Scientists at the University of Cambridge have used powerful new brain imaging techniques to reveal a neurochemical imbalance within specific brain areas in patients with obsessive-compulsive disorder (OCD). The study showed that the balance between glutamate (Glu) and γ-aminobutyric acid (GABA)—two major neurotransmitter chemicals—is disrupted in OCD patients in two frontal lobe regions of the brain, the anterior cingulate cortex (ACC), and the supplementary motor area (SMA). These chemical imbalances were related to OCD symptom severity, as well as habitual tendencies in a decision-making task. The study also found a similar but less pronounced neurochemical imbalance in healthy individuals who did not have OCD but who were still prone to habitual and compulsive behavior. These individuals were found to exhibit increased glutamate levels in one of the two brain regions.

Neuroscientists behind the study say the findings will open up new avenues for treating OCD, a psychiatric disorder that affects up to three percent of Western populations and can be deeply disabling. “Understanding obsessive-compulsive disorder is a central question for psychiatry,” said Trevor Robbins, PhD, from Cambridge’s Department of Psychology. We have now shown definitive changes in these key neurotransmitters in OCD sufferers.  Excess glutamate and reduced GABA is disrupting the neural circuitry in key regions of the OCD brain.” Robbins is senior author of the team’s published paper in Nature Communications, titled “Cortical glutamate and GABA are related to compulsive behaviour in individuals with obsessive compulsive disorder and healthy controls.”

Severe OCD is a mental health disorder that causes untold misery for some sufferers. It can lead to loss of work and relationships, and social isolation. “Symptoms of intrusive thoughts and repetitive rituals can confine patients to their homes for months on end,” said Robbins. In extreme cases, the lack of control and sense of hopelessness caused by OCD can result in thoughts of suicide.

Current treatments for OCD are limited. While people with milder symptoms can benefit from some antidepressants, for those with severe symptoms there are few options—often extreme—such as deep-brain stimulation and even neurosurgery to remove the anterior cingulate cortex entirely.

The Wolfson Brain Imaging Centre at Cambridge is home to one of only seven ultra-powerful 7-Tesla Magnetic Resonance Spectroscopy (MRS) scanners in the U.K. For their reported study, researchers scanned 31 clinically diagnosed OCD sufferers, and 30 healthy volunteers as a control group.

The team used the MRS technology to measure levels of glutamate and GABA in regions of the cerebral cortex, the outermost and most highly developed part of the human brain. Glutamate is an “excitatory” neurochemical: it facilitates electrical impulses that fire neurons to send information around brain networks. GABA is an “inhibitory” neurotransmitter that works in opposition to glutamate by dampening neural excitability, creating a balance.

“… we hypothesised that changes in the neurochemical properties of two key regions of fronto-striatal circuitry relevant to compulsivity—the SMA and ACC—will be more evident in OCD and probably expressed in the healthy population as a function of the transdiagnostic dimension of compulsivity,” the team noted. “There is considerable evidence of hyperactivity in OCD in certain cortical regions based on blood oxygenation level dependent (BOLD) neuroimaging, which presumably is a consequence of changes in the excitatory/inhibitory balance in cortical networks resulting from changes in glutamate (Glu) and γ-aminobutyric acid (GABA) neurotransmission.”

However, despite previous suggestions that neurotransmitter balance is linked with OCD, there have been inconsistent findings using less powerful proton magnetic resonance spectroscopy to directly measure regional levels of the neurotransmitters, the team commented. “Evidence for neurochemical dysregulation mediating compulsive behaviour has been hindered by a lack of high resolution quantification of Glu and its metabolite glutamine (Gln), as well as GABA using 1H-MRS at field strengths of 3T or lower.” Lead author Marjan Biria, PhD, who conducted the work in Robbins’ Cambridge lab, further explained, “Standard MRS scanners can be quite crude, not picking up the glutamate signal very accurately. The 7-Tesla machine allows us to separate the overlapping signals and measure glutamate and GABA more precisely.”

In addition to carrying out the scans, the researchers conducted tests and questionnaires with all participants to gauge obsessive-compulsive and habitual tendencies. The test used 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 Robbins. “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.”

The results showed that individuals with clinical OCD had higher levels of glutamate and lower levels of GABA in the anterior cingulate cortex, compared with people without OCD. “… participants with OCD had significantly higher levels of Glu and lower levels of GABA in the ACC and a higher Glu:GABA ratio in that region,” the team noted.

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. Robbins added, “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.” The authors further noted, “Despite the lack of absolute changes in Glu in the SMA in OCD, we found that clinical symptoms (YBOCS-compulsivity subscale) were significantly positively related to the SMA Glu levels, which adds weight to recent suggestions that increased SMA activity is a neuroendophenotype for OCD.”

The anterior cingulate cortex and the supplementary motor area are both centrally involved in deciding the balance between our conscious goals and more automatic habits. The research suggests that “compulsions arise from a dysregulated brain system for controlling habits” the scientists noted. Summarising their findings, the team wrote, “Within the SMA, trait and clinical measures of compulsive behaviour are related to glutamate levels, whereas a behavioural index of habitual control correlates with the glutamate:GABA ratio. Participants with OCD also show the latter relationship in the ACC while exhibiting elevated glutamate and lower GABA levels in that region.” The investigators say the study highlights SMA mechanisms of habitual control relevant to compulsive behaviour that are at work in both healthy sub-clinical individuals, and those with OCD. “The results also demonstrate additional involvement of anterior cingulate in the balance between goal directed and habitual responding in OCD.”

Robbins noted. “Our findings are a major piece of the puzzle for understanding the mechanisms behind OCD. The results suggest new strategies for medication in OCD based on available drugs that regulate glutamate. In particular, drugs that inhibit presynaptic glutamate receptors.” A presynaptic receptor is the part of a nerve cell that controls release of neurotransmitter chemicals. “Some treatments already target glutamate imbalance in a roundabout way,” added Biria. “Now we have the evidence for why certain approaches seem to have some beneficial effects.”

The researchers say 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 is showing some promise for treatment of OCD.

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