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.

Single gene might explain dramatic differences among people with schizophrenia

Some of the dramatic differences seen among patients with schizophrenia may be explained by a single gene that regulates a group of other schizophrenia risk genes. These findings appear in a new imaging-genetics study from the Centre for Addiction and Mental Health (CAMH).

The study revealed that people with schizophrenia who had a particular version of the microRNA-137 gene (or MIR137), tended to develop the illness at a younger age and had distinct brain features – both associated with poorer outcomes – compared to patients who did not have this version. This work, led by Drs. Aristotle Voineskos and James Kennedy, appears in the latest issue of Molecular Psychiatry.

Treating schizophrenia is particularly challenging as the illness can vary from patient to patient. Some individuals stay hospitalized for years, while others respond well to treatment.

"What’s exciting about this study is that we could have a legitimate answer as to why some of these differences occur," explained Dr. Voineskos, a clinician-scientist in CAMH’s Campbell Family Mental Health Research Institute. "In the future, we might have the capability of using this gene to tell us about prognosis and how a person might respond to treatment."

"Drs. Voineskos and Kennedy’s findings are very important as they provide new insights into the genetic bases of this condition that affects thousands of Canadians and their families," said Dr. Anthony Phillips, Scientific Director at the Canadian Institutes of Health Research Institute of Neurosciences, Mental Health and Addiction.

Also, until now, sex has been the strongest predictor of the age at which schizophrenia develops in individuals. Typically, women tend to develop the illness a few years later than men, and experience a milder form of the disease.

"We showed that this gene has a bigger effect on age-at-onset than one’s gender has," said Dr. Voineskos, who heads the Kimel Family Translational Imaging-Genetics Research Laboratory at CAMH. "This may be a paradigm shift for the field."

The researchers studied MIR137 — a gene involved in turning on and off other schizophrenia-related genes — in 510 individuals living with schizophrenia. The scientists found that patients with a specific version of the gene tended to develop the illness at a younger age, around 20.8 years of age, compared to 23.4 years of age among those without this version.

"Although three years of difference in age-at-onset may not seem large, those years are important in the final development of brain circuits in the young adult," said Dr. Kennedy, Director of CAMH’s Neuroscience Research Department. "This can have major impact on disease outcome."

In a separate part of the study involving 213 people, the researchers used MRI and diffusion tensor-magnetic resonance brain imaging (DT-MRI). They found that individuals who had the particular gene version tended to have unique brain features. These features included a smaller hippocampus, which is a brain structure involved in memory, and larger lateral ventricles, which are fluid-filled structures associated with disease outcome. As well, these patients tended to have more impairment in white matter tracts, which are structures connecting brain regions, and serving as the information highways of the brain.

Developing tests that screen for versions of this gene could be helpful in treating patients earlier and more effectively.

"We’re hoping that in the near future we can use this combination of genetics and brain imaging to predict how severe a version of illness someone might have," said Dr. Voineskos. "This would allow us to plan earlier for specific treatments and clinical service delivery and pursue more personalized treatment options right from the start."

(Image: Akelei van Dam)

Mental picture of others can be seen using fMRI

It is possible to tell who a person is thinking about by analyzing images of his or her brain. Our mental models of people produce unique patterns of brain activation, which can be detected using advanced imaging techniques according to a study by Cornell University neuroscientist Nathan Spreng and his colleagues.

"When we looked at our data, we were shocked that we could successfully decode who our participants were thinking about based on their brain activity," said Spreng, assistant professor of human development in Cornell’s College of Human Ecology.

Understanding and predicting the behavior of others is a key to successfully navigating the social world, yet little is known about how the brain actually models the enduring personality traits that may drive others’ behavior, the authors say. Such ability allows us to anticipate how someone will act in a situation that may not have happened before.

To learn more, the researchers asked 19 young adults to learn about the personalities of four people who differed on key personality traits. Participants were given different scenarios (i.e. sitting on a bus when an elderly person gets on and there are no seats) and asked to imagine how a specified person would respond. During the task, their brains were scanned using functional magnetic resonance imaging (fMRI), which measures brain activity by detecting changes in blood flow.

They found that different patterns of brain activity in the medial prefrontal cortex (mPFC) were associated with each of the four different personalities. In other words, which person was being imagined could be accurately identified based solely on the brain activation pattern.

