Original source: Physics World
A new ultrasensitive nanoscale optical probe that can monitor the bioelectric activity of neurons (and other cells that generate electrical impulses) could help researchers better understand how neural circuits function at hitherto unexplored scales by measuring the activity of huge numbers of individual neurons at the same time. The device could also help in the development of high-bandwidth brain-machine interfaces in the future.
“Scientists have wanted to harness the unprecedented spatiotemporal resolution capability of light to detect electrophysiological signals from electrogenic cells (neurons and heart cells) for over 50 years,” says Ali Yanik of the University of California Santa Cruz, who led this new research effort. “This goal has remained elusive, however, for lack of electro-optical translators than can efficiently convert electrical activity into high photon-count optical signals.
“In this work, we have developed a novel electro-plasmonic nanoantenna that allows for extracellular (that is, non-invasive), high signal-to-noise ratio and real-time optical recording of electrophysiological signals for the first time.”
Poor spatial resolution and bio-incompatibility
Today, researchers monitor the electrical activity of neurons using microelectrode arrays, but these cannot simultaneously address large numbers of neurons. The technique also suffers from poor spatial resolution. The extremely limited bandwidth of the electronic wiring in these devices – created by the very nature of electrons – is a bottleneck too, explains Yanik.
“We have turned to photons for the same reason that the telecommunications industry moved to fibre-optics – because light offers a 109-fold enhanced multiplexing and information carrying capability. By converting bioelectric signals into photons, we are now able to transmit large-bandwidth neural activity optically.”
Although optical biosensors already exist, many of these require that genetic modifications be made to cells so that fluorescent molecules can be inserted into cell membranes. This means that these techniques cannot be employed in human cells.
Plasmonic biosensors for their part detect biomolecules by sensing the effective refractive index changes that occur in their close vicinity. “Label-free biosensing technologies are today relatively advanced and we have already used them to directly detect the Ebola virus, for example,” says Yanik. “However, optically detecting the dynamics of local electrical fields produced by neurons and other excitable cells remains difficult. This is because the plasmonic resonances of the noble metals commonly employed in these probes have low sensitivity to these small electric fields.”
Novel nanoantenna loading mechanism
Yanik’s lab at UCSC’s Baskin School of Engineering together with co-workers at the University of Notre Dame, have now overcome this problem using a novel nanoantenna loading mechanism based on concepts adapted from RF communications. They began by fabricating nanoscale plasmonic nanoantennas less than 100 nm in diameter and then coated them with a biocompatible nanoscale electrochromic polymer, poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS), which is highly sensitive to a local electric field.
“In this coupled system, PEDOT:PSS acts as an electric-field-controlled load that enables active and reversible tuning of the plasmonic nanoantenna resonance – in the same way that a tuneable load circuit can control the resonance frequency of an ordinary radio antenna,” explains Yanik. “The local electric field generated by spiking neurons or cardiomyocytes as they fire controls the doping state of the electrochromic polymer and thus the capacitive and inductive load of the individual nanoantennas and their far-field optical response or resonance wavelength.”
This local field-controlled loading mechanism produces strong variations in the light spectra scattered from the cells, he tells Physics World. “In this way, we can observe local field oscillations from diffraction-limited volumes remotely by tracing the resonance wavelength of the electro-plasmonic nanoantennas.”
The new technique is fundamentally different to genetically-encoded voltage-sensitive fluorescence reporters, he adds. “Our nanoprobes work in the same way as microelectrode arrays, but the read-out mechanism is intrinsically optical and requires no fluorophore translators.
“Our devices have 106-fold enhanced cross sections of 104nm2 compared to the typical values of just 10-2nm2 for voltage-sensitive fluorescence dyes, and this what allows us to realize high photon count measurements from diffraction-limited spots.”
Thanks to the strong light scattering characteristics of plasmonic resonances, the researchers say they demonstrated high signal-to-noise ratio measurements from a single nanoantenna that is orders of magnitude stronger than those possible with fluorescent molecules. And, thanks to the large photon counts possible with the new probes, they can perform high-temporal resolution electric-field measurements at kilohertz frequencies using three orders of magnitude lower-intensity light (11 mW/mm2), which allows for a real-time measurement without heating up biological cells.
The researchers say they would now they like to adapt their electro-plasmonic nanoelectrodes for brain implants using fibre-optics technology. “We believe this photonic approach holds great promise for future applications in this area,” says Yanik. “For example, electrical brain-computer interfaces have been attracting significant interest lately but using electronics for these interfaces poses fundamental challenges for the reasons mentioned earlier.
“Optical fibres could come into their own here and we could use a single fibre operating at 1014 bits/second to create a flexible, biocompatible and high-bandwidth information highway between the human brain and the outside world. Given that the brain processes 1016 bits of information per second (equivalent to Netflix’s entire information output every 10 seconds), using photonics is an inevitability.
As well as being implanted, the probes could also be synthesized as nanoparticles suspended in a colloidal solution with surface proteins attached to them so that they bind to specific cell types, he adds. These devices could be injected into the bloodstream or an organ.
“The critical feature sizes of these devices are 10 to 15 microns,” says team member Ahsan Habib, who is lead author of this study. “Recent experiments have shown that smaller size implants lead to a dramatically reduced inherent immune response. In this sense, our electro-plasmonic probes with nanoscale dimensions are particularly advantageous for long-term operation.”
This work, which is reported in Science Advances 10.1126/sciadv.aav9786, was supported by grants from the National Science Foundation.