Low-Cost ‘Cooling Cure’ Could Avert Brain Damage in Oxygen-Starved Babies

When babies are deprived of oxygen before birth, brain damage and disorders such as cerebral palsy can occur. Extended cooling can prevent brain injuries, but this treatment is not always available in developing nations where advanced medical care is scarce. To address this need, Johns Hopkins undergraduates have devised a low-tech $40 unit to provide protective cooling in the absence of modern hospital equipment that can cost $12,000.

The device, called the Cooling Cure, aims to lower a newborn’s temperature by about 6 degrees F for three days, a treatment that has been shown to protect the child from brain damage if administered shortly after a loss of oxygen has occurred. Common causes of this deficiency are knotting of the umbilical cord or a problem with the mother’s placenta during a difficult birth. In developing regions, untrained delivery, anemia and malnutrition during pregnancy can also contribute to oxygen deprivation.

In a recent issue of the journal Medical Devices: Evidence and Research, the biomedical engineering student inventors and their medical advisors reported successful animal testing of the Cooling Cure prototype. The device is made of a clay pot, a plastic-lined burlap basket, sand, instant ice-pack powder, temperature sensors, a microprocessor and two AAA batteries. To activate it, just add water.

The device could help curtail a serious health problem called hypoxic ischemic encephalopathy, which is triggered by oxygen deficiency in the brain. Globally, more than half of the newborns with a severe form of this condition die, and many of the survivors are diagnosed with cerebral palsy or other brain disorders. The problem is particularly acute in impoverished regions where pregnant women do not have easy access to medical specialists or high-tech hospital equipment. The inventors say Cooling Cure could address this issue.

“The students came up with a neat device that’s easy for non-medical people to use. It’s inexpensive and user-friendly,” said Michael V. Johnston, a Johns Hopkins School of Medicine pediatric neurology professor who advised the undergraduate team. Johnston also is chief medical officer and executive vice president of the Kennedy Krieger Institute, an internationally recognized center in Baltimore that helps children and adolescents with disorders of the brain, spinal cord and musculoskeletal systems.

First neutron scattering experiments on brain tissue reveal weaknesses in formaldehyde preservation, reducing reliability of post-mortem analysis

These results are the first step in a project to push back the limits of  existing dMRI imaging technology, to improve diagnosis and investigate potential treatments for brain diseases.

The first analysis of biological processes within brain tissue using neutrons at the Institut Laue-Langevin has revealed that the common application of formaldehyde preservatives changes, rather than maintains, fundamental properties such as rates of water diffusion. The mapping of cellular water in the brain is a key factor in the post-mortem analysis of several brain pathologies (including tumours and multiple sclerosis), with a view to earlier diagnosis and potential treatment. These results suggest the need for a review of existing research in this area.

The results are the first stage in the team’s own pioneering application of neutrons to understand in unprecedented detail the movement of cellular water within brain tissue. The analysis of this movement is generally performed by diffusion magnetic resonance imaging (dMRI), and provides the basis for diagnosing several brain diseases. These first results clearly demonstrate neutrons’ ability to ‘see’ the effects of these biological processes on a scale 10,000 times smaller than dMRI. In future ILL’s neutrons will analyse with unprecedented resolution cellular water dynamics in ex-vivo pathology-bearing brain tissue samples, thus helping doctors spot the early signs of these diseases and investigate potential treatments.

Cellular water is the major constituent of our body and its content may vary in brain regions depending on their specific composition. Water plays a key role in cell regulation, and its distribution and movement is an accurate indicator of cellular structure; this is because it interacts with different tissue components such as membranes and nerve fibres.

dMRI and other imaging techniques use water diffusion as a contrast method for revealing and characterising several brain pathologies (i.e. ischemia, tumours and, recently, inherited prion disease) on the micron scale 100 times thinner than a human hair. At this scale, however, the contribution of the macromolecular components cannot be separated and have to be averaged out instead.

As the standard imaging techniques used to detect the early signs of brain pathologies are limited in resolution, the use of preservation techniques to investigate pathological conditions in ex-vivo specimens has increased. However, there are concerns over the impact of these preservation processes on our tissues’ fundamental structural and compositional properties, and this has undermined confidence in this line of research.

