Essays on Science and SocietyNeuromodulation

Optical modulation goes deep in the brain

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Science  02 Aug 2019:
Vol. 365, Issue 6452, pp. 456-457
DOI: 10.1126/science.aay4350

Neurological disorders will affect more than one-third of us at some point in our lives (1). In just the next 10 years, the number of patients afflicted with a neurological disorder is projected to reach 1.1 billion worldwide (1). Yet safe and effective treatments for these conditions are largely lacking.

Deep brain stimulation (DBS) has proved to be one of the most effective therapies to date for neurological disorders ranging from Parkinson's disease to obsessive-compulsive disorder (2). However, such a treatment requires the implantation of electrodes deep in the brain to electrically stimulate the neurons that are thought to underlie these disorders. In addition to surgical and follow-up costs, which can reach up to $35,000 (3), implantation is highly risky and invasive and the electrical stimulation lacks cell specificity (2). High-precision, minimally invasive technologies for the modulation of deep brain neurons are needed.

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Potential candidates for noninvasive tissue-penetrating stimuli include electric (4, 5), magnetic (4, 6, 7), acoustic (8, 9), and optical signals (10). Transcranial brain stimulation techniques (4) such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) have been widely used in clinical research but lack spatial resolution and cell specificity, limiting their efficacy.

Optogenetics is a recently developed approach that harnesses genetically encoded light-gated ion channels called rhodopsins to achieve unprecedented precision in stimulating target neurons (11). The technique has hitherto required the insertion of invasive optical fibers for deep brain applications because the activating blue-green light is strongly scattered and absorbed by endogenous chromophores in brain tissue (12).

Overcoming the challenge of optical penetration depth will be the key to realizing noninvasive remote optogenetics with high clinical translation potential. Our recent study addressed this problem by applying a nanomaterial-assisted approach that “shifts” the existing optogenetic tools into the near-infrared region (13).

New Approach to Minimally Invasive DBS

To make optogenetics noninvasive, an obvious option is to use near-infrared light (NIR, 650 to 1350 nm), which can efficiently penetrate biological tissue and reach deep brain regions (10). However, the development of NIR-responsive rhodopsin variants has proved difficult: The optimal activation wavelengths of recently developed red-shifted rhodopsins all fall short of 650 nm (13).

We came up with a novel approach in which tissue-penetrating NIR light is locally converted to visible light in the deep brain to activate rhodopsin-expressing neurons (see the figure). To achieve this, we needed an optically unique material that functions much like a light bulb: Low-energy NIR photons turn the bulb on, leading to a high-energy visible emission. Such substances are called “upconversion materials.”

Exploiting “Upconversion” Nanoparticles

Ideal NIR-converting “light bulbs” must be small, efficient in light conversion, highly biocompatible, and have long-term stability. Lanthanide-doped upconversion nanoparticles (UCNPs) met these criteria (14). UCNPs are capable of converting incident NIR photons into visible emission at an efficiency that is orders of magnitude greater than that of multiphoton processes. As a result, a continuous-wave NIR laser diode of low power can drive intense UCNP-mediated upconversion emission.

To optimize their biocompatibility and long-term stability, we coated UCNPs with silica capable of chemically stabilizing the nanoparticles and preventing direct contact of their lanthanide-doped core with the tissue. The resulting monodispersed blue-emitting UCNPs (NaYF4:Yb/Tm@SiO2) of diameter ∼90 nm showed both minimum cytotoxicity and long-term stability: One month after injection, UCNPs still remained at the target site in the brain.

UCNPS Emit Blue Light Deep in the Brain

We reasoned that UCNP-mediated optogenetics would be feasible for transcranial stimulation of deep brain neurons, based on an evaluation of the upconversion efficiency of UCNPs and the transmittance of NIR light in brain tissue (13). To test this, we injected blue-emitting UCNPs into the ventral tegmental area (VTA) of the mouse brain, a region located ∼4.2 mm below the skull, and used in vivo fiber photometry to detect visible-light emission. Encouragingly, transcranial delivery of NIR pulses with a peak power of 2.0 W yielded upconverted blue emission of ∼0.063 mW/mm2. This emission strength is sufficient to activate the commonly used channelrhodopsin-2 (ChR2). We were thus motivated to harness UCNPs as optogenetic actuators of transcranial NIR to stimulate deep brain neurons.

Transcranial NIR Modulates Dopamine Release

We chose the VTA for an initial demonstration of transcranial NIR stimulation because of its medical implications (15). The VTA is a well-established node in the brain's reward system, and the dysregulation of dopamine (DA) release by VTA neurons is causally linked to many neurological disorders, such as major depression.

For this experiment, we injected blue-emitting UCNPs into the VTA of the mouse brain, as before. However, this time, we also injected virus encoding ChR2, which is activated by blue light. Transcranial NIR irradiation successfully evoked excitation of VTA DA neurons, which was confirmed by immunochemical labeling of the activated neurons.

