Why Do Some People Develop PTSD After a Brain Injury While Others Do Not? Scientists May Have Found a Possible Reason

Around 20 million people worldwide suffer a concussion or another type of traumatic brain injury (TBI) every year. After such an injury, the risk of depression, anxiety disorders, and post-traumatic stress disorder (PTSD) increases two- to fourfold. However, mental health symptoms do not develop in everyone who experiences a TBI.

Researchers at the University of California, San Diego, and the San Diego Veterans Affairs Healthcare System have identified an antibody that may be associated with resilience to some of the consequences of brain injury. Among U.S. Marines, those with higher levels of naturally occurring anti-NMDAR1 antibodies after TBI were less likely to develop symptoms of depression and PTSD than participants with lower levels of these antibodies.

The findings were published in the journal Molecular Psychiatry.

Anti-NMDAR1 antibodies target NMDA receptors — proteins that play an important role in forming memories and retaining new information in the brain. These antibodies are best known for their association with a rare autoimmune condition called anti-NMDA receptor encephalitis, which can cause memory problems and severe neurological symptoms.

However, the new study suggests that naturally occurring anti-NMDAR1 antibodies may act differently and, under certain conditions, may have a protective function.

The researchers analyzed blood samples and psychiatric assessment results from 1,025 U.S. Marines who served in Afghanistan during seven-month combat deployments between 2011 and 2013. Participants underwent assessments before and after deployment.

Among service members who had experienced a TBI during their lifetime, those in the highest quarter for naturally occurring anti-NMDAR1 antibody levels had depression symptom scores that were approximately 25% lower and PTSD symptom scores 22% lower after deployment than participants with lower antibody levels.

They were also significantly less likely to experience moderate or severe depression and less likely to require psychiatric medication after returning from a combat zone.

The antibodies were detectable in the blood for more than a year, suggesting that high anti-NMDAR1 levels may be a relatively stable individual characteristic. At the same time, the researchers found no association between antibody levels and anxiety. According to the researchers, the protective effect may be specific to depression and PTSD.

One possible explanation may be related to the size of the antibodies. The naturally occurring anti-NMDAR1 antibodies detected in the Marines were predominantly of the IgM class. These antibodies are too large to enter synapses — the tiny gaps between nerve cells through which chemical signals are transmitted.

Instead, they may bind to NMDA receptors located outside synapses. According to the researchers, these receptors may play an important role in brain damage following TBI. If IgM antibodies block them, they could partially protect neural tissue from further damage.

Previous experiments by the same research group in mice showed that anti-NMDAR1 antibodies could, in contrast, impair cognitive function. However, in those experiments, the researchers used IgG antibodies, which are considerably smaller. They can enter synapses and bind to receptors required for normal brain function.

“We hypothesized that the difference in size determines whether an antibody reaches receptors involved in brain injury or receptors needed for the brain’s everyday functioning,” explained study co-author Xiangjin Zhou, an associate professor in the Department of Psychiatry at the University of California, San Diego.

When the researchers tested this hypothesis in mice, it was supported by the results: smaller IgG antibodies impaired memory, whereas the larger IgM antibodies, by contrast, showed a protective effect.

Interestingly, the same NMDA receptors are also involved in the mechanism of action of ketamine, a drug approved in the United States for the treatment of depression and PTSD. However, ketamine’s effects are relatively short-lived, whereas naturally occurring anti-NMDAR1 antibodies may remain in the blood for a year or longer.

The researchers emphasize that the findings currently show only a correlation. The results do not prove that anti-NMDAR1 antibodies directly protect people from depression and PTSD after TBI. Further research is needed to determine how the antibodies work and whether their levels could be used to identify people at increased risk of mental health consequences following brain injury or to develop new treatments.