LAUSR

Deep brain stimulation (DBS) is a standard of care for carefully selected patients with movement disorders. Despite DBS success, many challenges remain; most of them devicerelated due to lagging of technological development. Nevertheless, the last decade has seen advances in potential “wireless” neuromodulation technologies through exposure to light (optogenetics), magnetic fields (magnetogenetics), or exogenous ligands (chemogenetics). A summary of these is given in Table 1. The most novel of these methods is magnetothermal deep brain stimulation (mDBS). To achieve mDBS, scientists select neurons that transgenically express the heat-sensitive transient receptor potential cation channel subfamily V member 1 (TRPV1, formerly the capsaicin receptor) and embed them with magnetic nanoparticles (composed of an iron-oxide core with polyethylene glycol coating), which when exposed to a low-frequency magnetic field produce heat activating TRPV1 and inducing neuronal firing. This technique has been demonstrated to stimulate neurons in vivo, and to influence motor behaviors in living animals. Recently, Hescham and coworkers applied mDBS to improve motor features in a mice model of parkinsonism. To induce expression of TRPV1, the authors stereotactically injected a lentiviral transgene in the subthalamic nucleus (STN) of healthy mice. After 6 to 8 weeks to allow for homogeneous levels of TRPV1 expression, the authors injected magnetic (mDBS) or non-magnetic nanoparticles (nmDBS) in the STN. Parkinsonism was induced bilaterally (intraperitoneal MPTP injection) or unilaterally (6-OHDA lesioning), with a third group of nonparkinsonian mice as controls. After 2 weeks, mice were placed in an alternating magnetic field for 3 min and motor activity evaluated during 5 minutes through an open field test. In the MPTP model, mobility of mDBS mice was significantly better than the nmDBS mice, but the effect wore off after 2.5 minutes (due to cooling of nanoparticles). In the 6-OHDA model, there was no improvement, but the evaluation was limited because half of the subjects were lost after the lesioning surgery. Prospective advantages of mDBS come from its stimulus and cell selectivity. Magnetic nanoparticles are not activated at average body temperatures but only when stimulated by magnetic fields (reaching deep structures with limited interaction with biological tissues) and revert to their basal state after a cooling down period. TRPV1 expression can be induced in specific neuronal populations, with a spatial resolution at the nanoscale, which allows for cell-specific and potentially multiple-site neurostimulation to address distinct clinical manifestations. However, these potential advantages pose major challenges for mDBS to be applied to human subjects. Preferential TRPV1 expression in the human STN for neurostimulation purposes would require transgenic manipulation, raising risks and ethical concerns given the need for viral vectors. Also, multiple procedures to deliver (or remove) magnetic nanoparticles would be required, and their long-term safety and durability remain to be established. Finally, the need for a portable device potent enough to sustain continuous stimulation (unavailable with current technology), might limit the potential “wireless” advantages. Altogether, mDBS represents a promising potentially “wireless” method of neurostimulation. Nevertheless, many issues still need to be addressed and resolved before moving from animal models to human subjects.