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Unravelling the complexities of the brain is a difficult task, but research by engineers, scientists and psychologists at HKU is helping to deepen our understanding. They are challenging previously-held notions, such as the idea that the brain is inactive when at rest and that certain regions of the brain operate independently of others. They are shedding new light on brain disorders. And they are exploring the brain-computer interface to help people with disabilities. Secrets of the Brain Cover Story 01 | 02 The University of Hong Kong Bulletin | May 2018
New functions of hippocampus unveiled to bring insights to causes and treatments of brain diseases. (Courtesy of Ed Boyden, MIT) A breakthrough discovery at HKU has deepened our understanding of the ‘heart’ of the brain – the hippocampus – and opened a new therapeutic path for brain-related diseases. THE ACTIVE LIFE OF THE BRAIN AT REST The hippocampus is believed to play an important role in memory and navigation and it has been the subject of a countless number of studies that mostly have fired up and activated this region of the brain to try to understand how it works. But what about when it is at rest? Is it still at work? The idea of a resting-state of the brain was first floated more than two decades ago, but neuroscientists have not been able to agree whether it even exists. Now, they may have some answers thanks to the work of a team of HKU biomedical engineers led by Professor Ed X Wu, Chair and Lam Woo Professor in Biomedical Engineering. The debate has focussed on whether signals picked up through functional magnetic resonance imaging (fMRI) of the brain at restingstate are just a consequence of blood flowing through multiple interconnected regions or signs of actual large-scale neural activity. Professor Wu’s inspired approach to this problem was to apply a basket of tools and measures, including one drawn from the team’s earlier work on the somatosensory thalamus that was published in 2016 in the Proceedings of the National Academy of Sciences of the United States of America (PNAS) . The thalamus is a region of the brain that acts as a relay for communication among sensory systems and the somatosensory system concerns touch, pain and the like. Previously, it was thought that communication was self-contained within each sensory system, so for example the somatosensory thalamus only communicated with the somatosensory cortex. But the researchers showed that at the low frequencies measured through resting-state fMRI, different sensory networks actually connected to each other. Somatosensation talked to the visual and auditory senses, so to speak. This offered a possible explanation of how the brain integrates different sensations. Light work The finding influenced the team to look further and investigate the effect of low-frequency stimulation in the hippocampus, said Dr Alex TL Leong, who with Dr Russell W Chan is one of the key members of Professor Wu’s team. “The role of the hippocampus in complex brain networks has not been well understood. The literature will tell you that there are many functions that it is important for, but at the end of the day there must be a unifying observation or underlying principle of how the hippocampus actually functions in the brain,” he said. To edge closer to that goal, the HKU researchers applied several kinds of investigations that both activated the hippocampus at low frequencies and revealed the impact on brain functions. They first combined fMRI with optogenetics, in which they genetically modified excitatory neurons in rats’ hippocampus so they were sensitive to light. An optical fibre delivered the light stimulation so the hippocampus could be turned ‘on’ at different frequencies, with the low range as low as 0.5 to 1 Hz. This resulted in the first important finding: at low frequencies, multiple areas beyond the hippocampus lit up, especially in the visual cortex, but at high frequencies, activity was confined to the hippocampus. Secondly, they found that low-frequency stimulation enhanced the connectivity of largescale resting-state fMRI sensory brain networks, including visual, auditory and somatosensory, and augmented sensory functions. Signals during resting-state “We already knew that the hippocampus interacts a lot with the cortex at high frequencies, particularly when it comes to memory functions. But here we show that this interaction is predominant at very low frequencies, too,” Dr Leong said. This finding indicated that there was an underlying neural basis to the fMRI signals picked up from the brain at resting-state. The researchers also tested whether disrupting normal hippocampus function would affect the results. They did this by knocking out the hippocampus pharmacologically, which caused connectivity to drop immediately in the treated rats. If the results had still held, that would have indicated the hippocampus was not involved in enhancing brain connectivity. The findings were published in PNAS in August, 2017 and received widespread coverage in the scientific and popular media. Professor Wu said the implications extended beyond simply understanding the brain. “Only when we understand the functions of the brain circuits or networks can we then design new therapeutic measures which are more effective for treating or curing brain disorders, such as Alzheimer’s disease, epilepsy and schizophrenia,” he said, adding their work complemented ongoing, high-level projects to understand the brain that have been initiated by both the Chinese and American governments. █ From left: Dr Russell W Chan, Professor Ed X Wu and Dr Alex TL Leong. Only when we understand the functions of the brain circuits or networks can we then design new therapeutic measures which are more effective for treating or curing brain disorders. Professor Ed X Wu 03 | 04 The University of Hong Kong Bulletin | May 2018 Cover Story
