The complexity of an emotion.

Andreas Lüthi from the Friedrich Miescher Institute in Basel disagrees. He and his team use experiments on mice to decipher the mechanisms behind normal and pathological fear in the brain. “We are only at the very beginning,” says the neuroscientist. “We might recognize certain circuits in the brain and know, for example, that the amygdala plays a key role in evaluating emotions related to specific situations. But our findings up to this point, such as neuronal activation that correlates to a mouse’s flight or freeze response, are ultimately just highly simplified descriptions of the brain’s activities.”

Lüthi and his team are studying what happens in a mouse’s brain when it responds to fear, for example, when it is placed in a wide-open space without a place to hide. To observe the activity in the brain, the researchers use novel imaging methods that have revolutionized the field of neurological research over the past several years. Such innovations include a miniaturized microscope that is attached to the head of a free-roaming animal and can differentiate between individual neurons in the brain.

Circuits and probabilities

Of course, the mouse’s fear cannot be mapped directly to activity in a single, isolated circuit; it is the product of interactions between multiple neuronalensembles. If one group of neurons fires, this increases the probability that another group will be activated, too. “The neuronal activity that we have discovered is not purely a representation of motor activity; it is contingent upon the animal’s expectations and the positive or negative evaluations that the animal associates with the situation,” reports Lüthi. If the mouse remembers repeatedly finding food in a particular room, that decreases its natural fear of the unprotected space. The activation cascades proceed differently in this situation than if the mouse were to recall an encounter with an aggressive rival.

The human brain also produces expectations based on past experiences. The fear of seizing up before an examination committee or a large audience can be so paralyzing as to cause a student to quit their training and avoid public speaking at all costs.

When fear becomes unmanageable, people seek out help. Undine Lang sees many such cases at UPK Basel. “Normally, these anxiety disorders can be treated easily. If the patient does not have any other disorders, the success rate is between 80 and 90 percent,” explains Lang. Yet pathological fear is often accompanied by comorbidities such as depression or secondary addictions. That makes the treatment more complicated. By the time patients arrive at UPK Basel, they usually have a long history of suffering. Many have tried unsuccessfully to regulate their anxieties with alcohol or narcotics. Psychotherapy, combined with medication as needed, is a far better treatment plan.

Focusing on strengths

In psychotherapy, patients and therapists work together to develop a strategy to stop anxiety in its tracks. “One way to achieve that is through acceptance and commitment therapy, or ACT, for short,” explains Lang. In this therapy, patients learn to accept their anxiety and develop the psychological flexibility they need to better handle their condition. What values are important to the patient? What skills, talents and strengths can they build on to shift mental resources away from their anxieties? In the past, Lang recalls, therapy used to focus primarily on combating symptoms. In most cases, this proved a waste of time, as the anxiety did not subside. Today, the goal is to find ways for the patient to, for instance, meet with friends, go to the gym or travel despite their anxiety.

UPK Basel is also studying alternative therapy options to improve treatment for people with conditions involving severe anxieties. “For us, the key task is to scientifically test whether a novel therapy is actually effective,” emphasizes Lang. Her list includes therapies employing psychedelic substances such as psilocybin and LSD, the potential of the gut-brain axis as well as movement and animal-assisted therapies and even digital therapies.

At the same time, basic researchers such as Andreas Lüthi are looking to lay the groundwork for new therapeutic approaches. In a 2021 article published in the journal Nature Communications, his team, together with a group of international colleagues, demonstrated how deactivation of a particular microcircuit buried deep within the brain allows mice to selectively unlearn the fear response. Someday, it may be possible to cure anxiety disorders using a similar approach. But for now, these discoveries are simply a first step in the right direction.