Abstract The ability to noninvasively modulate and image the brain with spatial and temporal precision is highly desirable for understanding brain circuits in health and disease. Transcranial magnetic stimulation (TMS) is a method for stimulating the superficial cortex with high spatial and temporal precision, and its effects can be aimed at deeper targets by leveraging the trans-synaptic connectivity of brain circuits. Functional magnetic resonance imaging (fMRI) has high spatial resolution but limited temporal precision, and the opposite holds for electroencephalography (EEG). These three noninvasive electromagnetic methods have recently been combined to achieve high spatial and temporal precision of concurrent modulation and imaging of the brain. This approach, however, has various significant technical limitations, including mutual electromagnetic artifacts decreasing the signal-to-noise ratio and delaying the acquisition of imaging/EEG data, TMS acoustic noise co- activating auditory pathways, and the inability to adaptively adjust the TMS coil position within the MRI scanner for optimal targeting. The overarching objective of this project is to address these limitations by developing and integrating an array of novel technologies. We will develop a compact, energy efficient, quiet, as well as MRI- and EEG-compatible TMS coil. The TMS coil will be actuated with a custom MRI-compatible robotic system, allowing adaptive optimization of the coil position and orientation based on imaging feedback. The neural circuit responses to the stimulation will be imaged with a newly developed a flexible, head-conforming array of MRI coils combining local magnetic field shimming and RF receiving to achieve high signal-to-noise ratio and fast image acquisition. The brain activity will be simultaneously recorded both before and after TMS with high temporal resolution and low noise using a novel wireless EEG system. To meet the technical challenges of creating such as a system operating inside MRI scanners, our team has developed several breakthrough technologies that will work synergistically to reduce or eliminate couplings between system components and enhance the stimulation precision and imaging speed and sensitivity. Once developed, the robotically-actuated TMS-EEG-fMRI system will enable systematic interrogation of human brain circuits inside an MRI scanner with spatial and temporal flexibility and precision that are impossible to achieve with current technology. The integrated system will be easy-to-use, and platform-agonistic thus having the potential for immediate and scalable impact. First-time adaptive optimization of the TMS coil placement in the MRI scanner will be demonstrated for brain-state-triggered engagement of a deep brain target. In summary, the proposed robotically- actuated TMS-EEG-fMRI system will enable modulation and imaging of brain circuits with enhanced anatomical and functional precision that can lead to advances in neuroscience research and therapeutic interventions.

Project Narrative The overarching objective of this project is to enable multimodal noninvasive stimulation and recording of human brain circuits with high anatomical and temporal precision. The project is to create a closed-loop brain interface that integrates simultaneous neural recording and high-fidelity MRI acquisition with steerable transcranial stimulation. The proposed brain interface is a new noninvasive tool for studying human brain circuits in vivo and for therapeutic interventions.