The results suggest that the brain codes the personality traits of others in distinct brain regions and this information is integrated in the medial prefrontal cortex (mPFC) to produce an overall personality model used to plan social interactions, the authors say.

"Prior research has implicated the anterior mPFC in social cognition disorders such as autism and our results suggest people with such disorders may have an inability to build accurate personality models," said Spreng. "If further research bears this out, we may ultimately be able to identify specific brain activation biomarkers not only for diagnosing such diseases, but for monitoring the effects of interventions."

Research advances understanding of the human brain

Advanced neuroimaging techniques are giving researchers new insight into how the human brain plans and controls limb movements. This advance could one day lead to new understanding of disease and dysfunction in the brain and has important implications for movement-impaired patient populations, like those who suffer from spinal cord injuries.

Randy Flanagan (Psychology and Centre for Neuroscience Studies), working with colleagues at Western University, used functional magnetic resonance imaging (fMRI) to uncover what regions of the human brain are used to plan hand actions with the left and right arm. This study, spearheaded by Jason Gallivan, a Banting postdoctoral fellow at Queen’s found that by using the fMRI signals from several different brain regions, they could predict the limb to be used (left vs. right) and hand action to be performed (grasping vs. touching an object), moments before that movement is actually executed.

“We are trying to understand how the brain plans actions,” says Dr. Gallivan. “By using highly sensitive analysis techniques that enable the detection of subtle changes in brain activity patterns, we can reveal which of a series of actions a volunteer is merely intending to do, seconds later. Mapping and characterizing these predictive signals across the human brain allows us to pinpoint the key brain structures involved in generating normal, everyday behaviours.”

In another study, Dr. Flanagan and doctoral student Jonathan Diamond examined how the brain learns object mechanical properties, knowledge that is essential for skilled manipulation. They found that, through experience, humans use mismatches between predicted and actual fingertip forces and between predicted and actual object motions to build internal representations, or models, of the mechanical properties of the objects.

“The goal of this work is to understand the representations underlying skilled manipulation,” explains Dr. Flanagan. “This is important because it will enable us to better characterize deficits in manipulation tasks that often result from stroke and neurological diseases.”

Dr. Flanagan, Dr. Gallivan, and Ingrid Johnsrude (Psychology and Centre for Neuroscience Studies) have recently been awarded a CIHR operating grant to support ongoing neuroimaging work.

Both research papers were published in the Journal of Neuroscience. Read Dr. Flanagan’s paper here and read the joint paper here.

(Image: Getty Images)

The great orchestral work of speech

What goes on inside our heads is similar to an orchestra. For Peter Hagoort, Director at the Max Planck Institute for Psycholinguistics, this image is a very apt one for explaining how speech arises in the human brain. “There are different orchestra members and different instruments, all playing in time with each other, and sounding perfect together.”

When we speak, we transform our thoughts into a linear sequence of sounds. When we understand language, exactly the opposite occurs: we deduce an interpretation from the speech sounds we hear. Closely connected regions of the brain – like the Broca’s area and Wernicke’s area – are involved in both processes, and these form the neurobiological basis of our capacity for language.

The 58-year-old scientist, who has had a strong interest in language and literature since his youth, has been searching for the neurobiological foundations of our communication since the 1990s. Using imaging processes, he observes the brain “in action” and tries to find out how this complex organ controls the way we speak and understand speech.

Making language visible

Hagoort is one of the first researchers to combine psychological theories with neuroscientific methods in his efforts to understand this complex interaction. Because this is not possible without the very latest technology, in 1999, Hagoort established the Nijmegen-based Donders Centre for Cognitive Neuroimaging where an interdisciplinary team of researchers uses state-of-the-art technology, for example MRI and PET scanners, to find out how the brain succeeds in combining functions like memory, speech, observation, attention, feelings and consciousness.

The Dutch scientist is particularly fascinated by the temporal sequence of speech. He discovered, for example, that the brain begins by collecting grammatical information about a word before it compiles information about its sound. This first reliable real-time measurement of speech production in the brain provided researchers with a basis for observing speakers in the act of speaking. They were then able to obtain new insights about why the complex orchestral work of language is impaired, for example, after strokes and in the case of disorders like dyslexia and autism.

