Unravelling the brain: Dr Ed Wu on non-invasive neuroscience

29 August 2016

Invasive clinical procedures are often considered a major limitation of medical science, particularly in the field of neuroscience, which deals with devastating neurodegenerative diseases like Alzheimer’s and Parkinson’s.

Dr Ed X Wu’s cutting-edge research into fMRI (Functional Magnetic Resonance Imaging) might take us a step closer to developing non-invasive methods to address these diseases and unravel the mysteries of brain.

“A biopsy is still used plenty in our healthcare system. But it’s a very painful, invasive process and we can’t biopsy every region of brain,” says Wu, who is an avid proponent of diagnosis using imaging and even nanotechnology; avoiding resorting to complicated surgery.

Neuroscience and biomedical application of imaging systems

But long before working in the field of neuroscience, Wu spent his early career devoting time to engineering medical imaging systems such as high field MRI and the world’s first 3D PET (Positron Emission Tomography) scanner, which is now a mainstream medical imaging tool used by doctors to detect diseases in the human body.

It was the challenge presented by unanswered questions in neuroscience that first sparked Wu’s interest when he was at Columbia University leading the NMR (Nuclear Magnetic Resonance) micro-imaging laboratory and working as an Associate Professor of Radiology and Bioengineering. Being surrounded by scholars in the field further deepened his fascination with neuroscience.

However, it was the mystery of the human brain and the intricate links between life sciences and engineering that committed him to the field. The fact that he himself has an engineering background also helped.

Wu began pushing for the biomedical applications of sophisticated imaging systems, and when he eventually returned to Hong Kong, he set up the 7T MRI Research laboratory (Laboratory of Biomedical Imaging and Signal Processing) at the University of Hong Kong.

“I was on research but my heart and mind was on fundamental applications of biomedical imaging, in particular MRI. So we set up a lab; pushing the technological development as well as the biomedical applications,” explained Wu, who is also a professor in the Department of Electrical and Electronic Engineering at HKU. “My group and I continue to look at brain functions and heart structure and come up with biophysical methods to look at the in vivo biology.”

He also developed diffusion MRI methods to study the micro-structural tissue properties of the heart, brain, and other organs and tissues in normal and diseased conditions. Similarly, he developed high-order diffusion MRI techniques to use water molecules as a ubiquitous marker to probe and characterise the tissue information at the microscopic scale. He was successful in employing functional MRI (fMRI) methods to map visual and auditory systems in vivo in rodent models.

Understanding the brain

Much of Wu’s work involves understanding the mechanisms of the human brain, which he calls the best machinery ever engineered by nature. He acknowledges that science still doesn’t fully understand it, but applications of quantitative engineering can help connect the missing dots. Imaging methods in particular look at biological systems to understand their functions and how they are implemented.

From visual to auditory to memory systems, we know that signals reach the brain, are processed by the mid-brain and end up in the cortex to infiltrate several areas of brain. But we do not yet know how these systems proceed and are understood by the cortex.

Moreover, the brain is made up of millions of neurons. Traditionally we use electrophysiology to study them. But we need better technology to be able to do massive recording and look at brain functions and interactions at a larger scale, rather than just local activity.

In the recent years there has been a worldwide recognition of the urgency of research into the frontiers of neuroscience. In 2013 the Obama administration announced a public-private research initiative called BRAIN (Brain Research through Advancing Innovative Neurotechnologies), to understand the human brain and find ways to prevent and even cure various brain disorders.

“The hope is that if we can understand brain, we can solve a lot of diseases. But right now the main barrier to understanding the brain is the technology required,” said Wu.

And this is where Wu’s novel combination of optogenetics with large-scale fMRI readout to dissect the functions and dynamic properties of long-range brain networks and connectivity in vivo comes in.

fMRI and Optogenetic fMRI

After a person is placed in an imaging device, a stimulus, like music, is introduced. As soon as a song plays, the ear will respond and send a signal all the way up to the brain (and to its different parts). At the same time the imaging machine scans the brain continuously; so scientists are able to see the parts of brain that are stimulated as the song plays, showing the regions involved. This is FMRI, a very powerful tool widely used to map brain functions. It was first developed 20 years ago and researchers have been working constantly to perfect it over the years.

