The highly contentious proposal to map the entire output of a human brain just got a huge boost yesterday. Researchers at the Howard Hughes Medical Institute in Virginia published the first brain activity map (BAM) of any creature ever recorded. With this initial achievement, the brush has been cleared so to speak, such that scaling this capability up to larger animals — and to humans — is no longer unimaginable. It is now time to pave the road.

Just last month, we published footage of a small transparent fish, the zebrafish, which showed in detail how moving prey were represented in its brain. Since then the ante has now been upped, with this whole brain raster that captures over 80% of the animal’s 100,000 neurons and refreshes every 1.3 seconds, burning a terabyte of data storage every hour. How is this possible?

The fastest car down the track is not the one with the highest boost turbo, most powerful engine, or the smoothest exhaust. It is the one whose elements match and transition with perfection. In building a device capable of recording the activity of almost every neuron contained within a volume 800x600x200 microns per side, the authors optimized a technique called light sheet microscopy, which they had used previously to image developing embryos. The first thing the researchers did was speed up the piezo-based scanning mirrors tenfold, so that the entire brain is covered just as fast as the dynamics of the imaging dye used to visualize neuron activity would permit.

The imaging dye fluoresces when the neurons spike and calcium ions move into the cell, but it is not quite fast enough to catch every spike when the neurons are firing fast. It does however, do a pretty good job of catching most spikes, and gives a nice picture of what is going on in the brain. The Orca Flash 4.0 camera from Hamamatsu is the fastest available for the job, and it does not constrain the microscope control system. The researchers also tuned the step size of the scan to be roughly the size of the neurons in the zebrafish brain and therefore optimize the resolution.

For larger brains to be scanned in this way, the setup will need to be turned inside out somehow, so that the laser illumination is done from many points inside the brain, and the imaging done from without. Micro spotlights placed in the ventricles, across axon tracts, and in other remote corners will be tough to non-destructively position, as will the detectors. Furthermore, most brains are nowhere near as transparent as that of the zebrafish, and the large mammalian axons are ensheathed with light-scattering myelin. The other challenge is to get your imaging agent expressed in every neuron you want to track. This is not an issue if the gene for it is put into the germ line (the embryo), but for adults the only immediately imaginable way to do it would be use a virus like rabies, which migrates from neuron to neuron across synapses and writes itself into the cells’ DNA in the process.

Considering the progress we have seen in just a few months, the above are not roadblocks but rather obstacles to be cleared. Funding the BAM will be a good start, but even in the absence of presidential mandate, the drive to map our own brains in this way will continue until its goal is achieved.

Now read: How to create a mind, or die trying

Research paper: doi:10.1038/nmeth.2434 – “Whole-brain functional imaging at cellular resolution using light-sheet microscopy”