Experiments using signals delivered to the unconscious mind have reduced the physical effects of phobia. The findings have implications for treatment and for our understanding of human consciousness. ONE CONSCIOUSNESS, UNDIVIDED The unconscious mind – when neuronal activity occurs (as recorded in functional magnetic resonance imaging, or fMRI) but there is no corresponding awareness of conscious experience – has an almost mythical status thanks to Sigmund Freud, who was a great populariser of its influence over our actions and conscious selves. But among philosophers and psychologists, its nature has been much debated. Is it really separate from the conscious mind? What determines whether neurons are conscious or unconscious? Dr Lau Hakwan of the Department of Psychology, who trained as both a philosopher and neuroscientist, has entered into the fray with the modest goal of seeing whether a little science can shed light on the matter. “Philosophy, after centuries of thinking, has led us to this point where we think the qualitative subjective experience is the core crucial conceptual component of consciousness. But how do you actually translate that concept into an experiment?” he said. Working with an international team of collaborators, he helped design and run an experiment on phobias that was able to tap into the unconscious mind and transmit more pleasant signals when phobia-associated signals arose. The results were published in the Proceedings of the National Academy of Sciences of the United States of America in March, 2018. The methodology they used was complicated and involved bypassing the conscious brain so as not to trigger the phobia directly. This was important because otherwise subjects might quit or be resistant to the experiment. Counter-conditioning Unconscious representations of phobias were first mapped by showing subjects photos of creatures that were related to their phobias, but themselves not frightening (for example, other insects or reptiles if they feared spiders or snakes) while they underwent fMRI. The researchers were able to see the detailed pattern of areas of brain activity triggered by the images and this guided them in the main part of the experiment, which was to associate those patterns of brain activity with a positive reward. The subjects played a game that used unrelated images to tap into the target unconscious regions and were told that they had won money whenever those patterns of brain activity representing the phobic objects were activated. “This approach comes from a method in psychology called ‘counter-conditioning‘. You re-expose the patient to the feared object and try to re-associate that object with a positive rather than a negative feeling,” he said. “The problem is, people tend not to enjoy that very much. In extreme cases, like posttraumatic stress disorder (PTSD), asking people to live through trauma is very difficult. As a neuroscientist, I have tried to translate exposure therapy into the brain by pairing a good feeling with the brain representation of the feared object.” The results were intriguing because while the subjects subsequently had a lowered physiological response after seeing a photo of their feared object – such as sweating less and having less activity in the associated region of the brain – they did not report that they felt any less afraid. “The experiment here is basically a way of going under the conscious hood, trying to tamper with people’s unconscious representations and hoping that would actually change their everyday experience,” Dr Lau said. “We have definitely done something about the brain-fear response, but it has not yet translated into the conscious experience.” The ‘hard’ problem The results are nonetheless important both for possible treatment of such things as PTSD – particularly as it can bypass the triggers of stress or fear – and for our understanding of the interplay between the unconscious and conscious mind. “If it were true that one part of your brain is conscious and one part not conscious, and the two work independently, then tampering with only the unconscious part may not do much good. It would just help the unconscious part to be less afraid, but you would still consciously be afraid. “We, on the other hand, think that these are the same representations in the brain for both processes. So tampering with the representations when you are unconscious would eventually translate to a conscious experience. That’s what we plan to demonstrate next.” Dr Lau concedes that consciousness is a difficult thing to solve entirely through science – it is not trivial to explain why subjects should feel a certain way when neurons can be seen firing, even if we can map out the patterns of such firing. For this reason, and also because of modern resistance against the Freudian perspective, it is often challenging to get funding for projects about consciousness. “In philosophy we traditionally think of consciousness as the ‘hard’ problem because it is not easy to explain the subjective from the objective and scientific point of view. But a problem doesn’t have to be a scientific problem for science to shed light on it,” he said. █ By learning to pair a reward with the unconscious activation of the brain pattern representing the animal, participants can overcome the fear response to an animal. The experiment here is basically a way of going under the conscious hood, trying to tamper with people’s unconscious representations and hoping that would actually change their everyday experience. Dr Lau Hakwan 05 | 06 The University of Hong Kong Bulletin | May 2018 Cover Story
How we see objects in the world may depend on what we are looking at. This finding is upending our understanding of the workings of the brain. VISION CHALLENGED In one line of experiments focussed on 3D vision, subjects were asked to indicate whether an object was in front of or behind a reference point while their brain activity was also monitored with fMRI. The object was a simple surface or a face, and it turned out that not only did the two affect position judgments differentially, but there were also more depthrelated neurons activated in the brain in response to faces during the task. An upsidedown face was also used but it did not have the same impact on sensitivities as a face with upright orientation. Advantage of recognition “The result was surprising because technically, the task did not involve processing what the object was or its orientation,” she said. “The whole novelty of this research is that the networks we are looking at are not solely modular or standalone. 