by Susanne Ahmari, MD, PhD
Editors note: Susanne Ahmari, MD, PhD, is an Assistant Professor of Psychiatry at the University of Pittsburgh. There she leads the Translational OCD Laboratory, where researchers take a multidisciplinary approach to OCD research. She received the 2018 Breakthrough Award from the International OCD Foundation — a $500,000 research grant — the largest ever provided to a researcher by the IOCDF.
Obsessive compulsive disorder (OCD) is a chronic, severe mental illness that affects 2-3% of people worldwide, and has been identified by the World Health Organization as a leading cause of disability. This severity and high prevalence highlights the need for improved treatments for OCD, particularly with respect to medications. Currently, selective serotonin reuptake inhibitors (SRIs) remain the first-line medication treatment for OCD, but only approximately 10% of patients experience remission with SRI treatment. Currently, we know very little about how the brains of people with OCD are different when compared with the brains of healthy individuals. By gaining a greater understanding of these differences and why they might be occurring, we can potentially open up new pathways to discover improved treatments, including new and more effective medications.
WHAT WE CURRENTLY KNOW ABOUT ABNORMAL BRAIN FUNCTION IN OCD
Brain imaging studies conducted over the past 25 years have consistently revealed hyperactivity in key regions of the brain in people with OCD. Hyperactivity has been observed in brain regions that are involved in making decisions (the orbitofrontal cortex, or OFC), selecting actions (the striatum), and regulating the flow of sensory information to the cortex (thalamus). This excessive brain activity has been seen in people with OCD both when their OCD symptoms are triggered, and when they are just resting. However, we have almost no knowledge of the molecular and cellular changes that may be contributing to this abnormal brain function.
CHANGES IN GENE EXPRESSION IN THE OCD BRAIN
In order to start to solve this problem, our lab performed one of the first studies to examine gene expression in post-mortem brain tissue samples from people who had OCD during their lives. Specifically, we examined tissue samples from the OFC and striatum. Gene expression is the process through which a cell produces new molecules by using the cell’s genes (i.e. DNA) as an instruction manual. Cells can increase or decrease the quantity of new protein molecules that they produce by increasing or decreasing gene expression. Our research found abnormal levels of gene expression when we looked at the OCD brains. Specifically, in the OFC, we found lower levels of a group of genes associated with transmitting electrical communication signals between neurons. This exciting finding led us to a larger question: what is causing these changes in gene expression in people with OCD?
WHAT CAUSES CHANGES IN OFC GENE EXPRESSION IN THE OCD BRAIN?
One possible explanation for our findings is that the thalamus — the brain region that regulates the flow of sensory information to other parts of the brain, including the OFC — is sending signals that are too strong in people with OCD. To try to compensate for this over-activity, the OFC may be trying to “turn down the volume” on the receiving end. Our theory is that the OFC changes the gene expression in the synapses that receive these overly-loud signals from the thalamus. If true, this would shift our way of thinking about the brain circuits involved in OCD, by placing greater emphasis on the thalamus, which is important for filtering sensory information from the outside world to the decision-making centers of the brain. Testing this theory is the next step in this exciting research that has been funded by the IOCDF Breakthrough Award. We have already begun performing experiments to test this idea.
IOCDF GRANT-FUNDED STUDY ON POST-MORTEM GENE EXPRESSION
In the first part of this project, we will directly examine gene expression in the thalamus of post-mortem brain tissue from people with OCD. We will then compare this to gene expression in people who didn’t have OCD and are matched for age, sex, and ethnicity. We are predicting that in people with OCD we will see increases in expression of genes that are important for “rhythmic firing.” Abnormalities in rhythmic firing could explain the overly-loud signals that we suspect the OFC may be receiving. By using an approach called RNA-sequencing (RNA-seq) to identify the changes in gene expression, we can directly test this idea while also exploring possibilities that we have not predicted. This will allow us to perform analyses that may uncover the gene expression networks that are most affected in OCD patients.
In the second part of the project, we will perform more precise analysis of the changes in gene expression we observed in the OFC. We will do this by localizing them to specific cell layers and cell types. In addition, we will determine whether, in people with OCD, the networks of neurons in the OFC have a reduced number of contact points — a possible alternative explanation for the decreases in OFC gene expression that we observed in our initial study.
Finally, in the third part of the project, we will assess gene expression in the OFC and striatum of a second group of people with major depressive disorder (MDD). Since OCD co-occurs at a high rate with mood disorders including MDD, it is important to perform this experiment to determine if the observed changes in gene expression are specifically related to OCD, or are instead associated with either depression or medications such as SRIs.
POTENTIAL RESULTS OF THIS STUDY
During the three-year time frame supported by the IOCDF Breakthrough Award, we will gain significant knowledge about molecular changes in the brains of OCD patients that may help us to explain abnormal brain activity patterns that lead to symptoms. These studies will give us new and important information about gene expression in the thalamus and OFC, two key brain regions that have been implicated in the disease process in people with OCD. In addition, this project will allow us to localize these observed molecular changes to specific cell-types and cell layers within the cortex. In turn, we can use this information to build models for how abnormal activity is generated in the brains of people with OCD. Since it is not possible to directly assess abnormal activity at the level of neurons and brain circuitry in living people (except in very rare circumstances, for example, during surgery for deep brain stimulation), these experiments will provide a crucial window into the functioning of the OCD brain. Importantly, all data generated from this project will be put into a publicly accessible forum after completion of the project, so that other OCD researchers can use the data in their own studies and take advantage of this rare resource for advancement of the entire field.
VISION OF THE IOCDF BREAKTHROUGH AWARD
The vision of the IOCDF Breakthrough Award is to fund studies that may ultimately find a cure or preventive strategy for OCD — in other words, keeping OCD from taking hold, or reducing symptoms as close as possible to zero. As a psychiatrist and neuroscientist who treats people with OCD, I am absolutely committed to this goal of finding real cures for OCD. We have treatments that can be effective for OCD — for example, exposure therapy has been effective in up to 70% of people enrolled in clinical trials, and 50-60% of people have partial responses to SRIs. However, anyone who works with people suffering from OCD knows that these numbers are misleading. A partial medication response may be helpful, but not necessarily transformative. Even though exposure and response prevention (ERP) can be extremely effective, it is often incredibly difficult for patients to complete, and expert treatment providers can be hard to come by. It is therefore clear that we need improved treatments.
Relative to other major psychiatric illnesses such as schizophrenia and major depressive disorder, OCD has not benefited from novel and effective treatments over the past 5–10 years. One potential contributing factor to this discrepancy is our lack of knowledge regarding the molecular pathology of OCD. Post-mortem gene expression studies offer a possible solution to this crucial problem. These studies funded by the IOCDF Breakthrough Award are therefore an important step towards uncovering new information that can help us understand how OCD develops. Through this knowledge, we can ultimately design more specific and effective treatments.
Finally, if you have OCD, you have a unique opportunity to make an incredibly invaluable contribution to this long-term goal by signing up as a brain donor at braindonorproject.org
Thank you to the IOCDF’s anonymous donors for funding the Breakthrough Award!