Some people's brain chemistry makes them resilient to stress

A multitude of studies have shown that the world is becoming less resilient and that what lies behind this decline is increasing work, familial and societal stress.

But there may be hope on the horizon. A new study has identified a novel biomarker indicating resilience to chronic stress. This biomarker is largely absent, the researchers say, in people suffering from major depressive disorder, and this absence is further associated with pessimism in daily life.

The study was published in the journal Nature Communications.

The researchers used brain imaging to identify differences in the neurotransmitter glutamate within the medial prefrontal cortex (which, among other things is involved with thinking about one’s state and forming expectations) before and after study participants underwent stressful tasks. They then followed the participants for four weeks, using a survey protocol to regularly assess how participants rated their expected and experienced outcomes for daily activities.

What the researchers say: “To our knowledge, this is the first work to show that glutamate in the human medial prefrontal cortex shows an adaptive habituation to a new stressful experience if someone has recently experienced a lot of stress,” the senior author told us. “Importantly, this habituation is significantly altered in patients with depression. We believe this may be one of the first biological signals of its kind to be identified in relation to stress and people who are clinically depressed.”

“Learning more about how acute and chronic stress affect the brain may help in the identification of treatment targets for depression,” added another of the study’s authors.

It’s long been known that stress is a major risk factor for depression. “In many ways, depression is a stress-linked disorder,” the researchers said. “It’s estimated that 80 percent of first-time depressive episodes are preceded by significant, chronic life stress.”

Around 20 percent of the U.S. population will meet the criteria for a major depressive disorder during their lifetimes. Experts are predicting rates of depression to climb even further in the wake of the ongoing COVID-19 pandemic.

“The pandemic has created more isolation for many people, while also increasing the number of severe stressors and existential threats they experience,” the lead author said. “That combination puts a lot of people at high risk for becoming depressed.”

Although the link between stress and depression is clearly established, the mechanisms underlying this relationship are not. Experiments with rodents have shown an association between the response of glutamate—the major excitatory neurotransmitter in the mammalian brain—and stress. The role of glutamate in humans with depression, however, has been less clear. (Excitatory neurotransmitters have excitatory effects on the neuron—brain cell. This means they increase the likelihood that the neuron will leap into action.)

The 88 participants in the current study included people without a mental health disorder and unmedicated patients diagnosed with a major depressive disorder. Participants were surveyed about recent stress in their lives. They then underwent experiments using a brain scanning technique known as magnetic resonance spectroscopy.

While in the scanner, participants were required to alternate between performing two tasks that served as acute stressors: Putting their hand up to the wrist in ice water and counting down from the number 2,043 by steps of 17 while someone evaluated their accuracy. I’m glad for them that they weren’t called to do both at the same time.

Brain scans before and after the acute stressors measured glutamate in the medial prefrontal cortex. Previous research has also found that this brain area is involved in regulating adaptive responses to stress.

Participants submitted saliva samples while in the scanner, allowing the researchers to confirm that the tasks elicited a stress response by measuring the amount of the stress hormone cortisol in the sample.

In healthy individuals, the brain scans revealed that glutamate change in response to stress in the medial prefrontal cortex was predicated by individual levels of recent perceived stress. Healthy participants with lower levels of stress showed increased glutamate in response to acute stress, while healthy participants with higher levels of stress showed a reduced glutamate response to acute stress.  This adaptive response was comparatively absent in the patients diagnosed with depression.

“The decrease in the glutamate response over time appears to be a signal, or a marker, of a healthy adaptation to stress,” the researchers said. “And if the levels remain high that appears to be a signal for maladaptive responses to stress.”

The experiment also included a group of healthy controls who underwent scanning before and after performing tasks. Rather than stressful tasks, however, the controls were asked to place a hand into warm water or to simply count out loud consecutively. Their glutamate levels were not associated with perceived stress, and they did not show a cortisol response.

To expand their findings, the researchers followed participants for four weeks after scanning. Every other day, the participants reported on their expected and experienced outcomes for activities in their daily lives. The results showed that glutamate changes that were higher than expected based on an individual’s level of perceived stress predicted an increased pessimistic outlook—a hallmark for depression. (Probably due to their fear that the researchers were going to ask them to count down from whatever by 105.4 while their hand was in icy water.)

“We were able to show how a neural response to stress is meaningfully related to what people experience in their daily lives,” the lead author concluded. “We now have a large, rich data set that gives us a tangible lead to build upon as we further investigate how stress contributes to depression.”

So, what? The importance of this study is magnified by the fact that glutamate is one of the three main reward neurochemicals—the others being dopamine and oxytocin. Among other things it opens the brain to learning, to change and to persuasion.

The study, incidentally, illuminates the mental state of those who stormed the Capitol on Jan 6. From the statements they made during the insurrection and afterwards to interviewers and the FBI, we know that most of them were depressed, that they were unable to change their opinions (in spite of overwhelming evidence), and that they were stressed through job, income and culture insecurity.

All this would signal a glutamate problem similar to the one described in this study. Part of the nation’s depression and neurochemical inability to change could have led to our loss of democracy.

Well, I got that off my chest.