I’ll never forget it. They strapped electrodes to my wrist, cranked up a black dial on a frightening electronic device encrusted with switches and knobs, and shocked me repeatedly with jolts of electricity. No, this was not torture and the memory is not a traumatic one. I was inside the laboratory of Dr. Daniela Schiller, a psychologist at Mt. Sinai Medical School in New York City, experiencing the same treatment that she and her coworkers used to discover a new way to alter traumatic memories. The latest research from her team provides a method to blot out traumatic memories that are stored in a part of the brain called the amygdala, not just suppress them as current treatments for PTSD do, but to alter the memory itself.
Just as the participants in this study did, I watched a computer screen while my right wrist was wired up to an electrical stimulator to deliver a painful shock. A second set of sensing electrodes, two black Velcro strips with wires attached, were strapped like rings around the pads of two fingertips on my left hand. These sensed the amount of nervous perspiration I produced. Sweaty palms are an involuntary reaction to threat; part of the body’s fight-or-flight response that braces the mind and body to defend against an attacker or flee to safety. The heart pounds, stomach churns, muscles twitch with adrenalin-fueled energy, sweat beads up on our forehead and mental focus sharpens to rev up all systems in the body to survive a potentially deadly danger.
These are the bodily sensations of fear, and they are the same reactions in people suffering panic attacks and other anxiety disorders. Fear is a life-saving rapid response, but in some people with anxiety disorders or PTSD, the overwhelming fear becomes debilitating. The problem inside the brain is that panic is triggered inappropriately by stimuli that are unrelated to real threats. Terror can grip them without warning, sometimes crippling their lives. Sleep may become impossible. Others may fear venturing outside or cannot fly in a plane. A military veteran may panic suddenly upon hearing a sound connected in their memory to a past trauma.
New research published this week in the Proceedings of the National Academy of Sciences reports a new discovery of how the brain records and regulates threatening memories. To understand this new finding, it is helpful to know more about threat memories and how PTSD, panic attacks, and other anxiety disorders are treated currently.
Treating anxiety disorders
Current behavioral therapy for treating anxiety disorders utilizes exposure therapy. This is based on animal research in which a painful stimulus becomes associated with another stimulus that is not in itself dangerous. For example, if a rat hears the sound of a bell and then receives a mild electrical shock, it will quickly learn that the bell heralds a nasty jolt of pain to follow. Sound the bell again and the rat freezes in fear even if you do not shock it. This conditioned fear response is how many of us learned as children not to stick hairpins into an electric outlet or play with matches.
Eventually we lost our fear of matchboxes and electric outlets after many subsequent experiences with them that were harmless. This is how exposure therapy works. A soldier who survived a harrowing roadside bombing in Afghanistan might develop extreme anxiety about driving a car. Therapists may treat this disabling fear by having the person drive in a safe environment repeatedly until the terror of the bombing connected in his memory with driving gradually subsides. This can be helpful, but frequently exposure therapy is not effective.
“Some of the bravest people I know are people with PTSD,” Schiller told me as I sat wired up to her experimental apparatus, because unlike individuals who may indeed be fearless, people with PTSD courageously cope with ceaseless terror and persevere in their daily lives.
Rather than suppress the fear, it would be better to break the connection in memory between the bombing incident and the normal experience of riding in a car.
“That memory can change is a natural process that is occurring every day of our lives. We pretty much create a false memory on a daily basis,” Schiller says. So rather than suppress the fear, the scientists set out to change the conditioned fear response recorded inside the brain.
Memory track overdub
Scientists have learned a great deal about how memories are recorded and how emotional memories are suppressed. A paired structure deep inside the brain called the amygdala is an important focus of activity for threat detection, learning, and controlling the body’s emotional and physiological response to danger. The prefrontal cortex, just behind the forehead, can inhibit neural activity in the amygdala and suppress its reaction to a threatening experience. This circuitry from the prefrontal cortex is how exposure therapy suppresses anxiety and fear.
Neuroscientists have also recently learned that when a specific memory is recalled, it becomes vulnerable for a certain window of time to being altered or even eliminated. Recalling a memory is something like pulling a book off the library shelf for review. The book is now subject to alteration or destruction, and it must be placed back in the proper place on the shelf. Disrupt a person’s attention in the middle of browsing, and the book can be easily misfiled. The process of reshelving a memory immediately after it is recalled is called reconsolidation, and research has uncovered the details of how this works down to the specific molecules in synapses that encode information.
