Deep Brain Stimulation shows promise for patients with chronic, treatment resistant Anorexia Nervosa

In a world first, a team of researchers at the Krembil Neuroscience Centre and the University Health Network have shown that Deep Brain Stimulation (DBS) in patients with chronic, severe and treatment-resistant Anorexia Nervosa (anorexia) helps some patients achieve and maintain improvements in body weight, mood, and anxiety.

The results of this trial, entitled Deep Brain Stimulation of the Subcallosal Cingulate Area for Treatment-Refractory Anorexia Nervosa: A Phase I Pilot Trial, are published in the medical journal The Lancet. The study is a collaboration between lead author Dr. Nir Lipsman a neurosurgery resident at the University of Toronto and PhD student at the Krembil Neuroscience Centre; Dr. Andres Lozano, a neurosurgeon, at the Krembil Neuroscience Centre of Toronto Western Hospital and a professor and chairman of neurosurgery at the University of Toronto, whose research lab was instrumental in conducting the DBS research; and Dr. Blake Woodside, medical director of Canada’s largest eating disorders program at Toronto General Hospital and a professor of psychiatry at the University of Toronto.

The phase one safety trial investigated the procedure in six patients who would likely continue with a chronic illness and/or die a premature death because of the severity of their condition. The study’s participants had an average age of 38, and a mean duration of illness of 18 years. In addition to the anorexia, all patients, except one, also suffered from psychiatric conditions such as major depressive disorder and obsessive-compulsive disorder. At the time of the study, all patients currently, or had previously, suffered multiple medical complications related to their anorexia – altogether, the six patients had a history of close to 50 hospitalizations during their illnesses.

Study participants were treated with Deep Brain Stimulation (DBS), a neurosurgical procedure that moderates the activity of dysfunctional brain circuits. Neuroimaging has shown that there are both structural and functional differences between anorexia patients and healthy controls in brain circuits which regulate mood, anxiety, reward and body-perception.

Patients were awake when they underwent the procedure which implanted electrodes into a specific part of the brain involved with emotion, and found to be highly important in disorders such as depression. During the procedure, each electrode contact was stimulated to look for patient response of changes in mood, anxiety or adverse effects. Once implanted, the electrodes were connected to an implanted pulse generator below the right clavicle, much like a heart pacemaker.

Testing of patients was repeated at one, three, and six-month intervals after activation of the pulse generator device. After a nine-month period following surgery, the team observed that three of the six patients had achieved weight gain which was defined as a body-mass index (BMI) significantly greater than ever experienced by the patients. For these patients, this was the longest period of sustained weight gain since the onset of their illness. Furthermore, four of the six patients also experienced simultaneous changes in mood, anxiety, control over emotional responses, urges to binge and purge and other symptoms related to anorexia, such as obsessions and compulsions. As a result of these changes, two of these patients completed an inpatient eating disorders program for the first time in the course of their illness.

“We are truly ushering in a new of era of understanding of the brain and the role it can play in certain neurological disorders,” says Dr. Lozano. “By pinpointing and correcting the precise circuits in the brain associated with the symptoms of some of these conditions, we are finding additional options to treat these illnesses.”

While the treatment is still considered experimental, it is believed to work by stimulating a specific area of the brain to reverse abnormalities linked to mood, anxiety, emotional control, obsessions and compulsions all of which are common in anorexia. In some cases after surgery, patients are then able to complete previously unsuccessful treatments for the disease. The research may not only provide an additional therapy option for these patients in the future, but also furthers practitioners’ understanding of anorexia and the factors that cause it to be persistent.

“There is an urgent need for additional therapies to help those suffering from severe anorexia,” says Dr. Woodside. “Eating disorders have the highest death rate of any mental illness and more and more women are dying from anorexia. Any treatment that could potentially change the natural course of this illness is not just offering hope but saving the lives for those that suffer from the extreme form of this condition.”

A leading international expert in the field of DBS research, Dr. Lozano has been exploring the potential of DBS to treat a variety of conditions. Most recently, his team began the first ever DBS trial of patients with early Alzheimer’s disease, and showed that stimulation may help improve memory. This trial has now entered its second phase and expanded to medical centres in the United States.

Stanford psychologists uncover brain-imaging inaccuracies

Pictures of brain regions “activating” are by now a familiar accompaniment to any neurological news story. With functional magnetic resonance imaging, or fMRI, you can see specific brain regions light up, standing out against the background like night owls’ apartment windows.

It’s easy to forget that these brain images aren’t real snapshots of brain activity. Instead, each picture is the result of many layers of analysis and interpretation, far removed from raw data.

"It’s just one representation of brain activity," said Matthew Sacchet, a PhD student in the Neurosciences Program at the Stanford School of Medicine. "As you process the data, it can change."

