Project Summary/Abstract We will develop a novel technology for noninvasive transcranial magnetic stimulation (TMS) of the human brain. TMS is a standard tool in experimental brain science and is FDA cleared for treatment of depression, obsessive- compulsive disorder, and migraine as well as pre-surgical brain mapping. However, the underlying high-power electromagnetic pulse technology has substantial limitations. First, the temporal waveform of conventional TMS pulses is exclusively sinusoidal with fixed shape and duration. Second, pulse trains used for neuromodulation can only contain pulses with the same amplitude as well as current direction and require relatively long intervals be- tween most types of pulses. Similar limitations apply to other sequences of TMS stimuli, such as paired-pulse paradigms. We previously developed TMS technology with more controllable pulse parameters; however, these devices still have many critical restrictions in the adjustability of the shape and sequences of pulses. These limita- tions of TMS technology are significant because an increasing body of literature shows that changing the pulse shape can cause more selective activation as well as more potent and reliable neuromodulation. Increasing the functional selectivity of TMS through manipulation of its temporal waveform is important because the spatial focal- ity, and hence the ability to target TMS precisely, is limited by fundamental physical constrains that have been reached by state-of-the-art coil designs. Enhancing neuromodulation effects is critical too, since they form the basis of both research and therapeutic applications. We will address these limitations of existing TMS technology by developing and testing a novel device—modular pulse synthesizer TMS (MPS-TMS)—that can generate practically any user-defined pulse shape and combine pulses with different characteristics into arbitrary sequences and trains. In addition to its unprecedented flexibility, MPS-TMS can generate all conventional pulse types, including those from FDA cleared TMS systems. The aims of this project start with device hardware and software development and testing. Subsequently, we will demonstrate the functionality of MPS-TMS in a challenging real-world applica- tion: the efficient generation of quadripulse stimulation (QPS), which is one of the strongest and most reliable TMS neuromodulation protocols available. The generation of QPS with conventional technology is problematic as it requires the combination of four inefficient monophasic TMS machines and is very limited in pulse repetition rate. In addition to replicating efficiently the QPS pulse shape and train sequence, we will leverage the flexibility of MPS- TMS and conduct model-based optimization of the QPS waveform to achieve equivalent neurostimulatory effect while minimizing coil heating, as coil heating is a key limiter of pulse repetition rates. In a demonstration of MPS- TMS in healthy human subjects, we will compare the neuromodulation effectiveness and coil heating of QPS with the optimized pulse shape to those of standard QPS. The outcomes of this project will provide the field of noninva- sive brain stimulation with a more flexible tool that can enable advances in the lab and the clinic.

Project Narrative Transcranial magnetic stimulation (TMS) is approved or holds promise for studying and treating various psychiatric and neurological illnesses. However, existing TMS treatments have limited and variable efficacy. This project will develop a novel TMS device (MPS-TMS) that allows more flexible control over the characteristics of brain stimulation; this can enable us to study the brain better and to optimize medical therapies.