Researchers at the Laureate Institute for Brain Research (LIBR) in Tulsa have identified an abnormal link between the autonomic and central nervous systems, specifically via communication between the heart and part of the brain’s frontal cortex in women with generalized anxiety disorder (GAD).
The team’s objective was to test whether individuals suffering from GAD show dysfunction in the neural circuitry underlying cardiovascular arousal and whether that may be associated with certain disorder-related symptoms such as anxiety and body sensation. To conduct the study, they completed a randomized clinical trial of 58 adult female participants (29 with GAD and 29 matching healthy comparisons).
During the study they stimulated the cardiovascular system using a medicine called isoproterenol, which mimics the effects of adrenaline but, unlike adrenaline, cannot cross the blood-brain-barrier to directly impact brain activity. Intravenous infusions of isoproterenol or saline were administered during functional magnetic resonance imaging, allowing them to assess whether the brains of patients with GAD differ in the processing of information received from the body, a function known as “interception.”
The main findings were that patients with GAD differed significantly from healthy participants on several variables, but only during the lower of two dosages of isoproterenol. Specifically, they perceived their heartbeats to be more intense and had relatively higher heart rates and lower neural activity in the ventromedial prefrontal cortex, a brain area known to regulate the autonomic nervous system and to facilitate feelings of fear or safety. Self-reported anxiety was significantly higher only for those with GAD compared to healthy participants in response to either dose.
The research findings, “Association of Generalized Anxiety Disorder with Autonomic Hypersensitivity and Blunted Ventromedial Prefrontal Cortex Activity During Peripheral Adrenergic Stimulation,” were published in the Feb. 2, 2022, edition of JAMA Psychiatry.
For lead author Adam Teed, a postdoctoral associate at LIBR, the fact that the abnormal results observed for those with GAD occurred during lower, but not higher, doses of medicine was the primary finding from the study: “Administering isoproterenol allowed us to provide causal evidence that an abnormally sensitive cardiovascular system and an abnormally insensitive frontal cortex in GAD patients lowers their ability to regulate bodily arousal. This could help to explain why they experience anxiety so frequently and in a wide variety of contexts.” The authors hope that their study prompts further research into the ventromedial prefrontal cortex as a therapeutic target for novel treatments helping individuals with GAD to regulate physiological and emotional responses to stress.
Beyond the novel link revealed by this study, it is noteworthy that cardiovascular hypersensitivity was observed for GAD patients at all. This is because the Diagnostic and Statistical Manual of Mental Disorders (DSM–5), the standard classification system used by mental health professionals in the United States, describes autonomic symptoms, such as sweating, rapid heart rate or shortness of breath, as being less prominent in GAD than other anxiety disorders, such as panic disorder.
As senior author Sahib Khalsa, M.D., Ph.D., a psychiatrist and principal investigator at LIBR put it, “this study shows us that anxiety is not only something that happens within our brains but within our bodies as well.” Thus, these findings show that abnormal functioning of the autonomic nervous system is not only a factor in GAD, but it occurs in combination with abnormal functioning of certain areas of the brain. Such associations are what Khalsa believes to be the most important product of this research: “It is the interaction between our brain and body that may be essential for determining whether an innocuous situation creates a state of fear in individuals with GAD. We need to better understand how this abnormal physiological response relates to the functional impairments that commonly interfere with the daily lives of such individuals.”
The research team was led by Khalsa, who is also an associate professor in TU’s Oxley College of Health Sciences, and Teed, with additional authors from LIBR, including Martin Paulus, M.D. (LIBR/TU), as well as The University of Oklahoma, the University of California at Los Angeles and the University of California at San Diego.
The research was supported by the National Institute of Mental Health, The William K. Warren Foundation and the National Institute of General Medicine Sciences, and was conducted at LIBR between January 2017 and November 2019.
For more information about the project, contact Sahib Khalsa, M.D., Ph.D., at the Laureate Institute for Brain Research at firstname.lastname@example.org.
The Laureate Institute for Brain Research opened its doors 10 years ago to address one of Oklahoma’s worst health factors, mental health. As scientists and researchers discover the ways in which a person’s mental health is directly linked to their overall physical condition, LIBR, in collaboration with The University of Tulsa, is using new neuroscience tools and resources to answer old questions about Oklahoma’s health crisis.
LIBR was founded by the William K. Warren Foundation when then scientific director Wayne Drevets and five other colleagues from the National Institutes of Health in Washington, D.C., transferred to Tulsa in 2009. Today, the organization includes seven principal investigators (PI) who have tenure track or tenure appointments in the OU-TU School of Community Medicine. The goal then and now is to conduct neuroscience-based research that will improve the diagnosis or prognosis of individuals with mental illness. LIBR Director Martin Paulus said the institute strives to respect the dignity of each patient while leveraging leading talent and technology to discover the causes of and cures for disorders related to mood, anxiety, eating and memory. “We’re trying to use neuroscience to find better ways to develop mental health interventions,” he said.
