Animal research provides clues to obsessive compulsive disorder

On, off; on, off; on, off; on, off. Charles Walker, a British member of Parliament, has to turn the light switch on and off exactly four times before he leaves the room, otherwise his mind fills with dread that something bad will happen to him. He also feels the need to wash his hands frequently, often hundreds of times a day.

As you may have guessed, Walker suffers from obsessive compulsive disorder (OCD), a condition that takes him to “dark places”, as he described in a profile last year in Britain’s The Daily Telegraph.

Two out of every 100 people suffer from OCD, a condition that can be debilitating and destructive. To be “a little OCD” is a phrase that’s widely heard nowadays, uttered by unaffected individuals who simply have quirky habits. Sadly, this trivialises a disorder that the World Health Organisation has classified as an important cause of illness-related disability.

OCD consists of obsessions and compulsions which can develop to such an extent that they are a handicap to daily life. The first part of this disorder are obsessive thoughts, which recur frequently and can lead to severe anxiety. The second part is compulsive behaviour: repetitive actions performed to reduce the anxiety associated with the obsessive thoughts.

By imaging the brain, scientists have identified dysfunctional activity between regions thought to be linked to OCD. The first of these involves neural circuits located between a region in the front of the brain, called the orbitofrontal cortex, and cerebral structures located deeper at the base of the brain.

Another key area of research is communication in the brain between the neocortex and the striatum, a part of the brain related to decision-making, planning and response to reward, as well as problematic behaviour such as addiction and repetitive actions.

Scientists studying animal models of OCD are uncovering the disorder’s physiological roots. Dogs can be afflicted with a form of OCD called canine compulsive disorder (CCD), where they engage in behaviour such as flank- and blanket-sucking, tail chasing, and chewing.

Scientists studying brain scan images of Dobermans with CCD observed they have brain abnormalities similar to those reported in humans with OCD. According to Dr Nicholas Dodman of Tufts University in the United States, “dogs exhibit the behavioural characteristics, respond to the same medication, and have a genetic basis to the disorder, and we now know have the same structural brain abnormalities as people with OCD.”

Importantly, both OCD and CCD often respond to similar treatments, evidence for the utility in studying this condition in animal models. More commonly, scientists study mouse models of human diseases to uncover new insight and to test treatments.

To do this, scientists employ techniques such as optogenetics, which uses light to stimulate neurons that have been genetically modified to make them sensitive to light. Simply by applying a light beam using fibre-optic probes to particular brain regions, specific cells can be activated or inhibited, while neighbouring cells remain unaffected.

Researchers at Columbia University in the US, led by Dr Susanne Ahmari, used optogenetics to repeatedly stimulate specific circuits linking the brain’s cortex and striatum, which led to repetitive grooming behaviour.

Repeated grooming is an expression of obsessive behaviour, and these OCD mice can groom themselves so much that they develop skin lesions. Not only does this implicate these neural circuits in OCD, it opens up the possibility of targeting this brain region therapeutically.

Optogenetics can also be used to stimulate the right neurons to reduce OCD behaviour. Researchers at MIT led by Dr Eric Burguière work with a mutant mouse model of OCD, which fails to express a gene called Sapap3.

These mice show a deficiency in behavioural inhibition that causes compulsive grooming, which can be effectively treated by fluoxetine, a drug used to treat OCD in people.

When the scientists used light to stimulate specific neurons in the cortex that send messages to the striatum, this greatly reduced compulsive behaviour. Conversely, the compulsive behaviour recurred when there was no stimulation.

“Our discoveries show that selective stimulation of the circuit can re-establish normal behaviour in mice that originally presented pathological repetitive behaviour, similar to the behaviour observed in certain patients suffering from obsessive compulsive disorders,” Burguière says.

Neuropsychiatrists at the University of Iowa working with the Sapap3-deficient OCD mouse model have recently uncovered a link between compulsive behaviour and obesity. Dr Michael Lutter and Dr Andrew Pieper found that grooming behaviour could be normalised by breeding the OCD mouse with an obesity mouse model that lacks the brain protein known as MC4R. Interestingly, the offspring of one OCD parent and one obese parent had not only normal breeding behaviour, they also were of normal weight.

Although obesity and OCD behaviour may seem unrelated, Lutter believes that the connection may be rooted in the evolutionary need to eat safe, clean food in times of abundance, and to lessen this drive when food is scarce.

Pieper hopes that the studies will yield new treatments. “The next step will be to determine how these two pathways communicate with one another, in hopes of identifying new ways to develop drugs to treat either of these disorders,” he says.

OCD can be treated with antidepressant medications such as selective serotonin reuptake inhibitors (SSRIs). Serotonin is a chemical messager, known as a neurotransmitter, used by nerve cells to communicate with each other. Because OCD is caused by abnormal signalling between nerve cells, SSRIs are believed to help by preventing the reuptake of serotonin by nerve cells, thus increasing the availability of serotonin to signal between cells.

Another type of treatment for OCD is cognitive behavioural therapy (CBT), a form of “talk therapy”. Scientists at Concordia University in Canada are studying how CBT can be used to access false beliefs about a patient’s memory to reverse an often debilitating symptom of OCD: compulsive checking. Research has shown OCD patients may compulsively check their actions because of low confidence in their memory.

Gillian Alcolado, a PhD candidate in clinical psychology, explains: “Checking is a big problem for many people with OCD. They’re often unable to lead normal lives because they can’t trust they’ve completed a simple task like turning off the stove. To reduce compulsive checking, Alcolado and her course supervisor, Adam Radomsky, have developed an intervention that targets low confidence in memory.

Researchers from Université Laval in Canada have recently reported that about half of patients with extreme OCD responded well to a form of psychosurgery called bilateral anterior capsulotomy. At the end of the study, three out of the 19 patients had recovered from their OCD, and three had their symptoms reduced.