COURTESY OF ISRAEL LIBERZONIsrael Liberzon discovered his natural proclivity for post-traumatic stress disorder (PTSD) research when he arrived at the University of Michigan (UM) and Veterans Administration Ann Arbor Medical Center in the 1980s. There, he encountered numerous combat veterans with the condition. “The veterans tended not to like the doctors, who they thought couldn’t relate to them. It was always very natural and easy for me to relate to my veteran patients, to understand where they were coming from,” says Liberzon. “I didn’t have the barriers of communication that other clinicians had because I had the combat experience in common with the patients.”
Liberzon had served a mandatory three years in the Israeli Defense Forces starting at age 18. There, he trained as a combat paramedic and became part of an airborne unit, treating soldiers and civilians wounded in combat zones.
He says he feels fortunate to have made personal connections with such patients. Most that he treated in the UM VA system were Vietnam War veterans, but there were also older vets who’d served in World War II and the Korean War. “It was fascinating because they were experiencing things and dealing with things that were forty years old, and they still had a profound effect on their daily life,” Liberzon says. One of his most memorable patients had been a WWII pilot, who, on the way back from a bombing raid over Germany, had to use his parachute to land, and it was completely shot up on the way to the ground. “He was dealing with nightmares from this memory 50 years later.”
Liberzon saw these patients as individuals, but in the aggregate they represented a major scientific question. “To me, it was one of the most fascinating questions in psychiatry, but also in psychology and neuroscience—how experiences are translated into biology, and how those biological changes can lead to psychological symptoms and behavior changes,” says Liberzon.
There is nothing more fascinating to me than the function of the brain.
Since his experience in the VA, Liberzon has devoted his career to trying to answer these questions. He was the first UM staffer to take on both clinical and laboratory PTSD research. His lab created the first rodent model of the symptoms and neural physiology seen in PTSD patients. And Liberzon’s studies have contributed to novel and increasingly comprehensive models of the causes and effects of PTSD.
Liberzon was born in Ukraine, in the Soviet Union, in 1958. He says that his attraction to science and medicine came from his parents, who were both rural doctors. “Being a physician was not a lucrative profession in the Soviet Union, but my parents were dedicated to helping people,” he says. “That was really influential and instills expectations in you that life should be dedicated to something important and useful.”
Deep in the Cold War, in 1971, the family emigrated to Haifa in Israel. They were among the first wave of Jewish families given permission to relocate from the Soviet Union. “It was just the beginning, and it was serendipitous that we were allowed to leave,” says Liberzon.
The 13-year-old Liberzon adapted to Israeli culture, learning the language easily, integrating well at school, and making friends. He also relished the climate of Haifa. “The weather was terrific. We were less than a mile from the beach and spent half the year there swimming and hanging out.”
In 1976, Liberzon joined the Israeli Defense Forces—a national requirement for all Israeli adults. “I am not used to talking about my military experience much,” he says. “But I did realize how intrigued I was by the process of learning how to take care of people. It was an amazing discovery for me that solidified my interest in medicine.”
After becoming a civilian again in 1979, he wanted to go to medical school, which in Israel is a competitive, six-year program that combines undergraduate and graduate studies. Because Liberzon’s high school grades were not good enough, he first enrolled in Hebrew University in Jerusalem, studying biology, to bring his grades up. “Being in college was great! After the military, it was so easy and pleasant. I couldn’t believe that all I had to do was to go to classes and do some homework,” he says.
When he had completed his biology courses in the spring of 1980, he was accepted to the Sackler Faculty of Medicine at Tel Aviv University, where he started his formal medical training. Significant milestones followed: Liberzon participated in military engagements, including the Lebanon War in 1982, for which he served as the chief medic of the airborne sappers, which are combat engineers. He also got married, welcomed his first child, and had his first taste of scientific research, completing a thesis on respiratory physiology. Then he did a psychology rotation that cemented the direction of his career. “There is nothing more fascinating to me than the function of the brain,” he says.
Putting PTSD on the clinical map
After medical school, Liberzon did a postdoc in physiology at the Technion—Israel Institute of Technology in Haifa and sought a way to combine his interest in clinical psychiatry with neurobiology research. But he soon realized that the tools necessary to advance these fields were still lacking. In the 1980s, neuroimaging instruments such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) were yet to be developed. On the research side, there was also resistance to using animal models to study psychiatric disorders, says Liberzon.
Nevertheless, he decided that the best opportunity for merging clinical and basic research was in the U.S., and he joined UM’s department of psychiatry as a resident in 1988. With his family about to expand with another son on the way, he says, Ann Arbor seemed like a nice place to raise kids (he later had two more children).
In 1980, the American Psychiatric Association, which publishes the Diagnostic and Statistical Manual of Mental Disorders, added PTSD as a disorder in its third edition. Yet when Liberzon arrived in Ann Arbor, UM had no PTSD research program, and there was still a debate among psychiatrists about whether PTSD was a valid diagnosis.
To help the veterans they worked with at the medical center, Liberzon and the other clinicians held individual and group psychotherapy sessions and also prescribed pharmaceuticals, including sleeping aids. But the interventions were insufficient, and there was a dearth of scientific research to back up the approaches to PTSD care because few studies on the condition were being conducted.
