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Neurotechnologies Plenary Detail

Abstracts and Speaker Biographies

Neurophotonic strategies for observing and controlling neural circuits
Ed Boyden,
Massachusetts Insitute of Technology (USA)

To enable the understanding and repair of complex biological systems such as the brain, we are creating novel optical tools that enable molecular-resolution maps of large scale systems, as well as technologies for observing and controlling high-speed physiological dynamics in such systems. First, we have developed a method for imaging large 3-D specimens with nanoscale precision, by embedding them in a swellable polymer, homogenizing their mechanical properties, and exposing them to water - which causes them to expand isotropically manyfold. This method, which we call expansion microscopy (ExM), enables scalable, inexpensive diffraction-limited microscopes to do large-volume nanoscopy, in a multiplexed fashion. Second, we have developed a set of genetically-encoded reagents, known as optogenetic tools, that when expressed in specific neurons, enable their electrical activities to be precisely driven or silenced in response to millisecond timescale pulses of light. Finally, we are developing novel reagents and systems to enable the imaging of fast physiological processes in 3-D with millisecond precision. In this way we aim to enable the systematic mapping, control, and dynamical observation of complex biological systems like the brain.

Ed Boyden is a professor of Biological Engineering and Brain and Cognitive Sciences at the MIT Media Lab and McGovern Institute. His group develops tools for analyzing and repairing complex biological systems such as the brain, and applies them systematically to reveal ground truth principles of biological function as well as to repair these systems. These technologies include expansion microscopy and optogenetic tools. Amongst other recognitions, he has received the Breakthrough Prize in Life Sciences (2016), the Grete Lundbeck Brain Prize (2013), the NIH Director's Pioneer Award (2013), and was elected to the American Academy of Arts and Sciences (2017).

Optical assessment of cerebral autoregulation
Sergio Fantini, 
Tufts Univ. (USA)

Cerebral autoregulation (CA) is a homeostatic mechanism that maintains a relatively constant cerebral blood flow (CBF) in the presence of changes in the cerebral perfusion pressure (CCP), defined as the difference between mean arterial pressure (MAP) and intracranial pressure (ICP). Given the importance of adequate and consistent brain perfusion, CA is critical for brain viability and is known to be impaired in a number of neurological disorders. Global brain measurements of dynamic CA have been performed with transcranial Doppler ultrasound (to sense the blood flow velocity in the middle cerebral artery) and finger plethysmography (to measure systemic MAP as a surrogate for CCP). Optical methods offer the advantage of providing local measurements of cerebral blood flow and CA, thus allowing for local assessment and spatial mapping of CA. Optical techniques for the non-invasive assessment of CA include near-infrared spectroscopy (NIRS) and diffuse correlation spectroscopy (DCS). I will describe our approach to CA assessment with NIRS, complemented by the novel technique of coherent hemodynamics spectroscopy (CHS), and our findings of the expected enhancement in CA during hyperventilation-induced hypocapnia. I will also report dynamic traces of local CBF measured with NIRS-CHS and DCS during transient changes in MAP. Optical techniques offer the potential to address the challenge of continuous monitoring of local cerebral autoregulation at the bedside and in a critical care environment.

Sergio Fantini is Professor of Biomedical Engineering and principal investigator of the "Diffuse Optical Imaging of Tissue Laboratory" (DOIT Lab) at Tufts University. His research interests are on non-invasive techniques based on diffuse optics to assess cerebral perfusion, detect breast cancer, and quantify tissue oxygenation. A technique developed in the DOIT Lab, coherent hemodynamics spectroscopy (CHS), exploits transient and oscillatory hemodynamic changes to extract physiological information on blood-perfused tissue. His research resulted in eleven patents and about two hundred scientific publications. He co-authored with Prof. Irving Bigio (Boston University) a textbook on "Quantitative Biomedical Optics."

Photobiomodulation and the brain: a new clinical paradigm
Michael Hamblin, Wellman Ctr. for Photomedicine (USA)

Photobiomodulation (PBM) describes the use of red or near-infrared light to stimulate, heal, regenerate, and protect tissue that has either been injured, is degenerating, or else is at risk of dying. One of the organ systems of the human body that is most necessary to life, and whose optimum functioning is most worried about by humankind in general, is the brain. The brain suffers from many different disorders that can be classified into three broad groupings: traumatic events (stroke, traumatic brain injury, and global ischemia), degenerative diseases (dementia, Alzheimer's and Parkinson's), and psychiatric disorders (depression, anxiety, post traumatic stress disorder). There is evidence that all these seemingly diverse conditions can be beneficially affected by applying light to the head. There is even the possibility that PBM could be used for cognitive enhancement in normal healthy people. In this transcranial PBM (tPBM) application, near-infrared (NIR) light is often applied to the forehead because of the better penetration (no hair, longer wavelength). Some workers have used lasers, but recently the introduction of inexpensive light emitting diode (LED) arrays has allowed the development of light emitting helmets or "brain caps".

