Remarkable Success In Patients With Major Depression

For the first time, physicians from the Bonn University Hospital have stimulated patients’ medial forebrain bundles.

Researchers from the Bonn University Hospital implanted pacemaker electrodes into the medial forebrain bundle in the brains of patients suffering from major depression with amazing results: In six out of seven patients, symptoms improved both considerably and rapidly. The method of Deep Brain Stimulation had already been tested on various structures within the brain, but with clearly lesser effect. The results of this new study have now been published in the renowned international journal “Biological Psychiatry.”

After months of deep sadness, a first smile appears on a patient’s face. For many years, she had suffered from major depression and tried to end her life several times. She had spent the past years mostly in a passive state on her couch; even watching TV was too much effort for her. Now this young woman has found her joie de vivre again, enjoys laughing and traveling. She and an additional six patients with treatment resistant depression participated in a study involving a novel method for addressing major depression at the Bonn University Hospital.

Considerable amelioration of depression within days

Prof. Dr. Volker Arnd Coenen, neurosurgeon at the Department of Neurosurgery (Klinik und Poliklinik für Neurochirurgie), implanted electrodes into the medial forebrain bundles in the brains of subjects suffering from major depression with the electrodes being connected to a brain pacemaker. The nerve cells were then stimulated by means of a weak electrical current, a method called Deep Brain Stimulation. In a matter of days, in six out of seven patients, symptoms such as anxiety, despondence, listlessness and joylessness had improved considerably. “Such sensational success both in terms of the strength of the effects, as well as the speed of the response has so far not been achieved with any other method,” says Prof. Dr. Thomas E. Schläpfer from the Bonn University Hospital Department of Psychiatry und Psychotherapy (Bonner Uniklinik für Psychiatrie und Psychotherapie).

Central part of the reward circuit

The medial forebrain bundle is a bundle of nerve fibers running from the deep-seated limbic system to the prefrontal cortex. In a certain place, the bundle is particularly narrow because the individual nerve fibers lie close together. “This is exactly the location in which we can have maximum effect using a minimum of current,” explains Prof. Coenen, who is now the new head of the Freiburg University Hospital’s Department of Stereotactic and Functional Neurosurgery (Abteilung Stereotaktische und Funktionelle Neurochirurgie am Universitätsklinikum Freiburg). The medial forebrain bundle is a central part of a euphoria circuit belonging to the brain’s reward system. What kind of effect stimulation exactly has on nerve cells is not yet known. But it obviously changes metabolic activity in the different brain centers.

Success clearly increased over that of earlier studies

The researchers have already shown in several studies that deep brain stimulation shows an amazing and–given the severity of the symptoms– unexpected degree of amelioration of symptoms in major depression. In those studies, however, the physicians had not implanted the electrodes into the medial forebrain bundle but instead into the nucleus accumbens, another part of the brain’s reward system. This had resulted in clear and sustainable improvements in about 50 percent of subjects. “But in this new study, our results were even much better,” says Prof. Schläpfer. A clear improvement in complaints was found in 85 percent of patients, instead of the earlier 50 percent. In addition, stimulation was performed with lower current levels, and the effects showed within a few days, instead of after weeks.

Method’s long-term success proven

“Obviously, we have now come closer to a critical structure within the brain that is responsible for major depression,” says the psychiatrist from the Bonn University Hospital. Another cause for optimism among the group of physicians is that, since the study’s completion, an eighth patient has also been treated successfully. The patients have been observed for a period of up to 18 month after the intervention. Prof. Schläpfer reports, “The anti-depressive effect of deep brain stimulation within the medial forebrain bundle has not decreased during this period.” This clearly indicates that the effects are not temporary. This method gives those who suffer from major depression reason to hope. However, it will take quite a bit of time for the new procedure to become part of standard therapy.

Producing new neurones under all circumstances: a challenge that is just a mouse away …

Improving neurone production in elderly persons presenting with a decline in cognition is a major challenge facing an ageing society and the emergence of neuro-degenerative conditions such as Alzheimer’s disease. INSERM and CEA researchers recently showed that the pharmacological blocking of the TGFβ molecule improves the production of new neurones in the mouse model. These results incentivise the development of targeted therapies enabling improved neurone production to alleviate cognitive decline in the elderly and reduce the cerebral lesions caused by radiotherapy.

