Will brain maps solve mental maze?
Hacking the brain to reveal the hidden secrets of obsessive-compulsive disorder
The quest to unravel obsessive compulsive disorder.
The computer screen and joystick are similar to those used with many virtual-reality games. It’s just that these players compete while lying inside a highly sensitive MRI scanner.
In one challenge, the youths manoeuvre through a maze of corridors, searching for brightgreen dollar signs. Another tests their ability to recognize an error on the screen. All the while, the scanner is photographing “slices” of their brains. The ultimate reward is far more than a game: In the first clinical trial of its kind, those multi-band images are mapping the unknown territory of obsessive-compulsive disorder.
The goal of psychologist Rachel Marsh is to uncover what goes wrong in the brain circuits of people with OCD, among the most intransigent of mental conditions.
Several investigators are tracking an intriguing but often overlooked neurochemical in patients. And still others are studying an antibiotic commonly used to treat acne, which they hope could be one of the missing pieces of the agonizing OCD puzzle.
With recent technological advances, Marsh and her colleagues are doing what their counterparts in other branches of medicine have been doing for more than a century: putting OCD under the microscope in the search for its biomarkers, the concrete signs of mental disorders that could revolutionize how they get diagnosed, treated and perhaps even prevented.
“This is an illness that really gets people off track in their lives,” said Helen Blair Simpson, director of the Center for Obsessive-Compulsive and Related Disorders at Columbia. “And it tortures them.”
Approximately one in 40 American adults will be affected by obsessive-compulsive disorder at some point in their life, twice the rate of schizophrenia, according to the U.S. National Institute of Mental Health. The average age of onset for OCD is 19, earlier than most other mental illnesses. And more than 5o per cent of people with an OCD diagnosis have severe symptoms.
All of these individuals battle persistent, intrusive thoughts, such as a fear of germs or a need for symmetry in their environment. They respond to these obsessive thoughts with ritualistic, repetitive behaviours: compulsions, such as counting their footsteps, excessively bathing, or endlessly checking that a door is locked.
Just as a car depends on a well- oiled transmission, the brain relies on smooth-running neural circuits. Experts think that in OCD, misfiring occurs across those circuits, especially in the frontal and mid-brain regions. Core neural functions are then disrupted, including goal-directed versus habitdriven behaviour, fear control, error detection and reward processing.
This breakdown triggers the symptoms of OCD, as well as a kind of feedback loop from which patients are unable to escape.
Marsh’s previous imaging research indicated that when OCD patients played a virtual-reality game, their brains’ reward circuits were not activated the way they were in control subjects. Her hypothesis for the current work is that she will see the same pattern but that it will return to normal after treatment.
The current, multi-year study, being led by the New York State Psychiatric Institute, part of Columbia University Medical Center, aims to enrol as many as 80 children and teenagers, is generating thousands of images — so many, in fact, that Marsh is having a supercomputer built to catalogue and analyze the massive amount of data.
Other institute scientists are studying these brain circuits in mice, all with a singular goal.
“The holy grail,” Marsh said, “is we see the same patterns of brain activation.”
When an evolutionary impulse misfires
Obsessive-compulsive disorder is a type of anxiety disorder. And anxiety, which is something virtually every human being has experienced, has an evolutionary purpose.
“The difference between anxiety and other disorders, like schizophrenia, is there’s nothing normal about hearing voices. But anxiety is a safe emotion to have. It keeps you out of trouble,” said Moira Rynn, director of child and adolescent psychiatry at Columbia University. Until, of course, it goes awry. For people with OCD, it’s a case of form following dysfunction. One main theory is that when the balance of activity is disturbed within the frontal lobe and mid-brain, cognitive and motor functions are affected.
The result: repetitive behaviours, or compulsions.
People use O CD asa catch phrase :‘ That’ s so O CD .’ But it is very different from that. I know how much my son suffers.
“A compulsion is like an itch,” said Jordan, a New Jersey high school student who asked to be identified only by his first name. “It gets worse and worse if you don’t itch it. It drives you crazy.”
Jordan’s “brand” of OCD falls into the “just right” category. “I need to have everything feel just right,” he said. “When it’s not, it’s the most excruciating thing imaginable. It’s a feeling that just takes over you. You can never be happy again. You can’t go on. Everything is on the line.”
Every day, every hour, every minute. “Every move has to be meticulous.”
Jordan has felt this way, he says, “as long as I can remember.”
The worries can come when he least expects them, and the rituals change all the time. Last year the 17-year-old took part in a clinical trial at the New York State Psychiatric Institute, which is on Manhattan’s Upper West Side, but he found only partial relief. Hoping to get better control of his symptoms, he travelled to Wisconsin in January for a weeks-long inpatient program.
“People use OCD as a catchphrase: ‘That’s so OCD,’ ” said Jordan’s mother, Meg. “But it’s very different from that. I know how much my son suffers.”
No one is sure why the disorder develops, although there are clearly genetic components with some people. Studies suggest that early-onset OCD is the most hereditable. Often it begins with what may seem like childhood tics. When Jordan was 4, he would have a meltdown if his sleeves didn’t reach all the way to his wrist. When he was 7, he had to constantly rearrange the items on his desk at school. At 12, he found it impossible to stop asking his teachers if he was doing the right thing.
