Abstract
Non-invasive or minutely invasive and wireless brain stimulation that can target any region of the brain is an open problem in engineering and neuroscience with serious implications for the treatment of numerous neurological diseases. Despite significant recent progress in advancing new methods of neuromodulation, none has successfully replicated the efficacy of traditional wired stimulation and improved on its downsides without introducing new complications. Due to the capability to convert magnetic fields into local electric fields, MagnetoElectric NanoParticle (MENP) neuromodulation is a recently proposed framework based on new materials that can locally sensitize neurons to specific, low-strength alternating current (AC) magnetic fields (50Hz 1.7kOe field). However, the current research into this neuromodulation concept is at a very early stage, and the theoretically feasible game-changing advantages remain to be proven experimentally. To break this stalemate phase, this study leveraged understanding of the non-linear properties of MENPs and the nanoparticles’ field interaction with the cellular microenvironment. Particularly, the applied magnetic field’s strength and frequency were tailored to the M-H hysteresis loop of the nanoparticles. Furthermore, rectangular prisms instead of the more traditional “spherical” nanoparticle shapes were used to: (i) maximize the magnetoelectric effect and (ii) improve the nanoparticle-cell-membrane surface interface. Neuromodulation performance was evaluated in a series of exploratory in vitro experiments on 2446 rat hippocampus neurons. Linear mixed effect models were used to ensure the independence of samples by accounting for fixed adjacency effects in synchronized firing. Neural activity was measured over repeated 4-minute segments, containing 90 seconds of baseline measurements, 90 seconds of stimulation measurements, and 60 seconds of post stimulation measurements. 87.5% of stimulation attempts produced statistically significant (P < 0.05) changes in neural activity, with 58.3% producing large changes (P < 0.01). In negative controls using either zero or 1.7kOe-strength field without nanoparticles, no experiments produced significant changes in neural activity (P > 0.05 and P > 0.15 respectively). Furthermore, an exploratory analysis of a direct current (DC) magnetic field indicated that the DC field could be used with MENPs to inhibit neuron activity (P < 0.01). These experiments demonstrated the potential for magnetoelectric neuromodulation to offer a near one-to-one functionality match with conventional electrode stimulation without requiring surgical intervention or genetic modification to achieve success, instead relying on physical properties of these nanoparticles as “On/Off” control mechanisms.
This in vitro neural cell culture study explores how to exploit the non-linear and anisotropic properties of magnetoelectric nanoparticles for wireless neuromodulation, the importance of magnetic field strength and frequency matching for optimization, and demonstrates, for the first time, that magnetoelectric neuromodulation can inhibit neural responses.
•MENPs can induce local action potentials, not just sub-threshold neural activation•MENPs-based wireless stimulation is activated by external magnetic fields, thus not requiring any surgical interference, and does not require any brain tissue genetic modification•Magnetic fields propagate through both skull and tissue with no interference and signal destruction and can localize energy in any site deep in the brain•MENPs can be used for both excitation and inhibition of neural activity via application of AC and DC magnetic fields, respectively•MENPs’ physical properties, e.g., the magnetoelectric effect and magnetic anisotropy, are used as “On/Off” switches to control neural activation mechanisms•The MENP neuromodulation efficacy can be improved by using rectangular-prism-shaped nanoparticles, thus achieving both the increase of the magnetoelectric effect and the significant improvement of the nanoparticle-surface interface. The latter is critical to ensure the MENPs become an integral part of the membrane, thus allowing the magnetoelectric control of local ion channels in the neuronal membrane, in turn enabling the wirelessly controlled MENP neuromodulation.