3D sensitivity would be Studying vision and how we process what we see is a popular and accessible way for neuroscientists to study the brain. For a long time, they thought they had some things worked out: vision was guided by a hierarchical system divided into basic low-order tasks, such as orientation, luminance, depth and motion, and high-order tasks that impart meaning and recognition to the things we look at, with different parts of the brain responsible for each. But research by young scientists like Dr Dorita HF Chang of the Department of Psychology is showing that vision processing, like many matters to do with the brain, is a lot more complicated than the early science indicated. Dr Chang has been focussing on low-order functions in particular. The original thinking was that these were processed almost independently, so if an object moved up or down, the neurons responsible for motion would simply detect the motion and let the considered a low-level feature and you would think it should not be influenced by higher-level meaning, but that seems to be happening here.” Another set of experiments focussed on the luminance (reflection of light) of objects. Participants were asked to indicate which of two objects was more luminous. There were various pairs of objects – patches of colour, upright faces, upside-down faces, faces of a different race than the participant, and faces of a similar race. Previous studies on high-order processing had shown that people are better at processing faces of their own race. It now turns out that this advantage also holds for low-order processing, too. “The traditional school of thought would have said that race shouldn’t matter because luminance sensitivity is an early critical response and shouldn’t be modulated by meaning. But again, we have found that basic visual responses somehow get modulated by this contextual information,” she said. Dr Chang has also begun to study how the brain processes sound, to see how visual training affects auditory processing and vice versa – which would lend further support to the notion that the hierarchical, compartmentalised view of the brain needs a rethink. “We’ve been showing that we really need to consider an interaction between brain regions to support visual functioning, and to extrapolate that to understand interactions between vision and other modalities as well,” she said. Getting a clearer picture will be a long slow process, given the complexity of the brain and the fact that this line of investigation represents a paradigm shift in our understanding of how the brain functions. “One hundred years from now, we’ll know a lot more,” Dr Chang added. █ regions responsible for high-order tasks deal with identifying the object. But Dr Chang has found otherwise. In a series of experiments, she has demonstrated that the nature of the objects can alter the sensitivity of neurons, as measured by functional magnetic resonance imaging (fMRI). The more familiar an object is to us, the more sensitive our low-order neurons become to its motion. Moreover, people who are trained to become familiar with a previously-unknown object develop heightened sensitivity to its motion over time. Put another way, experience affects what was supposed to be a purely biological function. “Ultimately, what we perceive is not just a reconstruction of which neuron is firing, but a product of experience,” she said. One object that humans are highly experienced in recognising is the human face and Dr Chang used that insight to construct tests that support her point. Sample images shown to participants in the 3D experiments. Faces (upright or inverted) and non-face surfaces were depicted in terms of special 3D stimuli called stereograms. These stereograms provide separate images to the left and right eyes when special glasses are worn. The resulting percept is of an object in 3D, the position (in depth) of which was required to be judged by the observer in these experiments. fMRI results from the 3D experiments superimposed on the brain of a representative participant. Depth judgments don’t require explicit identification of object content. Yet, human observers’ behavioural sensitivity to judging the position of objects along the depth plane is significantly altered by object meaning. Corresponding context-based modulations of depth responses are found along intermediate (V3), dorsal (parietal), and ventral (inferotemporal) cortex. Face (upright) Face (inverted) Curvature-matched surface Task: Is the object in front of (‘near’) or behind (‘far’) the surrounding reference? Areas that are affected by object context during depth judgments [Face (upright) vs Curvature-matched surface] 10 2.5 t(11) p < .02 Ultimately, what we perceive is not just a reconstruction of which neuron is firing, but a product of experience. Dr Dorita HF Chang 07 | 08 The University of Hong Kong Bulletin | May 2018 Cover Story
Genetic variations that affect the structure and function of the brain are helping scientists better understand the mechanisms of brain disorders, such as schizophrenia and major depression. THE ROOTS OF DISORDER neurons to establish properly functioning neuronal networks. “But in animals, if this gene is excessively activated or expressed, it can lead to too much pruning of neurons. Indeed, one of the consistent differences in the brains of patients with schizophrenia is that there is a reduction in brain volume,” Professor Sham said. Interestingly, they also found evidence of an overlap between genes associated with schizophrenia and those with mutations responsible for intellectual disability. “We now have a number of new leads into the molecular changes associated with schizophrenia although there is still a long way to go before we have a detailed understanding of the mechanisms.” Other insights Taking that understanding forward, Professor Sham and his colleagues have also been investigating the impact of genetic variations on gene expression (or activity). They gathered evidence from GWASs about the gene The astonishing frontiers that have opened over the past decade or so with the completion of the human genome project and the development of new genotyping technologies are leading to a deeper understanding of the brain and the potential for new treatments for disorders. Professor Sham Pak-chung, Suen Chi-Sun Professor in Clinical Science and Chair Professor of Psychiatric Genomics, has been at the forefront of this research. He participated in an international consortium that in 2014 reported on the largest molecular genetic study of schizophrenia or any psychiatric disorder, a genome-wide association study (GWAS) involving 36,989 schizophrenia patients and 