A new technology for monitoring neural activity allows scientists to simultaneously follow the nervous system’s cellular conversations at hundreds of different sites within the brain. The new probes are expected to give scientists a much clearer picture of how different parts of the brain work together to process information.
The $5.5 million collaboration led by researchers at HHMI’s Janelia Research Campus also involved scientists at Janelia, the Allen Institute, and University College London (with grant funding from Gatsby and Wellcome). The team has worked over the past four years with engineers at imec, an international nanoelectronics research center in Leuven, Belgium, to build and test powerful new devices for detecting neural activity within the brains of living animals.
The devices, called Neuropixels probes, place hundreds of recording electrodes across a large span of a rodent’s brain, so that researchers can collect more meaningful data in a single experiment than other technologies currently allow. The team is targeting mid-2018 for the Neuropixels probes to be available for purchase by research laboratories.
With nearly 1,000 electrical sensors positioned along a probe thinner than a human hair but long enough to access many regions of a rodent’s brain simultaneously, the new technology could greatly speed up neuroscience research, says Timothy Harris, senior fellow at Janelia, leader of the Neuropixels collaboration.
“You can [detect the activity of] large numbers of neurons from multiple brain regions with higher fidelity and much less difficulty,”
Neuropixels probe. Credit: Timothy Harris Lab, Janelia Research Campus
Neuropixels probes are similar to electrophysiology probes that neuroscientists have used for decades to detect extracellular electrical activity in the brains of living animals — but they incorporate two critical advances. The new probes are about as long as a mouse brain — so they pass through and collect data from many different brain regions at the same time.
And recording electrodes are densely packed along their length, making it easier for researchers to pinpoint the cellular sources of brain activity. Finally, each of the new probes incorporates a nearly complete recording system – reducing hardware size, cost and eliminating hundreds of output wires.
Highlights of the data presented in the paper include the fact that with each probe, scientists see hundreds of well resolved single neuron signal traces. This is the first report of a large (10 mm), dense (100 sites/mm) implantable neural recording device.
Each probe can record simultaneously across multiple brain regions, and researchers have recorded from more than 700 neurons using two Neuropixels probes. The probes yielded high neuron count and excellent signal-to-noise performance with no special techniques required.
The results show that the probes, together with new methods of data analysis, can be used to track the activity of hundreds or even thousands of individual cells in disparate brain regions.
There are currently more than 400 prototype Neuropixels probes in testing at research centers worldwide, including 20 labs affiliated with Gatsby and Wellcome such as the Sainsbury Wellcome Centre, eight HHMI labs and are being used at large scale by researchers at the Allen Institute.
“At the Allen Institute for Brain Science, one of our chief goals is to decipher the cellular-level code used by the brain. The Neuropixels probes represent a significant leap forward in measurement technology and will allow for the most precise understanding yet of how large coalitions of nerve cells coordinate to give rise to behaviour and cognition.”
Janelia group leader Albert Lee, whose team has also been using Neuropixels prototypes and providing feedback on their development, says the ability to collect data from many different brain regions simultaneously will also reduce the number of experiments needed to glean a big-picture view of what happens in the brain when an animal performs a particular task.
A single experiment can now replace a series of experiment each focused on a different brain region, he says.
close-up view of a silicon wafer containing multiple Neuropixels probes. Credit: Timothy Harris Lab, Janelia Research Campus
The Neuropixels project was launched in 2013, with an ambitious goal of dramatically advancing the technology available for detecting electrical activity in the brain. Although some labs did have the ability to record activity from hundreds of neurons at the same time, such experiments were costly and technically difficult, and the electrophysiology probes available to most researchers at the time had 16-64 sensors, limiting the number of cells users could monitor in an experiment.
Harris and his colleagues agreed it was time to move things forward in a big way.
“Janelia is a place where people are willing to push the envelope on what you might be able to do,”
Harris says. Rather than figuring out how to squeeze a few more sensors on an existing probe, Janelia scientists began talking about designing a new generation of probes that could record from hundreds of neural sites at once — and then manufacturing enough of them to supply the neuroscience community at an affordable cost.
Engineering And Fabrication
Harris consulted with semiconductor engineers who told him the idea was feasible.
But it was clear from the outset that the development costs would be high. Fabricating hundreds of electrodes and placing them on a device slender enough to be inserted into the brain of a living animal was simply beyond the capacity of academic facilities, Harris says.
“With the new probes, we’re not really at the bleeding edge of technology, but we are far beyond the fabrication capabilities available to research laboratories,”
he explains. The probes that Janelia’s neuroscientists wanted would have to be made by professional semiconductor engineers using state-of-the-art equipment.
The project was likely to look risky to a typical government granting agency, Harris says.
“We needed 5 million dollars, to make one thing,”
he notes. So he appealed to other sources. Recognizing an opportunity to accelerate the pace of neuroscience research, HHMI, the Allen Institute, the Gatsby Charitable Foundation, and Wellcome agreed to fund the endeavor.
Imec, a state-of-the-art maker of silicon microcircuits, agreed to design and fabricate the devices. The nonprofit research center has expertise and facilities that were needed for the project, but does not usually manufacture products on an industrial scale.
James J. Jun, Nicholas A. Steinmetz, Joshua H. Siegle, Daniel J. Denman, Marius Bauza, Brian Barbarits, Albert K. Lee, Costas A. Anastassiou, Alexandru Andrei, Çağatay Aydın, Mladen Barbic, Timothy J. Blanche, Vincent Bonin, João Couto, Barundeb Dutta, Sergey L. Gratiy, Diego A. Gutnisky, Michael Häusser, Bill Karsh, Peter Ledochowitsch, Carolina Mora Lopez, Catalin Mitelut, Silke Musa, Michael Okun, Marius Pachitariu, Jan Putzeys, P. Dylan Rich, Cyrille Rossant, Wei-lung Sun, Karel Svoboda, Matteo Carandini, Kenneth D. Harris, Christof Koch, John O’Keefe & Timothy D. Harris Fully integrated silicon probes for high-density recording of neural activity Nature 551, 232–236 (09 November 2017) doi:10.1038/nature24636