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Chemical Imbalances in Frontal Regions of Brain Key to OCD

Scientists have uncovered a "major piece of the puzzle" in understanding obsessive-compulsive disorder (OCD), which could open up new lines of treatment.

Compulsive behaviours – such as obsessive checking, washing, and ordering objects – are types of perseverative behaviour that affected up to 3% of Western populations and were "potentially harmful", highlighted the authors of a new UK study, published in Nature Communications, that investigated the neurochemical basis of compulsive behaviour.

"Symptoms of intrusive thoughts and repetitive rituals can confine patients to their homes for months on end," said Professor Trevor Robbins, from the department of psychology at the University of Cambridge. In extreme cases, the lack of control and sense of hopelessness caused by OCD can result in thoughts of suicide, he added.

Just how compulsive behaviour was related to levels of neurotransmitters, and its underlying neural mechanisms, remained "unclear", the authors said, who pointed out that there had been "little analysis of neurochemical correlates of compulsive behaviour to illuminate its underlying neural mechanisms". 

New Method of Brain Scanning Technique Used

For the study, University of Cambridge researchers used a new method of brain scanning, called 7-Tesla proton magnetic resonance spectroscopy (MRS), to measure neurotransmitter levels in two different brain regions – the anterior cingulate cortex and supplementary motor area.

"Standard MRS scanners can be quite crude, not picking up the glutamate signal very accurately," explained Dr Marjan Biria, lead author of the study. "The 7-Tesla machine allows us to separate the overlapping signals and measure glutamate and GABA [gamma aminobutyric acid] more precisely."

The scanning technique made it possible to assess the balance of excitatory and inhibitory neurotransmission by measuring glutamate, an "excitatory" neurochemical, and GABA, an "inhibitory" neurotransmitter, levels in the anterior cingulate cortex and the supplementary motor area of 30 healthy volunteers and 31 participants with clinically diagnosed OCD. Participants were fluent English speakers and were matched for age, sex, and IQ. 

In addition to scans, the researchers conducted tests and questionnaires with all participants to gauge obsessive-compulsive and habitual tendencies, using a computer-based task to establish a link between an action and reward. The scientists then uncoupled this link and observed whether participants continued to respond as a measure of habit.

"We tested whether people were more prone to repeating the same responses, like a habit, or adapting their behaviour to better pursue goals," said Professor Trevor Robbins, from the department of psychology at University of Cambridge and senior author. "Compulsions and habits are not the same, but impaired regulation of habits can be the basis of compulsions and shift people away from their goal-directed behaviour."

Chemical Imbalances in the Brain Key to OCD Severity

The researchers revealed that the balance between glutamate and GABA was "disrupted" in OCD patients in the two frontal regions of the brain. "An imbalance between neurochemicals in parts of OCD patients' brains is key to decision-making and habit," the authors highlighted.

"Chemical imbalances were related to OCD symptom severity, as well as habitual tendencies in a decision-making task," the authors said, and added that a similar but less pronounced neurochemical imbalance was also detected in healthy individuals with milder compulsive tendencies.  

However, only clinical OCD sufferers showed excess glutamate and reduced GABA in their anterior cingulate cortex, explained the authors, compared to people without OCD. Additionally, the severity of OCD symptoms, along with the inclination towards habitual and compulsive behaviour, was related to higher glutamate levels in the supplementary motor region. This was found to be the case in OCD patients, as well as in healthy participants with milder compulsive tendencies.

"In the supplementary motor area, which is a likely controller of the habit system, even the more mildly repetitive behaviour of healthy volunteers was related to the glutamate-GABA ratio," highlighted Prof Robbins.

The anterior cingulate cortex and the supplementary motor area were both centrally involved in deciding the balance between a person's conscious goals and more automatic habits, the authors explained. The research suggested that "compulsions arise from a dysregulated brain system for controlling habits".

"Understanding obsessive-compulsive disorder is a central question for psychiatry. We have now shown definitive changes in these key neurotransmitters in OCD sufferers," said Prof Robbins. "Excess glutamate and reduced GABA is disrupting the neural circuitry in key regions of the OCD brain."

Paving the Way for New OCD Treatments

The common associations found across all participants suggested that compulsivity is a universal phenomenon related to frontal brain regions. The study results may pave the way for new neuromodulatory treatments for OCD that could rebalance levels of neurotransmitters in these brain circuits, the authors hypothesised.

Current treatments for OCD were limited, emphasised the authors, particularly for those with severe symptoms for whom there are few options, and which are "often extreme" – such as deep-brain stimulation and neurosurgery to remove the anterior cingulate cortex entirely.

Dr Paul Blenkiron, consultant psychiatrist and spokesperson for the Royal College of Psychiatrists, pointed out that, although current recommended treatments, including CBT and SSRI medication, were effective, "at least 1 in 4 people will still have symptoms ".

The study's findings were a "major piece of the puzzle" for understanding the mechanisms behind OCD, said Prof Robbins, which could lead to new strategies for medication in OCD based on available drugs that regulate glutamate – in particular, drugs that inhibit presynaptic glutamate receptors, he said.

"Some treatments already target glutamate imbalance in a roundabout way," explained Dr Biria, but "now we have the evidence for why certain approaches seem to have some beneficial effects".

The researchers said that raised glutamate levels may prove to be a biomarker for OCD. This could guide new therapies, including medication, but also non-invasive use of magnetic stimulation through the scalp, an approach which was showing some promise for treatment of OCD, they added.

Funding for the study was provided by the Wellcome Trust. TWR consults for Cambridge Cognition and receives research grants from Shionogi Inc and Sirgartan. He also has editorial honoraria from Springer Nature and Elsevier. KDE receives editorial honoraria from Karger Publishers. CTR. receives a research grant from Siemens Healthcare. All other authors declared no conflicts of interest.