Sacchet works in the lab of Stanford psychology Associate Professor Brian Knutson, who studies reward processing in a small area of the brain known as the nucleus accumbens. Precisely how that structure activates is at the heart of an ongoing debate about reward circuits – a subject that holds relevance for our understanding of everything from addiction to financial risk-taking.

Unfortunately, according to a paper from Knutson and Sacchet, hundreds of research papers on this circuit may be unintentionally biased. When the labs processed their fMRI findings, many used a one-size-fits-all strategy that skewed which regions of the brain appeared to be activating.

"I honestly think most people want good data," said Knutson. "I’m excited that we can make this kind of research more rigorous."

The paper appeared in the journal NeuroImage.

Too much smoothing

Functional magnetic resonance imaging measures changes in blood flow in the brain. It’s a powerful tool, but the signal fMRI actually detects – the result of the magnetic differences between oxygenated and deoxygenated blood – is noisy.

Researchers need to statistically process the data in order to make the resulting data interpretable. One of the most common approaches is known as “spatial smoothing,” which involves averaging the activity of each brain region with that of its neighbors.

But fMRI has only been in use since the mid-1990s. Many of the most common analyses in use today are holdovers from older, lower-resolution types of imaging and seem to have some undesired effects on the finer-grained signals fMRI can provide.

Knutson and Sacchet found that when researchers process fMRI data with a traditional “smoothing kernel” of 8mm, they end up averaging their images over too large an area. Activity in smaller brain structures can then be overlooked, or even shifted to areas that receive more blood flow and where the blood oxygenation level-dependent signal is stronger.

"It might seem strange that a systematic bias like that could bias the whole field," Knutson said. "But if half the people use 8mm and half use 4mm, you might end up with very different results, and it could add up."

Reward structure

These statistical pitfalls are particularly glaring when studying the small, structurally complex nucleus accumbens.

Findings from the Knutson Lab, which has been using the smaller, 4mm smoothing kernel for years, suggest that different parts of the nucleus accumbens have different functions. The forward portion seems to distinguish between positive or negative stimuli, reacting specifically to rewards. Meanwhile, the rear section responds more to the intensity of the motivation.

While some other labs have corroborated this finding, others only found activation in the rear half of the structure.

These contradictory findings now appear to have been skewed. Because the back of the nucleus accumbens is larger and surrounded by more blood-infused gray matter than the front, the smoothing step made it appear as if all the nucleus accumbens’ activity originated far to the rear.

A collaborator in Germany already has taken the paper’s advice, Sacchet said. “She had a colleague reanalyze her data and found the same thing we found.”

Knutson emphasized that the research paper doesn’t mean “the methods are bunk.” Simply improving the way scientists process signals can enhance their ability to locate specific brain functions.

"There may be a debate, but you can resolve that debate with data," he said.

Some brain cells are better virus fighters

Viruses often spread through the brain in patchwork patterns, infecting some cells but missing others. New research at Washington University School of Medicine in St. Louis helps explain why. The scientists showed that natural immune defenses that resist viral infection are turned on in some brain cells but switched off in others.

“The cells that a pathogen infects can be a major determinant of the seriousness of brain infections,” says senior author Michael Diamond, MD, PhD, professor of medicine. “To understand the basis of disease, it is important to understand which brain regions are more susceptible and why.”

While some brain infections are caused by bacteria, fungi or parasites, often the cause is a virus, such as West Nile virus, herpesvirus or enteroviruses.

For their study, now available online in Nature Medicine, the researchers focused on granule cell neurons, a cell type that rarely becomes infected. They compared gene profiles in granule cells from the cerebellum with the activity in cortical neurons in the cerebral cortex, which are more vulnerable to infection.

The comparison revealed many differences, including a number of genes in cortical neurons that were less well-expressed—meaning that for those specific genes there were fewer copies of mRNA, the molecules that relay genetic information from DNA to the cell’s protein-making mechanisms.

Next, the researchers transferred individually 40 of those genes into cortical neurons and screened the cells for susceptibility to viral infection. The test highlighted three antiviral genes that are induced by interferon, an important immune system protein. When the expression level of these genes increased in cortical neurons, the cells’ susceptibility to viral infection decreased.

The researchers also identified mechanisms that make some of these changes in genetic programming happen: regulatory factors known as microRNA, and differences in the way DNA is modified in the cell nucleus, both of which can affect gene expression levels.

Some of the genetic changes are only helpful against specific viral families, while others are effective against a broader spectrum of viruses and bacteria. The scientists can’t say yet if the differences in infection susceptibility are driven by the need to prevent infection or if they are a byproduct of changes that help neurons in particular brain regions perform essential functions.

To learn more about how these innate immune genes help cells resist infection, Diamond and his colleagues are disabling them in the brains of mice.

Is this peptide a key to happiness?

What makes us happy? Family? Money? Love? How about a peptide?