To address these concerns Dr Francesca Natali from the Italian CNR (Consiglio Nazionale delle Ricerche), in collaboration with Dr Yuri Gerelli, a scientist from the Institut Laue-Langevin, the world’s flagship centre for neutron science, Prof. J. Peters from France’s Joseph Fourier University in Grenoble (UJF), and Dr Calogero Stelletta from the University of Padova in Italy compared the behaviour of cellular water in ex-vivo bovine tissue preserved using two common preservation techniques: chemical fixation, using formaldehyde solutions, and cryo-preservation, where cells or whole tissues are cooled to sub-zero temperatures.

The researchers obtained fresh post-mortem bovine brains from an Italian slaughter-house and applied the different preservation techniques. These samples were then investigated using incoherent quasi-elastic neutron scattering (QENS) on the high-resolution IN5 spectrometer at the Institut Laue-Langevin (ILL).

Neutrons are an ideal probe for the investigation of biological materials at the atomic scale. As they produce no damaging radiation effects, they can accurately map any change in the samples over time.

From this analysis Dr Francesca Natali and her colleagues identified a significant reduction of water movement as a result of the introduction of the formaldehyde-based preservation solutions (potentially due to the formation of cross-links between proteins, within which free water may become trapped, reducing its mobility). This effect was not seen in the samples that underwent cryo-preservation.

As well as these findings, the results of this study also demonstrate for the first time the power of neutrons to model cellular water diffusion within brain tissue; this new modeling technique could help dMRI specialists push back the limits of existing imaging technology, to improve their diagnoses and investigate potential treatments for brain pathologies.

In a separate study, the same team are investigating how the movement and distribution of cellular water in brain tissue is affected by myelin, an electrical insulator that forms protective layers known as sheaths around brain cell axons. Myelin is responsible for speeding up electrical impulses as they travel along tissue fibres. Many neurodegenerative autoimmune diseases, including multiple sclerosis, are caused by the degradation of myelin over time. The neutron scattering team’s new understanding of the impact on research results of preservation techniques will enhance its atomic-scale investigations into the conditions underlying autoimmune diseases and the potential for treatment.

Mapping blank spots in the cheeseboard maze

IST Austria Professor Jozsef Csicsvari together with collaborators succeeds in uncovering processes in which the formation of spatial memory is manifested in a map representation • Researchers investigate timescale of map formation • Inhibitory interneurons possibly involved in selection of map

During learning, novel information is transformed into memory through the processing and encoding of information in neural circuits. In a recent publication in Neuron, IST Austria Professor Jozsef Csicsvari, together with his collaborator David Dupret at the University of Oxford, and Joseph O’Neill, postdoc in Csicsvari’s group, uncovered a novel role for inhibitory interneurons in the rat hippocampus during the formation of spatial memory.

During spatial learning, space is represented in the hippocampus through plastic changes in the connections between neurons. Jozsef Csicsvari and his collaborators investigate spatial learning in rats using the cheeseboard maze apparatus. This apparatus contains many holes, some of which are selected to hide food in order to test spatial memory. During learning trials, animals learn where the rewards are located, and after a period sleep, the researchers test whether the animal can recall these reward locations. In previous work, they and others have shown that memory of space is encoded in the hippocampus through changes in the firing of excitatory pyramidal cells, the so-called “place cells”. A place cell fires when the animal arrives at a particular location. Normally, place cells always fire at the same place in an environment; however, during spatial learning the place of their firing can change to encode where the reward is found, forming memory maps.

In their new publication, the researchers investigated the timescale of map formation, showing that during spatial learning, pyramidal neuron maps representing previous and new reward locations “flicker”, with both firing patterns occurring. At first, old maps and new maps fluctuate, as the animal is unsure whether the location change is transient or long-lasting. At a later stage, the new map and so the relevant new information dominates.

The scientists also investigated the contribution of inhibitory interneuron circuits to learning. They show that these interneurons, which are extensively interconnected with pyramidal cells, change their firing rates during map formation and flickering: some interneurons fire more often when the new pyramidal map fires, while others fire less often with the new map. These changes in interneuron firing were only observed during learning, not during sleep or recall. The scientists also show that the changes in firing rate are due to map-specific changes in the connections between pyramidal cells and interneurons. When a pyramidal cell is part of a new map, the strengthening of a connection with an interneuron causes an increase in the firing of this interneuron. Conversely, when a pyramidal cell is not part of a new map, the weakening of the connection with the interneuron causes a decrease in interneuron firing rate. Both, the increase and the decrease in firing rate can be beneficial for learning, allowing the regulation of plasticity between pyramidal cells and controlling the timing in their firing.

