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.

Project narrative Despite an exponential increase in scientific and clinical applications, non-invasive electromagnetic brain stimulation remains limited by its inability to focus the stimulation to the subcortex; this is a major limitation given the critical roles that subcortical structures play in both health and disease. Utilizing neurons’ propensity to time- lock to the amplitude modulation (AM) of an electric field (E-field) created by the superposition of two E-fields oscillating at different frequencies generated by scalp electrodes has been suggested as a solution to this problem, since the AM maximum occurs in between the scalp electrodes where the two E-fields have equal amplitude and can therefore be focused to the subcortex. Scalp electrodes, however, generate very weak stimulation effects in humans; in this proposal we therefore seek to investigate this technique using TMS coils instead of scalp electrodes which induce much stronger E-fields and could therefore result in both effective and specific subcortical stimulation, thus opening new avenues for treatment of a wide range of diseases involving subcortical structures as well as providing a new lens into subcortical physiology.