Compulsive no more

MIT study sheds light on what causes compulsive behavior, could improve OCD treatments.

By activating a brain circuit that controls compulsive behavior, MIT neuroscientists have shown that they can block a compulsive behavior in mice — a result that could help researchers develop new treatments for diseases such as obsessive-compulsive disorder (OCD) and Tourette’s syndrome.

About 1 percent of U.S. adults suffer from OCD, and patients usually receive antianxiety drugs or antidepressants, behavioral therapy, or a combination of therapy and medication. For those who do not respond to those treatments, a new alternative is deep brain stimulation, which delivers electrical impulses via a pacemaker implanted in the brain.

For this study, the MIT team used optogenetics to control neuron activity with light. This technique is not yet ready for use in human patients, but studies such as this one could help researchers identify brain activity patterns that signal the onset of compulsive behavior, allowing them to more precisely time the delivery of deep brain stimulation.

“You don’t have to stimulate all the time. You can do it in a very nuanced way,” says Ann Graybiel, an Institute Professor at MIT, a member of MIT’s McGovern Institute for Brain Research and the senior author of a Science paper describing the study.

The paper’s lead author is Eric Burguière, a former postdoc in Graybiel’s lab who is now at the Brain and Spine Institute in Paris. Other authors are Patricia Monteiro, a research affiliate at the McGovern Institute, and Guoping Feng, the James W. and Patricia T. Poitras Professor of Brain and Cognitive Sciences and a member of the McGovern Institute.

Controlling compulsion

In earlier studies, Graybiel has focused on how to break normal habits; in the current work, she turned to a mouse model developed by Feng to try to block a compulsive behavior. The model mice lack a particular gene, known as Sapap3, that codes for a protein found in the synapses of neurons in the striatum — a part of the brain related to addiction and repetitive behavioral problems, as well as normal functions such as decision-making, planning and response to reward.

For this study, the researchers trained mice whose Sapap3 gene was knocked out to groom compulsively at a specific time, allowing the researchers to try to interrupt the compulsion. To do this, they used a Pavlovian conditioning strategy in which a neutral event (a tone) is paired with a stimulus that provokes the desired behavior — in this case, a drop of water on the mouse’s nose, which triggers the mouse to groom. This strategy was based on therapeutic work with OCD patients, which uses this kind of conditioning.

After several hundred trials, both normal and knockout mice became conditioned to groom upon hearing the tone, which always occurred just over a second before the water drop fell. However, after a certain point their behaviors diverged: The normal mice began waiting until just before the water drop fell to begin grooming. This type of behavior is known as optimization, because it prevents the mice from wasting unnecessary effort.

This behavior optimization never appeared in the knockout mice, which continued to groom as soon as they heard the tone, suggesting that their ability to suppress compulsive behavior was impaired.

The researchers suspected that failed communication between the striatum, which is related to habits, and the neocortex, the seat of higher functions that can override simpler behaviors, might be to blame for the mice’s compulsive behavior. To test this idea, they used optogenetics, which allows them to control cell activity with light by engineering cells to express light-sensitive proteins.

When the researchers stimulated light-sensitive cortical cells that send messages to the striatum at the same time that the tone went off, the knockout mice stopped their compulsive grooming almost totally, yet they could still groom when the water drop came. The researchers suggest that this cure resulted from signals sent from the cortical neurons to a very small group of inhibitory neurons in the striatum, which silence the activity of neighboring striatal cells and cut off the compulsive behavior.

“Through the activation of this pathway, we could elicit behavior inhibition, which appears to be dysfunctional in our animals,” Burguière says.

The researchers also tested the optogenetic intervention in mice as they groomed in their cages, with no conditioning cues. During three-minute periods of light stimulation, the knockout mice groomed much less than they did without the stimulation.

Scott Rauch, president and psychiatrist-in-chief of McLean Hospital in Belmont, Mass., says the MIT study “opens the door to a universe of new possibilities by identifying a cellular and circuitry target for future interventions.”

“This represents a major leap forward, both in terms of delineating the brain basis of pathological compulsive behavior and in offering potential avenues for new treatment approaches,” adds Rauch, who was not involved in this study.

Graybiel and Burguière are now seeking markers of brain activity that could reveal when a compulsive behavior is about to start, to help guide the further development of deep brain stimulation treatments for OCD patients.

How electrodes in the brain block obsessive behaviour

Deep brain stimulation helps some people with obsessive-compulsive disorder (OCD), but no one was quite sure why it is effective. A new study offers an explanation: the stimulation has surprisingly pervasive effects, fixing abnormal signalling between different parts of the brain.

A small number of people with difficult-to-treat OCD have had electrodes permanently implanted deep within their brain. Stimulating these electrodes reduces their symptoms.

To work out why stimulation has this effect, Damiaan Denys and Martijn Figee at the Academic Medical Center in Amsterdam, the Netherlands, and colleagues recorded neural activity in people with electrodes implanted into a part of the brain called the nucleus accumbens. This region is vital for conveying motivational and emotional information to the frontal cortex to guide decisions on what actions to take next. In some people with OCD, feedback loops between the two get jammed, leading them to do the same task repeatedly to reduce anxiety.