“The brain, as it is developing, has little hiccups,” Rynn explained. “Everybody has their own trajectory. Most kids, the hiccups smooth out and pass, but for a small, significant subset of others, they do not.”
There are two traditional treatments for OCD, often given together: cognitive behavioural therapy and medication, with drugs chiefly targeting the neurotransmitter serotonin. In combination, these treatments alleviate all but minimal symptoms in up to 40 per cent of adults. To have all symptoms disappear is rare.
Serotonin has long been the diva of human brain chemicals and, along with dopamine, has hogged the spotlight as researchers looked for new psychiatric treatments. But recently, scientists turned their attention to the amino acid glutamate. Some think this other neurotransmitter could be one of the chief culprits in OCD.
An accidental discovery in 2007 proved to be the breakthrough. Researchers at Duke University Medical Center had been examining how certain proteins provide a kind of infrastructure for the brain’s neurons. When they genetically eliminated the Sapap3 protein from the OCD loop, the mice being studied turned anxious and exhibited obsessivecompulsive grooming behaviour.
Sapap3 assists in glutamate’s modulation after it carries a signal between neurons. Without the protein, the nervous rodents cleaned themselves so often and so vigorously that they developed bloody facial sores.
“People talk about serotonin this and serotonin that,” psychiatrist Suck Won Kim, an OCD expert at the University of Minnesota Medical Center, wrote when the Duke study was released. “But the brain is a circuit and it’s a serious mistake to think that one neurotransmitter works alone ... This new finding will change the story of OCD.”
It did. Others began to look for glutamate- modulating medications already approved by the Food and Drug Administration. Clinical trials tested two drugs thought to prevent excessive glutamate from overstimulating neurons; one is normally prescribed for amyotrophic lateral sclerosis, the other for Alzheimer’s disease.
At the New York State Psychiatric Institute, the researchers decided to consider a different medication. They turned to a broad-spectrum antibiotic called minocycline, which is used mainly for acne and infections as disparate as cholera and gonorrhea.
Animal investigations and other brain studies suggested minocycline might work for OCD by rebalancing glutamate levels critical to the obsession-compulsion pattern. Another significant factor: The drug was approved for use in children and adolescents with acne, meaning it had already cleared a huge safety hurdle.
Maybe minocycline could prove pivotal, Rynn and Simpson thought.
The main problem was they needed funding, and there wasn’t necessarily money available from the National Institute of Mental Health. Not only does NIMH allocate a relatively paltry $30 million a year to OCD — compared with $200 million for schizophrenia — but it also had recently reorganized research priorities toward disease mechanisms and biomarkers of mental illness, rather than clinical trials and treatments. No problem. Rynn and Simpson wanted to investigate not only the clinical effects of minocycline treatment but also its possible mechanism of action, which was directly in line with NIMH’s new goals.
NIMH bought the idea, providing nearly half a million dollars over three years. Starting in 2012, children, adolescents and young adults, ages 8 to 20, were recruited and randomly assigned either minocycline or a placebo to test whether the antibiotic changed glutamate levels in the mid-brain region. Afterward, each of the 50 participants was told what he or she had received and, if it was the minocycline, was given the opportunity of continuing on the medication. Because the results are still being evaluated, the researchers don’t yet know exactly how many did.
A network moves From theory to action
Even when Marsh, Rynn and Simpson are not collaborating on specific projects, their work often overlaps. Marsh relies on data from Simpson’s trials for some of her research and turns to clinicians such as Rynn for access to patients already in treatment.
The suffering inherent with OCD was what initially piqued Simpson’s interest years ago. Only later did she realize how much anxiety issues had affected people with whom she was close. Simpson knows the mysteries of the disorder remain daunting; solving them has become her own mission. In the meantime, she and her colleagues are buoyed by victories such as Cory Muraglio.
The 22-year-old college student, who lives on Long Island, took part in a minocycline pilot trial. Before that, he was barely able to attend high school, scared of being contaminated by germs or poisoned by drinking water, and fearful that something dire would happen to his family. His obsessions gave rise to ritualized compulsions.
Sometimes it was repeating a series of words at certain parts of the day, or washing his hands a specific number of times. But always the behaviour arose out of an overwhelming sense of dread.
“When the rituals would start, I would try to resist,” he recounted recently. “But it’s like drowning. It was mental, physical, completely overwhelming, and if I was at school I couldn’t pay attention because of the thoughts that were in my head and the amount of energy and time they took up.”
Eventually, even school was too much. “He wasn’t bathing; he couldn’t change his clothes. It was horrible,” said his father, Steve.
Once a week for three months, Steve drove Cory to the New York Psychiatric Institute’s OCD clinic in Manhattan, where his son received regular doses of minocycline. Slowly, almost imperceptibly, the anxiety slipped away. What happened next occurred just as gradually, but by the end of the 12-week study, Cory’s life was dramatically different.
“I can’t remember the moment I realized it,” he said. “I was pretty much symptomless.”