The new research therefore shows that not only excitatory neurons modify their behaviour and exhibit plastic connection changes during learning, but also the inhibitory interneuron circuits. The researchers suggest that inhibitory interneurons could be involved in map selection – helping one map dominate and take over during learning, so that the relevant information is encoded.

Intuition results from training

A game of Japanese chess reveals how experts develop their capacity for rapid problem-solving

The superior capability of experts to rapidly solve problems depends largely on their intuition, and it has long been known that this is related to experience and training. Although many psychological models relating to the development of intuition have been proposed to explain this phenomenon, none have been validated, and the underlying neural mechanisms remain a mystery.

Keiji Tanaka and colleagues from the Cognitive Brain Mapping Laboratory and Support Unit for Functional Magnetic Resonance Imaging at the RIKEN Brain Science Institute have now shown that activity in the basal ganglia of the brain, which is related to the automatic, rapid information processing or intuition characteristic of experts, develops during the course of training. The work provides a first insight into the neural response of the brain to extended training and hints at ways to improve the efficiency of training experts in industry.

In earlier work, another research team led by Tanaka showed that amateur players of the Japanese chess-like game of shogi plotted their best next-moves consciously using the human brain’s highly developed cerebral cortex. In contrast, they found that in professional players an important part of this process was unconscious or intuitive and had shifted to the head of the caudate nucleus in the basal ganglia, a much older part of the brain. This would leave the cortex free for higher-level strategy, the researchers suggested. Yet it remained unclear as to whether this shift of neural activity was entirely due to training, or dependent to some extent on pre-existing ability.

Tanaka’s most recent experiments involved training 20 novices for 15 weeks in mini-shogi, a simplified version of shogi. After about two weeks and again at the end of the 15-week program, the intuition of the volunteers was tested through their ability to come up with the best next-move to end-phase patterns of mini-shogi games. To ensure the answers were intuitive, each problem was presented for just two seconds and participants had to respond within three seconds. During this process, brain activity was recorded using functional magnetic resonance imaging (fMRI). The researchers found that activity in the caudate nucleus developed over the training period, whereas activity in the cortex remained unchanged.

“This work should open a fruitful interaction between the cognitive psychology of expertise development and biological studies of the basal ganglia,” says Tanaka. “We now would like to elucidate what computations the caudate nucleus conducts in generating the best next-move.”

Path Found to a Combined MRI and CT Scanner

A technology that better targets an X-ray imager’s field of view could allow various medical imaging technologies to be integrated into one. This could produce sharper, real-time pictures from inside the human body, says a researcher who hopes to one day build such a unified imager.


Ge Wang, the director of Rensselaer Polytechnic Institute’s Biomedical Imaging Center, in Troy, N.Y., calls his vision omni-tomography. Mixing and matching imaging techniques, such as computed tomography, magnetic resonance imaging, and single-photon emission computed tomography, could improve biomedical research and facilitate personalized medicine, says Wang, an IEEE Fellow.


To fit these imaging methods together, Wang and his collaborators have been developing a technology called interior tomography. In standard CT, X‑rays pass through two-dimensional slices of the body, and then a computer processes the data to build up a picture. If the scanner is trying to image the aorta, for instance, it will X-ray a whole section of the chest, including the points where the body ends and the open air begins. That boundary provides the image-building algorithm with defined edges and the background information it needs to operate. But interior tomography focuses only on structures inside the body, which reduces the patient’s radiation exposure. “If you’re only interested in the heart, why bother to cover your whole chest with X-rays?” says Wang.

Narrowing the view, however, eliminates the usual reference points needed to create an image conventionally. Interior tomography relies on a different set of hints. The new technique uses information about how substances within the body (such as blood) and air pockets alter X-rays to provide the algorithm with a base for reconstructing the image. It can even use old X-ray images of the same patient to help out.

Focusing on a specific region has advantages, particularly with patients too big for conventional scanners. “If an object is wider than the X-ray beam width, classic theory says you cannot do an accurate reconstruction,” says Wang. That’s not a concern with interior tomography, he says.