We also detected real-time VTA DA release using fast-scan cyclic voltammetry. Substantial DA release temporally locked to NIR stimulation was observed in the ventral striatum, a projection target of the VTA DA neurons. These proof-of-concept experiments establish UCNP-mediated NIR optogenetics as a viable, minimally invasive method to modulate the activity of deep brain systems with high spatiotemporal and cell type specificity.

A Multifunctional Upconversion Toolbox

An advantage of UCNPs is that their emission can be precisely tuned to a particular wavelength by controlling energy transfer via selective lanthanide-ion doping (14). This allows for multiplex compatibility with the current toolbox of light-activated channels. For example, incorporation of lanthanide-ion Tm3+ into Yb3+-doped host lattices leads to blue light emission that can activate ChR2-expressing neurons, and the Yb3+-Er3+ combination results in green light emission that activates archaerhodopsin (Arch) for neuronal inhibition.

To demonstrate UCNPs' utility for neuronal inhibition, we used mice that underwent chemically induced seizures. These mice were genetically engineered to express Arch within the hippocampus, where green-emitting UCNPs were also injected. Transcranial NIR delivery efficiently suppressed hippocampal hyperexcitability and alleviated seizure symptoms.

Nanoparticle-mediated noninvasive optogenetics

(A) Schematic principle of upconversion nanoparticle (UCNP)–mediated near-infrared light (NIR) upconversion optogenetics. (B) Transcranial NIR stimulation of the ventral tegmental area (VTA) for modulating dopamine release in the mouse brain. (C) Electron micrographs of UCNPs distributed in the VTA tissue. Yellow arrows indicate UCNPs. ChR2, channelrhodopsin-2.


In the future, blended UCNPs with distinct sets of excitation and emission wavelengths may lead to simultaneous neuronal activation and inhibition within a single region or across multiple deep brain regions.

Challenges for Higher Efficiency and Biocompatibility

The NIR upconverison technique we developed holds great potential. Nonetheless, two key challenges need to be addressed.

The first is the enhancement of stimulation efficacy. NIR is known for its ability to heat tissue. Therefore, stimulation parameters must be carefully tuned to optimize the trade-off between safety and efficacy. In the future, it might be possible to achieve enhanced NIR conversion yield by molecular engineering of UCNPs. Efforts should be devoted to the development of novel methods for the synthesis and surface engineering of UCNPs (14).

A second challenge lies in the improvement of UCNPs' biocompatibility. Although UCNPs currently must be injected stereotactically, cutting-edge colloidal chemistry may enable the creation of robotic nanoparticles capable of crossing the blood-brain barrier (16). Once in the brain, these particles could anchor onto specific neurons via exceptionally precise molecular recognition processes.

Conversion as a Generalized Approach to a Noninvasive Future

From a conceptual perspective, NIR upconversion optogenetics represents a new type of approach to noninvasive stimulation of deep brain neurons that relies on local energy conversion. In this approach, tissue-penetrating signals are transformed by a local converter into a signal capable of triggering ion channels or receptors for the modulation of neuronal activity. A previous study used nanoparticles to convert alternating magnetic fields into heat for activating deep brain neurons expressing heat-sensitive receptors (6). Future efforts may underpin changes such as the transformation of NIR or ultrasound into heat (17) or the conversion of x-rays into visible light (18).

A monumental step toward using such techniques to treat human neurological disorders would be the development of genetically encoded energy converters that can be virally delivered to neurons. When combined with recently developed technology for noninvasive gene delivery to the brain (19), truly noninvasive high-precision deep brain stimulation may be realized.

Overcoming the challenges outlined above will depend on cross-disciplinary collaborations that expand the approaches in tool development. It is too soon to predict which technique will emerge at the forefront of next-generation noninvasive brain stimulation technology. However, we believe that achievements such as NIR upconversion optogenetics are rapidly unlocking numerous development routes and paving the way toward a bright therapeutic future.

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Shuo Chen

Shuo Chen received his undergraduate and master's degrees from Tsinghua University and his Ph.D. from the University of Tokyo. He then completed a postdoctoral fellowship at the RIKEN Center for Brain Science. He is now a postdoctoral fellow at UC Berkeley, where he is investigating the network and synaptic mechanisms of hippocampal replay sequences. His research interests include minimally invasive methods to record and manipulate brain activity and how long-term memory is formed, stored, and recalled.

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Bozhi Tian

Bozhi Tian received his undergraduate and master's degrees from Fudan University and his Ph.D. from Harvard University. After postdoctoral training at Massachusetts Institute of Technology and Harvard Medical School, Tian started his lab in the Department of Chemistry at the University of Chicago in 2012. His current research involves bioelectronics, semiconductor-enabled probing of subcellular biophysics, and the chemical dynamics at soft-hard interfaces.

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