Medtronic, we propose to develop and validate safe MRI excitations in the presence of DBS implants that will pave the way for future studies of the interaction between the DBS implant and the patient' brain using functional MRI.