What’s more, Wang’s team has shown that this concept can be generalized for use in imaging methods other than CT scanning, including MRI. And that could lead to a true fusion of major medical imaging techniques. In part that’s because the technique allows the use of smaller X-ray detectors, which in turn makes it possible to fit more scanners into the same machine. 


There are already systems that combine two imaging methods—PET and CT or SPECT and CT, for instance. But those systems usually apply different methods in sequence rather than simultaneously, making it harder to see biological processes in action. The combination of CT and MRI has never been attempted before, but Wang says it’s possible now.


In fact, he and his collaborators in Australia, China, and the United States recently came up with a top-level engineering design for a CT-MRI scanner. They hope to present their design in June at the International Meeting on Fully Three-Dimensional Image Reconstruction in Radiology and Nuclear Medicine, in California. Applying interior tomography to MRI imaging allows the use of a weaker magnetic field, which is one way the design compensates for the incompatibility between powerful magnets in the MRI and rotating metal parts in the CT scanner. 


Wang’s team does not yet have the funding to build a combination CT-MRI scanner, but putting the two technologies together could prove useful. MRI gives high contrast and allows doctors to measure functional and even molecular changes; CT provides greater structural detail. Together, they might allow doctors to get a superior picture of processes in action, such as changes during a heart attack, or serve as a guide to a surgical procedure. The technology would be ideal for imaging vulnerable plaques, suggests Michael Vannier, one of Wang’s collaborators and a radiology professor at the University of Chicago. Vulnerable plaques are buildups on artery walls that are particularly unstable and prone to causing heart attack or stroke. A combination of structural, functional, and molecular information is needed to tell just how dangerous the plaque may be. “In the long run, we think putting many imaging modes together will give you more information,” Wang says.


Interior tomography “is certainly an interesting concept that takes the interest in combining modalities to the ‘ultimate’ level of a single device,” says Simon Cherry, director of the Center for Molecular and Genomic Imaging at the University of California, Davis. While omni-tomography is technically feasible, Cherry wonders whether it will make sense from a clinical and economic perspective. “There are some that say too many of our health-care dollars are spent on imaging, especially in the pursuit of defensive medicine. This will be an expensive machine,” he says. “These are the issues that may well determine whether this approach is successful.” 


Innovative neurology text includes patient videos

Practical Neurology Visual Review, a powerful educational tool for mastering the clinical practice of neurologic diagnosis, is now available in a fully revised and updated Second Editon.

Co-authors are neurologists Jose Biller, MD, of Loyola University Chicago Stritch School of Medicine and Alberto J. Espay, MD, of the University of Cincinnati.

The book previously was known as Practical Neurology DVD Review. It includes online videos of 131 real-world scenarios, and more than 370 multiple-choice questions. QR codes in the book allow easy access to videos via smart phone scanning.

Neurological problems are increasing due to the growing elderly population. But current assessment formats for the education of resident doctors, fellows and medical students underemphasize bedside teaching, Biller and Espay write in the introduction. “Faculty members strained by the pressures of many competing demands may not be in a position to oversee trainees performing physical examinations during their training.”

Practical Neurology Visual Review provides new venues for teaching and learning the essentials of neurology. The videos show patients with both common and unusual neurological problems, ranging from very easy to extremely challenging. The videos are used to teach five fundamental principles of bedside neurology: description and localization of findings, differential diagnosis, evaluation, management and counseling. Each clinical vignette is accompanied by a succinct written discussion.

"This audiovisual electronic teaching format may be somewhat unorthodox," Biller and Espay write. "However, it is actually more effective in its approach because the technology lends itself to displaying the skills necessary for a physician to form a patient’s neurological diagnosis."

Human brain research made easier by database

Researchers will be able to access samples from more than 7,000 donated human brains to help study major brain diseases, thanks to a new on-line database, launched by the Medical Research Council (MRC) today.

The UK Brain Banks Network database speeds up access to donated brain samples held across 10 brain banks in the UK and allows researchers studying Multiple Sclerosis, Alzheimer’s, Parkinson’s and a range of other neurodegenerative and developmental diseases to track down human tissue samples for their work.

Thanks to a unique collaboration between the MRC and five leading charities, the database will help scientists from academia and industry investigate the underlying causes of major brain diseases and understand how they take hold in our bodies.