Michael R Hamblin Ph.D. is a Principal Investigator at Wellman Center for Photomedicine, Massachusetts General Hospital, and an Associate Professor Harvard Medical School. He has interests in photodynamic therapy and photobiomodulation. He has published 386 peer-reviewed articles, is Editor/Associate Editor for 10 journals and serves on NIH Study-Sections. He has an h-factor 82 and >26,000 citations. He has authored/edited 23 textbooks on PDT and photomedicine including SPIE proceedings. Dr Hamblin was elected as a Fellow of SPIE in 2011, 1st Endre Mester Lifetime Achievement Award Photomedicine from NAALT in 2017, and Outstanding Career Award from Dose Response Society in 2018.

High-speed optical imaging of brain-wide activity 
Elizabeth Hillman,
Columbia Univ. (USA) 

The past decade has seen dramatic improvements in optical reporters of neural activity. However, capturing the activity of a large numbers of neurons throughout the brain at high speeds remains a significant challenge. Swept confocally aligned planar excitation (SCAPE) microscopy is a novel, high-speed 3D cellular imaging technique which combines the benefits of light sheet imaging with confocal descanning principles, enabling high signal to noise 3D imaging of living samples through a simple single, stationary objective lens. We have demonstrated SCAPE on a wide range of organisms including freely crawling Drosophila larvae, the whole brain of behaving adult Drosophila, zebrafish brain and the awake mouse cortex. We are now developing a range of new SCAPE systems including a higher resolution system for smaller samples as well as near infra-red excitation implementations for deeper imaging into the living brain. A second technique that we have developed for capturing brain-wide neural activity is wide-field optical mapping (WFOM) for imaging both neural activity and hemodynamics over the entire dorsal cortical surface in awake, behaving mice. Both SCAPE and WFOM are yielding new high-speed, real time views of brain-wide activity in awake,
behaving animals, providing fundamentally new views of spontaneous activity and behavior. I will present our latest progress on high-speed imaging technique development, and showcase our work applying these techniques to understand whole-brain activity in the context of awake behavior.

Elizabeth M. C. Hillman is a Professor of Biomedical Engineering and Radiology at Columbia University and Director of the Laboratory for Functional Optical Imaging within Columbia's Zuckerman Mind Brain Behavior Institute. Prior to joining Columbia in 2006, she was junior faculty at Harvard Medical School and completed her PhD and undergraduate training in Physics at University College London. Dr Hillman's research focuses on the development and application of novel in-vivo optical imaging and microscopy techniques for in-vivo brain imaging, including her recent development of SCAPE microscopy for high-speed 3D imaging. Dr Hillman is the recipient of the SPIE 2018 Biophotonics Technology Innovator Award. 

Photoacoustic microscopy of the cerebral microvasculature
Song Hu, 
Univ. of Virginia (USA) 

Functional integrity of the brain relies on the delicate balance between the energy demand imposed by the neural activity and the oxygen supply provided by the ubiquitously presented microvasculature. Subtle changes in the autoregulation of microvascular diameter, blood oxygenation or blood flow can lead to devastating brain disorders, including but not limited to stroke and dementia. Prevention and treatment of the cerebral microvascular dysfunction require in-depth understanding of the disease mechanisms at the level of single microvessels. However, such mechanistic studies have been hindered by the lack of technologies capable of imaging the microvascular structure and function in the living brain without possible influence by angiogenic agents and/or general anesthesia. Here, I will present our recent progress on photoacoustic microscopy (PAM), which enables label-free comprehensive characterization of the microvascular structure (diameter, tortuosity and density), mechanical property (resistance, wall shear stress, reactivity and permeability) and hemodynamics (blood perfusion, oxygenation and flow) in the awake mouse brain. Moreover, combining the blood perfusion, oxygenation and flow extracted from individual microvessels allows quantification of regional oxygen extraction fraction and metabolism in the brain.

Song Hu is an Assistant Professor of Biomedical Engineering and a Faculty Member of the Neuroscience Graduate Program, Robert M. Berne Cardiovascular Research Center and Emily Couric Cancer Center at the University of Virginia. His research focuses on the development of PAM and its applications in neuroscience, cardiovascular biology, cancer and regenerative medicine. Recently, his lab has developed multi-parametric PAM for label-free simultaneous imaging of blood perfusion, oxygenation and flow at the microscopic level in vivo and has extended this enabling technology to the awake mouse brain by developing a first-of-a-kind head-restrained PAM.

