Enhancing the spatial control of non-invasive brain stimulation by magnetic temporal interference

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Project Summary/Abstract Electromagnetic brain stimulation is a safe and proven way of controlling neural activity non-invasively with no implanted hardware or injected biochemical agents. Transcranial magnetic stimulation (TMS) is FDA approved for treatment of drug resistant depression and obsessive compulsory disorder with a range of other clinical applications under investigation. Its use in neuroscience research has also seen rapid expansion in recent years due to its ability to test causality by non-invasively perturbing neural activity. The most critical limitation of TMS is its inability to focus the stimulation depth-wise in a spatially selective manner; the electric field (E-field) is always maximal in the superficial region, closest to the stimulating coil. This is a major limitation given the critical role that subcortical structures play in both health and disease. Using the superposition, or “temporal interference”, of E-fields oscillating at different frequencies to create an amplitude modulation (AM) maximum at a given target in the subcortex has been suggested as a work-around to this problem. While the E- fields are still strongest in the superficial region, the neurons time-lock to the AM oscillation rather than the oscillations of the individual E-fields, yielding enhanced stimulation in the subcortical superposition zone. A recent study demonstrated the feasibility of this concept in a mouse model using electrical stimulation delivered via two electrode pairs at opposing sides of the skull. Although these pre-clinical animal data were very promising, the use of scalp electrodes will be problematic for human translation due to the high conductivity ratio between the scalp and skull tissues that shunts the current and leads to very weak E-fields inside the cranium of humans. In this F32 project, we propose developing a temporal interference approach using magnetic stimulation (TiMS) which could be a more translatable technique to humans than electrical stimulation. Unlike electrical stimulation, magnetic fields efficiently pass through the human skull inducing clearly suprathreshold E-fields in the brain that can directly depolarize neurons. Firstly, the theoretical feasibility of the proposed technique in terms of stimulation efficiency and safety limits will be investigated by computational modeling. The theoretical results will then be validated in a phantom head model using a low-power system usually used for MRI shimming that is currently in place in our lab. Finally, based on these computational results and the experimental verification of the idea, we will design, build, and validate a prototype device capable of delivering effective intracranial TiMS by connecting custom made TMS coils to an in-house MRI gradient amplifier system. The end goal of the project is to have a novel device prototype capable of non-invasive brain stimulation that is steerable along the depth dimension and ready to be used in non-human primate models for pre-clinical testing and ultimately in humans.