Why do people respond to stress and trauma so differently? The emerging field of neuroresilience may have answers

Before she completed her doctoral degree in clinical and health psychology at the University of Florida in Gainesville, Aliyah Snyder, PhD, had a very different dream: to go to the Olympics and compete in skeleton, a winter sledding sport.

After earning her bachelor's degree in psychology at the Florida Institute of Technology, where she was a varsity rower, Snyder moved to New England to coach rowing. Her then boyfriend, who was a bobsledder in Lake Placid, New York, encouraged her to give skeleton a try. She was immediately hooked - barreling headfirst down a twisting, icy track on a small sled appealed to her adventurous side. She attended a development camp where she practiced alongside professionals and was recruited by the Israeli national skeleton team (she has dual citizenship). Snyder trained for two years with the team in the hopes of making it to the Olympics, but several concussions forced her into early retirement.

"Nobody knew to tell me that it was time to stop. Medical care was lacking in this area in 2007-2008," Snyder says, explaining that her symptoms came on gradually and intensified to the point that she had trouble with daily functioning.

She recalls a time, at the height of her symptoms, when she got lost in a grocery store and forgot why she was there. She bought Mountain Dew and cough drops, even though she didn't like or need either item. Snyder also experienced other symptoms, including issues with balance, staring episodes, and motion sickness and panic attacks in the car, symptoms she'd never experienced before her skeleton career.

"I was having attention and executive functioning problems that are hard to put into words," she says, using a term that refers to the mental processes responsible for focus, working memory, organizing, and self-control.

Snyder moved in with her mom as she focused on healing. It took about a year for her to get to a place where she was able to function almost normally, though some symptoms, such as headaches and trouble concentrating, persisted. Snyder worked in a bike shop for a while and eventually started volunteering at a memory-disorders research laboratory.

As she went through her own healing process, she recalled some of what she had learned in college about a field known as neuropsychology: the study of how a person's cognition and behavior are related to brain and nervous system functioning. She decided she wanted to learn more about how to help people like herself who suffered from concussion symptoms, so she applied, and was accepted into, a doctoral program at the University of Florida.

Snyder now directs the Holistic Interventions for Brain Health and Recovery (HI-BHaR) clinic at the University of Florida's Brain Injury, Rehabilitation, and Neuroresilience Center, which provides multi-disciplinary therapeutic approaches to healing for patients with brain injury, post-viral conditions like long COVID, and other neurological conditions.

At a few academic medical centers across the country, multidisciplinary centers that focus on the brain are implementing an emerging field of study known as neuroresilience, the ability to return to homeostasis after a traumatic event - whether the underlying reason is a concussion, a psychological trauma, or chronic stress.

Giulio Pasinetti, MD, PhD, director of the Center for Molecular Integrative Neuroresilience at the Icahn School of Medicine at Mount Sinai in New York City, has spent decades studying the biological mechanisms that may influence the ability to recover from trauma and stress, but the term "neuroresilience" is a relatively new way to describe what he's researching, he says.

"Twenty years ago … the term [neuro]resilience was not used," he says. "Now we are moving into the concept of resilience as a medical term … [We observe that] some people are much more resilient than others."

Pasinetti, through his research with mice, has tried to answer why that is and is investigating how health care providers might use knowledge of the mechanisms to more effectively treat - and even prevent - severe, long-term symptoms following brain or psychological trauma.

He is also studying how neuroresilience relates to protection against neurodegeneration, like that which is caused by Alzheimer's disease.

A multidisciplinary approach to the brain

One key to unlocking the mysteries of neurodegenerative diseases such as Alzheimer's may be to take a more multidisciplinary approach to research, says Marc Diamond, MD, director of the Center for Alzheimer's and Neurodegenerative Diseases, part of the Peter O'Donnell Jr. Brain Institute at the University of Texas Southwestern (UT Southwestern) Medical Center in Dallas.

"Science is getting more and more complicated, and it's often very siloed because it is hard for any one researcher to have expertise that spans multiple disciplines," Diamond says. His team at UT Southwestern consists of experts in an array of specialties who study the problem of neurodegeneration across biological scale, from atoms to organisms. This means the faculty have a range of expertise, including computer science, structural and molecular biology, biochemistry, animal models, and neurology. "Disease encompasses problems that must be understood at the level of atomic interactions, cell biology, and human physiology, which means that a complete understanding is challenging for one type of approach."

Diamond launched the center in 2014 with the intention of reimagining research into neurodegeneration. By having experts in very different specialties under one roof and holding monthly meetings in which principal investigators share their latest work, Diamond says his team has found ways to collaborate and push beyond what is possible when specialists work in separate departments.