The research is published in the journal EMBO Molecular Medicine.

New neurones are formed regularly in the adult brain in order to guarantee that all our cognitive capacities are maintained. This neurogenesis may be adversely affected in various situations and especially:

- in the course of ageing,
- after radiotherapy treatment of a brain tumour. (The irradiation of certain areas of the brain is, in fact, a central adjunctive therapy for brain tumours in adults and children).

According to certain studies, the reduction in our “stock” of neurones contributes to an irreversible decline in cognition. In the mouse, for example, researchers reported that exposing the brain to radiation in the order of 15 Gy is accompanied by disruption to the olfactive memory and a reduction in neurogenesis. The same happens in ageing in which a reduction in neurogenesis is associated with a loss of certain cognitive faculties. In patients receiving radiotherapy due to the removal of a brain tumour, the same phenomena can be observed.

Researchers are studying how to preserve the “neurone stock”. To do this, they have tried to discover which factors are responsible for the decline in neurogenesis.

Contrary to what might have been believed, their initial observations show that neither heavy doses of radiation nor ageing are responsible for the complete disappearance of the neural stem cells capable of producing neurones (and thus the origin of neurogenesis). Those that survive remain localised in a certain small area of the brain (the sub-ventricular zone (SVZ)). They nevertheless appear not to be capable of working correctly.

Additional experiments have made it possible to establish that in both situations, irradiation and ageing, high levels of the cytokine TGFβ cause the stem cells to become dormant, increasing their susceptibility to apoptosis (PCD) and reducing the number of new neurones.

“Our study concluded that although neurogenesis reduced in ageing and after a high dose of radiation, many stem cells survive for several months, retaining their ‘stem’ characteristics”, explains Marc-Andre Mouthon, one of the main authors of the research, that was conducted in conjunction with José Piñeda and François Boussin.

The second part of the project demonstrated that pharmacological blocking of TGFβ restores the production of new neurones in irradiated or ageing mice.

For the researchers, these results will encourage the development of targeted therapies to block TGFβ in order to reduce the impact of brain lesions caused by radiotherapy and improving the production of neurones in the elderly presenting with a cognitive decline.

Reframing Stress: Stage Fright Can Be Your Friend

Fear of public speaking tops death and spiders as the nation’s number one phobia. But new research shows that learning to rethink the way we view our shaky hands, pounding heart, and sweaty palms can help people perform better both mentally and physically.

Before a stressful speaking task, simply encouraging people to reframe the meaning of these signs of stress as natural and helpful was a surprisingly effective way of handling stage fright, found the study to be published online April 8 in Clinical Psychological Science.

"The problem is that we think all stress is bad," explains Jeremy Jamieson, the lead author on the study and an assistant professor of psychology at the University of Rochester. "We see headlines about ‘Killer Stress’ and talk about being ‘stressed out.’" Before speaking in public, people often interpret stress sensations, like butterflies in the stomach, as a warning that something bad is about to happen, he says.

"But those feelings just mean that our body is preparing to address a demanding situation," explains Jamieson. "The body is marshaling resources, pumping more blood to our major muscle groups and delivering more oxygen to our brains." Our body’s reaction to social stress is the same flight or fight response we produce when confronting physical danger. These physiological responses help us perform, whether we’re facing a bear in the forest or a critical audience.

For many people, especially those suffering from social anxiety disorder, the natural uneasiness experienced before giving a speech can quickly tip over into panic. “If we think we can’t cope with stress, we will experience threat. When threatened, the body enacts changes to concentrate blood in the core and restricts flow to the arms, legs, and brain,” he explains. So, “cold feet” is a real physiological response to threat, not just a colorful expression.

"Lots of current advice for anxious people focuses on learning to ‘relax,’—you know, deep, even breathing and similar tips," says Jamieson. Such calming techniques, write the authors, may be helpful in situations that do not require peak performance. But when gearing up for a high-stakes exam, a job interview, or, yes, a speaking engagement, reframing how we think about stress may be a better strategy.

