We may have unlocked some of the secrets of treating anxiety and depression

If you’ve ever suffered from anxiety or depression, you’ll be aware of cognitive behavioural therapy (CBT). It’s commonly used to treat such conditions by focusing on coping strategies to break negative mental cycles.

During years of treatment, CBT has been shown to be a potent technique for tackling a range of conditions, from phobias to post-traumatic stress disorder (PTSD), but the neurological reasons for its effectiveness have largely remained a mystery.

A new study from the University of Texas Health Science Center attempts to throw a light on this mystery, and the brain’s reaction to CBT by simulating the psychological therapy on chronically stressed rats.

“We used a procedure called extinction learning,” says David Morilak, professor of  pharmacology and lead author of the study. “The rats were first taught to fear a neutral stimulus, a tone, that was paired with a brief mild footshock. So the tone ‘predicts’ something bad is about to happen, and after only a few pairings, the rats have learned to fear the tone because they freeze when they hear it.

“Extinction is then another form of learning, in which we next expose them, in a different context, to the same tone several times without any shock. They learn that in that context, the tone does not predict shock, and they stop freezing.”

The researchers honed in on an areas of the rats’ medial prefrontal cortex (mPFC) called the infralimbic cortex; a part of the brain that’s important for creating fear, and one that tends to be dysregulated in those with depression and PTSD. Such psychiatric disorders share a number of characteristics, with chronic stress being a risk factor as well as a common symptom as a type of impairment called cognitive inflexibility – an inability to adapt to changes in the world:

“In PTSD, the extreme response that soldiers acquire to cues that signal imminent danger is important to survival, and is adaptive in that environment,” explains Morilak. “But when they return to the home environment, the same cues do not signal danger, and they have to modify those responses to function optimally in that environment. In depression, people tend to interpret everything in their world within a very rigid framework – it is negative, it is threatening, and it is their fault, and information to the contrary does not change those perceptions.”  

In both of these cases, cognitive inflexibility is consistent with a tendency for the mPFC to have a decreased functionality. In a nutshell, the “extinction learning” given to the rats was an attempt to kick-start cognitive flexibility and improve activity in the infralimbic cortex.

Stressed rats

To create cognitive inflexibility in their rats, the researchers exposed the animals to a different stressor every day for two weeks, with the unpredictability and chronic nature of this making the experience psychologically stressful.

After this period, the rats were put through an attentional set-shifting test (AST), where they had to find a Cheerio in a gauntlet of different cues. After they found the reward, the rules were changed and the animals had to shift their approach to find a new piece of food. The stressed rats performed more poorly in the test, linked to a reduced response in the mPFC.

A different part of the experiment measured coping behaviour in the rats using a test called the “shock probe defensive burying test”. In this test, the rats were faced with an electrified probe in their cage.

“Some will adopt what we call a passive coping style – they turn away from the probe and freeze,” says Morilak. “Others assume a more active response, burying the probe with the bedding in their cage. We have shown that the active response reduces stress, and it is well known in the human literature that active coping is healthier and more effective than passive coping.”

The study, published in JNeurosci, revealed that chronic stress shifts coping mechanisms from an active to a more passive style, but when the rats were treated with extinction therapy, more were found to actively do something about the problem; i.e., the electric probe.

Improving CBT

The “therapeutic” effects of extinction therapy in rats are thought to be analogous to exposure therapy and cognitive behavioral therapy (CBT) in humans, although Morilak acknowledges that rat brains are less complex than human brains, and that illnesses such as PTSD have a number of complex symptoms, from avoidance behaviour to aggression.

“Rats can’t tell us how they feel, and we do not attempt to create a ‘depressed’ rat,” he notes. “But we can recreate behavioural changes that resemble symptoms in human illnesses, and relate them to dysfunction in the same brain regions. This allows us to study those processes in rat brains in ways that are meaningful to understanding what is going on in the human brain.”

One part of the study saw rats injected with a virus that allowed the researchers to selectively shut off the mPFC during the extinction procedure. The subsequent lack of improvement in their stress is a strong indication that this area of the brain is essential to the beneficial effects of the “therapy”. The researchers believe that, taken together, these results could be key to understanding the neurological processes behind CBT in humans.   

“Aside from learning about the basic functions of the mPFC, which is important, the significance of this research is that it gives us a valid model to study the mechanisms of behavioural therapy,” Morilak tells Alphr.

“Hopefully, once we identify the mechanisms responsible for the therapeutic effect, we can potentially improve therapy, for example by combining it with drugs that might specifically enhance those processes responsible for restoring activity in the mPFC.”