Device lets docs stay ‘tuned in’ to brain bloodflow

For Dr. John Murkin, the medical device business is all about “making a better mouse trap.”

The Schulich School of Medicine & Dentistry professor is part of a team of Western and Lawson Health Research Institute (LHRI) researchers studying a new technology that may change the way patients undergoing cardiac surgery are monitored and managed in the hospital.

The device, known as CerOx, non-invasively monitors cerebral blood flow and helps physicians and nurses assess brain perfusion in real time. Murkin, who has been involved in the machine’s development, said this information could be used to support critical treatment decisions made to protect the patient from potential complications.

“We use near-infrared light routinely in all hospitals to measure oxygen saturation in the brain. That’s been out for 30 years,” Murkin said. “This new device is not just measuring oxygen saturation; it’s also measuring blood flow to the brain, in real time, and non-invasively.

“If a patient has a brain injury, the more you know about the brain, the better you are at being tuned into their needs.”

In cardiac surgery, cerebral monitoring significantly reduces complications, including permanent stroke.

An anesthetist at London Health Sciences Centre and a researcher at LHRI, Murkin has studied cognitive and neurological outcomes in cardiac surgery for more than three decades. He said there has been an unmet clinical need for a noninvasive tool that provides accurate, real-time measurements of cerebral blood flow in these highly vulnerable patients.

Currently, 11 different studies have evaluated CerOx in different applications.

“We’ve seen the potential of the machine and we’re convinced it works,” he added. “If you don’t know what’s going on in the brain, you can’t help. But, when you start to monitor this, and you see changes in blood flow, in oxygen saturation and its because of the blood pressure or hemoglobin, or whatever it is, if you pick things up early enough, you can hopefully avoid any possible complications.

“If you can monitor in real time, you can act in real time.”

The device is expected to be used primarly by physicians in neuro-critical care areas.

“While the device can alert you to potential problems, the next part is what are you going to do about it? You still need to act,” he said. “We want to start looking at what are some of the therapeutic interventions we can use to improve outcomes.”

CerOx was developed by U.S.- and Israel-based Ornim Medical, of which Murkin is a member of their scientific advisory board.

Turmeric compound boosts regeneration of brain stem cells

A bioactive compound found in turmeric promotes stem cell proliferation and differentiation in the brain, reveals new research published today in the open access journal Stem Cell Research & Therapy. The findings suggest aromatic turmerone could be a future drug candidate for treating neurological disorders, such as stroke and Alzheimer’s disease.

The study looked at the effects of aromatic (ar-) turmerone on endogenous neutral stem cells (NSC), which are stem cells found within adult brains. NSC differentiate into neurons, and play an important role in self-repair and recovery of brain function in neurodegenerative diseases. Previous studies of ar-turmerone have shown that the compound can block activation of microglia cells. When activated, these cells cause neuroinflammation, which is associated with different neurological disorders. However, ar-turmerone’s impact on the brain’s capacity to self-repair was unknown.

Researchers from the Institute of Neuroscience and Medicine in Jülich, Germany, studied the effects of ar-turmerone on NSC proliferation and differentiation both in vitro and in vivo. Rat fetal NSC were cultured and grown in six different concentrations of ar-turmerone over a 72 hour period. At certain concentrations, ar-turmerone was shown to increase NSC proliferation by up to 80%, without having any impact on cell death. The cell differentiation process also accelerated in ar-turmerone-treated cells compared to untreated control cells.

To test the effects of ar-turmerone on NSC in vivo, the researchers injected adult rats with ar-turmerone. Using PET imaging and a tracer to detect proliferating cells, they found that the subventricular zone (SVZ) was wider, and the hippocampus expanded, in the brains of rats injected with ar-turmerone than in control animals. The SVZ and hippocampus are the two sites in adult mammalian brains where neurogenesis, the growth of neurons, is known to occur.

Lead author of the study, Adele Rueger, said: “While several substances have been described to promote stem cell proliferation in the brain, fewer drugs additionally promote the differentiation of stem cells into neurons, which constitutes a major goal in regenerative medicine. Our findings on aromatic turmerone take us one step closer to achieving this goal.”

Ar-turmerone is the lesser-studied of two major bioactive compounds found in turmeric. The other compound is curcumin, which is well known for its anti-inflammatory and neuroprotective properties.

Protein pairing builds brain networks

Neural networks are formed by the interconnection of specific neurons in the brain. The molecular mechanisms involved in creating these connections, however, have so far eluded scientists. Research led by Jun Aruga from the RIKEN Brain Science Institute has now identified an interaction between two proteins that is crucial for making connections between specific types of neurons, with implications for some neurological disorders.