The researchers took fMRI scans as participants rested. In 13 people with OCD and implanted electrodes, there was continuous and excessive exchange of signals between the nucleus accumbens and the frontal cortex that was not seen in 11 control subjects. When the electrodes were activated, though, the neural activity of both brain regions in the people with OCD became virtually identical to that in the controls.

The researchers also used EEGs to monitor electrical activity in the brain as the 13 people with OCD viewed images linked with their obsessions, such as cleaning toilets. This time, the team observed excessive activity in the frontal cortex – and again, this activity disappeared when the electrodes were activated.

"The most striking thing is that stimulation doesn’t just affect the nucleus accumbens, but the whole network linked up with the cortex," says Figee.

The study suggests that the electrodes do more than normalise brain activity at the site where they are implanted, as had been assumed. Rather, they appear to repair entire brain circuits that had been faulty. “It resets and normalises these circuits,” says Figee.

Thomas Schlaepfer at the University of Bonn, Germany, points out that such work may allow researchers to use deep brain stimulation to learn about the causes of OCD as they treat it. “It will serve as a research platform informing us about the underlying neurobiology of such disorders,” he says.

(Image courtesy: Michael S. Okun)

Exploring the Brain’s Relationship to Habits

The basal ganglia, structures deep in the forebrain already known to control voluntary movements, also may play a critical role in how people form habits, both bad and good, and in influencing mood and feelings.

"This system is not just a motor system," says Ann Graybiel. "We think it also strongly affects the emotional part of the brain."

Graybiel, an investigator at the McGovern Institute of the Massachusetts Institute of Technology and professor in MIT’s department of brain and cognitive sciences, believes that a core function of the basal ganglia is to help humans develop habits that eventually become automatic, including habits of thought and emotion.

"Many everyday movements become habitual through repetition, but we also develop habits of thought and emotion," she says."If cognitive and emotional habits are also controlled by the basal ganglia, this may explain why damage to these structures can lead not only to movement disorders, but also to repetitive and intrusive thoughts, emotions and desires."           

Graybiel’s research focuses on the brain’s relationship to habits—how we make or break them—and the neurobiology of the habit system. She and her team have identified and traced neural loops that run from the outer layer of the brain—“the thinking cap,” as she calls it—to a region called the striatum, which is part of the basal ganglia, and back again. These loops, in fact, connect sensory signals to habitual behaviors.

Her work ultimately could have an impact not just on such classic movement disorders as Parkinson’s and Huntington’s diseases, but in other conditions where repetitive movements commonly occur, such as Tourette Syndrome, autism, or obsessive-compulsive disorder, the latter when sufferers experience unwanted and repeated thoughts, feelings, ideas, sensations or behaviors that make them feel driven to do something, for example, repeatedly washing their hands.

Moreover, the research could have an immediate value for trying to understand “what happens in the brain as addiction occurs, as bad habits form, not just good habits,” she says. “There are many psychiatric and neurologic conditions in which these same brain regions are disordered.

"These conditions may in part be influenced by the very system we are working on," Graybiel adds. "We are working with models of anxiety and depression, stress and some of these movement disorders."

It turns out that the emotional circuits of the brain have strong ties to the striatum, she says. Graybiel’s research suggests that activity in the striatum strongly affects the emotional decisions that people make: whether to accept a good outcome or a potentially bad one, for example, and that there are circuits favoring good outcomes, and, surprisingly, other circuits that favor bad ones.

"This work ties into new research suggesting that there are brain systems for ‘good’ and brain systems for ‘bad,’" she says. "What is intriguing is that we may have identified the circuits that decide between the two."

Scientists explore the illusion of memory

A memory might seem like a permanent, precious essence carved deep into the circuits of the brain. But it is not. Instead, scientists are discovering that a memory changes every time you think about it.

"Every time you recall a memory, it becomes sensitive to disruption. Often that is used to incorporate new information into it." That’s the blunt assessment from one of the world’s leading experts on memory, Dr. Eric Kandel from Columbia University.

And that means our memories are not abstract snapshots stored forever in a bulging file in our mind, but rather, they’re a collection of brain cells — neurons that undergo chemical changes every time they’re engaged.

So when we think about something from the past, the memory is called up like a computer file, reviewed and revised in subtle ways, and then sent back to the brain’s archives, now modified slightly, updated, and changed.

As scientists increasingly understand the biological process of memory, they are also learning how to interrupt it, and that means they might one day be able to ease the pain of past trauma, or alter destructive habits and addictions, as though shaking an Etch A Sketch, erasing the scribbles on the mind, and starting fresh.

In his McGill University lab, researcher Karim Nader routinely erases the memory of his laboratory rats. But first he has to give them a memory and he does that by putting them in an isolation cubicle, playing a tone, and then delivering a small electrical shock to their feet.

