There is a disorder characterized by uncertainty, anxiety and regret after making decisions. In medical jargon, it is called obsessive-compulsive disorder (OCD), and it is characterized by a pattern of undesired fears and thoughts, or obsessions, which provoke repetitive behaviors, known as compulsions. Rituals and repetitive acts take over daily life. It is the so-called doubting disease: what if the gas is still on? What if the front door isn’t shut? That uncertainty can drive those with OCD to constant behaviors that can condition their daily lives. The scientific community has spent years trying to decipher what causes those obsessions and compulsions, how and why. Some studies point to a breakdown in brain connectivity. A study published this Tuesday in Nature Communications expounds on this idea, suggesting that an imbalance in the levels of two neurotransmitters — glutamate and GABA — in two areas of the brain could be the cause of those compulsive behaviors.
The study, by researchers at Cambridge University, uses sophisticated imaging techniques to measure the levels of glutamate and GABA in two parts of the brain related to the development of OCD: the anterior cingulate cortex and the supplementary motor area. “Glutamate and GABA are the main excitatory and inhibitory neurotransmitters in the brain. Glutamate facilitates the connection between neurons, while GABA reduces or inhibits neural communication. In OCD, it is believed that the interaction between these neurochemicals is interrupted in certain parts of the brain, causing symptoms like compulsions and intrusive thoughts,” explains Marian Biria, researcher in the Psychology Department of Cambridge University and author of the study.
Previous studies had already pointed in that direction, with studies in animal models and genetic and neurochemical studies in humans that suggest abnormally high glutamate levels in OCD, as the authors admit in their article. But there had also been “inconsistent findings,” with contradictory results, through the use of certain imaging techniques. In their work, the Cambridge researchers used a 7-tesla magnetic resonance imaging spectroscopy scanner (3-tesla MRI scanners are typically used) to detect the chemical composition of the tissues and measure the levels of glutamate and GABA in the relevant brain areas. “These regions are part of the largest cortico-striato-thalamo-cortical circuit, which plays a crucial role in the regulation of motor and cognitive function and decision-making. Decision-making is particularly affected in patients with OCD, and, therefore, they have reduced confidence and more doubts, which is required for conflict resolution. That is where the anterior cingulate cortex comes in, as we know that it is involved in processes like conflict resolution, error prediction and decision-making in uncertain circumstances. The supplementary motor area communicates with the anterior cingulate, but it is also involved in the control of automatic habits, which can be the basis of compulsive behavior,” Biria explains.
After analyzing td 31 patients with OCD and 30 healthy participants, the Cambridge researchers found that the imbalance in glutamate levels, compared to GABA levels, in the supplementary motor area, was associated with compulsive behavior in all participants. In the patients with OCD, the phenomenon was also visible in the anterior cingulate cortex. ‘The participants with OCD had significantly higher levels of glutamate and lower levels of GABA in the anterior cingulate cortex,” the study says.persists. There are people who spend all day that way, and it limits their lives. It is the doubting disease,” the specialist explains. It occurs in between 3% and 7% of the population. “There is a lot of underdiagnosis, which is why the margin is so wide,” the specialist says. Around 5% of patients are resistant to conventional treatment, such as antidepressants and psychotherapy.
After analyzing data from 31 patients with OCD and 30 healthy participants, the Cambridge researchers found that the imbalance in glutamate levels, compared to GABA levels, in the supplementary motor area, was associated with compulsive behavior in all participants. In the patients with OCD, the phenomenon was also visible in the anterior cingulate cortex. “The participants with OCD had significantly higher levels of glutamate and lower levels of GABA in the anterior cingulate cortex,” the study says.
Biria indicates that the imbalances in neurotransmitters can “affect the functioning and connectivity of the brain’s neural circuits.” That is, they interrupt the normal signaling and communication between neurons. “For example, the altered levels of glutamate can affect the activation of glutamate receptors, which leads to abnormal excitatory transmission. Similarly, the interruptions in the GABA levels can affect the inhibitory signaling, which plays a fundamental role in maintaining a balanced neural network. Disturbances in the neurotransmission of glutamate or GABA can translate into neural hypo or hyperactivity,” the researcher summarizes. That imbalance contributes to OCD symptoms.
For Soriano-mas, the Cambridge study “is not new conceptually but technically.” “Neurobiological models of OCD are well-described: there are five frontal-striatal circuits that are each in charge of a different behavior — such as motor, motivational, cognitive — and we have already described how they are altered in OCD. Each circuit has two sub circuits, one that excites it and one that inhibits it. For it to work well, excitation and inhibition have to be balanced. The hypothesis is that these circuits are dysregulated because there is excessive excitatory power from glutamate and a decrease in inhibitory power from GABA,” explains the scientist, whose research also confirms the role of glutamatergic transmission in the development of OCD.
Soriano-Mas points out three pieces of evidence from the study: “The relationship between glutamate and GABA differs in patients with OCD, and a relationship between glutamate and the severity of obsessive symptoms, even in people with subclinical symptoms [with certain compulsive behaviors but without an OCD diagnosis] is also observed. They also use a neuropsychological task which gives a value that indicates the preference to use response strategies based on inflexible habits, characteristic of OCD, or flexible, goal-oriented habits, observing that the use of habit-based strategies is associated with glutamate levels in OCD patients.”
The study takes steps towards showing what happens in the brain of someone with OCD, but there are still unanswered questions, Soriana-Mas admits. “We need to see how that deregulation causes these symptoms and what strategies we have to bring order.” For now, therapeutic options are limited: cognitive behavioral therapy, which exposes patients to their obsessions, causing them to experience anxiety but without resorting to compulsions to relax themselves; and pharmacological treatment with serotonin reuptake inhibitors. In the worst cases, for treatment-resistant patients, deep-brain stimulation is used, with electrodes being placed in certain regions to modulate brain activity, but it only works in half of cases. “We haven’t yet understood how to treat this dysregulation. Treatments that regulate glutamate transmission have been tested and show some effect, but not as much as serotonin reuptake inhibitors, which are probably not acting on those circuits but on the anxiety levels caused by obsession.” Ibáñez regrets that glutamatergic drugs “have been tested in sparse populations and with inconclusive results,” but argues that this study provides “evidence that they are an avenue to be explored.”
Biria trusts, however, that describing the neurochemical imbalance in the brain opens the door to identifying other drugs, such as new treatments that reduce glutamate levels or psychosurgery strategies: “There is plenty of evidence that suggest that the anterior cingulate may not be functioning correctly in OCD. In fact, in very serious patients, surgeons eliminate the anterior cingulate cortex. That is one of the few examples that has shown a beneficial effect of psychosurgery. Deep brain stimulation through implanted electrodes is also designed to reduce activity in that region, a new treatment reserved for very serious patients who have been failed by pharmacological and psychological treatments.”
The Cambridge researcher admits that not everything begins and ends at the brain regions studied. “There are other regions and brain networks that could be relevant in the origin and development of OCD symptoms, like the orbitofrontal cortex. However, these regions interact with the anterior cingulate, which has important outputs to the striatum, and also with some of the control structures, like the lateral frontal cortex and the parietal cortex. An imbalance in the anterior cingulate cortex and the supplementary motor area could potentially influence other neural networks implicated in the physiopathology of OCD.”
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