It has become commonplace that mental stress is bad for health and people with mental disorders are known to have a higher risk of developing heart disease, diabetes, and significantly shortened life expectancy. Fear is an emotion that in certain contexts can have its constructive effect on personal experience. But when the fear continues for a long time, it can become a source of pathology and lead to mental illness.
The defense system of the amygdala
The fear defense system is an innate system that organizes species-typical defensive responses to threats that promote survival. Activation of defensive behavior begins with an arousal reaction processed by the amygdala that occurs without conscious awareness. The conscious perception of this reaction is the feeling of anxiety. In situations of unavoidable threat, mammals react with tonic immobility. This terminal defense has the function of deactivating the predator’s killing reflex when the mammal has been captured. In humans, this defense is characterized by experiences of numbness, fear, perceptual distortions such as derealization, depersonalization and despair. A similar defense response is collapsed immobility (in humans, for example, fear-induced fainting due to brain hypoxia). The last answer is quiescent immobility, which occurs in the aftermath of periods of acute stress when the mammal is back in a safe environment and recovery is needed.
This defensive response is the brain mechanism underlying clinical conditions such as chronic pain syndromes or prolonged exhaustion. These defense reactions have specific neurohumoral pathways that include the amygdala, hypothalamus, periaqueductal gray, and the sympathetic and vagal nuclei. Innate stimuli or external threats can trigger the fear defense system. In humans, for example, exposure to noise or aversive auditory stimuli represents a natural stimulus that activates the amygdala. Exposure to psychosocial stressors, such as low income and poor housing are widespread external threats that activate the fear defense system with detrimental effects on health and survival. Attachment experiences with parents play a critical role in the acquisition of complex cognitive and affective behaviors and play a unique role in fear conditioning.
Therefore, early adversities in the caregiver such as abuse (physical, emotional, sexual) or neglect of the child’s emotional needs (for example, due to mental disorders of parents or early loss of people who care for people or social adversity) are very powerful stressors for neurodevelopment. These effects are particularly processed by the amygdala and the medial prefrontal cortex. This brain structure is important for social cognition and the regulation of emotions and behavior. Emotions are the main motivational system of human beings and intra- and inter-personal regulators. They can be negatively influenced by character aspects and also by voluntary bad habits (smoking itself, alcohol abuse, drugs of abuse and even common medications).
How the amygdala changes with chronic fear
The amygdala is the brain center of fear processing. Physiologists came to this conclusion in the 1960s when they analyzed the effects of fear on cats. The reaction of these animals to a stimulus that scares them for a certain time, activates the amygdala and triggers their reaction of anger, especially if against a threat they cannot face. More recent studies of neuroimaging applied to animals and humans, have shown that following a mental (or psychological) stress of repeated fear the amygdala accelerates its metabolism, produces free radicals (oxidative stress) and can also undergo actual inflammation. The latter is evident from the cellular infiltrates of cerebral macrophages (microglìa). The increased metabolic activity of the amygdala can induce activation of the bone marrow and thus increased the release of inflammatory cells resulting in increased vascular inflammation.
All this simply through the pathways of the sympathetic nervous system (adrenaline) that regulate fear itself. The same pathways have been elucidated in a sample of patients with psoriasis, a chronic inflammatory skin disease: The increase in the metabolic activity of the amygdala led to the activation of the hematopoietic system with an increase in the release of activated monocytes that stimulate the inflammation and atherosclerosis. Other neuroimaging studies have shown that amygdala activity was associated with basal visceral adiposity, as well as increased visceral adiposity and adiposity-independent development of diabetes mellitus. Again, these detrimental health effects were primarily mediated by the increased pro-inflammatory production of white blood cells induced by activation of the fear defense system. Another practical demonstration of how chronic stress compromises the immune defenses.
