How Does Genetic Risk for OCD Affect Brain Function During Working Memory Tasks?

What you need to know

• People with OCD and their unaffected relatives show reduced activity in brain regions involved in working memory compared to healthy controls.
• Higher genetic risk for OCD predicts increased activity in a brain region called the orbitofrontal cortex during demanding working memory tasks.
• These brain activity patterns may represent a biological marker (endophenotype) for OCD that is linked to genetic risk.

Working Memory and Brain Activity in OCD

Working memory refers to our ability to temporarily hold and manipulate information in our minds. It allows us to keep track of things like phone numbers, shopping lists, or instructions as we use them. Research has shown that people with obsessive-compulsive disorder (OCD) often have difficulties with working memory, especially when tasks become more demanding.

This study aimed to investigate how working memory is affected in OCD at both the behavioral and brain levels. The researchers were particularly interested in whether unaffected relatives of people with OCD would show similar patterns, which could indicate a genetic component. They also directly examined how genetic risk for OCD relates to brain activity during working memory tasks.

The study included three groups of participants:

1. People diagnosed with OCD
2. Unaffected first-degree relatives of people with OCD (parents, siblings, or children)
3. Healthy control participants with no family history of OCD

All participants completed a working memory task called the n-back task while their brain activity was measured using functional magnetic resonance imaging (fMRI). In this task, participants see a series of numbers and have to indicate when a number matches one shown a certain number of positions back in the sequence. As the number of positions back increases (from 1-back to 2-back to 3-back), the task becomes more challenging and requires more working memory resources.

Key Findings on Working Memory Performance

The study found that both people with OCD and their unaffected relatives showed poorer performance on the working memory task compared to healthy controls, especially at the most difficult level (3-back). This suggests that working memory difficulties may run in families affected by OCD, even in family members who don’t have the disorder themselves.

Brain Activity Differences

When examining brain activity during the task, the researchers found some important differences:

1. Reduced activity in fronto-parietal regions: Both people with OCD and their relatives showed decreased activity in several brain areas involved in working memory, including:

   • Inferior parietal lobule
   • Superior parietal lobule
   • Dorsolateral prefrontal cortex

   These regions are part of a network that supports working memory functions like maintaining and manipulating information. The reduced activity, especially during the more difficult task levels, may reflect less efficient use of this network in people with OCD and those at genetic risk.

2. Increased activity in orbitofrontal cortex: Higher genetic risk for OCD (measured by a polygenic risk score) predicted increased activity in a region called the medial orbitofrontal cortex during the more demanding working memory conditions.

The orbitofrontal cortex is not typically considered a core working memory region. In OCD, increased activity here may reflect excessive monitoring or checking behaviors that interfere with efficient task performance. Importantly, this relationship was found across all participants and was related to genetic risk rather than having an OCD diagnosis.

Implications and Conclusions

These findings provide several important insights:

1. Working memory difficulties in OCD likely have a genetic component, as they are seen in unaffected relatives as well.

2. Altered brain activity patterns during working memory tasks may serve as a biological marker or “endophenotype” for OCD. Endophenotypes are measurable traits that fall between genes and observable symptoms. They can help researchers understand how genetic risk leads to disorder development.

3. The link between genetic risk and orbitofrontal cortex activity suggests this region may play a key role in how OCD develops. Increased activity here might reflect a tendency toward over-monitoring that, when combined with other factors, could contribute to OCD symptoms.

4. The combination of reduced activity in typical working memory regions and increased activity in the orbitofrontal cortex may help explain the cognitive difficulties seen in OCD. It suggests an imbalance where regions involved in monitoring and checking may interfere with efficient information processing.

While this study provides valuable new information, it’s important to note some limitations. The sample size was relatively small for genetic analyses, so the findings need replication in larger studies. Additionally, the OCD group was heterogeneous in terms of symptoms, medication use, and comorbidities, which is representative of real-world OCD but can make it harder to draw specific conclusions.

Conclusions

• Working memory difficulties and associated brain activity patterns may be influenced by genetic risk for OCD.
• Increased activity in the orbitofrontal cortex during demanding cognitive tasks may be a key feature linking genetic risk to OCD development.
• These findings provide new insight into the biological pathways involved in OCD and may help guide future research into prevention and treatment strategies.