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Jane Wagner’s words, “reality is the leading cause of stress amongst those in touch with it,” highlight the dire truth that day-to-day life is stressful and, all too often, traumatic. Stress and trauma are not rare and isolated events; it is estimated that 70% of the world’s population is exposed to trauma [1]. However, resilience is the norm rather than the exception. Approximately 6% of trauma-exposed individuals will develop posttraumatic stress disorder (PTSD). Like all psychiatric symptomology, stress response symptoms occur along a continuum and many people will experience some level of symptoms with great variability across populations [2].

Currently, given the shared experience of stress and trauma secondary to COVID-19 as well as civil and political unrest on top of everyday stressors, we are facing compound stress seeping in and disrupting many aspects of our lives—leading to increased anxiety, depression, impaired sleep and poor nutrition. This goes without mentioning the added mental burden of safety precautions, separation from loved ones, fear for our own lives and well-being as well as those of our loved ones, and the economic burden of job loss or financial instability. Struggle, in one form or another, is something most everyone is going through right now, and yet many people are questioning why they aren’t “OK.” Neurobiological and behavioral studies both suggest stressors that are perceived to be uncontrollable, inescapable, unpredictable and unmanageable all lead to increased distress and impairment [1]. Returning to baseline is to be expected, either with stressor relief or psychological adaptation. These are unprecedented times; we are living through a globally shared significant trauma. For those who were already experiencing stress- and trauma-related symptoms, these times may have caused a worsening of symptoms while for others it could reflect an onset of symptoms. Either way, these are normal reactions to a highly abnormal set of circumstances and there are neurobiological underpinnings to these symptoms.

Evolutionarily speaking, the stress response is beneficial and advantageous for the sake of human survival [3] and is shaped to regulate multiple physiological responses regarding threats and opportunities [4]. The stress response is not genetically fixed or otherwise predetermined, but rather follows the developmental plasticity that causes variability in stress responses between one person and another—even for a single individual, responses can vary across time and specific circumstances—allowing an individual to fine-tune and adapt their stress response according to their histories, events and environments [5]. The stress response is a very delicate, refined response that has multiple physiological components including the hypothalamic pituitary (HPA) axis responsible for adrenocorticotropic hormone (ACTH) which stimulates cortisol, a stress hormone that when chronically increased has been implicated in impairment of neurogenesis and neuroplasticity [6] as well as opiate-like peptide production. The stress response also includes the autonomic nervous system which is responsible for epinephrine and norepinephrine production, primary pilots of the fight-or-flight reactions. These physiological responses are orchestrated by a specific brain region called the amygdala—the leader of the amygdaloid complex comprising 13 nuclei that include the hippocampus, hypothalamus and the prefrontal cortex (PFC)—sending signals to the hypothalamus and activating the stress response [7].

As finely calibrated as the stress response is, any alteration in intensity or duration of the stressor can lead to malfunctioning of any of its components. For example, there is evidence that, while acute stress can cause improved cognition [8, 9], chronic stress is linked with cognitive deficits  explained by synaptic loss and neurotransmitter disturbance in certain brain regions such as the PFC and hippocampus [10-12]. On the other hand, the intensity of the stressor effect is still unclear and can be related to multiple outcomes ranging from increased arousal to a blunting of response that is sometimes expressed as an “escape” mechanism [13]. It is theorized that the correlation between stress intensity and learning, memory and plasticity takes an inverted “u” shape where increased intensity increases arousal to a certain point where the stress effects peak and any further increase in intensity starts causing decreased arousal [14].

In PTSD, recent evidence from neuroimaging studies has showed decreases in grey matter volume that is measured as cortical thickness in certain brain regions including the prefrontal cortex, the limbic system comprising the amygdala and hippocampus, and the striatum [15, 16]—all regions that play an important role in stress response. Any decrease of neuronal density causes alterations and potential dysfunction in the stress response. Furthermore, subgroups of PTSD have trauma frequency-based findings. For example, in a subgroup exposed to one traumatic incident, grey matter reductions were found in the bilateral medial PFC (mPFC), anterior cingulate cortex (ACC), left hippocampus and amygdala, while the subgroup exposed to chronic long-term trauma showed grey matter reductions in the left insula, striatum, amygdala and middle temporal gyrus but not the mPFC. One hypothesis to decipher this is that for acute single-incident traumas—especially in childhood—mPFC is easily impaired due to its increased susceptibility to stress as it fully develops later during adolescence [17].

To say that the stress response varies among people and populations is an understatement—but nonetheless findings in patients with PTSD showcasing the neurobiology of trauma prove that the stress and trauma response is not only an emotional or cognitive experience, but in fact many physiological and neurobiological alterations are happening that underlie these reactions. Importantly, there is evidence that these neurobiological alterations can be reversed through methods such as psychotherapy, which has been shown to increase neuroplasticity [18], and neuroprotective drugs used in reducing neurotoxicity and decreasing progression of—sometimes even reversing—synaptic dysconnectivity that underlies stress-related psychopathologies [19, 20]. Furthermore, resilience-building activities that can be carried out on an individual level with little to no need for equipment, special space, cost, etc. (such as meditation, practicing gratitutde and exercise) can have a great impact, not only making people feel better but also helping to support cognitive reframing and attention control—all of which can reverse synaptic dysconnectivity alterations and increase neuroplasticity on a longer term basis [1, 21, 22]. In these challenging times, in the COVID-19 era, it is important to remember that stress has wide-reaching effects, that likely few people are 100% “OK,” and that any symptoms or neurobiological changes one might experience are not a permanent sentence and there are many things that can be done to improve our well-being.

About the Author

Dr. Samar Fouda is a postdoctoral associate at the Clinical Neurosciences Division of the National Center for PTSD and Yale School of Medicine. Samar's research interests include neuroimaging in stress- and trauma- related psychopathologies, neuropsychopharmacology, and suicidality, with particular interest in child and adolescent psychiatry. Samar has a medical degree from Egypt and is applying to psychiatry residency in the next match cycle.


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