Wireless and precise stimulation of deep brain structures could have important applications to study intact brain circuits and treat neurological disorders. Herein, we report that magnetoelectric nanoparticles (MENs) can be guided to a targeted brain region to stimulate brain activity with a magnetic field. We demonstrated the nanoparticles’ capability to reliably evoke fast neuronal responses in cortical slices ex vivo. After fluorescently labeled MENs were intravenously injected and delivered to a targeted brain region by applying a magnetic field gradient, a magnetic field of low intensity (350–450 Oe) applied to the mouse head reliably evoked cortical activities, as revealed by two-photon and mesoscopic imaging of calcium signals and by an increased number of c-Fos expressing cells after stimulation. Neither brain delivery of MENs nor the magnetic stimulation caused significant increases in astrocytes and microglia. Thus, MENs could enable a non-invasive and contactless deep brain stimulation without the need of genetic manipulation.
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F. e. a. Hummel, Effects of non-invasive cortical stimulation on skilled motor function in chronic stroke. Brain 128, 164–174 (2005).
C. e. a. Miniussi, Efficacy of repetitive transcranial magnetic stimulation/ transcranial direct current stimulation in cognitive neurorehabilitation. . Brain Stimulation 1, 326–336 (2008).
A. Demirtas-Tatlidede, ..., A. Pascual-Leone, Non-invasive brain stimulation in traumatic brain injury. Journal of Head trauma rehabilitation 27, 274-292 (2012).
T. Wagner, Valero-Cabre, A., Pascual-Leone, A., Noninvasive human brain stimulation. Annual Review of Biomedical England 9, 527–565 (2007).
N. Sollmann, Hauck, T., Tussis, L., Ille, S., Maurer, S., Boeckh-Behrens, T., Ringel, F., Meyer, B., Krieg, S.M., Results on the spatial resolution of repetitive transcranial magnetic stimulation for cortical language mapping during object naming in healthy subjects. BMC Neuroscience 17, (2016).
R. Sparing, Mottaghy, F.M. , Noninvasive brain stimulation with transcranial magnetic or direct current stimulation (TMS/tDCS)-From insights into human memory to therapy of its dysfunction. Methods 44, 329–337 (2008).
A. R. Brunoni, Nitsche, M.A., Bolognini, N., Bikson, M., Wagner, T., Merabet, L., Edwards, D.J., Valero-Cabre, A., Rotenberg, A., Pascual-Leone, A., Ferrucci, R., Priori, A., Boggio, P.S., Fregni, F., Clinical research with transcranial direct current stimulation (tDCS): challenges and future directions. Brain Stimulation 5, 175-195 (2012).
T. K. Gradinaru V., Zhang F., Mogri M., Kay K., Schneider B., Deisseroth K., Targeting and readout strategies for fast optical neural control in vitro and in vivo. Journal of Neuroscience 27, 14231–14238 (2007).
L. Fenno, Yizhar, O., Deisseroth, K. , The development and application of Optogenetics. Annual Review of Neuroscience 34, 389–412 (2011).
R. Chen, G. Romero, M. G. Christiansen, A. Mohr, P. Anikeeva, Wireless magnetothermal deep brain stimulation. Science 347, 1477-1480 (2015).
H. Huang, Delikanli, S., Zeng, H., Ferkey, D.M., Pralle, A., Remote control of ion channels and neurons through magnetic-field heating of nanoparticles. Nature Nanotechnology 5, 602–606 (2010).
A. Bystritsky, Korb, A. S., Douglas, P. K., Cohen, M. S., Melega, W. P., Mulgaonkar, A. P., et al. , A review of low-intensity focused ultrasound pulsation. Brain Stimulation 4, 125–136 (2011).
K. Yue et al., Magneto-electric nano-particles for non-invasive brain stimulation. PloS one 7, e44040 (2012).
R. Guduru et al., Magnetoelectric 'spin' on stimulating the brain. Nanomedicine (Lond) 10, 2051-2061 (2015).
J. A. Kozielski K., Gilbert H., Yu Y., Erin O., Francisco D., Alosaimi F., Temel Y., Sitti M., Injectable nanoelectrodes enable wireless deep brain stimulation of native tissue in freely moving mice. BioRivx, (2020).
P. M. e. al., Size-dependent intranasal administration of magnetoelectric nanoparticles for targeted brain localization. Nanomedicine: Nanotechnology, Biology, and Medicine 32, (2021).
E. Burgess, M. Sylvester, ..., M. M. Boggiana, Effects of Transcranial Direct Current Stimulations (tDCS) on Binge-eating disorder. International Journal of Eating Disorders 49, 930-936 (2016).
P. Wang et al., Colossal Magnetoelectric Effect in Core-Shell Magnetoelectric Nanoparticles. Nano Lett 20, 5765-5772 (2020).
D. T. Ping Wang, Elric Zhang, Mackenson Telusma, Dwayne McDaniel, Ping Liang, Sakhrat Khizroev., Scanning probe microscopy study of cobalt ferrite-barium titanate coreshell magnetoelectric nanoparticles. Journal of Magnetism and Magnetic Materials 516, (2020).
e. a. Wang P., Colossal Magnetoelectric Effect in Core-Shell Magnetoelectric Nanoparticles. Nano Letter 20, 5765–5772 (2020).
T. J. W. Tsai-Wen Chen, Yi Sun, Stefan R. Pulver, Sabine L. Renninger, Amy Baohan, Eric R. Schreiter, Rex A. Kerr, Michael B. Orger, Vivek Jayaraman, Loren L. Looger, Karel Svoboda, Douglas S. Kim, Ultrasensitive fluorescent proteins for imaging neuronal activity. Nature 499, (2013).