When Paulus joined the LIBR staff in 2014, he set a goal to create a large data set that would allow researchers to investigate mental health prognosis and diagnosis through behavioral processes, neuroimaging, neuromodulation, psychophysiology and bioassays. LIBR’s largest research project, the Tulsa 1000 (T-1000) study, began recruiting participants with mood, anxiety, eating and substance disorders to complete more than 24 hours of baseline testing. The 1,000th and final individual was enrolled in 2018 with the goal of determining whether neuroscience-based measures can be used to predict outcomes in patients with mental illness.
Data Analytics Lead Rayus Kuplicki (B.S. ’09, M.S. ’11, Ph.D. ’14) has been heavily involved in the technical setup and analysis of T-1000 since its inception. He said the standardization of this initial data collection at the institute is critical for quality research. “My work has made it possible to take raw data from thousands of participants and compute the quantifiable traits that we compare across groups,” he explained.
Data analysis of T-1000 participants continues and has generated more than 40 scientific papers, currently in progress. TU graduate students in the areas of psychology, engineering and biology contribute to T-1000 research through subsets of data analysis. Biology doctoral student Bart Ford is collaborating with LIBR PI Jonathan Savitz to examine the link between latent viruses and depression. “It is well established that early life stress and childhood trauma increase the risk of physical and mental health problems later in life, but the biological mechanisms by which this occurs are not well understood,” Ford said. “Dr. Savitz and I wondered if people who experience childhood abuse and neglect are perhaps more vulnerable to a common latent herpes virus called cytomegalovirus (CMV).”
The virus is usually harmless in otherwise healthy individuals but can weaken the immune system over time. Savitz and Ford studied a group of individuals with major depressive disorder and found that higher levels of self-reported childhood abuse and neglect were associated with a greater likelihood of testing positive for CMV. They then used the T-1000 cohort to replicate the study and discovered the same results with similar effects in size. The findings were published in the prestigious “JAMA Psychiatry” journal earlier this year. “We interpret this to mean that the stress of abuse and neglect during development may render a person susceptible to a CMV infection,” Ford stated. “This could suggest CMV contributes to later life health problems that are often seen in survivors of abuse.”
According to Savitz and Ford, T-1000 is beneficial in understanding the biological causes, mechanisms and outcomes of mental health disorders, and consequently, can help identify therapeutic targets that will lead to treatments of the sources and after-effects of mental illness.
In addition to T-1000, another primary project ongoing at LIBR is the Adolescent Brain Cognitive Development (ABCD) initiative, a study of more than 11,878 children, ages 9 and 10, at 21 different sites nationwide. LIBR researchers have conducted detailed assessments of 743 of the participants. Follow-up visits and scans will continue for 10 years to examine the course of wellness and mental illness during the second decade of life when mental health disorders tend to emerge. One of the first papers the data generated in 2018 was accepted to the journal “NeuroImage” and entitled “Screen media activity and brain structure in youth: Evidence for diverse structural correlation networks from the ABCD study.”
Robin Aupperle is another LIBR PI and assistant professor of community medicine who uses neuroscience and psychological research to improve mental health and gain insight into the causes of anxiety, depression and trauma. She is interested in identifying factors that support resilience to college-related stress and strategies to optimize a student’s psychological well-being. Paulus said meta-analyses show one in three students will develop significant anxiety and depression during their first year of college — a major reason why some students choose to drop out of school. That’s why Aupperle developed the four-week TU Tough program that teaches the skills and mindset necessary for mental toughness to effectively respond to stressful or challenging situations. “This is the idea that our abilities are not set in stone — that we can learn, improve and adapt,” she explained. “Likewise, our ability to be resilient in the face of stress is not hard-wired but can be built and strengthened through practicing certain skills as we seek out and face challenges.”
Aupperle is a mentor to graduate students such as TU clinical psychology Ph.D. student Tim McDermott. His predoctoral training grant application to the National Institute of Mental Health received a qualifying score for funding, which will support McDermott’s research to study the brain circuits underlying people’s ability to manage their emotional reactions. Understanding the brain circuits involved in the processing and regulating of emotions could potentially inform future anxiety and depression treatments. “We will examine whether individuals can learn to regulate their prefrontal cortex activation during emotional processing in response to feedback about their brain activation during functional magnetic resonance imaging (fMRI) scanning,” he said.
As an assistant in the TU Tough project, McDermott has led lectures in TU Tough modules and supervised small group leaders during breakout discussions. He also has managed data processing and analysis for fMRI neuroimaging scans performed before and after TU Tough treatment. Prepared by lead author Elisabeth Akeman (BS ’15) as well as Aupperle and McDermott, a recently published manuscript in the journal “Depression and Anxiety” reports findings from the first two cohorts of TU Tough. The research shows students who complete the program (compared to those who did not) experienced lower rates of self-reported stress and depression symptoms throughout their first semester of college, particularly as measured during finals week. Aupperle explained TU Tough is a strong example of LIBR research that can improve the overall mental health of Oklahomans. “By taking measures to improve resilience to stress and mental health among TU students, we are benefiting the community in general,” she said.“Supporting the health and well-being of our students is the equivalent to supporting the health and well-being of our community.”
