Investigating chronic inflammation as a pathway for cognitive dysfunction in depression

First, thank you for the invitation to update Cambridge Cognition on their 2018 research grant. Since I was awarded this grant, I have almost completed my PhD in clinical psychology at Temple University, Philadelphia. In fact, I am in the final straight: completing my clinical internship year at Massachusetts General Hospital/Harvard Medical School. I will be staying on as a postdoc at Massachusetts General Hospital’s Depression Clinical Research Program where I hope to continue my research investigating immune-based mechanisms underpinning cognitive dysfunction in depression.

What did winning the grant mean for you?

The research grant from Cambridge Cognition was one of the first grants I won. Winning the grant was hugely motivating in and of itself as rejection, rather than success, is the norm within academia. Moreover, the provision of 150 licenses to use CANTAB assessments was also materially important as it provided me with a rigorous, reliable, and validated assessment platform to assess dimensions of cognitive functioning in my study.

What was your study aiming to find?

When depressed, many individuals experience deficits in memory, executive function and mental flexibility. However, not only do depressed individuals exhibit these cognitive deficits, but they can also persist when depression is in remission. My research study focused on trying to understand whether immune dysfunction played a mechanistic role underpinning persistent cognitive dysfunction in depression. The study was significantly delayed by the COVID-19 pandemic and recruitment was only completed in May 2021. However, since recruitment concluded we have been able to clean and analyze these data and we were excited to see the results!

There is accumulating evidence that dysregulation of the immune system may explain the persistence of cognitive dysfunction in remitted depression. Chronic, low-grade inflammation is linked with poor cognitive functioning across a range of medical and psychological disorders, including in people with depression. Our hypothesis was that persistent chronic inflammation may explain why we see persistent cognitive problems in individuals with a history of depression. We were particularly interested to see whether inflammation in remitted depression was linked with a specific pattern of cognitive difficulties.

With this goal in mind, we recruited people who were participants in a National Institute of Mental Health-funded longitudinal research study run by my mentor, Dr. Lauren Alloy. In the parent study, participants were recruited when they were 13 years old and invited back for annual repeated assessments to assess immune function, two cognitive abilities (working memory and cognitive flexibility), and depression. As part of the Cambridge Cognition-funded study, we brought 80 of these individuals back (around 10 years after they had initially joined the study) into the Mood and Cognition Laboratory at Temple University. We used the CANTAB in addition to other commonly used instruments to comprehensively assess multiple dimensions of cognitive functioning, including working memory and cognitive flexibility. We assessed their immune function by measuring levels of C-Reactive Protein and other inflammatory cytokines, for example interleukin-6.

Which CANTAB tests did you use in your study?

For the executive function domain, we used Spatial Working Memory, Stop Signal Task, One Touch Stockings of Cambridge, and Intra-Extra Dimensional Set Shift (in addition to the Digit Span and Test of Everyday Attention Visual Elevator Task). For the memory domain, we used the Paired Associates Learning test in addition to the Hopkins Verbal Learning Test. We used the reaction time test to measure psychomotor speed.

We used the CANTAB results for the cross-sectional analyses. The CANTAB tasks predominantly make up the index of executive function as well as one of the two tasks used to make up the episodic memory index. 

What were your results?

We found that individuals with chronic low-grade inflammation and a history of depression performed worse on tests of executive function and memory, even when age, current depressive symptoms, IQ, and socioeconomic status was accounted for. When we re-administered the two CANTAB cognitive tests that individuals had completed throughout the parent study, we found a consistent pattern whereby individuals with chronic low-grade inflammation and a history of depression consistently performed worse on working memory (holding and manipulation information in our mind) tests, but not on cognitive flexibility tests. These results are preliminary as they are based on a very small sample. But they do suggest that it is depressed individuals who exhibit a pro-inflammatory phenotype who are at risk of having persistent difficulties with their memory and executive functioning. Furthermore, evidence indicates that higher-level executive functions – abilities that that play a critical role in self-regulation and the pursuit of distal goals – are most vulnerable.

Identifying immune-based mechanisms underpinning cognitive dysfunction in depression provides an opportunity to potentially identify treatment targets and my goal is to continue this line of research by using rigorous experimental designs to better examine potential immune-based mechanisms underpinning cognitive dysfunction in depression. Ultimately, the objective is to provide immune-based targets that will inform future treatments aiming to treat this particularly debilitating aspect of depression: cognitive dysfunction.

What advice would you give to anyone considering applying for a CANTAB research grant?

I would definitely encourage anyone who has an interest in integrating measures of cognitive functioning into their research to apply for the CANTAB research grant. I wish that I knew the secret to writing a successful grant proposal, but I know that I always benefit from getting input from multiple people on the proposal!

Tags : cantab | cantab research grant | depression