Fast in vivo volumetric imaging of the brain

Na Ji, Univ. of California, Berkeley (USA)

To understand computation in the brain, one needs to understand the input-output relationships for neural circuits and the anatomical and functional relationships between individual neurons therein. Optical microscopy has emerged as an ideal tool in this quest, as it is capable of recording the activity of neurons distributed over millimeter dimensions with sub-micron spatial resolution. Here, I will describe our recent work where we use Bessel beam to achieve video-rate (30 Hz) volumetric imaging of the brain.

Na Ji studied chemistry and physics as an undergraduate in the University of Science and Technology of China and later a graduate student at University of California Berkeley. In 2006, she moved to Janelia Research Campus, Howard Hughes Medical Institute and worked with Eric Betzig on improving the speed and resolution of in vivo brain imaging. She started her own group in Janelia in 2011, where, in addition to imaging technology development, her lab apply the resulting techniques to outstanding problems in neurobiology. She is now an associate professor in the Department of Physics and Department of Molecular & Cellular Biology at the University of California, Berkeley.

Known tricks for new applications in neuroscience challenges: fNIRS to investigate transcranial brain stimulations
Hanli Liu,
Univ. of Texas at Arlington (USA) 

In recent years, different forms of non-invasive, transcranial brain stimulations, such as transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS) and transcranial alternate current stimulation (tACS), have been investigated as promising neuromodulation tools to treat a variety of neurological brain disorders. Furthermore, transcranial photobiomodulation (tPBM) using NIR laser or light emitting diodes (LEDs) has also demonstrated promises to improve human memory and cognition. However, underlying principles or
mechanisms of these transcranial brain stimulations are far from understood. There is an urgent need to investigate stimulation-induced changes in cerebral hemodynamics and brain circuitry. This pressing need for a better understanding of the stimulation-related neurophysiology may provide the functional near infrared spectroscopy (fNIRS) community with new research opportunities to develop multi-modal technology, methodology, and data analysis to meet this area of neuroscience challenges. In this talk, I will present three examples of using fNIRS to study transcranial brain stimulations: (1) how fNIRS can be utilized to quantify upregulation of cerebral cytochrome-c-oxidase and hemodynamics in response to tPBM using 1064-nm laser, (2) what direction of information flow occurs before tDCS, during low current tDCS, during high current tDCS and after high current tDCS by applying the Phase Transfer Entropy (PTE) analysis on multi-channel fNIRS measurements, and (3) whether and how tPBM with 1064-nm laser would change or alter human cortical networks and neuro-vascular coupling during and after tPBM. I will also demonstrate the novel application of cross wavelet coherence to quantify neuro-vascular coupling.
Hanli Liu received her PhD degree in physics from Wake Forest University, followed by postdoctoral training at the University of Pennsylvania. She is a Full Professor of Bioengineering and Distinguished University Professor at the University of Texas at Arlington. She is also a Fellow of American Institute for Medical and Biological Engineering. Her expertise lies in the field of near-infrared spectroscopy of tissues, functional brain imaging, transcranial photobiomodulation, and their clinical applications. Recently, she received an NIH grant by the BRAIN (Brain Research through Advancing Innovative Neurotechnologies) initiative, which will apply fNIRS to investigate brain circuitry under transcranial laser stimulation.

Super-duper bioluminescent probes for next generation neuroscience
Takeharu Nagai,
Osaka Univ. (Japan)

Bioluminescence imaging is the gold-standard way in the biological study owing to its superior signal-to-background ratio and capacity for long-term measurement. Moreover, since the excitation light is absent unlike fluorescence imaging, unrestricted optogenetic manipulation is easily combined to the imaging. Here, we present the novel fiber-free imaging system,
SNIPA that can detect electrophysiological field potential dynamics in a brain with the use of a bioluminescent voltage indicator that we developed recently. With this system, we successfully monitored the activity of primary visual cortex (V1) simultaneously from "three" freely behaving mice for ~7 hours, and found that the novel type of V1 activation, associated with interaction with other mice. Consequently, SNIPA brought the merits of bioluminescence imaging to neuroscientists and would be useful to investigate socially related activity of various brain regions.

Takeharu Nagai took BS in 1992 and MS in 1994 at College of Biological Science and Department of Agricultural Science, Tsukuba University, respectively. He got Ph.D in 1998 from University of Tokyo. He became a researcher of Brain Science Institute, RIKEN in 1998, and then became a JST PRESTO researcher in 2001. In 2005, he promoted to a professor in Research Institute for Electronic Science, Hokkaido University. In 2012, he moved to The Institute of Scientific and Industrial Research, Osaka University. He was given
a title of Distinguished Professor of Osaka University in 2017. His laboratory is now developing fluorescent/bioluminescent proteins to decipherer how few number elements such as proteins and cells can cause singularity in biological system. His laboratory is also developing glowing plant that would be usable for electrical power free lightning devices.