Connections between neurons are made via synapses—small gaps across which chemicals called neurotransmitters pass, relaying signals from a presynaptic neuron to a postsynaptic neuron. Aruga and his colleagues focused on a protein called mGluR7, which is found only at synapses with a specific type of postsynaptic neuron in an area of the brain involved in forming memories.

“mGluR7 is located on the presynaptic side of connections made with hippocampal local inhibitory neurons,” explains Aruga. “Previous studies have proposed that this protein prevents neurotransmitter release from the presynaptic neuron when the neurotransmitter glutamate binds to it.”

The researchers discovered that the localization of mGluR7 to specific synapses is determined by the presence of another protein called Elfn1. This protein is found on the other side of the same synapses, directly opposite mGluR7. When the researchers artificially introduced Elfn1 into cultured cells, mGluR7 became associated with the same cells, and they showed that this was due to a physical interaction between the two proteins. Conversely, deleting Elfn1 in the brains of mice reduced the amount of mGluR7 at the synapses.

These changes interfered with the process of strengthening connections at synapses, which takes place during memory formation, and caused patterns of brain waves that indicated abnormally high levels of electrical activity. Genetically altered mice also exhibited other symptoms that resembled human conditions.

“Deleting Elfn1 increased the susceptibility of mice to seizures,” explains Aruga. “It also enhanced behaviors similar to attention deficit hyperactivity disorder (ADHD).”

Indeed, the researchers found that humans with epilepsy and ADHD also had a faulty version of the gene encoding Elfn1, suggesting that a deficit in the ability of Elfn1 to localize mGluR7 and form specific connections in neural networks is important in some neurological conditions.

“In combination, the human and mouse results implicate the Elfn1–mGluR7 complex in the pathophysiology of epilepsy and ADHD, at least in part,” explains Aruga, although he remains cautious at this early stage of research. “Because of sample size limitations, the human genetics result is not conclusive, but we are now awaiting the results of follow-up studies with additional subjects.”

(Image caption: In the two brain regions IPF (lateral prefrontal cortex) and V4, a region of the visual system, the brain activity oscillates in a specific frequency range. Credit: © Stefanie Liebe, MPI for biological Cybernetics)

Synchronous oscillations in the short-term memory

School children and university students are often big fans of the short-term memory – not least when they have to cram large volumes of information on the eve of an exam. Although its duration is brief, short term memory is a complex network of neurons in the brain that includes different brain regions. To store the information, these regions must work together. Researchers from the Max Planck Institute for Biological Cybernetics in Tübingen have now discovered that the participating regions must be active at the same time to enable us to form short-term memories of things that happen.

When we see something, signals from the eyes are processed in areas of the cerebral cortex located at the back of the head. For short-term memory, in contrast, regions in the front part of the cerebral cortex must be active. In order for us to remember something we have seen briefly, these far-apart regions of the brain must collate their information.

How this works can only be examined in apes. Scientists from Nikos Logothetis’s Department at the Max Planck Institute for Biological Cybernetics in Tübingen measured the electrical activity in an optic region and in the front area of the brain while the animals had to remember different images.

In the process, the scientists observed electrical vibrations, known as theta-band oscillations, in the two regions of brain. Surprisingly, these oscillations did not arise independently, but were synchronous. The more synchronously active the regions, the better the animals were able to remember an image.

Accordingly, the functioning of short-term memory can be envisaged as two revolving doors: While the memory is at work, the two doors move in time with each other and, in this way, facilitate the more effective exchange of information.

The study shows how important synchronised brain oscillations are for the communication between the different regions of the brain. Almost all higher intellectual capacities result from the complex interplay of specialised neuronal networks in different parts of the brain.

Neurons See What We Tell Them to See

Neurons programmed to fire at specific faces—such as the famously reported “Jennifer Aniston neuron”—may be more in line with the conscious recognition of faces than the actual images seen. Subjects presented with a blended face, such as an amalgamation of Bill Clinton and George W. Bush, had significantly more firing of such face-specific neurons when they recognized the blended or morphed face as one person or the other. Results of the study led by Christof Koch at the Allen Institute for Brain Science, and carried out by neuroscientists Rodrigo Quian Quiroga at the University of Leicester, Alexander Kraskov at University College London and Florian Mormann at the University of Bonn, under the clinical supervision of the neurosurgeon Itzhak Fried at the University of California at Los Angeles Medical School, are published online today in the journal Neuron.