The neurochemical changes underlying human emotions and social behavior are largely unknown. Now though, for the first time in humans, scientists at UCLA have measured the release of a specific peptide, a neurotransmitter called hypocretin, that greatly increased when subjects were happy but decreased when they were sad.

The finding suggests that boosting hypocretin could elevate both mood and alertness in humans, thus laying the foundation for possible future treatments of psychiatric disorders like depression by targeting measureable abnormalities in brain chemistry.

In addition, the study measured for the first time the release of another peptide, this one called melanin concentrating hormone, or MCH. Researchers found that its release was minimal in waking but greatly increased during sleep, suggesting a key role for this peptide in making humans sleepy.

The study is published in the March 5 online edition of the journal Nature Communications.

"The current findings explain the sleepiness of narcolepsy, as well as the depression that frequently accompanies this disorder," said senior author Jerome Siegel, a professor of psychiatry and director of the Center for Sleep Research at UCLA’s Semel Institute for Neuroscience and Human Behavior. "The findings also suggest that hypocretin deficiency may underlie depression from other causes."

(Image: ALAMY)

Bees get a buzz from caffeine

You may need a cup of coffee to kick start the day but it seems honeybees also get their buzz from drinking flower nectar containing caffeine.

Publishing in Science, researchers have shown that caffeine improves a honeybee’s memory and could help the plant recruit more bees to spread its pollen.

In tests honeybees feeding on a sugar solution containing caffeine, which occurs naturally in the nectar of coffee and citrus flowers, were three times more likely to remember a flower’s scent than those feeding on just sugar.

Study leader Dr Geraldine Wright, Reader in Neuroethology at Newcastle University, explained that the effect of caffeine benefits both the honeybee and the plant: “Remembering floral traits is difficult for bees to perform at a fast pace as they fly from flower to flower and we have found that caffeine helps the bee remember where the flowers are.

“In turn, bees that have fed on caffeine-laced nectar are laden with coffee pollen and these bees search for other coffee plants to find more nectar, leading to better pollination.

“So, caffeine in nectar is likely to improve the bee’s foraging prowess while providing the plant with a more faithful pollinator.”

In the study, researchers found that the nectar of Citrus and Coffea species often contained low doses of caffeine. They included ‘robusta’ coffee species mainly used to produce freeze-dried coffee and ‘arabica’ used for espresso and filter coffee. Grapefruit, lemons, pomelo and oranges were also sampled and all contained caffeine.

Co-author Professor Phil Stevenson from the Royal Botanic Gardens, Kew and the University of Greenwich’s Natural Resources Institute said: “Caffeine is a defence chemical in plants and tastes bitter to many insects including bees so we were surprised to find it in the nectar.  However, it occurs at a dose that’s too low for the bees to taste but high enough to affect bee behaviour.”

The effect of caffeine on the bees’ long-term memory was profound with three times as many bees remembering the floral scent 24 hours later and twice as many bees remembering the scent after three days.

Typically, the nectar in the flower of a coffee plant contains almost as much caffeine as a cup of instant coffee. Just as black coffee has a strong bitter taste to us, high concentrations of caffeine are repellent to honeybees.

Dr Wright added: “This work helps us understand the basic mechanisms of how caffeine affects our brains. What we see in bees could explain why people prefer to drink coffee when studying.”

Dr Julie Mustard, a contributor to the study from Arizona State University, explains further: “Although human and honeybee brains obviously have lots of differences, when you look at the level of cells, proteins and genes, human and bee brains function very similarly. Thus, we can use the honeybee to investigate how caffeine affects our own brains and behaviours.”

This project was funded in part by the Insect Pollinators Initiative which supports projects aimed at researching the causes and consequences of threats to insect pollinators and to inform the development of appropriate mitigation strategies.

Population declines among bees have serious consequences for natural ecosystems and agriculture since bees are essential pollinators for many crops and wild flowering species. If declines are allowed to continue there is a risk to our natural biodiversity and on some crop production.

Professor Stevenson said: “Understanding how bees choose to forage and return to some flowers over others will help inform how landscapes could be better managed. Understanding a honeybee’s habits and preferences could help find ways to reinvigorate the species to protect our farming industry and countryside.”

Even mild traumatic brain injuries can kill brain tissue

Scientists have watched a mild traumatic brain injury play out in the living brain, prompting swelling that reduces blood flow and connections between neurons to die.

“Even with a mild trauma, we found we still have these ischemic blood vessels and, if blood flow is not returned to normal, synapses start to die,” said Dr. Sergei Kirov, neuroscientist and Director of the Human Brain Lab at the Medical College of Georgia at Georgia Regents University.

They also found that subsequent waves of depolarization – when brain cells lose their normal positive and negative charge – quickly and dramatically increase the losses.

