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Key points
- Fear is stored in nerve cells in the frontal cortex of the brain.
- “Simple” fears can often be overcome by repeated exposure in a safe environment.
- In severe anxiety and post-traumatic stress disorder, fear is so encoded in the brain that a different approach is required.
- MDMA and psilocybin can reduce activity in the amygdala and increase neuroplasticity, allowing people to approach their fears.
by Mikael Palner, Ph.D.
For a short period of time, I tried rock climbing. I wanted to enjoy it, but my legs shook when I stood on the rock, and my hands were so moist that I kept slipping. Even though I knew that I was supported by the rope, I felt like I was going to die. I'm sure most people are familiar with that acute, terrifying feeling of anxiety.
Fear of heights in mice
Fear and anxiety are perfectly normal physiological phenomena, intrinsic to all animal species. They are also some of the emotional reactions we know most about.
Researcher Jun Liu of Drexel University College of Medicine in Philadelphia has, among other things, studied fear of heights in mice. He inserted an electrical wire into the amygdala of a mouse—an area of the brain that we know is involved in fear. When he lifted the mouse off the floor, some specific nerve cells began to generate electrical signals: He was able to identify nerve cells in the amygdala that became active when the mouse was exposed to danger.
But why is it that perfectly safe situations can also cause fear and anxiety? And where do those memories of fear “hide” in the brain?
Ivan Pavlov's drooling dogs
In one of the most classic experiments in neuroscience, Russian neurologist Ivan Pavlov trained dogs by whistling before giving them food. At first the dogs would salivate only when they got food, but Pavlov noticed that after a while, the dogs began to salivate preemptively when they heard the whistle.
This discovery, later called Pavlonian conditioning, is also used in fear research, where a fearful experience— such as an electric footshock—is paired with a non-fearful cue, like a light turning on.
After learning that the footshock and light are paired, animals exhibit a behavior when the light turns on that is like the one they exhibit when they receive a footshock.
Where do we store memories of frightening experiences?
A team of researchers led by Jun-Hyeong Cho of the University of California, Riverside, has used Pavlonian conditioning to investigate where the memory of light = foot shock is stored in the brain.
First, they used a special technique whereby nerve cells were colored red. Then they exposed the mice to a light and a footshock and looked for red nerve cells in the brain.
They found nerve cells in the amygdala, hippocampus, and frontal cortex that were colored red when the mice were exposed to a combination of light and footshock. They were able to follow the development of these nerve cells as the memory of light = foot shock was encoded in the brain over the following days of conditioning experiments. They discovered that nerve cells in the frontal cortex started forming new connections to other nerve cells in the frontal cortex—new synapses—as the memory of fear was saved. However, nerve cells in the hippocampus and amygdala stayed the same.
The notion that light = footshock was therefore "saved" in the brain by the formation of new synaptic connections between nerve cells in the frontal cortex.
Can you delete fear?
The groundbreaking part of Cho’s study was that when they turned off the fear-encoding nerve cells in the frontal cortex, the mice were no longer frightened when the light was turned on. It showed that these nerve cells are necessary for mice to remember that the light and the footshock are connected.
One of the most effective ways to overcome fear is repeated exposure to a frightening stimulus in a safe environment, a technique of cognitive behavioral therapy. As an example, my own fear of heights gradually improved after spending more time dangling from a rope.
When Jun-Hyeong Cho and his team conducted a similar experiment with mice, they found that the nerve cells in the frontal cortex that remembered the fear became less and less active when the mice were exposed to the light without a subsequent footshock.
Can all fears be unlearned?
Fear of heights and footshock are simple fearful conditions. And it is easy to use cognitive behavioral therapy to expose a person to their fear in a safe environment. But in some cases, as with post-traumatic-stress disorder (PTSD), fear is so encoded in the brain that it's hard to control the body’s reaction—even in a safe environment—making it very hard to expose people without getting a massive fear response and possibly a new traumatic event. In severe anxiety and PTSD, there is therefore often a need for more than just exposure in safe environments.
MDMA and psilocybin as a new approach to fear
One way to unlearn fear is to use drugs that enable a person to approach their fearful memories—under the guidance of a therapist—without a massive body response and, as a result, promote changes in nerve-cell connections.
MDMA (also called ecstasy) has recently been shown to have a beneficial effect in reducing anxiety and PTSD, and psilocybin has in multiple studies shown positive effects on end-of-life anxiety. These substances work partly by reducing the activity of the amygdala, thereby creating a smaller acute fear response. In addition, they increase neuroplasticity, the brain's ability to form new synapses. These drugs are always combined with therapy, in what is called psychedelic-assisted psychotherapy. The goal of psychedelic therapy for PTSD and anxiety is to change the connections between the nerve cells that remember the fearful events.
MDMA and psilocybin are not yet approved for treatment in the U.K., U.S., or E.U. But MDMA has just undergone a major clinical trial in the United States with positive results. Psilocybin has also shown positive results, especially for end-of-life anxiety, and is currently being assessed in several clinical trials. In Australia, certain authorized psychiatrists will soon be able to prescribe MDMA and psilocybin for specific treatment-resistant mental illnesses, and maybe the rest of the world will follow soon.
Mikael Palner, Ph.D., is associate professor and head of Preclinical Imaging Core Facility at the University of Southern Denmark. He is a research team leader at the neurobiology research unit at Rigshopitalet in Denmark and an independent consultant in translational pharmacology. Dr Palner has a Ph.D. in neuroscience from the University of Copenhagen and a M.Sc. in biotech engineering.