Then how can people reap the benefits of being stressed without being overwhelmed by dread? To answer that question, Jamieson and co-authors Matthew Nock, of Harvard University and Wendy Berry Mendes of the University of California in San Francisco, turned to the Trier Social Stress Test. Developed in 1993 by Clemens Kirschbaum and colleagues, this experiment relies on fear of public speaking and has become one of the most reliable laboratory methods for eliciting threat responses.

In the study, 69 adults were asked to give a five-minute talk about their strengths and weaknesses with only three minutes to prepare. Roughly half of the participants had a history of social anxiety and all participants were randomly assigned to two groups. The first group was presented information about the advantages of the body’s stress response and encouraged to “reinterpret your bodily signals during the upcoming public speaking task as beneficial.” That group also was asked to read summaries of three psychology studies that showed the benefits of stress. The second group received no information about reframing stress.

Participants delivered their speech to two judges. On purpose, the judges provided negative nonverbal feedback throughout the entire five-minute presentations, shaking their heads in disapproval, tapping on their clipboards, and staring stone-faced ahead. If study subjects ran out of things to say, the judges insisted that they continue speaking for the full five minutes. Following the speech, participants were asked to count backwards for five minutes in steps of seven beginning with the number 996. The evaluators again provided negative feedback throughout and insisted that participants start over if they made any mistakes.

Confronted with scowling judges, participants who received no stress preparation experienced a threat response, as captured by cardiovascular measures. But the group that was prepped about the benefits of stress weathered the trial better. That group reported feeling that they had more resources to cope with the public speaking task and, perhaps more tellingly, their physiological responses confirmed those perceptions. The prepped group pumped more blood through the body per minute compared to the group that did not receive instruction.

Surprisingly, this study also found that individuals who suffer from social anxiety disorder actually experienced no greater increase in physiological arousal while under scrutiny than their non-anxious counterparts, despite reporting more intense feelings of apprehension. This disconnect, argue the authors, supports the theory that our experience of acute or short-term stress is shaped by how we interpret physical cues. “We construct our own emotions,” says Jamieson.

Rare primate’s vocal lip-smacks share features of human speech

The vocal lip-smacks that geladas use in friendly encounters have surprising similarities to human speech, according to a study reported in the Cell Press journal Current Biology on April 8th. The geladas, which live only in the remote mountains of Ethiopia, are the only nonhuman primate known to communicate with such a speech-like, undulating rhythm. Calls of other monkeys and apes are typically one or two syllables and lack those rapid fluctuations in pitch and volume.

This new evidence lends support to the idea that lip-smacking, a behavior that many primates show during amiable interactions, could have been an evolutionary step toward human speech.

"Our finding provides support for the lip-smacking origins of speech because it shows that this evolutionary pathway is at least plausible," said Thore Bergman of the University of Michigan in Ann Arbor. "It demonstrates that nonhuman primates can vocalize while lip-smacking to produce speech-like sounds."

Bergman first began to wonder about the geladas’ sounds when he began his fieldwork in 2006. “I would find myself frequently looking over my shoulder to see who was talking to me, but it was just the geladas,” he recalled. “It was unnerving to have primate vocalizations sound so much like human voices.”

That was something that he had never experienced in the company of other primates. Then Bergman came across a paper in Current Biology last year proposing vocalization while lip-smacking as a possible first step to human speech, and something clicked.

Bergman has now analyzed recordings of the geladas’ vocalizations, known as “wobbles,” to find a rhythm that closely matches human speech. In other words, because they vocalize while lip-smacking, the pattern of sound produced is structurally similar to human speech.

In both lip-smacking and speech, the rhythm corresponds to the opening and closing of parts of the mouth. What’s more, Bergman said, lip-smacking might serve the same purpose as language in many basic human interactions—think of how friends bond through small talk.

"Language is not just a great tool for exchanging information; it has a social function," Bergman said. "Many verbal exchanges appear to serve a function similar to lip-smacking."