Read more

Mistaking OCD for ADHD Has Serious Consequences

On the surface, obsessive compulsive disorder (OCD) and attention deficit/hyperactivity disorder (ADHD) appear very similar, with impaired attention, memory, or behavioral control. But Prof. Reuven Dar of Tel Aviv University’s School of Psychological Sciences argues that these two neuropsychological disorders have very different roots — and there are enormous consequences if they are mistaken for each other.

Prof. Dar and fellow researcher Dr. Amitai Abramovitch, who completed his PhD under Prof. Dar’s supervision, have determined that despite appearances, OCD and ADHD are far more different than alike. While groups of both OCD and ADHD patients were found to have difficulty controlling their abnormal impulses in a laboratory setting, only the ADHD group had significant problems with these impulses in the real world.

According to Prof. Dar, this shows that while OCD and ADHD may appear similar on a behavioral level, the mechanism behind the two disorders differs greatly. People with ADHD are impulsive risk-takers, rarely reflecting on the consequences of their actions. In contrast, people with OCD are all too concerned with consequences, causing hesitancy, difficulty in decision-making, and the tendency to over-control and over-plan.

Their findings, published in the Journal of Neuropsychology, draw a clear distinction between OCD and ADHD and provide more accurate guidelines for correct diagnosis. Confusing the two threatens successful patient care, warns Prof. Dar, noting that treatment plans for the two disorders can differ dramatically. Ritalin, a psychostimulant commonly prescribed to ADHD patients, can actually exacerbate OCD behaviors, for example. Prescribed to an OCD patient, it will only worsen symptoms.

Study Shows Working Memory Is Driven By Prefrontal Cortex And Dopamine

One of the unique features of the human mind is its ability re-prioritize its goals and priorities as situations change and new information arises. This happens when you cancel a planned cruise because you need the money to repair your broke-down car, or when you interrupt your morning jog because your cell phone is ringing in your pocket.

In a new study published in the Proceedings of the National Academy of Sciences (PNAS), researchers from Princeton University say that they have discovered the mechanisms that control how our brains use new information to modify our existing priorities.

The team of researchers at Princeton’s Neuroscience Institute (PNI) used functional magnetic resonance imaging (fMRI) to scan subjects and find out where and how the human brain reprioritizes goals. Unsurprisingly, they found that the shifting of goals takes place in the prefrontal cortex, a region of the brain which is known to be associated with a variety of higher-level behaviors. They also observed that the powerful neurotransmitter dopamine – also known as the “pleasure chemical” – appears to play a critical role in this process.

Using a harmless magnetic pulse, the scientists interrupted activity in the prefrontal cortex of the participants while they were playing games and found they were unable to switch to a different task in the game.

“We have found a fundamental mechanism that contributes to the brain’s ability to concentrate on one task and then flexibly switch to another task,” explained Jonathan Cohen, co-director of PNI and the university’s Robert Bendheim and Lynn Bendheim Thoman Professor in Neuroscience.

“Impairments in this system are central to many critical disorders of cognitive function such as those observed in schizophrenia and obsessive-compulsive disorder.”

Previous research had already demonstrated that when the brain uses new information to modify its goals or behaviors, this information is temporarily filed away into the brain’s working memory, a type of short-term memory storage. Until now, however, scientists have not understood the mechanisms controlling how this information is updated.

The brain of OCD sufferers is more active when faced with a moral dilemma

Patients with obsessive-compulsive disorder are characterised by persistent thoughts and repetitive behaviours. A new study reveals that sufferers worry considerably more than the general population in the face of morality problems.

Along with the help of experts from the Barcelona’s Hospital del Mar and the University of Melbourne (Australia), researchers at the Hospital de Bellvitge in Barcelona have proven that patients with obsessive-compulsive disorder, known as OCD, are more morally sensitive.

"Faced with a problem of this type, people suffering from this type of anxiety disorder show that they worry considerably more," as explained to SINC by Carles Soriano, researcher at the Catalan hospital and one of the lead authors of the work published in the journal Archives of General Psychiatry.

How the brain controls our habits

Habits are behaviors wired so deeply in our brains that we perform them automatically. This allows you to follow the same route to work every day without thinking about it, liberating your brain to ponder other things, such as what to make for dinner.

However, the brain’s executive command center does not completely relinquish control of habitual behavior. A new study from MIT neuroscientists has found that a small region of the brain’s prefrontal cortex, where most thought and planning occurs, is responsible for moment-by-moment control of which habits are switched on at a given time.

“We’ve always thought — and I still do — that the value of a habit is you don’t have to think about it. It frees up your brain to do other things,” says Institute Professor Ann Graybiel, a member of the McGovern Institute for Brain Research at MIT. “However, it doesn’t free up all of it. There’s some piece of your cortex that’s still devoted to that control.”

The new study offers hope for those trying to kick bad habits, says Graybiel, senior author of the new study, which appears this week in the Proceedings of the National Academy of Sciences. It shows that though habits may be deeply ingrained, the brain’s planning centers can shut them off. It also raises the possibility of intervening in that brain region to treat people who suffer from disorders involving overly habitual behavior, such as obsessive-compulsive disorder.