High resolution imaging of the deep brain is no longer impossible, thanks to adaptive optics two-photon endomicroscopy, a technique developed by scientists from the Hong Kong University of Science and Technology (HKUST).
Techniques for neuroscience research in recent decades have vastly improved, allowing researchers to learn more about synaptic pathways, neurodegenerative diseases, and the intricacies of the brain. Despite numerous impressive discoveries, however, it is difficult for researchers to observe certain details and activities of the human brain as experiments usually have to remain non-invasive in live subjects, limiting the information that can be collected in studies, particularly with the type of technology available for neuroscience research today.
One of the most prominent problems with neuroscience research today — obtaining information about brain morphology and function with high spatial and temporal resolution, and through non-invasive means — may be one step closer to being resolved, thanks to technological advancement. There are several methods today which fall short of this goal in one way or another, including magnetic resonance imaging (MRI) in its various forms, computed tomography (CT), positron emission tomography (PET), ultrasound, optical microscopy and even two-photon microscopy. Each of these methods have their own strengths and have contributed tremendously to discoveries in neuroscience, but still have restrictions in synaptic resolution, imaging of deep brain structures, or are susceptible to interference from other physiological tissues.
Adaptive optics two-photon endomicroscopy is an imaging technology that achieves neuroimaging of deep brain structures at high resolution. It was developed in a collaboration between Professor Qu Jianan from the Department of Electronic and Computer and Engineering at the Hong Kong University of Science and Technology (HKUST), and Professor Nancy Ip, Vice-President for Research and Development and the Morningside Professor of Life Science, also from HKUST. Their research leading to the development and optimisation of adaptive optics two-photon endomicroscopy, as well as its application in studying neuronal plasticity in the hippocampus, was published in Science Advances in September 2020.
Adaptive optics two-photon endomicroscopy can be broken down into several smaller techniques, which come together to make up this new method. First, there is endomicroscopy, which allows researchers to obtain images of biological tissue within the body in real-time. In this case, a miniature gradient refractive index (GRIN) lens is implanted in the brain, which acts as a relay (by inverting the image and extending the optical tube) for the microscope. Two-photon endomicroscopy is carried out by using a high-numerical aperture GRIN lens, so that subcellular structures can be observed at high resolution. However, since this is prone to aberrations which affect 3D imaging, adaptive optics is adopted, which compensates for the effects of the aberrations of the GRIN lens.
The research team further improved upon this technique, using direct wavefront sensing to compensate for the intrinsic aberrations of the GRIN lens prior to imaging. They were able to conduct imaging at high spatiotemporal resolution quickly and over a large volume, and used the technique to study somatic and dendritic activity of pyramidal neurons in the hippocampus, a deep brain structure which is traditionally difficult to image in detail. Professor Ip notes that scientists are now able to study structural synapses in the hippocampus as well as the firing activities of different neuronal populations, which “will facilitate our understanding of the molecular basis of learning and memory and its deregulation in memory dysfunctions in many neurological diseases.”
According to Professor Qu, “this technology enables imaging of other deep brain structures such as the striatum, the substantia nigra, and the hypothalamus. Thus, it is an exciting development and holds great potential for understanding brain functions and facilitating neuroscience research in the deeper parts of the brain.”
With the development of adaptive optics two-photon endomicroscopy and evidence of its success, new possibilities and avenues for research will likely be available. “The ability to conduct live imaging of the deep brain at high resolution has long been a challenge,” Professor Qu says. “With adaptive optics two-photon endomicroscopy, we can now study the structures and functions of the deep brain at an unprecedented resolution, which will greatly accelerate our progress in understanding the mechanisms of many neurodegenerative diseases and in developing related treatments.”