Couch Potatoes May Be Genetically Predisposed to Being Lazy

Studies show 97 percent of American adults get less than 30 minutes of exercise a day, which is the minimum recommended amount based on federal guidelines. New research from the University of Missouri suggests certain genetic traits may predispose people to being more or less motivated to exercise and remain active. Frank Booth, a professor in the MU College of Veterinary Medicine, along with his post-doctoral fellow Michael Roberts, were able to selectively breed rats that exhibited traits of either extreme activity or extreme laziness. They say these rats indicate that genetics could play a role in exercise motivation, even in humans.

“We have shown that it is possible to be genetically predisposed to being lazy,” Booth said. “This could be an important step in identifying additional causes for obesity in humans, especially considering dramatic increases in childhood obesity in the United States. It would be very useful to know if a person is genetically predisposed to having a lack of motivation to exercise, because that could potentially make them more likely to grow obese.”

In their study published in the American Journal of Physiology: Regulatory, Integrative and Comparative Physiology on April 3, 2013, Roberts and Booth put rats in cages with running wheels and measured how much each rat willingly ran on their wheels during a six-day period. They then bred the top 26 runners with each other and bred the 26 rats that ran the least with each other. They repeated this process through 10 generations and found that the line of running rats chose to run 10 times more than the line of “lazy” rats.

Once the researchers created their “super runner” and “couch potato” rats, they studied the levels of mitochondria in muscle cells, compared body composition and conducted thorough genetic evaluations through RNA deep sequencing of each rat.

“While we found minor differences in the body composition and levels of mitochondria in muscle cells of the rats, the most important thing we identified were the genetic differences between the two lines of rats,” Roberts said. “Out of more than 17,000 different genes in one part of the brain, we identified 36 genes that may play a role in predisposition to physical activity motivation.”

Now that the researchers have identified these specific genes, they plan on continuing their research to explore the effects each gene has on motivation to exercise.

Neuroscientists show ’jumping genes’ may contribute to aging-related brain defects

As the body ages, the physical effects are notable; wrinkles in the skin appear, physical exertion becomes harder. But there are also less visible processes going on. Inside aging brains there is another phenomenon at work, which may contribute to age-related brain defects.

In a paper published in the journal Nature Neuroscience CSHL Associate Professor Joshua Dubnau and colleagues show that so-called “jumping genes,” or transposons, increase in abundance and activity in the brains of fruit flies as they age.

Originally discovered at CSHL by Professor Barbara McClintock while working on maize (corn) in the 1940s, transposons are typically repeat DNA sequences that insert themselves into the DNA of an animal or plant.

The moniker “jumping genes” comes from the fact that when activated they can reinsert themselves, or transpose, into another part of the genome. In the course of doing so they are thought to either provide variations in genetic function or, especially in the germline, induce potentially fatal disruptive defects.

Jumping genes in the brains of fruit flies

The median lifespan of a fruit fly can be measured in days. The average fly lives for somewhere between 40-50 days. But they provide a powerful model with which to get at the genetics of things like aging and brain function, including memory.

Dubnau’s interest was piqued by an experiment in which his team showed that when the activity of a protein called Ago2 (Argonaute 2) was perturbed, so was long-term memory—which was tested using a trained Pavolvian response to smell. “This is a neurodegenerative defect that gets profoundly more apparent with age of the flies,” notes Dubnau.

Since Ago2 is known to be involved in protecting against transposon activity in fruit flies, Dubnau and colleagues in his lab, including Wanhe Li and Lisa Prazak, were compelled to look for transposons.

Though transposons have been shown to be active during normal brain development, they are silenced soon afterward. The implication is that they have some functional role in development.

When Dubnau’s group looked for transposons they found that there is a marked increase in transposon levels in the brain cells, or neurons, by 21 days of age in normal fruit flies. The levels were observed to increase steadily with age. These transposons, including one in particular called gypsy, were highly active, jumping from place to place in the genome.

When they blocked Ago2 from being expressed in fruit flies, transposons accumulated at a much younger age. In fact the levels of transposons in young Ago2 “knock-out” flies were equivalent to those in much older normal flies, and increased further still as the Ago2 knock-out flies aged.

