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NEUROPHOTONICS FEATURE


providing scientists with the right tools and information to study a variety of brain disorders, such as Alzheimer’s disease, Parkinson’s, autism, epilepsy and traumatic brain injuries. Scientists have been developing tools for exploring neural circuits that underlie brain function since the initiative’s inception. Michael Roukes, principal investigator


of the paper and Caltech’s Frank J Roshek professor of physics, applied physics and bioengineering, was one of five scientists who, from 2011, worked alongside the White House Office of Science and Technology Policy to jump-start what became the Brain initiative. Laurent Moreaux, Caltech senior


research scientist and lead author on the Perspectives paper in Neuron Journal, explained: ‘We initiated the project to address the fact many major brain nuclei in mammals remain inaccessible to optical physiology because of the intrinsic depth limitation of free space optical microscopy, due to fundamental phenomenon of light scattering in opaque tissues. ‘To bypass this depth limitation, we


envisioned using brain-implantable integrated photonics probes, similar in shape and size to the silicon shanks probe-based multi-electrode arrays, which would allow the ability to directly bring the microscope “into” the brain in a distributed fashion, and permit the use of functional imaging techniques to probe the activities of an unprecedented number of neurons at depth.’


Collaboration is key The Caltech researchers say this new integrated neurophotonics method ‘has far greater potential than any current approach.’ It leverages recent advances in microchip-based integrated photonic and electronic circuitry, combines these with those from optogenetics and works by using minute assemblies of optical microchips that can be implanted inside the brain at any depth. These are used in combination with fluorescent molecular reporters and optogenetic actuators, to optically monitor neurons and control their activity, respectively. The assemblies emit microscale beams of light to stimulate the genetically-modified neurons around them, and at the same time record the activity of these cells, revealing their function. Although the work is currently undertaken in animals, Roukes believes that it will ultimately be similarly used inside the human brain. ‘Dense recording at depth, that is the


key,’ he said. ‘We will not be able to record all of the activity of the brain any time soon. But could we focus on some of its important computational structures in specific brain


www.electrooptics.com | @electrooptics


regions? That’s our motivation.’ Moreaux agrees, stating in the paper:


‘Our aim is not solely to identify ways to increase the total number of neurons that can be recorded from simultaneously,’ he said. ‘Instead, we explore the possibility of achieving dense recording from within a targeted tissue volume, to ultimately achieve complete interrogation of local brain circuit activity. We use the word interrogation to denote recording and direct causal manipulation of a brain circuit’s individual neurons by the application of patterned, deterministic stimulation with single-neuron resolution.’


Problem solving The team believes that optogenetics can solve some of the problems related to neuroscience studies’ reliance on implanted electrodes to measure neurons’ electrical activity. This they say, on average, can reliably measure only a single neuron due to all the electrical activity in the brain. The brain does not use light to communicate, so optogenetics can make it easier to track large numbers of these signals. However, many optogenetic brain studies


are constrained by a significant physical limitation, explained Moreaux. ‘Brain tissue both scatters and absorbs light, which


“The overarching goal of integrated neurophotonics is to record what each neuron in that collection of 100,000 is doing in real time”


means that light shone in from outside the brain can travel only short distances within,’ he said. ‘Because of this, only regions less than about two millimetres from the brain’s surface can be examined optically. This is why the best-studied brain circuits are usually simple ones that relay sensory information, such as the sensory cortex in a mouse. They are located near the surface.’ Essentially, current optogenetics methods cannot easily offer information about circuits deeper in the brain. However, with this new integrated neurophotonics method, circuits buried deep in the brain could also benefit from valuable insight. The technique allows microscale elements of a complete imaging system to be implanted near complex neural circuits deeper in the brain, for example, the hippocampus region, associated with the formation of memory, and the striatum, which controls cognition. ‘This is one key advantage over an


electrode-based approach,’ said Moreaux,


‘which does not really allow for much in terms of multiplicity per electrode, since recording electrical signals depends on the electrode being in very close proximity with the recorded cell.’ Roukes likened it to functional magnetic


resonance imaging (fMRI), a similar technology which is currently used to image entire brains. ‘Each voxel, or three-dimension pixel, in an fMRI scan is typically about a cubic millimetre in volume and contains roughly 100,000 neurons,’ he said. ‘Each voxel, therefore, represents the average metabolic activity of all of these 100,000 cells. The overarching goal of integrated neurophotonics is to record what each neuron in that collection of 100,000 is doing in real time.’


High resolution


This means dense functional imaging of neuronal activity can now be used by the researchers in highly scattering neural tissue, providing cellular-scale resolution at arbitrary depths. Moreaux said: ‘Our approach is based on implanting an entire lensless imaging system within the brain itself, by distributing dense arrays of microscale photonic emitter and detector pixels positioned on a 3D spatial lattice. These pixel arrays are integrated onto narrow silicon shanks, which leverage recent advances in silicon-nanoprobe-based fabrication. Used with functional molecular reporters and optogenetic actuators, this novel instrumentation offers the prospect of approaching the interrogation of all neuronal activity from within 100,000 neurons in a mouse cortex.’ The team’s long-term goal is to disseminate the advanced instrumentation of integrated neurophotonics to enable multi-institutional collaborations that will pioneer advanced neuroscience research with this novel technology. Previously, said Roukes, this type of neurotechnology development has relied mostly on research led by a single lab or investigator. The team behind the Brain Initiative came together to bring the kind of large- scale partnerships to neuroscience research that have previously been seen in physical sciences. Now, Roukes says, integrated neurophotonics opens doors for such instrument-building teamwork. ‘Many of the building blocks have existed for a decade or more,’ he said. ‘But, until recently, there has just not been the vision, the will, and the funding available to put them all together to realise these powerful tools for neuroscience.’ For example, explained Moreaux, for


the micro light beam delivery within the tissue from the neurophotonic probe’s light emitters, researchers had to promote a shift


g March 2021 Electro Optics 17


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