Some neurons in the region of the brain known as the medial temporal lobe are observed to be extremely selective in the stimuli to which they respond. A cell may only fire in response to different pictures of a particular person who is very familiar to the subject (such as loved one or a celebrity), the person’s written or spoken name, or simply recalling the person from memory.

“These highly specific cells are an entry point to investigate how the brain makes meaning out of visual information,” explains Christof Koch, Chief Scientific Officer at the Allen Institute for Brain Science and senior author on the paper. “We wanted to know how these cells responded not just to a simple image of a person’s face, but to a more ambiguous image of that face averaged or morphed with another person’s face.”

For the trials, subjects were shown either the face of individuals such as Bill Clinton or George W. Bush (the “adaptor” image), and then an ambiguous face which was a blend of both faces. Primed with the Clinton image, subjects tended to recognize Bush’s face in the blended image, while subjects who saw Bush’s face first recognized the blended face as Clinton. That is, even though the blended images were identical, subjects tended to consciously perceive the identity of face to which they were not adapted.

Researchers wanted to know whether these selective neurons responded to the actual image on the screen, or whether they responded more to the perception that the image caused in the brain of the subject. When subjects recognized the ambiguous face as belonging to Clinton, their Clinton-specific neurons fired. However, when subjects recognized that same face as Bush, the neurons fired significantly less. These results indicated that conscious recognition of the face played a crucial role in whether the neurons fired, rather than the raw visual stimulus.

“This study provides further evidence that stimulus-specific neurons in the medial temporal lobe follow the subjective perception of the person, as opposed to faithfully reporting the visual stimulus the person sees,” explains Koch. “This distinction may help us glean insight into how the brain takes raw visual information and transforms it into something meaningful, which can be further modulated by other aspects of experience in the brain.”

How physical exercise protects the brain from stress-induced depression

Physical exercise has many beneficial effects on human health, including the protection from stress-induced depression. However, until now the mechanisms that mediate this protective effect have been unknown. In a new study in mice, researchers at Karolinska Institutet in Sweden show that exercise training induces changes in skeletal muscle that can purge the blood of a substance that accumulates during stress, and is harmful to the brain. The study is being published in the prestigious journal Cell.

“In neurobiological terms, we actually still don’t know what depression is. Our study represents another piece in the puzzle, since we provide an explanation for the protective biochemical changes induced by physical exercise that prevent the brain from being damaged during stress,” says Mia Lindskog, researcher at the Department of Neuroscience at Karolinska Institutet.

It was known that the protein PGC-1a1 (pronounced PGC-1alpha1) increases in skeletal muscle with exercise, and mediates the beneficial muscle conditioning in connection with physical activity. In this study researchers used a genetically modified mouse with high levels of PGC-1a1 in skeletal muscle that shows many characteristics of well-trained muscles (even without exercising).

These mice, and normal control mice, were exposed to a stressful environment, such as loud noises, flashing lights and reversed circadian rhythm at irregular intervals. After five weeks of mild stress, normal mice had developed depressive behaviour, whereas the genetically modified mice (with well-trained muscle characteristics) had no depressive symptoms.

“Our initial research hypothesis was that trained muscle would produce a substance with beneficial effects on the brain. We actually found the opposite: well-trained muscle produces an enzyme that purges the body of harmful substances. So in this context the muscle’s function is reminiscent of that of the kidney or the liver,” says Jorge Ruas, principal investigator at the Department of Physiology and Pharmacology, Karolinska Institutet.

The researchers discovered that mice with higher levels of PGC-1a1 in muscle also had higher levels of enzymes called KAT. KATs convert a substance formed during stress (kynurenine) into kynurenic acid, a substance that is not able to pass from the blood to the brain. The exact function of kynurenine is not known, but high levels of kynurenine can be measured in patients with mental illness. In this study, the researchers demonstrated that when normal mice were given kynurenine, they displayed depressive behaviour, while mice with increased levels of PGC-1a1 in muscle were not affected. In fact, these animals never show elevated kynurenine levels in their blood since the KAT enzymes in their well-trained muscles quickly convert it to kynurenic acid, resulting in a protective mechanism.

“It’s possible that this work opens up a new pharmacological principle in the treatment of depression, where attempts could be made to influence skeletal muscle function instead of targeting the brain directly. Skeletal muscle appears to have a detoxification effect that, when activated, can protect the brain from insults and related mental illness,” says Jorge Ruas.