Reconsolidation may sound odd, but it does make sense when one considers what memories are for in the first place. Fundamentally, memories allow us to use past experience to direct our behavior appropriately in the future. This means that memories need to be updated, because things change. Your memory of Obama has certainly changed since the first time you heard the name, for example. The memory has become richer, linked with many other experiences, and separated from others that are no longer relevant and forgotten.
“In principle, reconsolidation suggests that in order to change memories one must first retrieve them,” Schiller explains. She deduced that rather than trying to suppress the person’s fearful response to driving, for example, by repeated experiences driving in a safe environment, one might break the terrorizing connection between the traumatic memory of the roadside bombing and the normal experience of being inside an automobile. If the traumatic memory is recalled, it should become especially sensitive to being extinguished. The electrodes on my wrist were how Schiller and her team set out to test the idea.
A blue square flashed on the computer screen. Shortly thereafter a purple square appeared followed by a painful jolt of electricity that made my fingers clench automatically. Ouch! Meanwhile signals from the electrodes testing the perspiration on my fingers traced out a graph on a computer monitor that the scientists were watching. The trace being graphed out in real time shot up the instant I was shocked. Pain triggered my body’s flight-or-flight response.
The next time the purple box appeared on the screen the trace showing my perspiration level spiked again–even before I was shocked. My amygdala had already learned to associate the purple square with the shock. Seeing the purple square tripped my body’s fight-or-flight response just like driving would do for the veteran with PTSD. In contrast, the blue square appearing repeatedly on the screen caused no rise in my perspiration or anxiety. That blue square was safe. Subjects in these experiments will show the same automatic anxiety reaction to the purple square when tested days later.
Now if the scientists began to flash the purple square over and over again without giving the shock, the stress response to the purple square will diminish with time. This is because the prefrontal cortex has learned that bad things don’t always happen every time one sees the purple square, and it sends inhibitory signals to the amygdala to suppress its threat response. Schiller and colleagues, including among others neurobiologist Joseph LeDoux and psychologist Elizabeth Phelps of New York University, were able to see this happening by having the subjects participate in these experiments while inside an fMRI brain scanner. They saw that the prefrontal cortex was becoming active in addition to the amygdala during extinction, and the functional connections between it and the amygdala were growing stronger. However, when these subjects were tested a day later, the fingertip stress monitor showed that seeing the purple square often triggered the treat and fear reaction again. Exposure therapy helped, but the feared connection between the purple square and an electric shock was still recorded in memory inside the amygdala.
A new approach–recall and revise
Next the team tested whether the mechanism of reconsolidation could be exploited to break the connection between the purple square and the electrical shock. To do this, they simply reminded the person of this connection by flashing the purple square on the screen and delivering the shock. Then they followed up immediately with exposure therapy (flashing the square repeatedly without an electric shock). Doing this proved to be far more effective in reducing the stress response to the purple square than if they had used extinction therapy without first reminding the participants of the threat. By monitoring changes in the brain’s activity using an fMRI they could see how this was working inside neural circuits.
Two things could explain why extinction therapy during the reconsolidation period is more effective. It could be that the prefrontal cortex was strongly inhibiting the memory of threat connected to the purple square, or alternatively, the connection between the purple square and the painful shock stored in the amygdala could be diminished. The fMRI showed that the prefrontal lobes did not become activated when the purple square was flashed in people given extinction therapy during the period of memory reconsolidation. In essence the brain (amygdala) had forgotten the connection between the electric shock and the purple square, because the prefrontal cortex was not being activated to inhibit the threat memory. (To be precise, the experiments used various necessary controls that involved three colored squares, one that was used for extinction therapy and one that was used for extinction during the memory reconsolidation period, so that they could compare the efficacy of each approach in each individual.)
To put this new laboratory finding into a real-life scenario, imagine that you are bullied at the school bus stop by neighborhood thugs John and his delinquent brother Greg. Their sister Betty never bothers you, but every time you see John or Greg you become anxious and fearful. If days go by without either brother bothering you, your body’s threat response will gradually subside, but you haven’t forgotten that they are potential threats. An fMRI of your brain would show that your prefrontal cortex was suppressing the threat response in your amygdala from John or Greg attacking you in the past. This is how extinction operates at the level of neural networks.
One morning, John bullies you again when you arrive at the bus stop, but immediately after he reverses his behavior and is friendly toward you. Then days go by without any harassment from either brother. The next time you see John and Greg, what happens? Your body does not react in fear to the sight of John, but when Greg approaches your heart races.