"Typically, interesting collaborations come pretty much by chance," Diamond says, giving the example of experts sharing ideas over coffee at conferences. His role over the past decade has been to create an intentional environment where those collaborations are the norm. "You have two people working in complementary areas who bring different skills to a problem, so you get a whole that's greater than the sum of the parts."

For example, scientists at the center study the tau protein, which builds up in toxic tangles to cause diseases like Alzheimer's. By using computational models and human cells, the researchers published findings that identified one of the structural differences that distinguishes functional tau from the pathogenic form. Researchers have since built on this knowledge to make other discoveries that may help identify diagnostics and treatments for neurodegenerative disease in the future. Those discoveries required expertise in computational models, biochemistry, and neuropathology.

"We have come to realize that neurodegeneration is a complex interaction of protein structure and cell biology, brain anatomy, and the immune system," Diamond says. "So we really have to work together to get our hands around the problem, even as we are focused on developing specific ways to diagnose and treat neurodegenerative diseases."

Understanding neuroresilience

It wasn't until the 1950s that scientists began to understand the role of neurotransmitter dysfunction in depression. Since then, knowledge about the connection between the physiology of the brain and psychological and behavioral disorders has deepened, yet many of the mechanisms that play a role in neurodegeneration remain mysterious.

In his lab, Pasinetti works across disciplines - combining expertise in neurology, neuroscience, critical care, sleep medicine, clinical immunology, genetics and genomics, and pharmacology - to uncover the biological markers that are associated with susceptibility to chronic stress, cognitive decline, and psychological disorders brought on by trauma.

Experiments in mouse models have demonstrated that inflammation could trigger a series of events that result in neurodegeneration. Pasinetti's lab has identified genes that contribute to the immune response that can cascade to cause damage to brain function and result in neurodegenerative disease as well as psychological and behavioral disorders. Pasinetti and his colleague Eun-Jeong Yang, PhD, also identified a specific immunological link that connects neuroresilience to stress. They additionally found that the immune system might play a role in sex differences in stress-induced depression, with female mice showing greater susceptibility.

"If we understand the mechanism [causing psychological harm] … in the future we can define a better approach to treating anxiety and depression and promoting resilience," Pasinetti says.

Currently, his lab is studying the role that dietary supplements of polyphenols, a group of compounds found in plants, has in promoting resilience against stress and the role of the gut microbiome in psychological and cognitive resilience.

In experiments conducted over the past 15 years, Pasinetti and his team have induced mice into depressive states and then treated them with specially concentrated polyphenol supplements. The results have suggested that the supplements help regulate the inflammatory immune response, making the mice better able to recover from stress more quickly.

And while Pasinetti's findings are promising for the future of treating and perhaps preventing a range of brain disorders - from depression to Alzheimer's - they're still very much in the preclinical stage, which means it could be some time before they result in practical solutions for patients.

Bringing psychology into the clinic

While Diamond's and Pasinetti's labs dig deep into the mechanisms of neuroresilience, Snyder's work is focused on understanding and offering effective treatments for patients actively dealing with neurological disorders, particularly those related to brain injury or post-viral conditions. In many ways, her specialty in neuropsychology serves as a bridge between disciplines.

"We're uniquely situated at the intersection of cognition, emotion, and physiological regulation and how they are impacted by injury and illnesses," she says.

Often, Snyder finds she is educating clinicians to help them understand the overlap between symptoms that are oversimplified as purely psychological and those that are considered organic, resulting from a physical problem.

"They are not separate systems, and the implementation of that is very lacking," Snyder says. "[Symptoms like anxiety] can be a feature of the dysregulation and illness. To speak like it is exclusively a psychological issue is alienating for patients."

In her work with patients, Snyder employs evidence-based therapeutic interventions, many of which were effective for her when she was recovering from her brain injury more than a decade ago.

One example is the use of mindfulness practices, which direct a patient to meditate on what is happening in the present moment. Snyder advises some patients, especially those who are experiencing anxiety and memory problems, to practice self-talk and narration. By telling themselves what they are doing in the moment, patients are brought into the present, helping them to calm their nervous system from anxious thoughts about the past or future. Such self-talk may also help patients encode memories by encouraging them to pay more attention.

Other examples of interventions include cognitive behavioral therapy and heart rate variability training.

These skills have helped Snyder through her own recovery, but progress has not always been linear. Over the years, she's experienced other setbacks, including being diagnosed with long COVID. As lingering autonomic dysfunction still impacts her ability to cope with stress, Snyder continues to turn to the skills that helped her through her initial recovery, and she hopes to share them with others experiencing similar challenges.

"That is a focus of my clinic: to help people understand the autonomic nervous system and emotional regulation and give them skills based on that knowledge," Snyder says.