Depression is a common psychiatric disorder worldwide. The World Health Organization (WHO) estimates that more than 350 million people are affected.

Strategic or Random? How the Brain Chooses

Many of the choices we make are informed by experiences we’ve had in the past. But occasionally we’re better off abandoning those lessons and exploring a new situation unfettered by past experiences. Scientists at the Howard Hughes Medical Institute’s Janelia Research Campus have shown that the brain can temporarily disconnect information about past experience from decision-making circuits, thereby triggering random behavior.

In the study, rats playing a game for a food reward usually acted strategically, but switched to random behavior when they confronted a particularly unpredictable and hard-to-beat competitor. The animals sometimes got stuck in a random-behavior mode, but the researchers, led by Janelia lab head Alla Karpova and postdoctoral fellow Gowan Tervo, found that they could restore normal behavior by manipulating activity in a specific region of the brain. Because the behavior of animals stuck in this random mode bears some resemblance to that of patients affected by a psychological condition called learned helplessness, the findings may help explain that condition and suggest strategies for treating it. Karpova, Tervo and their colleagues published their findings in the September 25, 2012, issue of the journal Cell.

The brain excels at integrating information from past experiences to guide decision-making in new situations. But in certain circumstances, random behavior may be preferable. An animal might have the best chance of avoiding a predator if it moves unpredictably, for example. And in a new environment, unrestricted exploration might make more sense than relying on an internal model developed elsewhere. So scientists have long speculated that the brain may have a way to switch off the influence of past experiences so that behavior can proceed randomly, Karpova says. But others disagreed. “They argue that it’s inefficient, and that it would be at odds with what some people call one of the most central operating principles of the brain – to use our past experience and knowledge to optimize behavioral choices,” she notes.

Karpova and her colleagues wanted to see if they could create a situation that would force animals to switch into this random mode of behavior. “We tried to create a setting that would push the need to create behavioral variability and unpredictability to its extreme,” she says. They did this by placing rats in a competitive setting in which a computer-simulated competitor determined which of two holes in a wall would provide a sugary reward. The virtual competitor, whose sophistication was varied by the experimenters, analyzed the rats’ behavior to predict their future choices.

“We thought if we came up with very sophisticated competitors, then the animals would eventually be unable to figure out how to outcompete them, and be forced to either give up or switch into this [random] mode, if such a mode exists,” Karpova says. And that’s exactly what happened: When faced with a weak competitor, the animals made strategic choices based on the outcomes of previous trials. But when a sophisticated competitor made strong predictions, the rats ignored past experience and made random selections in search of a reward.

Now that they had evidence that the brain could generate both strategic and random behavior, Karpova and her colleagues wanted to know how it switched between modes. Since that switch determines whether or not an animal’s internal model of the world influences its behavior, the scientists suspected it might involve a brain region called the anterior cingulate cortex, where that internal model is likely encoded.

They found that they could cause animals to switch between random and strategic behavior by manipulating the level of a stress hormone called norepinephrine in the anterior cingulate cortex. Increasing norepinephrine in the region activated random behavior and suppressed the strategic mode.  Inhibiting release of the hormone had the opposite effect.

Karpova’s team observed that animals in their experiments sometimes continued to behave randomly, even when such behavior was no longer advantageous. “If all they’ve experienced is this really sophisticated competitor for several sessions that thwarts their attempts at strategic, model-based counter-prediction, they go into this [random mode], and they can get stuck in it for quite some time after that competitor is gone,” she says. This, she says, resembles the condition of learned helplessness, in which strategic decision-making is impaired following an experience in which a person finds they are unable to control their environment.

The scientists could release the animals from this “stuck” state by suppressing the release of norepinephrine in the anterior cingulate cortex. “Just by manipulating a single neuromodulatory input into one brain area, you can dramatically enhance the strategic mode. The effect is strong enough to rescue animals out of the random mode and successfully transform them into strategic decision makers,” Karpova says. “We think this might shed light on what has gone wrong in conditions such as learned helplessness, and possibly how we can help alleviate them.” 

Karpova says that now that her team has uncovered a mechanism that switches the brain between random and strategic behavior, she would like to understand how those behaviors are controlled in more natural settings. “We normally try to use all of our knowledge to think strategically, but sometimes we still need to explore,” she says. In most cases, that probably means brief bouts of random behavior during times when we are uncertain that past experience is relevant, followed by a return to more strategic behavior – a more subtle balance that Karpova intends to investigate at the level of changes in activity in individual neural circuits.