Studying stress-related factors in animals is an important first step in understanding what ails us and how to fix it. But that research only goes so far, particularly when these factors also confer risk for post-traumatic stress disorder (PTSD) in human beings.
As part of a 5-year, $13.5 million grant through the National Institute of Mental Health, clinicians and neuroscientists at McLean Hospital plan to take what they’ve learned and apply that in a study involving men and women dealing with changes brought about by life-threatening experiences.
The research focus of Isabelle M. Rosso, PhD, director of the Anxiety and Traumatic Stress Disorders Laboratory, is designed to explore PTSD by looking at the role of two neuropeptides in relation to stress. It is one of five projects of the Silvio O. Conte Centers for Basic Neuroscience.
“People used to think that PTSD was directly and solely caused by a trauma, particularly combat trauma, but we now know that constitutional risk factors play a major role,” said Rosso. “Your genetics matter. Hormones and sex differences matter. Biology matters. Women are twice as likely to develop PTSD as men, and this is not entirely explained by social factors or differences in the types of trauma they experience.”
The study aims to recruit an equal split of 230 adult men and women with PTSD to look at the physiology and neural underpinnings of stress and arousal. The goal is to relate measures of arousal to individual differences in the stress peptides corticotropin releasing factor (CRF) and pituitary adenylate cyclase-activating polypeptide (PACAP). CRF and PACAP are involved in the normal and adaptive stress response, and they may be implicated in maladaptive responses that contribute to development of PTSD.
“It is normal to have an initial severe physiological stress response to a traumatic event, and for most people, this response abates during the first few months after trauma exposure,” Rosso said. “A small proportion of people after a traumatic event continue to have very pronounced and debilitating symptoms for much longer and are ultimately diagnosed with PTSD. We want to understand whether variations in PACAP and CRF help explain individual differences in stress and arousal within people with PTSD.”
The study will involve measuring PACAP and CRF from blood samples and examining how these neuropeptides relate to different ways to assess arousal.
“When a clinician diagnoses somebody with PTSD, one of the major types of clinical symptoms is hyperarousal,” said Rosso. “People with PTSD are hypervigilant for reminders of their trauma. We can assess these clinical symptoms of hyperarousal using clinical interviews and see if they’re related to PACAP and CRF.”
It’s also possible to measure the physiology of arousal using fear- and anxiety-causing laboratory tasks. The project will include laboratory paradigms of fear conditioning and dark-enhanced startle.
“If you’re in a dark room and hear a loud noise, you’ll probably startle more than if the room is lit, and we can measure this as a change in your heart rate and other physiological reactions,” she explained. “People with PTSD will have a greater dark-enhanced startle on average.
So, we can measure their startle response, and ask whether variation in PACAP and CRF helps explain differences in these arousal responses.”
The imaging will focus on brain regions and networks involved in fear and anxiety, including the amygdala, the almond-shaped cluster of neurons in the brain that plays a central role in fear. The study will combine measures of function, anatomy, and neurochemistry of these brain networks.
The study also will be the first to look at whether sleep problems relate to PACAP and CRF, she said.
“Sleep disruption is one very understudied component of hyperarousal in PTSD,” said Rosso. “Over two-thirds of treatment-seeking people with PTSD report sleep problems. They have insomnia. They have nightmares. They have fragmented sleep.”
“People used to think that PTSD was directly and solely caused by a trauma, particularly combat trauma, but we now know that constitutional risk factors play a major role. Your genetics matter. Hormones and sex differences matter. Biology matters.”– Isabelle M. Rosso, PhD
Participants will be sent home with an actigraph to be worn on the wrist day and night to measure circadian rhythms and sleep. There will also be 3- and 6-month check-ins about their symptoms, particularly arousal.
“We want to see whether our baseline measures of PACAP, CRF, physiology, sleep, and imaging predict later trajectories of symptoms—above and beyond clinical symptoms,” she said.
Rosso said the interconnection of the projects under the Conte Center umbrella is important to the ultimate findings.
“PACAP and CRF are key regulators of stress and arousal across species, and all of the projects can inform each other,” she said. “While researchers know through animal literature and more limited human findings that CRF and PACAP regulate the stress response, we don’t fully understand what happens at the neurobiological level,” she said. “If these processes are disrupted in PTSD, it could help us understand why some people have different responses to trauma and develop long-lasting disturbances in arousal.”