113,075 controls. The researchers were able to detect 108 genetic loci (positions on a chromosome) associated with schizophrenia, a disease for which there currently are no biomarkers or diagnostic tests. “We have known for a long time that psychiatric disorders are likely to be complex and involve multiple genes, but we didn’t really have a good idea of how complex they are. It expressions of seven psychiatric disorders, including schizophrenia, and compared this with the changes in gene expressions produced by thousands of drugs that have gone through clinical or pre-clinical trials. These drugs may not be in use for various reasons or may be used for other purposes, but the research showed that some of these drugs may reverse the gene expression changes seen in psychiatric disorders. Promisingly, some anti-psychotic drugs showed up as a potential match for schizophrenia and some anti-psychotics and anti-depressants for bipolar disorder. “It would be much easier to use existing drugs than to try to develop new ones,” he said. In yet another study, Professor Sham has also started looking at the genetic origins of major depression with Professor Tatia Lee Mei-chun, May Professor in Neuropsychology and Chair Professor of Psychology. They recently obtained access to the UK Biobank, which has genetic data from half a million people. They are comparing the data with brain images of 10,000 people of that group, as well as detailed health and lifestyle information drawn from questionnaires, to see how these factors was only with the GWAS that we have been able to get answers,” Professor Sham said. They also showed that the associations were not random but converged on genes expressed in certain tissues and cellular types. Schizophrenia was associated with proteins involved in synaptic function – synapses are the connections that allow neurons in the brain to communicate with each other – as well as certain neurotransmitters. While it was previously known that the neurotransmitter dopamine played a part, the research also identified glutamate and gamma-aminobutyric acid as important, suggesting possible new targets for treatments. Professor Sham said the findings also supported the idea that schizophrenia may have origins early in life, long before the onset of clinical symptoms, and perhaps even before birth. The strongest schizophrenia-associated locus was found to contain a gene important in brain development. Normally, the process involves both creating and pruning back interact with each other and influence the risk of depression. Professor Sham is also Co-Director, with Professor Lee, of HKU’s State Key Laboratory of Brain and Cognitive Sciences, whose members are producing other insights on brain and mental health. For example, work by Professor Lee has shown how the brain changes in response to psychological stimulation such as meditation. Professor So Kwok-fai, Jessie Ho Professor in Neuroscience and Chair Professor of Anatomy, has shown how physical exercise may mitigate the effects of depression by reversing the reduction in neurogenesis in the hippocampus, thus enabling more new neurons to be created. And Professor Eric Chen Yu-hai, Chi-Li Pao Foundation Professor in Psychiatry, and his group have demonstrated the value of early intervention in improving the outcome of patients with psychosis. “Our overall strategy is to improve brain health and mental well-being by creating models that can integrate brain imaging, genetics, biomarkers and human behaviour,” Professor Sham said. █ We now have a number of new leads into the molecular changes associated with schizophrenia although there is still a long way to go before we have a detailed understanding of the mechanisms. Professor Sham Pak-chung 09 | 10 The University of Hong Kong Bulletin | May 2018 Cover Story
Engineers working at the brain-computer interface are developing technologies that enable people to control computer activity and even robotic devices with their minds, and reduce pain. UP FOR GRABS team have already developed a robotic hand prototype with the Institute of Biomedical Engineering of the Chinese Academy of Medical Sciences which can respond to sensory stimulation and grab objects. This won the best presentation award at the 2nd competition of China Brain-Computer Interface in 2015. The technology is being further refined to identify finger joint movements, so the potential range of movements can be increased. “We want to see how well the hand grips, and if there is any spasm because spastic motions can cause fingers to jerk. We’re trying to see if the robotic hand can make the grabbing motion smooth and fast,” he said. “This could help patients with spasms but also a lot of Imagine the scene on the paediatrics ward of the Duchess of Kent Children’s Hospital when Dr Hu Yong and his team asked for patient volunteers to help test an invention that uses electrical signals from the brain to direct activity in a computer game. The response was immediate enthusiasm. “Even though they could use computers with their hands, they very much liked playing the game without their hands,” said Dr Hu, a biomedical engineer who is Director of the Lab of Neural Engineering and Clinical Electrophysiology in the Department of Orthopaedics and Traumatology. Bringing such joy is one of the aims of his research, which seeks to develop new rehabilitation technologies for the physically elderly patients who have lost their normal hand function due to neurological disorders.” Trying to improve function Dr Hu said they also wanted to use the technology to improve function, rather than simply compensate for loss of function. One line of research is trying to help patients improve control over spasms by training their neural systems. This involves applying electric stimulation to subjects’ hands and asking them to mentally identify if it is the right or left hand while the computer monitors their brain activity. Another line of exploration involves an exoskeleton that can walk and move its arms in response to signals from the brain. This could conceivably be done through voice control, but Dr Hu said employing the brain-computer interface instead could help enhance neurological repair by activating the sensory and motor neuron system. The project is expected to start in 2018 and also involves colleagues from the Li Ka Shing Faculty of Medicine and Faculty of Engineering at HKU, as well