Other ongoing treatment studies at LIBR use behavioral activation or cognitive behavioral therapy (as part of ongoing studies in Aupperle’s lab) or novel intervention approaches such as the Float Clinic and Research Center led by PI Justin Feinstein. His studies use flotation as an intervention approach to mental illness, providing patients with a way to disconnect with the world and reconnect with signals firing in their bodies. His research was featured on the CBS This Morning’s “Pay Attention” series in 2018.
TU and LIBR’s unique partnership
Paulus is pleased with the substantial data collection, analyses and treatment LIBR has been able to provide to residents within its first decade. Although Oklahoma has a long way to go in improving its overall mental health, he explained LIBR intends to serve as the starting point for large sets of basic health information that support a biotech approach to mental health treatment and diagnosis. “We want to know how far we can develop, how advanced is our research and can we potentially establish startups that can be developed into effective treatments and commercial products,” Paulus said. In one example, LIBR Chief Technology Officer and physicist Jerzy Bodurka, created a way to use a real-time MRI to train a specific part of the brain to give instant feedback on if the training is effective. Paulus explained the training has reduced levels of depression in research participants, and Bodurka now is developing a turnkey system that will allow for scalability of the intervention at any site with MRI imaging capabilities.
Behind every principal or associate investigator stands a team of student researchers eager to get involved, serving as valuable assets for LIBR’s mission. When asked if TU depends on LIBR or if LIBR relies on TU, Paulus said the partnership is unique in that it is based on both concepts; while the institute focuses on quality research, TU is a generator of knowledge. “TU’s primary mission is teaching, but the goal of our faculty is to be top-level researchers,” Paulus said. “The research provides training opportunities for students, and we couldn’t train them if we didn’t have this relationship with TU.”
Close ties to LIBR are an incentive for students, especially those at the graduate level, to choose TU for advanced experience in their field of research. Students are invited to participate in rotations through the institute and contribute to the facility’s mental health mission. Although LIBR’s primary method of research is brain imaging, Paulus said there will be opportunities for additional biology-based research in the future as researchers pursue exciting advancements into the new decade.
The Laureate Institute for Brain Research (LIBR) in Tulsa is one of a kind — practicing state-of-the-art research techniques such as neuroimaging while also studying cyber behavior and conducting athletic concussion research. Located on the campus of the Laureate Psychiatric Clinic and Hospital, LIBR is an independently operated facility opened in 2009 to better understand the pathogenetic features of mental disorders.
Through the use of functional magnetic resonance imaging (fMRI), genetic testing, behavioral assessment and therapeutics, LIBR scientists are improving the early detection, prevention and treatment of major neuropsychiatric diseases. TU’s Tandy School of Computer Science has had a hand in LIBR’s development from the outset.
“Several students stepped in to research and help build the computer system,” said Pat Bellgowan, a former LIBR and TU School of Community Medicine faculty member who also served as director of cognitive neuroscience. “It’s a small institute that focuses specifically on biomedical research, so it was nice to find a partner that specializes in other areas, particularly in information processing and bioinformatics.”
While LIBR scientists are grateful for TU’s commitment to collaborate on projects and share critical manpower, students from several disciplines –– computer science, biology and psychology –– benefit from the priceless research opportunities that offer grant writing experience and publication in national journals.
One of TU and LIBR’s largest collaborative projects is a research initiative to explore the neurobiology of cyber trust. Through the evaluation of fMRI brain scans and the online behavior exhibited in different scenarios, LIBR, the TU Institute of Bioinformatics and Computational Biology, the Department of Psychology and the Institute for Information Security are working to reduce the risk of security attacks that occur in the cyber traffic of America’s armed forces.
Also at LIBR, Bellgowan and TU have pioneered national research in athletic-related concussions with the help of Golden Hurricane athletics. The Journal of the American Medical Association recently published LIBR’s research documenting a smaller hippocampal region of the brain and slower reaction times in TU football players with a history of concussions. The study is the most comprehensive ever to assess the effects of football specifically on college players.
“TU’s clinical expertise and the access we were given within the Golden Hurricane athletic department is unprecedented nationally,” Bellgowan said. “Other studies have evaluated older athletes, but no one has ever studied 20-year-olds until now.”
LIBR and TU are now preparing for the launch of their newest endeavor, the Tulsa 1,000, a groundbreaking project that will track and examine the moods of 1,000 Tulsa residents suffering from substance abuse and other mental health problems. A TU alumnus will coordinate the study, and TU students will assist with data intake and storage.
“LIBR wouldn’t be where it is today without the support of TU. The university is LIBR’s strongest partner and can be credited for much of its success,” Bellgowan said.
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