By the early 1990s, the psychiatry community and, importantly, government agencies responsible for awarding research funding accepted PTSD as a real and serious condition that warranted more study. Liberzon rose to the challenge. He became an assistant professor in 1992 and soon after received funding to study the neuroanatomy of PTSD.
PTSD animal models
When not seeing patients, Liberzon was at the lab bench. Working with Elizabeth Young and Huda Akil in UM’s Molecular and Behavioral Neuroscience Institute, Liberzon wanted to better understand the hormones and receptors underlying memory and stress responses, both of which are involved in PTSD. After reading publications suggesting that PTSD patients have faulty glucocorticoid receptor regulation, he wondered whether emotional activity in the brain was abnormal as a result of changes in these receptors. Glucocorticoids are the main hormones involved in stress responses. In 1994, Liberzon was among the first to demonstrate, in rats, that glucocorticoids can also modulate oxytocin receptor activity—important for the emotional attachment between individuals. “This was important because it allowed me to begin to unravel the potential link between changes in stress response, memory, and other systems that might regulate emotional attachment behaviors,” explains Liberzon.
It took about ten years to formulate this hypothesis and then get sufficient evidence that this could be what is going on in the brain of an individual with PTSD.
Liberzon next wanted to know how binding of the glucocorticoid stress hormones to oxytocin receptors might affect attachment behaviors and memory, given the role of oxytocin in both. His lab found that rodents under stress have increased glucocorticoid binding to oxytocin receptors in the brain. The study suggested that high levels of chronic stress can affect how the brain processes memories, emotions, and relationships with others.
With Young, Liberzon created a rat model of PTSD in which the animals have enhanced glucocorticoid receptor sensitivity, mimicking the neurological changes observed in clinical PTSD studies. The model has been increasingly influential due to its predictive power and is now among the most widely used in the field. Still, Liberzon says, because of the complexities of PTSD, there is no single, ideal animal model for the disorder.
A new hypothesis of the roots of PTSD
With the emergence of PET-based functional neuroimaging in the late 1990s, Liberzon, together with colleague Stephan Taylor, established a psychiatric neuroimaging program at UM to probe brain regions that function differently in people affected by mental disorders, including PTSD. In 1999, using PET, Liberzon showed that PTSD patients have exaggerated amygdala activation, suggesting that this part of the brain may contribute to the overreaction patients sometimes have to negative stimuli.
The study, according to Liberzon, was among the first to support the hypothesis that amygdala hyperactivity was at the root of PTSD. The idea was that an inappropriate fear response in those with PTSD could be due to the brain reacting intensely to negative stimuli (such as the sound of gunshots) even in an everyday, safe context (such as watching an action movie) as a result of a particularly traumatic memory.
Liberzon wasn’t satisfied with this theory because it could not explain why PTSD symptoms often occurred in the absence of a fear stimulus, sometimes even during sleep. Additionally, his rodent model of the disorder didn’t show enhanced fear conditioning, in which animals learn to pair a neutral cue with a negative experience such as an electric shock.
Because intense emotions are central components of PTSD symptoms in humans, Liberzon went on to focus on how emotion is processed in our brains. In a meta-analysis of fMRI data, he found that various regions of the human brain are involved with different features of emotional activity, suggesting that any of these brain regions, not just the amygdala, could be affected by a trauma and lead to PTSD.
Liberzon next tested whether abnormalities in a different part of the brain—the circuitry between the hippocampus and cortex, which modulates both the fear response and emotional systems—could explain PTSD behavior in a more comprehensive way than the initial amygdala hypothesis. Prior studies had shown that malfunctioning of this circuitry could lead to enhanced fear and impairments in determining whether something is safe or unsafe. Liberzon’s work was the first to show that these abnormalities occur in PTSD. In 2012, his lab demonstrated that an exposure to a single, prolonged stress in his PTSD rodent model resulted in normal conditioning and extinction of the conditioning. But, unlike wildtype animals, the PTSD model animals displayed an enhanced fear of the stress trigger even in safe contexts, suggesting that the hippocampus-cortex connections were not functioning properly.
The lab followed up with a study in 2014 that showed the same thing in patients, namely, that those with PTSD, unlike people without the disorder, had trouble using the information about their environments to deem something safe or unsafe. The results implied that the abnormal fear response in these patients could be due at least in part to flawed signaling between the hippocampus and cortex, and provided a novel view of PTSD pathophysiology that focused the field on the importance of these circuits.
“It took about ten years to formulate this hypothesis and then get sufficient evidence that this could be what is going on in the brain of an individual with PTSD,” says Liberzon.
Liberzon’s lab is currently studying underlying brain regions, including the hippocampus and the prefrontal cortex, and signaling pathways involved in how the brain processes both stressful and non-stressful situations in real time and how that is disrupted in PTSD. His group is also exploring how genetics combined with childhood trauma contribute to PTSD in adulthood.
Now, seeking a new challenge, Liberzon is leaving UM after 30 years. He recently accepted an offer to build a new Psychiatry and Behavioral Science Department at Texas A&M, a position he will start in August.
Liberzon is optimistic about the scientific progress in PTSD over the last 40 years. “We went from a black box of theories but no data, to accumulating a soup of information in the 1990s to begin to formulate hypotheses, to understanding the functions of single brain regions involved in PTSD in the 2000s, to now working on the neurocircuitry and molecular signatures of the abnormalities within the circuits.”