Researchers hope the increased understanding of this secondary damage in the hours following an injury will point toward better therapy for the 1.7 million Americans annually experiencing traumatic brain injuries from falls, automobile accidents, sports, combat and the like.  While strategies can minimize impact, no true neuroprotective drugs exist, likely because of inadequate understanding about how damage unfolds after the immediate impact.

Kirov is corresponding author of a study in the journal Brain describing the use of two-photon laser scanning microscopy to provide real-time viewing of submicroscopic neurons, their branches and more at the time of impact and in the following hours.

Scientists watched as astrocytes – smaller cells that supply neurons with nutrients and help maintain normal electrical activity and blood flow – in the vicinity of the injury swelled quickly and significantly. Each neuron is surrounded by several astrocytes that ballooned up about 25 percent, smothering the neurons and connective branches they once supported.

“We saw every branch, every small wire and how it gets cut,” Kirov said. “We saw how it destroys networks. It really goes downhill. It’s the first time we know of that someone has watched this type of minor injury play out over the course of 24 hours.”

Stressed neurons ran out of energy and became silent but could still survive for hours, potentially giving physicians time to intervene, unless depolarization follows. Without sufficient oxygen and energy, internal pumps that ensure proper polarity by removing sodium and pulling potassium into neurons, can stop working and dramatically accelerate brain-cell death.

“Like the plus and minus ends of a battery, neurons must have a negative charge inside and a positive charge outside to fire,” Kirov said. Firing enables communication, including the release of chemical messengers called neurotransmitters.

“If you have six hours to save tissue when you have just lost part of your blood flow, with this spreading depolarization, you lose tissue within minutes,” he said.

While common in head trauma, spreading depolarization would not typically occur in less-traumatic injuries, like his model. His model was chemically induced to reveal more about how this collateral damage occurs and whether neurons could still be saved. Interestingly, researchers found that without the initial injury, brain cells completely recovered after re-polarization but only partially recovered in the injury model.

While very brief episodes of depolarization occur as part of the healthy firing of neurons, spreading depolarization exacerbates the initial traumatic brain injury in more than half of patients and results in poor prognosis, previous research has shown. However, a 2011 review in the journal Nature Medicine indicated that short-lived waves can actually protect surrounding brain tissue. Kirov and his colleagues wrote that more study is needed to determine when to intervene.

One of Kirov’s many next steps is exploring the controversy about whether astrocytes’ swelling in response to physical trauma is a protective response or puts the cells in destruct mode. He also wants to explore better ways to protect the brain from the growing damage that can follow even a slight head injury.

Currently, drugs such as diuretics and anti-seizure medication may be used to help reduce secondary damage of traumatic brain injury. Astrocytes can survive without neurons but the opposite is not true, Kirov said. The ratio of astrocytes to neurons is higher in humans and human astrocytes are more complex, Kirov said.

New Form of Animal Communication Discovered

Sniffing, a common behavior in dogs, cats and other animals, has been observed to also serve as a method for rats to communicate—a fundamental discovery that may help scientists identify brain regions critical for interpreting communications cues and what brain malfunctions may cause some complex social disorders.

Researchers have long observed how animals vigorously sniff when they interact, a habit usually passed off as simply smelling each other. But Daniel W. Wesson, PhD, of Case Western Reserve University School of Medicine, whose research is published in Current Biology, found that rats sniff each other to signal a social hierarchy and prevent aggressive behavior.

Wesson, who drew upon previous work showing that, similar to humans, rodents naturally form complex social hierarchies, used wireless methods to record and observe rats as they interacted. He found that, when two rats approach each other, one communicates dominance by sniffing more frequently, while the subordinate signals its role by sniffing less. Wesson found that if the subordinate didn’t do so, the dominant rat was more likely to become aggressive to the other.

Wesson theorized the dominant rat was displaying a “conflict avoidance signal,” similar to a large monkey walking into a room and banging its chest. In response, the subordinate animal might cower and look away, or in the case of the rats, decrease its sniffing.

“These novel and exciting findings show that how one animal sniffs another greatly matters within their social network,” said Wesson, an associate professor of neurosciences. “This sniffing behavior might reflect a common mechanism of communication behavior across many types of animals and in a variety of social contexts. It is highly likely that our pets use similar communication strategies in front of our eyes each day, but because we do not use this ourselves, it isn’t recognizable as ‘communication’.”

Wesson’s findings represent the first new form of communication behavior in rats since it was discovered in the 1970s that they communicate through vocal ultrasonic frequencies. The research provides a basis for understanding how neurological disorders might impact the brain’s ability to conduct normal, appropriate social behaviors. 

Wesson’s laboratory will use these findings to better understand how certain behaviors go awry. Ultimately, the hope is to learn whether this new form of communication can help explain how the brain controls complex social behaviors and how these neural centers might inappropriately deal with social cues.