How a Concussion Can Lead to Depression Years Later

A head injury can lead immune-system brain cells to go on “high alert” and overreact to later immune challenges by becoming excessively inflammatory – a condition linked with depressive complications, a new animal study suggests.

The findings could help explain some of the midlife mental-health issues suffered by individuals who experience multiple concussions as young adults, researchers say. And these depressive symptoms are likely inflammation-related, which means they may not respond to common antidepressants.

An added complication is that aging already increases brain inflammation. So on top of normal aging concerns, people who have had a traumatic brain injury (TBI) experience added inflammation caused by magnified immune responses to so-called “secondary challenges,” such as a second head injury, infections or other stressors.

In mice, these high-alert cells in the brain - called microglia - had an exaggerated response to an immune challenge one month after a moderate brain injury. This increased brain inflammation corresponded with the development of depressive behaviors that were not observed in uninjured mice.

“If we had waited three, six or nine months, the symptoms probably would have gotten even worse,” said lead author Jonathan Godbout, associate professor of neuroscience at The Ohio State University and a researcher in the Institute for Behavioral Medicine Research.

“A lot of people with a history of head injury don’t develop mental-health problems until they’re in their 40s, 50s or 60s. That suggests there are other factors involved, and that’s why we’re looking at this two-hit idea - the brain injury being the first and then an immune challenge. It’s as if one plus one plus one equals 15. There can be a multiplier effect.”

The research is published online in the journal Biological Psychiatry.

This work applies to concussive brain injuries that result in a diffuse - or spread out - trauma to the brain. These are also concussive injuries from which people and animals recover fairly quickly, typically showing no problems with thinking or moving about a week after the injury to the brain.

In the study, researchers compared uninjured mice with mice that had experienced a moderate TBI. Injured mice showed some initial coordination problems, but those resolved within a week.

The injured mice also showed signs of depressive symptoms that improved within one month. Godbout and colleagues attributed those symptoms to the expected neuroinflammation that occurs after a traumatic brain injury. In these mice, most of the inflammation had cleared within seven days.

Thirty days after injury, researchers examined the brains of the injured mice to determine whether immune cells had remained on high alert since the injury. As expected, the injured brains contained microglia that had stayed in a “primed” state - meaning they were on standby to respond to a challenge to the immune system. The cells in the brains of uninjured mice did not have the same characteristics.