Xiang Wu1,Guosong Hong1
Stanford University1
Neuromodulation techniques, such as electrical deep-brain stimulation and optogenetics, are capable of selective activation or inhibition of certain subgroup of neurons, thus providing unprecedented opportunities for the dissection of complex neural circuitry and the treatment of neurological disorders such as Parkinson’s disease. The electric field or visible light used in the current predominant neuromodulation approaches, however, is strongly attenuated by the brain tissue, thus necessitating invasive implantation of stimulation electrode or optical fiber. Such invasive brain implants inevitably cause acute brain damage, chronic immune response, and physical tethering that interferes with the animal’s natural behavior. Therefore, it is desirable to develop new methods that can modulate neural activities with an implant-free and tether-free interface.<br/>To address these challenges, we designed a nanomaterial-based bio-interface in one of the biological transparence windows, the second near-infrared window (NIR-II, 1000-1700 nm), for remote and non-invasive deep-brain stimulation. NIR-II light exhibits reduced scattering than visible light and lower water absorption than longer wavelength NIR light, and is thus the optimal wavelength for deep-brain neuromodulation. Although no existing opsin responses to NIR-II photons, we got inspiration from the findings of Nobel laureate David Julius that rattlesnakes sense infrared irradiation through its thermal effect using transient receptor potential (TRP) channels. We hypothesized that TRP channels can also be used as NIR-II receptors in mammalian neurons. However, to activate deep-brain TRP channels, a high laser power is required, which inevitably leads to a high temperature increase on the brain surface, and as a result, altering the neural behaviors and even causing brain damage. To overcome this challenge, we designed nanotransducers named MINDS (macromolecular infrared nanotransducers for deep-brain stimulation) that strongly interact with NIR-II light. Specifically, MINDS consist of a NIR-II absorbing semiconducting polymer core with a photothermal conversion efficiency of 71% in the NIR-II window, and an FDA-approved amphiphilic polymer shell to facilitate water solubility and biocompatibility. As a result, through-scalp wide-field NIR-II illumination creates a local hotspot around MINDS up to a depth of 5-mm in the brain, while largely sparing the brain surface from heating. Consequently, MINDS act as an NIR-II sensitizer to remotely activate deep-brain TRP-expressing dopaminergic neurons in freely behaving mice without any brain implant or physical tethering, producing significant behavioral changes in a conditioned place preference test.<br/>The utility of this NIR-II neuromodulation technique sits between optogenetics and chemogenetics: it eliminates the chronic brain implants and fiber tethering required for optogenetics and features a more precise temporal control of activation and inactivation than chemogenetics. Therefore, the NIR-II neuromodulation approach reported here allows timely behavioral modulation of freely moving subjects with minimal chronic gliosis in the neural tissue and no interference to natural animal behaviors. With complete elimination of any brain implant and head tethering, our approach could afford wide applications in dissecting the complex neural circuits of normally behaving animals in a natural interaction environment, such as in the IntelliCage, in the future. <b>This work was recently published in <i>Nat. Biomed. Eng.</i> (Wu, X. <i>et al.</i> Tether-free photothermal deep-brain stimulation in freely behaving mice via wide-field illumination in the near-infrared-II window. <i>Nat. Biomed. Eng.</i> 6, 754-770 (2022)).</b>