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. 2017 Feb 8;93(3):509-521.e3.
doi: 10.1016/j.neuron.2016.12.031. Epub 2017 Jan 26.

Flexible Near-Field Wireless Optoelectronics as Subdermal Implants for Broad Applications in Optogenetics

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Free PMC article

Flexible Near-Field Wireless Optoelectronics as Subdermal Implants for Broad Applications in Optogenetics

Gunchul Shin et al. Neuron. .
Free PMC article

Abstract

In vivo optogenetics provides unique, powerful capabilities in the dissection of neural circuits implicated in neuropsychiatric disorders. Conventional hardware for such studies, however, physically tethers the experimental animal to an external light source, limiting the range of possible experiments. Emerging wireless options offer important capabilities that avoid some of these limitations, but the current size, bulk, weight, and wireless area of coverage is often disadvantageous. Here, we present a simple but powerful setup based on wireless, near-field power transfer and miniaturized, thin, flexible optoelectronic implants, for complete optical control in a variety of behavioral paradigms. The devices combine subdermal magnetic coil antennas connected to microscale, injectable light-emitting diodes (LEDs), with the ability to operate at wavelengths ranging from UV to blue, green-yellow, and red. An external loop antenna allows robust, straightforward application in a multitude of behavioral apparatuses. The result is a readily mass-producible, user-friendly technology with broad potential for optogenetics applications.

Keywords: ChR2; Chrimson; LED; NAc; VTA; dopamine; near-field communication; optogenetics; reward; wireless.

Figures

Figure 1
Figure 1. Designs and operational features of a thin, flexible wireless optoelectronic implants for optogenetic experiments
A) Schematic illustration of the overall construction, highlighting a freely adjustable needle with an μ-ILED at the tip end, connected to a receiver coil with matching capacitors, a rectifier and a separate μ-ILED indicator. B) Picture of a completed device (diameter ~9.8 mm) on top of fingertip and next to a US dime (diameter 17.91 mm) (insets) for size comparison. C) Scanning electron microscope images of an injectable needle with LED and coil trace with the dimension of 60 μm width, 18 μm thickness and 80 μm spacing, colorized to highlight the different components (blue: μ-ILED; yellow: polyimide; orange: copper). D) Images and corresponding finite element modeling results of the device before and after bending (left) the body of the device and stretching (right) the serpentine connection to the injectable needle, respectively.
Figure 2
Figure 2. Electrical, optical, mechanical, and thermal properties
A) Current-Voltage-Light output characteristics. B) Emission spectra associated with operation of devices built with different μ-ILEDs. C) Normalized light optical power as a function time after immersion of devices in warm saline solutions with temperatures of 37, 60 and 90 °C. D, E) Normalized light optical as a function of extension of the serpentine interconnect to the injectable needle and of the bending radius of the body of the device, respectively. F) Change in temperature adjacent to an operating μ-ILED (T: Theoretical, for the case of brain tissue; E: Experimental, for the case of a hydrogel) as a function of duty cycle of operation at different peak output powers (10, 20 and 50 mW/mm2). G) Current output from a photodiode placed adjacent to a μ-ILED operating at different pulse frequencies (5, 10 and 20 Hz), for a fixed duration of 20 ms. The rise and fall times are ~0.1 ms.
Figure 3
Figure 3. Modeling and experimental results for power transmission from loop antennas with different designs
A) Simulated light output power from a wireless device, as a function of in-plane position at four different heights from the bottom of an enclosure, for the case of a double loop antenna with turns at heights of 4 and 11 cm. B) Theoretical (lines) and experimental (symbols) results for the normalized light output power as a function of height for four different angular orientations between the coil and the loop antennas. The inset cartoons show tilted views of head of the animal. C, D, E, F) Wireless operation of thirteen devices mounted on a thin transparent support, placed at heights of 3, 6, 7 and 12 cm from the bottom. The insets show enlarged images of devices with position of A (red dotted square), B (green dotted square), C (blue dotted square) and normalized light output power.
Figure 4
Figure 4. Illustration of surgical procedures for implanting the device and recovered mouse for operation in the deep brain
A) Representative image of implantable device. B) Images of customized mounting clip and its procedure. C) Image after connecting with stereotaxic arm. D, E, F) Images of the surgical steps for holding and positioning the body of the device, and injecting the needle into the deep brain, respectively. G, H) Images of mouse after releasing of device from stereotaxic arm. I) Wireless operation of implanted device after suturing the skin. J, K, L) Images of recovered mouse after 1, 4 and 8 weeks from surgery, respectively.
Figure 5
Figure 5. Representative set up of the loop antenna around various animal apparatuses
A, C, E, G) The detailed layouts of the loop around a homecage, a real-time place preference (RTPP) box, an operant conditioning box and a water tank, respectively. B) Images of the loop and wirelessly operating devices and the corresponding mice with near field wireless implants in the homecage covered with lid. D) Images of double loop and wirelessly operating devices and corresponding mice with near field wireless implants in the RTPP box. F) Images of mouse with working device in the operant conditioning chamber containing metal components. H) Images of water tank with single loop antenna, working devices under the water and a swimming mouse that has working device
Figure 6
Figure 6. Wireless control of mesolimbic reward circuitry
A) Cartoon depicting unilateral ChR2 or Chrimson viral injection and near field wireless device implantation. Timeline outlining real time place preference behavioral testing. B) Heatmaps showing real-time mouse behavior following 20 Hz photostimulation of mice expressing ChR2 in the NAc of DAT-Cre+ and DAT-Cre−. C) Sagittal section highlighting ChR2 viral injection within the ventral tegmental area (VTA) and the targeted projection area of the nucleus accumbens (NAc). D) Corresponding coronal sections highlighting ChR2 viral expression within the VTA and NAc. Representative immunhistochemistry showing coronal sections of the NAc and VTA. All images show Nissl (blue), ChR2 (green), tyrosine hydroxylase (TH, red) staining. E, F, G) Stimulation of the NAc or VTA in DAT-Cre mice expressing ChR2 or Chrimson, respectively, drives a real-time place preference in time spent in stimulation side (both stimulation side minus non-stimulation side and % time on stimulation side). Data represented as mean ± SEM, n = 12 (DAT-Cre +), n = 5 (DAT-Cre −) for ChR2; and n =11 (DAT-Cre +), n = 8 (DAT-Cre −) for Chrimson. H) Timeline outlining operant self-stimulation behavioral testing. Schematic depicting operant box paradigm where an active nosepoke results in a 1 sec, 20 Hz photostimulation accompanied by a cue light and an inactive nosepoke results in no consequence. I, J) DAT-Cre mice expressing ChR2 developed a strong preference for the active nosepoke (20 Hz photostimulation) over 7 days in comparison to the inactive nosepoke or in comparison to DAT-Cre mice lacking ChR2 expression (one way repeated measures ANOVA, main effect of nosepoke ; main effect on stimulation, Tukey post hoc tests *p<0.05, **p<0.01, ***p<0.001). K) Data showing total number of active and inactive nosepokes in DAT-Cre + and DAT-Cre− mice across 7 days of operant self-stimulation (Two-way ANOVA, main effect of nosepoke,; main effect on cre condition, Bonferroni post hoc tests ***p<0.001). L) On day 8, ChR2 expressing mice were allowed to nosepoke in the absence of photostimulation. All mice showed a reduction in number of active nosepokes in the absence of photostimulation. Data represented as mean ± SEM, n = 6 (DAT-Cre +), n = 5 (DAT-Cre).

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