as the Hong Kong University of Science and Technology and the City University of Hong Kong. Apart from using the brain-computer interface to enable movement, Dr Hu and his team have also developed a device that uses transcranial direct current stimulation for pain relief in patients with chronic pain. Subjects were fitted with a cap of dry electrodes and a little box about the size of a mobile phone charger that sends signals to the brain to modulate the sensation of pain. In clinical trials, patients reported that the pain intensity was reduced by about 20 per cent on a scale of 1 to 10, in about 80 per cent of the cases. This approach could be particularly effective for problems like chronic lower back pain, which can flare up unexpectedly, he said. “It is not easy to guess when the pain will come and go. If you rely on taking painkillers, you would need to take them every day, but there are side effects to these drugs. This device can help patients feel more comfortable by reducing pain in their daily life,” he said. He hoped to be able to translate more research into clinical applications. “My Lab’s main concern is to develop new technologies that can benefit more and more people, especially the elderly. In future we may be able to provide a robotic assistant device at home that could help them with lifting heavy objects or doing simple daily activities, and improve their quality of life,” he said. █ disabled or impaired and improve the quality of life among the elderly. It is a fast-growing field thanks to advances in computer technologies. The technology tested at the children’s hospital is but one example of his work. The subjects there were fitted with a cap of electrodes that transmitted their brain signals to a computer as they mentally selected characters from a keyboard and moved a mouse around the screen. The technology is not yet 100 per cent accurate, but Dr Hu and his team are continuing to refine it in the hope that it may help people who cannot speak or type communicate with the world. A more immediately promising line of work uses robotics for rehabilitation. Dr Hu and his A trial of wireless brain-computer interface under the supervision of Dr Hu Yong. Brain-computer interface (BCI) Game Centre at the Duchess of Kent Children’s Hospital. A boy is playing a computer game by using BCI. If you rely on taking painkillers, you would need to take them every day, but there are side effects to these drugs. This device can help patients feel more comfortable by reducing pain in their daily life. Dr Hu Yong 11 | 12 The University of Hong Kong Bulletin | May 2018 Cover Story
HKU researchers show how poorer people are exposed to worse pollution than others by using an interdisciplinary approach that combines artificial intelligence, big data analytics and environmental management policy. THE INJUSTICE OF AIR POLLUTION measuring 100m x 100m. The model estimated the air quality for each of these areas in real time and had an accuracy of 82 per cent compared to the government readings, which was significantly better than the 50 to 60 per cent accuracy achieved by other data-driven models. To measure the human impact of air quality, the researchers collected data on social deprivation, including income, education level, profession, and housing ownership or rental, and found that people living in the most socially-deprived areas of Hong Kong were exposed to higher levels of PM2.5 (Particulate Matter of width 2.5 microns or less), a particularly harmful type of pollutant. “There is a statistically significant correlation between social deprivation and PM2.5 exposure, leading to environmental injustice,” Dr Lam said. The In 2016 The Economist unveiled the results of a year-long comparison of air pollution levels in 15 major cities in Asia, Europe and North America, in which Hong Kong was found to be the second most polluted, just behind Seoul. This result, coupled by growing wealth inequality in Hong Kong, motivated Professor Victor OK Li, Cheng Yu-Tung Professor in Sustainable Development and Chair of Information Engineering, and Dr Jacqueline CK Lam, Associate Professor, to embark on a study that sought to quantify the link between air pollution exposure and social deprivation through artificial intelligence and statistical techniques. They had just established the interdisciplinary HKU-Cambridge Clean Energy and Environment Research Platform (CEERP) with the University of Cambridge and the air pollution study districts of Yuen Long, Kwun Tong, Wong Tai Sin and Sham Shui Po were the hardest hit. In addition to defining the problem, the researchers also suggested remedies, such as funding tree-planting, pedestrianisation, and other schemes that reduce air pollution in the most affected areas. Personalised air pollution readings They are also in the process of taking their research to a new level through a HK$50 million Theme-based Research Scheme project, co-led by Professor Li and Dr Lam, called ‘Big Data for Smart and Personalised Air Pollution Monitoring and Health Management’. The project began in 2018 and is funded for five years and it will improve the quality of data collected and make the readings widely accessible to the public. Additional data will be gathered and fed into a deep-learning artificial intelligence model to sharpen accuracy and develop forecasting capabilities. New apps will be developed to tell people their air pollution exposure at any place and time in Hong Kong. Users would also have the option of inputting information from their Fitbits or other wearable devices about their personal activity levels and other health-related data, to obtain personalised air quality information. They may opt to receive alerts about avoiding active sports in certain areas with high pollution, or be shown how to avoid heavily-polluted areas as they move from one part of the city to another. A more intensive health study is also part of the project. Young asthma patients will be given electronic devices to measure individual air pollution exposure, lung capacity and inhaler use to understand how these factors may be correlated. Professor Lau Yu-lung and Dr Lee So-lun of the Department of Paediatrics and Adolescent Medicine are involved in this part of the study, which is among the first of its kind internationally. Furthermore, Professor John Bacon-Shone of the Faculty of Social Sciences is also helping the team develop