For the past 6 years Wu has been trying to find ways to better map brain functions, networks, and circuits.

It is already known that several parts of the brain are interconnected functionally, but network properties and how exactly they interact are not yet known. So Wu came up with the idea to combine what is known as octogenetic stimulation with fMRI.

In this method, light is projected in such a way that only certain cell types are stimulated, they can be made to either excite or de-excite to observe how the rest of the brain responds. This is unlike electrical stimulation wherein all cells get excited, making it difficult to read responses of specific parts of the brain.

In this way it is possible to see how the brain responds to particular manipulations, and brain properties can actually be mapped. This method is also effective in getting better insight into long-range circuit properties and functions and is done using synthetic bioengineering techniques.

Certain cell types can also be modified using this method so that when a light is shone, the cell will either turn on or turn off, which makes it possible to manipulate them. This gives reversible control of certain cell populations inside the brain, with millisecond precision. Currently, the trials are limited to animal models but this modification could be essential in disease treatment, although some human trials have started in the field known as optogenetics.

“The result is very exciting, the idea worked. We have been working on it for few years and we’re now in the process of publishing them,” said Wu on optogenetic neuromodulation with functional MRI. “Through this combined approach we found out that when it comes to brain circuits, particularly of long-range network, they are finely tuned for the low frequency.”

Wu explains that low frequency signals travel further and talk to the remote brain regions. These low frequency activities can influence or modulate brain functions.

Long-range network and brain diseases

Brain connectivity has now been associated with many diseases like Parkinson’s and Alzheimer’s. Wu is positive that if we understand brain connectivity and the properties of long-range circuits, we can utilise functional MRI connectivity measurement as a very powerful tool for both diagnosis and prognosis.

But with current technologies and methods, science still doesn’t understand the exact locations of long-range circuits and their mechanisms. But Wu insists that by exploring and dissecting long-range circuit properties, the area he has been working on, significant contributions can be made.

“The main thrust is to have a more fundamental understanding of brain’s long-range circuits,” he said. “Optogenetic and functional MRI mapping provide a unique way to look at dynamic brain properties through brain imaging, instead of slicing and putting them through electrodes, which is very invasive.”


“Technology is the biggest challenge, but we don’t fear it because whatever we need to develop, we’ll employ and do it in time,” said Wu. “But the transdisciplinary nature of research might pose a threat because there should be a willingness to embrace new technologies, work with people of different fields, understand them, and always keep up to date.”

In Hong Kong, the lack of people working in the field of neuroscience is another major problem. The city has the highest life expectancy in the world and yet not many researchers are working in the field to better understand the human brain and try to find ways to treat the brain diseases of old age. Hong Kong needs to be better equipped to address the increasing burden of the brain disorders of old age.

Back at his office at the University of Hong Kong, Wu is making final preparations to publish his papers on optogenetic functional MRI.

“I’m not a neuroscientist, I think only a few people can say they are. I’ll not put down my hat until I make some significant contribution,” said Wu who wants to continue working on exploring the fascinating way the human brain functions, without surgery and using the scanning techniques his team has perfected.

Dr Ed X Wu was awarded Outstanding Researcher Award in 2009 by HKU and was recipient of 2012 Croucher Senior Research Fellowship. He was an elected Fellow of American Institute for Medical and Biological Engineering (AIMBE) in 2011, International Society for Magnetic Resonance in Medicine (ISMRM) in 2013 and Institute of Electrical and Electronic Engineers (IEEE) in 2014. He is also a Fellow of UK Institution of Engineering and Technology (IET) and Hong Kong Institution of Engineers (HKIE). Wu obtained his Bachelor of Science in Electrical Engineering from Tianjin University, MS from University of Wisconsin- Madison and PhD from University of California- Irvine. He was an Associate Professor of Radiology and Bioengineering at Columbia University from 1995 to 2003 where he also led the NMR microimaging laboratory. In 2003 he joined the University of Hong Kong as a professor in Department of Electrical and Electronics Engineering. He is currently Lam Woo Chair Professor in Biomedical Engineering and the founding Director of the Laboratory of Biomedical Imaging and Signal Processing (7T MRI lab). He also served as Associate Dean (Research) from 2013 to 2016. 

To view Wu’s personal Croucher profile, please click here.