This blog is the fifth in a series of guest posts on technology and the brain to celebrate Scientific American Mind’s 10-year anniversary. The magazine’s special November/December issue similarly highlights the interface between code and thought in profiling a future, more digital YOU.
Imagine having to spot a single grain of cereal at the bottom of a bowl of milk. Now imagine a neuroscientist or physician having to peer through turbid brain tissue in search of a sick cell. The problem in either case is the same: light scatters. Just as tiny fat goblets in milk randomly redirect photons to give milk its white appearance, the estimated 100 billion nerve cells and 100 trillion synapses that store information, along with 400 miles of blood vessels, obscure our view of the brain below the cortical surface. Right now, tools to visualize this intricate mesh of cells, axons, dendrites and blood vessels are inadequate to make sense of the brain’s complexity.
Yet what if light scattering could be used to our advantage? We recently set out to explore this possibility by adapting an imaging method known as Optical Coherence Tomography (OCT). An optical version of ultrasound, OCT involves shining a light on a biological specimen and measuring how much light is reflected or scattered back. The strength and timing of these light “echoes” as they bounce off various tissue types and return to a detector are used to construct a three-dimensional picture. OCT is already used clinically in ophthalmology to make retinal images for diagnosing disease, albeit with shorter wavelengths. We hope that OCT will ultimately contribute to a better understanding of brain diseases such as traumatic brain injury, vascular dementia and Alzheimer’s disease.
The potential of this technique lies in the fact that it is non-invasive and safe: simply by shining a light on the brain, we can observe the microscopic structure of neural tissue. Other ways of observing the living human brain do not offer this combination of attributes. Magnetic resonance imaging, for example, is widely used to study human brain structure and function, yet it is limited to resolutions of millimeters (as depicted in figure A). In mice, fluorescence light microscopy can show us subcellular detail–but only because we can perform invasive manipulations to make molecules in the mouse brain glow. Better optical tools are needed for imaging the human brain.
Enter OCT. It can distinguish single and multiply scattered light based on the time light takes to return from the source to the detector, thus allowing us to see more than a millimeter into the brain. For context, imagine viewing the horizon at sunset. The outline of the sun appears hazy because photons are scattered multiple times by particles in the atmosphere. The haze is red because shorter blue wavelengths are scattered and diverted so much from their original path that they don’t reach your eye–the detector in this case. OCT works by only detecting photons that “echo” back within a certain amount of time and travel in a straight line, which can make a tissue’s outline appear sharp.
Our team at the University of California, Davis, has managed to highlight a range of tissue types in animals. We have found, for example, that neuronal cell bodies (seen as black spots on figure B below) scatter less light than does the mesh of dense connections that surrounds them. We can also distinguish between living and dead neurons based on their scattering signatures. Furthermore, we now know that axons fully wrapped in myelin, a fatty insulating sheath, scatter light more than other axons, which is helpful for focusing our attention on the fibers that can conduct neural impulses faithfully across long distances (figure C). Blood flow, too, varies in ways we can now identify to observe how nutrients get delivered to hungry neurons (figure D). In short, we found that simply paying heed to the basic properties of the brain’s components can reveal a great deal about the brain at the cellular level.
The millimeter imaging depth is a breakthrough for optical microscopy, but of course we would like to gaze deeper into the brain. Improving OCT’s penetration depth is a current area of investigation. The technique uses advanced technologies and methods developed by the telecommunications industry, namely fiber optics, which is important because it makes OCT affordable. More importantly, OCT does not require genetic engineering to make molecules glow under a microscope, but instead uses light that is harmlessly scattered by brain tissue.
The ability to study the brain by imaging its microscopic intrinsic properties is already opening up new investigations. Our group, for example, has managed to peer more than a millimeter deep into the living brains of mice and rats, and we have done this repeatedly for a month in mice that were surgically modified to model cerebrovascular disease. Because our techniques are label-free, potential clinical applications abound. Of course you still need an exposed cortex–the technique cannot penetrate the skull. Yet OCT could be used in humans who elect to undergo brain surgery, whether to implant probes for deep brain stimulation or to remove a tumor, among other reasons. OCT could then help guide those surgical procedures to avoid, say, slicing through blood vessels. Surgeons and neuroscientists could also collaborate with these patients to learn new things about the brain. OCT’s microscopic resolution is unprecedented in humans, which means the possibilities are endless.
>>Next in the series: “In the Future, Your Therapy and Education Will Be Tailored to Your Brain”