From The Quarterly, Summer 2014

Impressive progress is being made by Foundation- funded scientists to understand and more effectively treat post-traumatic stress disorder (PTSD). These researchers are addressing the relationship between traumatic experiences and the creation of long-lasting memories of the experiences that cause behavioral problems. Because of the “plasticity” of the brain (“neuroplasticity”) as it constantly adapts to new experiences, a trauma can cause long-lasting changes to brain structures. Memories of the experience can be stored and then persistently retriggered, leading some traumatized individuals to overreact to slight stressors or unexpected events. Scientists are working hard—and making great progress—to understand how this happens within the brain and what makes some people more prone (or others more resilient) to developing a “post-traumatic stress” response.

Victor Carrion, M.D., who received a NARSAD Young Investigator Grant in 2000, leads an innovative program of research at Stanford University Medical Center that focuses on the vulnerabilities of children and adolescents to stress and trauma. As the head of Stanford’s Early Life Stress and Pediatric Anxiety Program, Dr. Carrion and his team have established a special relationship with the Caesar Chavez Academy in East Palo Alto, California, a middle school in a highly distressed urban setting (as featured in a segment of the PBS “News Hour” on March 4, 2014). Many pupils are homeless and most have witnessed or been the victim of domestic and/or street violence. Dr. Carrion estimates nearly a third of children from low-income, high-crime neighborhoods have symptoms of traumatic stress.

“Here, ‘adverse childhood experiences’ means suicide, drugs, sexual abuse, starving,” Dr. Carrion says. “This is the constant life of these children. Not only do they live it, they have reminders of it in their own school.”

In addition to working with the youth, he and his colleagues have been using functional magnetic resonance imaging (fMRI) brain scans to examine how stress can alter brain structures in the young, developing brain. They have confirmed that anomalies in the prefrontal cortex* (the brain’s center for decision making and high-level information processing) and in vital brain structures such as the amygdala and hippocampus (central in learning and memory) develop in some youths who have experienced trauma and/or chronic stress.

While the family situation of at-risk children is not something doctors can directly change, Dr. Carrion says children “can learn to cope if we teach them how.” In the face of much skepticism, Dr. Carrion’s team has shown that biofeedback (learned control over breathing or heart rate, for example) and “mindfulness” training can have a real impact. Mindfulness training seeks to teach young people to stay in the present moment. This involves being actively aware of one’s feelings (for example, through group “checkins” in a therapy session) while also remaining focused on something specific and physiological, such as breathing in and out. In 2010, Dr. Carrion and colleagues published a treatment protocol called CCT, or Cue-Centered Therapy, for traumatized youths.

A key concept in CCT derives from the word “cue.” It points to what doctors and researchers understand to be the brain mechanism underlying post-traumatic stress. In PTSD it is not the trauma itself, but the memory of it, that is causing harm. Over millions of years, we (and other mammals) have evolved a response to stress that features the release of stress hormones such as cortisol. This induces the “fight-or-flight” response. It’s a healthy response to danger––but only when the danger represents a real threat.

For people with PTSD it is often difficult to “extinguish” traumatic memories. When a car backfires, it’s normal to be startled, but not normal to fall to the ground and begin crawling on your belly, as a traumatized war veteran suffering from PTSD might do. One way of approaching the problem is to deal directly with the “cue” (or trigger) that touches off the traumatic memory––to “sensitize” a person to it through repeated exposure, effectively replacing the “fear” memory with a memory of these exposures that involve no harm or threat.

Over the last two years, Bo Li, Ph.D., of Cold Spring Harbor Laboratory, 2014 Freedman Honorable Mention Prizewinner and 2010 NARSAD Young Investigator Grantee, has published remarkable findings that trace fear memories to a precise group of neurons in the central amygdala. Dr. Li was able to pinpoint these cells by training mice to respond to a harmless auditory cue in “Pavlovian” fashion. Whenever they hear a certain sound, which they are trained to associate with a mild foot shock, the mice freeze with fear. Once trained, the mice freeze whenever they hear the sound cue—even when they are not given a foot shock or exposed to any other discomfort. They are acting on the basis of their memory of the unpleasant experience. Dr. Li and other neuroscientists, including Richard L. Huganir, Ph.D., a 1999 NARSAD Distinguished Investigator Grantee, want to know much more about the neural mechanisms behind this reaction, with an eye to moving beyond exposure therapy in attempting to counter it.

Using genetic techniques to “tag” the neurons specifically involved in the fear response in the mouse brain, Dr. Li and his team have recently shown precisely how these neurons in the central amygdala are connected via long-range nerve fibers to the brainstem where the signal is translated into action: mouse muscle cells fire thousandths of a second after the cue is sounded. Precise neural and anatomical knowledge like this is very challenging to identify in the brain, and greatly advances the possibilities for more targeted and effective therapies.

In a bold program of research, Dr. Huganir, of Johns Hopkins University and an Investigator of the Howard Hughes Medical Institute, has been working since 2010 on ways to completely erase fear memories. Dr. Huganir notes that “erasure,” for all practical purposes, is what occurs in people with PTSD when “exposure” therapy succeeds: cues for an unwanted traumatic memory are effectively reprogrammed or replaced, so that they are associated with unthreatening thoughts.

This reprogramming is possible because of the brain’s plasticity, as mentioned in the opening of this article. As we move through life, second by second, day by day, our brain is constantly being reshaped, in a way that directly reflects our experiences. “By sculpting connections between neurons, learning creates new circuits, making new connections, strengthening some, weakening or removing others,” Dr. Huganir explains. “We’ve found that you can remove receptors from a synapse or add them to a synapse, and that this affects the strength of the connection. Or, if you remove a specific mechanism for adding receptors to a synapse, you can affect the ability of mice to retain a memory. They become forgetful.”

This is the train of thought that has led to Dr. Huganir’s remarkable work since 2010 on erasing fear memories. When the brain learns something, nerve cells are adding receptors around the synapses that connect neighboring cells, making connections stronger. Fear memories are learned by neurons in the amygdala. Dr. Huganir has learned in his mouse studies that a window in time opens about a day after a fearful memory is encoded and closes, usually within a week. During this period, a common type of glutamate receptor on nerve cells in the amygdala is replaced with a rare receptor subtype. (Both are variants of so-called AMPA receptors.) The rare subtype is unstable, and Dr. Huganir’s experiments show it can be removed entirely by activating another brain receptor called mGluR1.* When this happens, the mechanism by which a fear memory is encoded is reversed and the fear memory is erased.

Dr. Huganir has found that when behavioral therapy works in recently traumatized animals, it activates the mGluR1* pathway. He suspects that when this happens in the human brain, as in the mice in his experiments, the rare AMPA receptor subtype is destabilized, keeping the linkage between external cues that trigger a memory of a trauma and cause an overreaction in the stress system from fully forming. The caveat, he notes, is that the intervention must occur within that narrow window after a traumatic or stressful event––a day to a week after.

Dr. Huganir’s team is looking for ways to re-open or extend that very specific time window. He envisions a time when behavioral therapy can be combined with medications to activate the mGluR1* pathway, even beyond the brief time after a traumatic event, to prevent bad memories from forming.