A. Kaushilk, M. Nair et al., Magnetically guided central nervous system delivery and toxicity evaluation of magneto-electric nanocarriers. Scientific Reports 6, (2016).
S. W. Lankoff A., Wegierek-Ciuk A., Lisowska H., Refsnes M., Sartowska B., Schwarze P., Meczynska-Wielgosz S., Wojewodzka M, Kruszewski M., The effect of agglomeration state of silver and titanium dioxide nanoparticles on cellular response of HepG2, A549 and THP-1 cells. . Toxicology Letters 208, 197–213 (2012).
F. E, The role of surface charge in cellular uptate and cytotoxicity of medical nanoparticles. International Journal of Nanomedicine 7, 5577–5591 (2012).
T. S. Okuda-Shimazaki J., Kanehira K., Sonezaki S., Taniguchi A., Effects of Titanium Dioxide nanoparticle aggregate size on gene expression. International Journal of Molecular Science 11, 2383–2392 (2010).
M. Nair, Guduru R., Liang P., Hong J., Sagar V., Khizroev S., Externally ocntrolled on-demand release of anti-HIV drug using magneto-electric nanoparticles as carriers. Nature Communications 4, (2013).
S. A. Dilnawaz F., Mewar S., Sharma U., Jagannathan N.R., Sahoo S., The transport of non-surfactant based paclitaxel loaded magnetic nanoparticles across the blood brain barrier in a rat model. Biomaterials 33, 2936–2951 (2012).
A. Kaushik, Jayant, R., Nikkhah-Moshaie, R. et al., Magnetically guided central nervous system delivery and toxicity evaluation of magneto-electric nanocarriers. Scientific Reports 6, (2016).
E. Bullitt, Expression of C-fos-Like Protein as a marker for neuronal activity following noxious stimulation in Rats. Journal of Comparative Neurology 296, 517-530 (1990).
A. Hudson, Genetic reporters of neuronal activcity: c-Fos and GCamp6. Methods Enzymology 603, 197-220 (2018).
Y. A. Wu B., Quercetin inhibits c-fos, Heat Shock Protein, and Glial fibrillary acidic protein expression in injured astrocytes. Journal of Neuroscience Research 62, 730–736 (2000).
K. Y. Groves A., Jonnalagadda D., Rivera R., Kennedy G., Mayford M., Chun J., A functionally defined in vivo astrocyte population identified by c-Fos activation in a mouse model of multiple sclerosis modulated by S1P signaling: immediate-early astrocytes (ieAstrocytes). eNeuro, (2018).
L. P. Koziara JM, Allen DD, Mumper RJ., The blood-brain barrier and brain drug delivery. Journal of Nanoscience Nanotechnology 6, 2712–2735 (2006).
Y. Z. Y. J. Yu, M. Kenrick, K. Hoyte, W. Luk, Y. Lu, J. Atwal, J. M. Elliott, S. Prabhu, R. J. Watts, M. S. Dennis. , Boosting brain uptake of a therapeutic antibody by reducing its affinity for a transcytosis target. Science Translational Medicine 3, (2011).
J. Q. Qiao R., Huwel S., Xia R., Liu T., Gao F., Galla H., Gao M., Receptor-mediated delivery of magnetic nanoparticles across the blood-brain barrier. ACS Nano 6, 3304–3310 (2012).
J. A. Chu C., Lesniak W., Thomas A., Lan X., Linville R. et al., Optimization of osmotic blood-brain barrier opening to enable intravital microscopy studies on drug delivery in mouse cortex. Journal of Controlled Release 317, 312–321 (2020).
F. B. Zhang Q., Zhang Z. , Borneol, a novel agent that improves central nervous system drug delivery by enhancing blood-brain barrier permeability. Drug Delivery 24, 1037–1044 (2017).
X. D. Silasi G., Vanni M., Chen A, Murphy T., Intact skull chronic windows for mesoscopic wide-field imaging in awake mice. Journal of Neuroscience Methods 267, 141-149 (2016).
D. Barson, Hamodi, A.S., Shen, X. et al., Simultaneous mesoscopic and two-photon imaging of neuronal activity in cortical circuits. Nature Methods 17, 107–113 (2020).
M. A. A. Kerlin, V. Berezovskii, R.C. Reid, Broadly tuned response properties of diverse inhibitory neuron subtypes in mouse visual cortex. Neuron 67, 858-871 (2010).
K. S. Imai Y., Intracellular signaling in M-CSF-induced microglia activation: role of Iba1. Glia 40, 164–174 (2002).
E. W. Liedtke W., Bieri PL., Chiu FC., Cowan NJ., Kucherlapati R., Raine CS., GFAP is necessary for integrity of CNS white matter architecture and long-term maintenance of myelination. Neuron 17, 607–615 (1996).
We thank Tiffany Stewart, Wenhui Xiong, and Xingjie Ping for their experimental support.
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This publication was made possible with partial support from the N3 program of the DARPA of the Department of Defense (SK, XJ, and LP), the National Science Foundation (NSF) under the grant number ECCS-1935841 (SK and XJ), and from the pre-doctoral fellowship to TN of National Institute of Health grant number NIH-UL1TR002529 (A. Shekhar, PI), National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award, and the Indiana University Department of Medicine.
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Nguyen, T., Gao, J., Wang, P. et al. In Vivo Wireless Brain Stimulation via Non-invasive and Targeted Delivery of Magnetoelectric Nanoparticles. Neurotherapeutics (2021). https://doi.org/10.1007/s13311-021-01071-0
- Noninvasive brain stimulation
- Calcium imaging