“Language is an essential component of human culture, which distinguishes us from other species,” says Hagoort. “Young children understand language before they even start to speak. They master complex grammatical structures before they can add 3 and 13. Our brain is tuned for language at a very early stage,” stresses Hagoort, referring to research findings. The exact composition of the orchestra in our heads and the nature of the score on which the process of speech is based are topics which Hagoort continues to research.

London neuroscience centre to map ‘connectome’ of foetal brain

A state-of-the-art imaging facility at St Thomas’ Hospital in London has been awarded a 15m euro grant to map the development of nerve connections in the brain before and just after birth.

The Centre for the Developing Brain — which is partly funded by King’s College London (KCL) — has built a unique neonatal Magnetic Resonance Imaging Clinical Research Facility based in the intensive care unit of the Evelina Children’s Hospital at St Thomas’. It is one of two centres in the world — the other being at Imperial College — to have such a clinical research facility and associated scanner within a neonatal intensive care unit.

Over the next few years a team headed up by David Edwards, a consultant neonatologist and KCL Professor of Paediatrics and Neonatal Medicine, will build up a diagram of connections in the brain of babies as they develop in the womb and then after they are born. The aim is to understand how the human brain assembles itself from a functional and structural perspective. The resulting map is called a connectome and is the brain equivalent of the human genome. It will be made available to the research community to help improve understanding of neurological disorders.

Training speech networks to treat aphasia

About 80,000 people develop aphasia each year in the United States alone. Nearly all of these individuals have difficulty speaking. For example, some patients (nonfluent aphasics) have trouble producing sounds clearly, making it frustrating for them to speak and difficult for them to be understood. Other patients (fluent aphasics) may select the wrong sound in a word or mix up the order of the sounds. In the latter case, “kitchen” can become “chicken.” Blumstein’s idea is to use guided speech to help people who have suffered stroke-related brain damage to rebuild their neural speech infrastructure.

Blumstein has been studying aphasia and the neural basis of language her whole career. She uses brain imaging, acoustic analysis, and other lab-based techniques to study how the brain maps sound to meaning and meaning to sound.

What Blumstein and other scientists believe is that the brain organizes words into networks, linked both by similarity of meaning and similarity of sound. To say “pear,” a speaker will also activate other competing words like “apple” (which competes in meaning) and “bear”(which competes in sound). Despite this competition, normal speakers are able to select the correct word.

In a study published in the Journal of Cognitive Neuroscience in 2010, for example, she and her co-authors used functional magnetic resonance imaging to track neural activation patterns in the brains of 18 healthy volunteers as they spoke English words that had similar sounding “competitors” (“cape” and “gape” differ subtly in the first consonant by voicing, i.e. the timing of the onset of vocal cord vibration). Volunteers also spoke words without similar sounding competitors (“cake” has no voiced competitor in English; gake is not a word). What the researchers found is that neural activation within a network of brain regions was modulated differently when subjects said words that had competitors versus words that did not.

One way this competition-mediated difference is apparent in speech production is that words with competitors are produced differently from words that do not have competitors. For example, the voicing of the “t” in “tot” (with a voiced competitor ‘dot’) is produced with more voicing than the “t” in “top” (there is no ‘dop’ in English). Through acoustic analysis of the speech of people with aphasia, Blumstein has shown that this difference persists, suggesting that their word networks are still largely intact.

This Is Your Brain On Movies: Neuroscientists Weigh In On The Brain Science of Cinema

In movies, we explore landscapes far removed from our day-to-day lives. Whether experiencing the fantastical adventures of Star Wars or the dramatic throes of The English Patient, movies demand that our brains engage in a complex firing of neurons and cognitive processes. We enter into manipulated worlds where musical scores enhance feeling; where cinematography clues us into details we’d normally gloss over; where, like omniscient beings, we voyeuristically peek into others’ lives and minds; and where we can travel from Marrakech to Mars without ever having left our seat. Movies reflect reality, yet are anything but.

“Movies are highly complex, multidimensional stimuli,” said Uri Hasson, a neuroscientist and psychologist at Princeton University. “Some areas of the brain analyze sound bites, some analyze word context, some the sentence content, music, emotional aspect, color or motion.” Just as many people must come together to work on different elements of a movie’s script, score, visuals or costumes, he explained, so many areas of the brain must also be engaged in processing those disparate elements.

The relatively new field of neurocinematic studies seeks to untangle our neurological experience of film and, in doing so, learn not only the mechanisms behind movie watching but also how movies might teach us more about ourselves.

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