Accompanying this transposon accumulation were defects in long-term memory that mirrored those usually seen in much older flies, as well as a much-reduced lifespan. “Essentially the Ago2 knock out flies have no long-term memory by the time they are 20 days old, while normal flies have a normal long-term memory at the same age,” Dubnau reports.

In a previous paper the Dubnau lab, in collaboration with CSHL Assistant Professor Molly Hammell, established a connection between transposons and devastating neurodegenerative diseases such ALS (amyotrophic lateral sclerosis, or Lou Gehrig’s disease) and FTLD (frontotemporal lobar degeneration). The link was the protein TDP-43, which they showed controls transposon activity.

Taken together with the results in his team’s new paper, Dubnau proposes that a “transposon storm” may be responsible for age-related neurodegeneration as well as the pathology seen in some neurodegenerative disorders.

However, his studies so far don’t address whether transposons are the cause or an effect of aging-related brain defects. “The next step will be to activate transposons by genetically manipulating fruit flies and ask whether they are a direct cause of neurodegeneration,” Dubnau says.

Fatheads: How neurons protect themselves against excess fat

We’re all fatheads. That is, our brain cells are packed with fat molecules, more of them than almost any other cell type. Still, if the brain cells’ fat content gets too high, they’ll be in trouble. In a recent study in mice, researchers at Johns Hopkins pinpointed an enzyme that keeps neurons’ fat levels under control, and may be implicated in human neurological diseases. Their findings are published in the May 2013 issue of Molecular and Cellular Biology.

"There are known connections between problems with how the body’s cells process fats and neurodegenerative diseases such as Alzheimer’s, Parkinson’s and amyotrophic lateral sclerosis," says Michael Wolfgang, Ph.D., an assistant professor in the Department of Biological Chemistry at the Johns Hopkins University School of Medicine’s Institute for Basic Biomedical Sciences. "Now we’ve taken a step toward better understanding that connection by identifying an enzyme that lets neurons get rid of excess fat that would otherwise be toxic."

Wolfgang says one clue to the reason for the neurodegeneration/fat-processing connection is that neurons, unlike most cells in the body, seemingly can’t break down fats for energy. Instead, brain cells use fats for tasks such as building cell membranes and communicating information. At the same time, he says, they must prevent the buildup of unneeded fats. Neurons’ fat-loss strategy is rooted in the fact that a fat molecule attached to a chemical group called coenzyme A will be trapped inside the cell, while the coenzyme A-free version can easily cross the cell membrane and escape. With this in mind, Wolfgang, along with colleagues Jessica Ellis, Ph.D., and G. William Wong, Ph.D., focused their study on an enzyme, called ACOT7, which is plentiful in the brain and lops coenzyme A off of certain fat molecules.

The team created mice with a non-working gene for ACOT7 and compared them with normal mice. The scientists saw no obvious differences between the two types of mice as long as they had ready access to food, Wolfgang says. But when food was taken away overnight, so that the mice’s cells would start to break down their fat stores and release fat molecules into the bloodstream for use as energy, ACOT7’s role began to emerge. While the normal fasting mice were merely hungry, the mice lacking ACOT7 had poor coordination, a sign of neurodegeneration. More differences emerged when the researchers dissected the mice; most strikingly, the livers of mice missing ACOT7 were “stark white” with excess fat, Wolfgang says.

Wolfgang cautions that his group’s results are not quite a smoking gun for ACOT7’s involvement in human neurological disease, but says they add to existing circumstantial evidence pointing in that direction. He notes that a special diet that changes the levels of fats and sugars in the bloodstream – the so-called ketogenic diet – can prevent seizures in epileptics; in addition, one study found that patients with epilepsy have less of the ACOT7 enzyme than healthy people.

"We think ACOT7’s purpose is to protect neurons from toxicity and death by allowing excess fat to escape the cells," Ellis says. "Our next step will be to see whether this enzyme does indeed play a role in human neurological disease."

(Image: Courtesy of Sabrina Diano)