University of São Paulo’s research identifies brain activity associated with resistance to stress

Why are some people more resilient and others more vulnerable to adversity? Many factors – biological, psychological and social – influence how we react to difficulties. Among these, the control or lack of control that is perceived in stressful situations is one of the most important ever discovered. However, little is known about how the brain processes this information.

A study carried out at the Faculty of Medicine of Ribeirão Preto (FMRP) at USP and published in The Journal of Neuroscience investigated the neural activities involved in processing control over stress. The work was conducted by researcher Danilo Benette Marques under the guidance of professors João Pereira Leite and Rafael Naime Ruggiero, in collaboration with Matheus Teixeira Rossignoli and Lézio Soares Bueno-Júnior.

The researchers performed an experiment on rats in which a group of animals received mild foot shocks, which they could escape by jumping over a small wall. Equivalently, another group of animals received the same amounts, intensities and durations of shocks, but in an inescapable way. And finally, another group of subjects did not receive shocks. Meanwhile, the scientists recorded electrical activity from the hippocampus and prefrontal cortex, two brain regions that have been widely linked to the effects of stress and depression in previous studies.

“This experimental design manages to separate the effects of stress per se, that is, which occur for both controllable and uncontrollable stressors, and also manages to distinguish the effects of control and lack of control, which could be understood as a ‘psychological factor’ , because it just depends on how the individual perceives that situation”, explains Danilo.

Most animals that experience uncontrollable shocks fail to escape future presented aversive stimuli, even when these new stimuli are escapeable. This is a very classic psychological phenomenon known as learned helplessness.

On the other hand, animals that undergo a first exposure to controllable shocks become resistant to future stressors, even if these new stressors are uncontrollable and usually escape in tests carried out days later. Originally, this phenomenon was called “behavioral immunization”, as it resembles the immune resistance that the body acquires by facing and defeating an infectious agent or by taking a vaccine. Today, this behavior is better known as learned resistance.

Previous studies report a constellation of effects that occur only, or more markedly, in individuals exposed to uncontrollable stressors, but that do not occur if these are controllable. For example, only uncontrollable stress was associated with increased anxiety, social apathy, exaggerated fear, stomach ulcers, drug sensitivity, cognitive deficits, neuroplasticity deficits and even tumor growth.

The researchers investigated electrophysiological activities that could distinguish animals under stress and predict resistant or helpless animals. Previous studies have shown that pharmacological inhibition of the prefrontal cortex abolishes many of the protective effects of controlling stress. So, it was hypothesized that this area would be more active in a controllable situation. However, this is not what the group found. The study showed that, in fact, the main activities that distinguished the resistant and helpless animals were in the brain waves. Using signal analysis and machine learning techniques, the researchers identified a pattern of activity capable of predicting with great accuracy which animals became resistant to future stressors,

The distinctive neurobiology of resilience
A surprise from the study was that the more distinct neurophysiological pattern predicted resistant (resilient) rather than helpless (vulnerable) animals, which was predicted by the presence of the effects of stress per se but absence of the “neural signature of control over stress” . the stress”. This finding shows that there is a complex neurophysiology behind processes associated with resilience and that vulnerability to stress can, in fact, be due to the lack of these processes.

“Not long ago, it was believed that resilient individuals escaped the deleterious effects of stress that occurred in more vulnerable individuals. Seeking such alterations, evidence has been accumulating that, in fact, it is the resilient ones that present particular biological activities, which are absent in the most susceptible ones. In this sense, it is increasingly recognized that resilience is made up of active, unique and complex neurobiological processes”, says Danilo.

Chemical imbalance?
Findings showing patterns of electrical activity, which represent the dynamic interaction between brain regions, related to stress control suggest a complex neurobiology behind resilience and vulnerability to adversity. These results support the neural network hypothesis, which proposes that depression and resilience are related to information processing in neural networks in a broader and more complex way and not merely to neurochemical imbalances as previously believed.

The study also points to a specific role for theta oscillations in stress resistance. These oscillations represent one of the most studied biological rhythms in mammals and had already been widely related to cognitive processes, learning and memory and emotions. The present work helps to clarify the meaning of this neural activity and shows that it is related to the learning of resistance to stress and the adaptive aspects of coping with adversities.

In an even more recent study by the group, available as a preprint on the bioRxiv platform , the researchers also suggest that the synchrony of various brain regions at theta frequencies is involved in coping with stress, not only when it has an aversive value (e.g.: “ escape a shock”), but also with a positive value (e.g. “getting a reward”). Thus, the positive relationships between this brain activity and behavioral processes associated with resilience indicate a potential therapeutic use.

therapeutic potential
Traumatic experiences are risk factors for the origin of mental disorders that are quite common today, such as major depression, generalized anxiety and post-traumatic stress disorder. The prevalence of anxiety and depression has increased.

Although some patients respond to first-line treatments, a significant portion does not respond or responds only after several attempts at different treatments. In this sense, the identification of biological markers of treatment response (“biomarkers”) can contribute to more effective therapeutic decisions for psychiatric disorders.

“The discovery of an electrical activity in the brain associated with resistance to stress could serve as a biomarker, which could be verified by electroencephalography (EEG), and which would help to decide better personalized treatments for depression, anxiety and post-traumatic stress disorder” , says Rafael Ruggiero.

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In fact, a recent analysis of several studies known as a meta-analysis evaluated dozens of studies reporting potential EEG markers of response to treatments for depression and pointed to activity in theta in the frontal cortex as the most consistent, being reported by different groups of patients. research and for different treatments, such as medications, transcranial magnetic stimulation, deep brain stimulation and even placebo.

“The finding of a neural rhythm associated with resistance to stress can also help to optimize psychiatric treatments based on brain stimulation, so as to bring them closer to the ‘natural’ neurophysiological processes involved in resilience”, says João Leite.

In agreement with the group’s experimental findings, stimulation of the prefrontal cortex at theta rhythm, known as theta-burst stimulation , is used in the treatment of depression. Recently, this protocol was developed into a guided version based on customized frontal cortex functional connectivity data, which showed remission rates of resistant depression between 80-90% of patients.

Finally, the group believes that the combination of analyzes of the brain’s electrical activity and machine learning tools in patients can help decide and optimize treatments for stress-related mental disorders. Currently, the group is studying how neural oscillations are involved in other behavioral dimensions related to resilience or vulnerability to stress and intends to investigate the therapeutic potential of modulating these neural rhythms.