statistical techniques for data analysis. Dr Lam said they also intend to develop a happiness index to correlate air quality levels with emotional well-being. “We will make some of this information freely available to the public,” Professor Li said, adding that their work will benefit the healthcare and information technology industries, too, because they will be able to access the project’s technologies and database through a licensing arrangement and develop new apps and other products from them. The work also has relevance beyond Hong Kong. The air quality model from the first study has been applied in Shenzhen using that city’s data. It is ready for adoption by other cities that want to obtain a detailed picture of air pollution exposure for their residents. █ Professor Li’s team is currently recruiting postdocs and research associates, and anyone interested is welcome to contact him at recruit@ceerp.hku.hk became HKU-Cambridge CEERP’s first major study. Its results, released in January, 2018, provide the most detailed picture yet of air pollution in Hong Kong and the populations that are most affected. “The Government has only 16 air quality monitoring stations throughout the city, but air quality can actually change across just a few city blocks,” Professor Li said. “We wanted to provide a more accurate and fine-grained estimate of air quality.” He and his team combined relevant information – including not only the Government’s air quality readings, but traffic flow data, meteorological information and urban morphology – and input that into an artificial intelligence model that created 110,000 different virtual ‘stations’ across Hong Kong, each covering an area Constituency areas (shaded in red) with both the highest level of PM2.5 pollution concentration and the highest level of Social Deprivation Index. Visualisation of PM2.5 pollution estimates and Social Deprivation Index (SDI) at the constituency area level in Hong Kong. Darker colours correspond to higher values of air pollution and SDI. From left: Dr Wilton WT Fok, Professor Victor OK Li, Dr Jacqueline CK Lam, and PhD student Mr Yang Han introduce their research on air pollution-induced environmental injustice. The Government has only 16 air quality monitoring stations throughout the city, but air quality can actually change across just a few city blocks. Professor Victor OK Li 13 | 14 The University of Hong Kong Bulletin | May 2018 Research
Experts from HKU’s Department of Medicine collaborated with colleagues from the Department of Pharmacology and Pharmacy on research which confirms a long-held suspicion that the long-term use of proton pump inhibitors – medicines that suppress acid production in the stomach – is associated with increased risk of stomach cancer. The Acid Test and 2012. They discovered that 153 (0.24%) of the patients developed stomach cancer with a median follow-up of 7.6 years. During this timeframe, 3,271 (5%) of the patients were treated with PPIs, and they showed a 2.44-fold increase in risk of developing stomach cancer. More frequent use was associated with a higher cancer risk, with daily use linked to a 4.55-fold higher risk than that of a non-user. The effects of PPI use on stomach cancer development in patients who had received HP eradication therapy were compared to non-users, after adjusting for various differences in the baseline characteristics between the two groups. “The studies showed the longer PPIs were used, the greater was the risk of developing stomach cancer, rising to five-fold after more than a year, to more than six-fold after two or more years, and more than eight-fold after three or more years,” said Professor Leung. Professor Leung Wai-keung, Li Shu Fan Medical Foundation Professor in Gastroenterology, and Clinical Professor of the Department of Medicine, said the study focussed on patients being treated for Helicobacter pylori (HP) infection and being prescribed proton pump inhibitors (PPI). HP infection is considered to be the most important risk factor for stomach cancer development, estimated to increase chances of contracting it three-fold. He explained: “Helicobacter pylori is bacteria in the stomach. Its discovery was huge – and Australians Barry Marshall and Robin Warren won the Nobel Prize in Physiology or Medicine in 2005 for making that discovery. Prior to that, it was believed peptic ulcers were caused by stress and bad lifestyle such as sleep deprivation and spicy food. People are infected by HP bacteria as children, but for most it is asymptomatic and they only know about it much later if they develop symptoms such as pain, ulcers, bleeding or stomach cancer.” “We found that the long-term use of PPIs doubled the risk of stomach cancer development even after successful HP eradication. The risk rose in tandem with the dose and duration of PPI treatment.” Proton pump inhibitors are drugs commonly used for dealing with excess stomach acid, and to treat stomach ailments such as peptic ulcer, acid reflux, dyspepsia. They are sold over the counter to the patients directly in the UK and US (though not Hong Kong) and are frequently prescribed. Indeed, while acknowledging that PPI is a potent acid suppressant and an important drug, Professor Leung said it is over-prescribed. “The possible link between PPI usage and cancer has been made before, but what is unique to this study is that it only looks at patients who had been infected with HP and who had received treatment to eradicate it.” “Other studies have looked at general patients,” he added, “but this is a stronger message: Since HP therapy eradicates the infection it has been thought that it is safe to use PPIs, but this research says it is not safe. People have struggled to accept that this is true. We have had a lot of commentary on the paper and people are now beginning to accept that PPIs may have negative effect.” At the same time, Professor Leung emphasised: “This is an observational study and therefore not conclusive regarding causality, so we are not discouraging the use of PPIs completely but recommending that doctors regularly review the indications of a prescribed PPI and use the minimum effective dosage, frequency and duration.” Best evidence now However, he also said that this study, though observational, “may represent the best evidence we can get for now. The next level of research would be a controlled study which randomly assigns patients to either