An fMRI would show that there is less neural activity between your prefrontal cortex and amygdala when you see John than when you see Greg. In fact, your body’s defensive response when seeing John is no different from that provoked by seeing Betty. The explanation is that the recent bullying by John forced you to recall the memory of him as a bully, and doing that made the memory subject to being changed. When John began to behave in a friendly manner toward you while the recent bullying incident was being reshelved in your memory, the original conditioned reflex that connected him with a threat was modified by the new experience.
In contrast, your memory of Greg as an aggressor had not been recalled so the conditioned response to him recorded in your amygdala remained intact. Your fear response to seeing Greg in several subsequent friendly encounters was suppressed by the increased activity in your prefrontal cortex inhibiting the fear memory in your amygdala, but your prefrontal cortex did not intervene to suppress the fearful response to seeing John. The research shows that the process of extinction works far better if the traumatic memory is first recalled rather than extinction therapy given at any other time.
This fictional scenario conveys the gist of the new findings; how this might actually play out in real life goes well beyond the controlled findings in the laboratory experiments and several other factors would enter the mix and likely affect the outcome. The important concept is that extinction therapy works better if applied right after recalling the traumatic memory rather than if it is applied at other times, and that there is a critical window of opportunity to modify a memory during the brief period when it is being reconsolidated.
“We hope that the reconsolidation window would prove useful for treating PTSD,” Schiller says. “This would require some modifications in current therapy to specifically target this phase of memory.”
Professor of Neurobiology at the Weizmann Institute in Israel, Yadin Dudai, who was not involved in the study, agrees with Schiller that these new findings are a promising beginning for developing new treatments in the future, but more research is needed.
“In real life, PTSD is very persistent, it involves a very dense web of associations and lingers or even becomes intensified over years and decades,” Dudai explains. “Incidentally, I had a conversation last week with a colleague who experienced trauma in combat 40 years ago. This still haunts him at nights.”
People wishing for better therapies for anxiety disorders should welcome this new research but it is important not to overstate the new scientific understanding in terms of immediate new therapies. “We learn a lot from these studies on how elementary building blocks of memories are retained and updated, but we have to be careful in invoking excessive hope prematurely that results from models, as important as they are, will quickly translate into treatment,” Dudai says.
Nevertheless, new information about how connections from the prefrontal cortex to the amygdala operate in overcoming fears that are conditioned by experience, provides some interesting insights into why some people may be more likely to develop anxiety disorders or PTSD than others. These brain connections may be stronger in some people than in others.
Commenting on this new research, psychologist BJ Casey, Director of the Sackler Institute at Weill Cornell Medical College, (who was not involved in the study), says “These findings are very exciting and have important implications for novel evidence-based treatments of not only PTSD, but other forms of anxiety and stress related disorders such as phobias.” Drawing parallels to her own research on adolescents, she sees some interesting implications, because the prefrontal cortex is not fully developed in adolescents. Thus adolescents may not be able to suppress threat responses in the amygdala as effectively as in adults.
“We have previously shown diminished extinction learning in adolescents due to the maturational changes in the prefrontal cortex,” Casy says. The new findings using extinction therapy during the reconsolidation period could be especially effective in treating adolescent anxiety because it bypasses the need for regulation of emotional responses from the prefrontal cortex.
Despite the important value of this memory research in treating anxiety disorders, some may find the fact that scientists can change memories disconcerting. Dudai agrees, but observes: “Any development of a potential therapeutic tool is accompanied by justified concerns. Even swallowing Tylenol may be harmful.”
Schiller understands the concern too, but agrees with Dudai. “Like any finding in science, this finding can be misused, but it is our social responsibility to find treatments for PTSD, especially when putting soldiers and Special Forces at risk.”
As I watched my brain and body respond automatically to the threatening squares, I was astonished by how robotic it all seemed. There was nothing I could do to control it. I felt some sense of what it must be like for people living with anxiety disorders that overwhelm them suddenly in ways that are entirely beyond their ability to control. As researchers uncover how our brain encodes memory, updates it, and they trace the neurocircuitry that connects emotional fear and threat reactions to specific triggers, we are coming closer to developing better therapies that are based on neuroscience to overcome phobias and anxieties, and break the cycle of reliving horrific post-traumatic terrors.
Schiller, D., Kanen, J.W., LeDoux, J.E., Monfils, M.H., Phelps, E.A., Extinction during reconsolidation of threat memory diminishes prefrontal cortex involvement. Proc. Natl. Acad. Science, USA, on-line in advance of print, doi/10.1073/pnas.1320322110.