Although scientists can model diseases in the lab, to fully understand dementia and other brain-related disorders they need to study human brain tissue. A lot of research relies on donated brain tissue stored in brain banks across the UK. Until today, researchers had to apply to each brain bank in turn to find out if they held the samples they needed and find the ‘control’ samples (donated brains free from disease) for comparison – a long and drawn out process. Now samples can be found with the click of a button from one source.

Professor James Ironside, Director of the MRC UK Brain Banks Network, said:

“The database is the result of four years of painstaking planning and data analysis by very dedicated people. It will enable quick and easy access for researchers who are already working on neurological or psychiatric disease (perhaps in animal models or cells) and would like to translate their findings into human tissue and is very useful for those who are planning a grant application. The brain banks have already been given ethical approval, cutting out the need for researchers to go through a separate ethics application.

We must remember that vital research would not be possible without the generosity of those individuals who donate their brains to medical research. We’re working hard to make sure that the access for researchers studying brain samples is much easier. The next step is to improve the systems for those wishing to donate their brain to medical research.”

Five leading charities helped to supply data for the database; the MS Society, Parkinson’s UK, Alzheimer’s Society, Alzheimer’s Research UK and Autistica.

For more information about the database visit: http://www.mrc.ac.uk/brainbanksnetwork

Reward linked to image is enough to activate brain’s visual cortex

Once rhesus monkeys learn to associate a picture with a reward, the reward by itself becomes enough to alter the activity in the monkeys’ visual cortex. This finding was made by neurophysiologists Wim Vanduffel and John Arsenault (KU Leuven and Harvard Medical School) and American colleagues using functional brain scans and was published recently in the leading journal Neuron.

Our visual perception is not determined solely by retinal activity. Other factors also influence the processing of visual signals in the brain. “Selective attention is one such factor,” says Professor Wim Vanduffel. “The more attention you pay to a stimulus, the better your visual perception is and the more effective your visual cortex is at processing that stimulus. Another factor is the reward value of a stimulus: when a visual signal becomes associated with a reward, it affects our processing of that visual signal. In this study, we wanted to investigate how a reward influences activity in the visual cortex.”

Pavlov inverted

To do this, the researchers used a variant of Pavlov’s well-known conditioning experiment: “Think of Pavlov giving a dog a treat after ringing a bell. The bell is the stimulus and the food is the reward. Eventually the dogs learned to associate the bell with the food and salivated at the sound of the bell alone. Essentially, Pavlov removed the reward but kept the stimulus. In this study, we removed the stimulus but kept the reward.”

In the study, the rhesus monkeys first encountered images projected on a screen followed by a juice reward (classical conditioning). Later, the monkeys received juice rewards while viewing a blank screen. fMRI brain scans taken during this experiment showed that the visual cortex of the monkeys was activated by being rewarded in the absence of any image.

Importantly, these activations were not spread throughout the whole visual system but were instead confined to the specific brain regions responsible for processing the exact stimulus used earlier during conditioning. This result shows that information about rewards is being sent to the visual cortex to indicate which stimuli have been associated with rewards.

Equally surprising, these reward-only trials were found to strengthen the cue-reward associations. This is more or less the equivalent to giving Pavlov’s dog an extra treat after a conditioning session and noticing the next day that he salivates twice as much as before. More generally, this result suggests that rewards can be associated with stimuli over longer time scales than previously thought.

Dopamine

Why does the visual cortex react selectively in the absence of a visual stimulus on the retina? One potential explanation is dopamine. “Dopamine is a signalling chemical (neurotransmitter) in nerve cells and plays an important role in processing rewards, motivation, and motor functions. Dopamine’s role in reward signalling is the reason some Parkinson’s patients fall into gambling addiction after taking dopamine-increasing drugs. Aware of dopamine’s role in reward, we re-ran our experiments after giving the monkeys a small dose of a drug that blocks dopamine signalling. We found that the activations in the visual cortex were reduced by the dopamine blocker. What’s likely happening here is that a reward signal is being sent to the visual cortex via dopamine,” says Professor Vanduffel.

The study used fMRI (functional Magnetic Resonance Imaging) scans to visualise brain activity. fMRI scans map functional activity in the brain by detecting changes in blood flow. The oxygen content and the amount of blood in a given brain area vary according to the brain activity associated with a given task. In this way, task-specific activity can be tracked.