a PPI or placebo and that is unlikely to happen for several reasons; first, ethical, it could put some patients at risk, and second, timing – the study will take many years.” He suggested that H2-receptor antagonist, a less potent acid suppressant may be a safer alternative for the patient. “It is also cheaper so why not use it?” he said. “Some people erroneously believe that the most expensive drug is the best.” The findings, which are attracting a lot of attention, have been published in the latest issue of the prestigious international scientific journal, Gut . They could represent a major step in the prevention of stomach cancer, which is the fifth most common cancer and the third leading cause of cancer-related death in the world. It is particularly prevalent in East Asia, accounting for more than 70 per cent of the cases globally. █ Previous studies have suggested that the risk of gastric cancer development could be reduced by about 40 per cent by elimination of HP, yet a considerable proportion of patients continue to progress to stomach cancer even after successful HP eradication. $60-million question The team was able to look into the link between the two. “The reason we were able to focus on a possible link between the two was that the Department of Pharmacology and Pharmacy alerted us to the fact that they had identified a large cohort of HP patients while doing another study. This gave us the opportunity to ask the $60-million question: does PPI usage effect the development of stomach cancer?” To do so, they studied clinical data on more than 63,000 HP-infected patients who had received HP eradication therapy between 2003 From left: Dr Esther Chan Wai-yin, Associate Professor of Department of Pharmacology and Pharmacy; Professor Leung Wai-keung, Clinical Professor of Department of Medicine; and Dr Michael Cheung Ka-shing, Specialist in Gastroenterology and Hepatology, Department of Medicine. The studies showed the longer PPIs [proton pump inhibitors] were used, the greater was the risk of developing stomach cancer, rising to five-fold after more than a year, to more than six-fold after two or more years, and more than eight-fold after three or more years. Professor Leung Wai-keung 15 | 16 The University of Hong Kong Bulletin | May 2018 Research
When refining liquid-repellent surface technology, a team of mechanical engineers was bio-inspired. Mother Nature provides key to staying dry The porous surface the team designed is composed of honeycomb-shaped micro-cavities that are interconnected thereby ensuring stability, and which have a re-entrant structure which in turn ensures highly effective liquid repellency. Professor Wang said: “The robust liquidrepellent structure is 21-times more mechanically stable than similar surfaces. The key to the technology is the unique design of the liquid-repellent structures and the Liquid-repellent surfaces or coatings have myriad uses – from water-repellent clothing through self-cleaning buildings to frictionreducing surfaces for ships – but until recently the technology was either too expensive to produce, too unstable or simply not robust enough. Bio-inspiration is the key to the engineering team’s liquid-repellent breakthrough – material that is robust, versatile and cheap to produce. The technology has also just won the TechConnect Global Innovation Award for 2018. microfluidic-droplets-based fabrication. The former resolves effectively the conflict between liquid repellency and mechanical stability, while the latter offers low-cost and scalable production of well-defined structures with precision and controllability.” Oil and water Comparing the new product to existing ones, Professor Wang said: “Other technologies can repel oil or water, ours is capable of repelling both. In fact, our liquid-repellent structures can repel at least 10 types of liquids, including surfactant solutions and organic solvents, as well as oil and water. “Other technologies use chemistry to make the repellent, ours uses physical structure to repel liquids and is therefore more environmentallyfriendly. Some other technologies have used physical structure as the repellent too, but they are structurally weak, while ours is stable. And finally, while others are expensive to produce, ours is commercially viable as we can produce it on a large scale at low cost.” The cost for one square metre of material made with this technology is approximately HK$1, and the team has already signed an agreement with a major international company which intends to use it to make clothing. “We also have a deal pending with another international company which will use it for coating electronic devices such as mobile phones,” said Professor Wang. “Currently the coating they use is chemical and not envirofriendly. Ours has no environmentally-unfriendly elements in it.” The technology has several applications for clothing. As well as the obvious advantages for rainwear, it also means that clothes will have to be washed less often, which has implications for the environment as it reduces power usage. It can also be used on kitchenware, making kitchen surfaces easier to keep clean and cookware much easier to wash, and windows which will need to be washed far less frequently. There are lots of potential uses for transport too – water-repellent surfaces drastically reduce the drag on water vehicles, enabling cargo ships to move faster and saving on energy consumption. Liquid friction drag contributes to 60 to 70 per cent of the total drag for large cargo ships and 90 per cent for underwater vehicles. At present Professor Wang and his team are doing further work on underwater applications, such as military submersibles. “Liquid-repellent surfaces reduce the friction drag by creating an effective slip boundary enabling the ship to move faster and use less fuel,” he said. “We are also looking into further uses for the product in fields ranging from automobiles, chemical engineering and electronics to biomedical industry and advanced manufacturing.” █ Professor Rick Wang Liqiu and his team from the Department of Mechanical Engineering turned for inspiration to the springtail – an arthropod whose habitat is wet soil which is frequently flooded. Arthropods are invertebrates with an exoskeleton, segmented body and paired joint appendages and include insects, arachnids and crustaceans in their number. The springtail has adapted to its environment by evolving cuticles capable of repelling liquids and with high mechanical durability to resist friction from soil particles. Professor Rick Wang Liqiu (right) and Dr Zhu Pingan (left) from the Department of Mechanical Engineering showcase the liquid-repellent material they innovated. A piece of ordinary cloth (left) can become liquid-repellent (right) simply with a layer of porous surface material (middle). A soil-dwelling springtail with dew (body length: approximately 2.5mm). (Courtesy of Brian Valentine) Our liquid-repellent structures can repel at least 10 types of liquids, including surfactant solutions and organic solvents, as well as oil and water. Professor Rick Wang Liqiu 17 | 18 The University of Hong Kong Bulletin | May 2018 Research