Integration with the HPA hormonal axis
The neurochemical cascade induced by maladaptive activation of the amygdala-related fear defense system can result in long-term consequences such as inflammation, atherosclerosis, insulin-resistance and cardiovascular disease. Chronic activation of the amygdala leads to activation of the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal axis (HPA). The HPA axis cascade is highly effective in maintaining allostasis and adaptation to stressful stimuli. In depression, HPA axis activity is associated with high cortisol in the bloodstream and reduced inhibitory feedback. In solitary individuals, HPA axis activation is a consistent result. The HPA axis is mediated by the hormones ACTH and CRF and when stimulated it rapidly releases high concentrations of glucocorticoids.
This results in increased cell metabolism and spontaneous formation of oxygen and nitrogen radicals. The release of glucocorticoids follows the circadian rhythm, with the highest levels occurring in the morning and the lowest levels in the evening. Glucocorticoids govern physiological function, including immunity, insulin sensitivity, cardiovascular activity, reproduction and neurodegeneration. They work by modulating gene expression via their nuclear receptors. Previous results suggest that, beside the nucleus, glucocorticoid receptors can translocate into mitochondria and modulate mitochondrial gene expression. The normal regulation of mitochondrial function by corticosterone is associated with neuroprotection. Treatment with high doses of corticosterone is toxic to cortical neurons; while treatment with low doses, on the contrary, has a neuroprotective effect.
Oxidative stress and mental illness
Mental disorders are associated with increased inflammation. This relationship has been demonstrated for anxiety disorders (post-traumatic stress disorder, generalized anxiety disorder, panic disorder and phobic disorders), somatic symptom disorders and in particular for major depression. In depressed patients, inflammation is associated with neurochemical, neuroendocrine, and behavioral changes. Inflammatory processes increase the production of oxidant species (ROS and RNS) in both brain and peripheral nervous systems. Biomarkers of increased oxidative stress are indeed increased in depressive disorders. Oxidative stress causes premature aging, which is reflected in the shortening of telomeres in patients with major depression and plays a role in the onset and course of depression.
Furthermore, there is a negative correlation between depression and antioxidant status. In patients with major depressive disorder, long-term treatment with antidepressant drugs had positive effects on oxidative damage and inflammatory profile, as well as on antioxidant enzyme activities. Even the integration with molecules that modulate the oxidative and inflammatory state at the same time, seems to have an improving effect on the course of depressed patients, whether they take antidepressants or not. This is the case, for example, with omega-3 fatty acids; vitamin D seems to have a still unclear effect. Finally, psychotherapy can modulate oxidative stress even in patients with major depression. Additionally, through affective tagging (i.e. expressing feelings in words) it may reduce anxiety.
The clinical and social implications
At the population level, actions to overcome social disparities and increase safe and healthy environments would represent measures to reduce anxiety, inflammation and oxidative stress as possible fuses for the emergence of mental illness. But additional population-based approaches are legislative measures to promote antioxidant nutrition and a physically active lifestyle, as recommended by recent guidelines. At the individual level, pharmacological interventions could potentially be useful. Selective serotonin reuptake inhibitors (SSRIs) can reduce amygdala reactivity and oxidative stress. Beta-blockers attenuate central (including amygdala) and peripheral stress-induced catecholamine responses. Statins have anti-inflammatory and antioxidant effects and may be helpful in the course of mental disorders.
It has been at least since 2015, then, that there has been scientific evidence of how dietary supplementation with certain antioxidants has a positive impact on the modulation of anxiety, depression and obsessive-compulsive behaviors. Pilot trials with simple antioxidants such as N-acetyl-cysteine, coenzyme Q and vitamins C and E have been attempted; and the results were judged to be statistically significant. There are already proofs that other molecules such as taurine, melatonin, some polyphenols and minerals (like zinc and selenium) may have a similar effect. Finally, psychological interventions are useful. There are many evidence-based interventions to improve the adaptability of the fear defense system, improve emotional health and improve lifestyle, ranging from intensive mental health care, psychotherapy to mindful meditation to improve self-care. and relaxation.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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