The health of our oceans is facing threats on multiple fronts. One of the most serious is oxygen deprivation, which could devastate marine life and biodiversity. Marine biologist Dr Moriaki Yasuhara is part of an international team looking to find a solution. Oxygen in Oceans Takes a Dive plant life. Since 1950, low oxygen sites in coastal water bodies, such as estuaries and seas, have increased more than 10-fold. Dead zones “Clearly, this is not good news, but methods to alleviate the problem are relatively straightforward,” said Dr Yasuhara. “We need to address the issues which are causing oxygen levels to fall, namely climate change and nutrient pollution in our oceans. It is a combination of these two factors which increases what we refer to as dead zones, that is, places where the oxygen levels are too low to support marine life. Quite simply marine animals suffocate and die and fish avoid the areas.” Such is the situation that in 2016 the United Nations’ Intergovernmental Oceanographic Commission set up the Global Ocean Oxygen Network (GO 2 NE), comprising a team of scientists from around the world to search for solutions. Dr Yasuhara was asked to join the team and contribute his expertise as a paleoecologist, specialising in oxygen in historical and geological records. “Paleoecology relating to oxygen was part of my thesis,” said Dr Yasuhara. “The decline in ocean oxygen ranks among the most serious effects of human activities on the marginal marine environment, and the Asian coast including Hong Kong is one of the most seriously effected.” The Asian coastline is particularly bad because of the fast industrialisation of the area. Europe and the US had their industrial revolutions 200 years ago, but in Asia it has occurred in the last 50 to 100 years. Many countries in the region have begun developing relatively recently and very rapidly this century. Around Hong Kong, the waters are suffering especially because of rapid industrialisation and the sheer density of the population, meaning a relatively small area produces a lot of waste and pollutants. “Across Southeast Asia things could be dying out in the waters around us at a rapid rate,” said Dr Yasuhara. “For the US and Europe it has been a long-term problem, and there has even been some improvement recently as there is more regulation and awareness there.” On the plus side, he feels that Hong Kong could be a leader in instigating a drive to improve the situation in Asia. “In Hong Kong there is a good sense of what needs to be done to achieve conservation. NGOs work hard here and the younger generation is very aware. Hong Kong could take the lead in Asia on environmentallyfriendly production and reducing waste, as well as cleaning up the oceans. “Another problem in the wider Southeast Asia region is that there is not enough research, so we do not have enough information. In some countries data may exist but it is difficult to access – although sometimes that is simply the result of language barriers as there are many different languages in Asia. It’s important to have better data across the globe. At the moment the US and Europe – the northern hemisphere – have good data, but Southeast Asia does not. “As paleoecologists, we learn from history – we examine at the characteristics of ancient environments and their relationships to ancient lives. It is looking to the past to learn about the future. We need to find answers to how oxygen, or the lack of it, changes the marine ecosystem and biodiversity, how it is associated with long-term climate change and how it effects other things such as the acidification of our waters.” GO 2 NE’s report has attracted much attention, and been published or aired by more than 300 media organisations around the world. Dr Yasuhara said it is a major first achievement for the newly-formed group and the hope now is that governments will respond to the findings and introduce measures to reduce waste and improve water treatment. █ In early 2018, GO 2 NE produced its first paper revealing the network’s findings on the causes of oxygen deprivation, and offering solutions on how to raise oxygen levels. The report, which was published in the journal Science, was unique in that it covered both the open ocean and coastal waters. Among its worst discoveries was that the amount of water in the ocean containing near zero oxygen has increased more than four-fold in the last half-century. The scientists said they expect those oxygen levels to keep dropping, both as the Earth continues warming and because of eutrophication, which is when run-off from the land leads to excessive richness of nutrients in water causing dense growth of Low oxygen caused the death of these corals and others in Bocas del Toro, Panama. The dead crabs pictured also succumbed to the loss of dissolved oxygen. (Courtesy of Arcadio Castillo/Smithsonian) Low-oxygen zones are spreading around the globe. Red dots mark places on the coast where oxygen has plummeted to two milligrams per litre or less, and blue areas mark zones with the same low-oxygen levels in the open ocean. (Courtesy of GO2 NE working group. Data from World Ocean Atlas 2013 and provided by R J Diaz) Members of the Global Ocean Oxygen Network (GO2 NE) working group in Monterey, USA. (Courtesy of Francisco Chavez) We need to find answers to how oxygen, or the lack of it, changes the marine ecosystem and biodiversity, how it is associated with long-term climate change and how it effects other things such as the acidification of our waters. Dr Moriaki Yasuhara 19 | 20 The University of Hong Kong Bulletin | May 2018 Research
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