By Nicole Lookfong

The COVID-19 pandemic has created psychological consequences within the population, such as an increased risk for developing post-traumatic stress disorder (PTSD), by way of chronic stress, increased perception of threats, rising mortality rate, and limited resources^1. Normally, the prevalence of PTSD in the United States is 7-8%, with individuals experiencing symptoms such as avoidance, intrusive thoughts, negative alterations in cognition or mood, arousal, and reactivity symptoms^2,3. In the midst of the COVID-19 outbreak in June of 2020, the CDC released a survey that showed trauma/stressor-related disorder symptoms had risen by 26% because of the pandemic¹. In particular, emergency healthcare workers are becoming more susceptible to mental health problems, as prior to COVID-19, first-line responders’ risk of developing PTSD ranged from 10%-20%, and the risk was higher within the intensive care unit at 8%-30%^{4,5,6,7,8,9,10}. These healthcare workers’ risk for PTSD can increase during pandemics due to increased patient flow, high daily fatality rates, physical isolation to protect patients, and a high risk of contamination^11,12,13. Understanding the biological mechanism of PTSD and how it translates to behavioral symptoms is crucial to inhibit the severity of its progression.

One way to study the mechanism of PTSD is using fear conditioning in animal models, a form of classical conditioning that takes advantage of highly adaptive natural learning processes to generate fear memories towards normally unthreatening stimuli¹⁴. In fear conditioning, an unconditioned stimulus is paired with a neutral stimulus, allowing individuals to avoid aversive events by remembering the event’s contextual cues¹⁴. For example, picture a mouse hearing an auditory tone and receiving a foot shock at the same time (fig 1) ¹⁴. The auditory tone in this case is the neutral stimulus or the contextual cue, while the foot shock is the unconditioned stimulus or the traumatic event¹⁴. The mouse will start to associate the unconditioned stimulus (the foot shock) with the neutral stimulus (the auditory tone), forming a fear memory that results in the unconditioned stimulus (the foot shock) becoming a conditioned stimulus (fig 1)¹⁴. A conditioned stimulus is a specific context or cue that produces a response with the same physiological and behavioral effects as the unconditioned stimulus (foot shock), long after the trauma itself¹⁴. Individuals with PTSD may be aware of their conditioned stimuli, such as combat veterans who are reminded of potential bombs by everyday objects like unmarked packages¹⁴. However, those same veterans may see sudden movement in their periphery and experience a fear response they didn’t know they had, becoming hypervigilant to triggers and reminders of their trauma in order to avoid them¹⁴. Due to COVID-19, we wonder what contextual cues may become triggers for individuals who develop PTSD from the pandemic.

To understand how contextual cues become triggers, it is important to look at the neurophysiology behind PTSD. The amygdala, which is the primary region for fear and stress, has been extensively studied to understand mechanisms of fear memory formation in PTSD research^16,17. In the above example of the mouse who received a foot shock and auditory tone, sensory information about the neutral stimulus (auditory tone) and unconditioned stimulus (foot shock) enters the amygdala from sensory processing areas (fig. 1)¹⁶. While in the amygdala, the information about the neutral stimulus (auditory tone) and unconditioned stimulus (foot shock) converge, producing a memory of the conditioned stimulus (tone anticipating foot shock) (fig. 1)¹⁷. The amygdala then sends fear signals to the areas of the brain that regulate the fear memory’s behavioral and physiological consequences (fig. 1)¹⁷. Prolonged stress from the hyperactive behavioral and physiological response can lead to maladaptive changes to the hypothalamo-pituitary-adrenocortical (HPA) axis, leading to the development of PTSD¹⁸.

The HPA axis regulates the body’s response to stress through an increased release of glucocorticoids such as cortisol (fig. 2)¹⁸. Outputs from the amygdala stimulate corticotropin-releasing factor neurons in the hypothalamus, which results in the release of cortisol from the adrenal glands (fig. 2)^18,20. When a certain threshold is reached, cortisol can provide negative feedback to the HPA axis telling it to shut down the production of cortisol (fig. 2)^21,22. Individuals with PTSD can have a dysregulated HPA axis with varying cortisol levels.²³ Animal studies and postmortem studies show that early childhood trauma causes methylation on the glucocorticoid receptors in the hippocampus, which decreases the inhibition of the HPA axis stress response²⁴. Disruption of HPA axis function in PTSD results in an inability to inhibit other stress response circuits, leading to elevated levels of the neurotransmitter and hormone norepinephrine, triggering a fight-or-flight response²⁵. Norepinephrine can then project to various brain areas, including the amygdala, HPA axis, and prefrontal cortex, to interact with corticotropin-releasing factor neurons²⁶. As a result, fear memories are acquired and consolidated, leading to increased stress response reactivity and PTSD symptoms including hypervigilance and arousal²⁶.

In addition to regulation of the HPA axis by cortisol and norepinephrine, the HPA axis is also regulated by the prefrontal cortex (PFC) and the hippocampus^18,27. Both regions are crucial for modulating the stress response and regulating PTSD symptoms^18,27. In the PFC, the dorsolateral and ventromedial regions work together to format abstract thought and goal-directed behavior²⁷. However, when activity in the PFC is altered by chronic or traumatic stress, individuals can experience intrusive thoughts and fear responses, resulting in problems with attention and appropriate emotion regulation^28,29,30. PTSD severity has been shown to increase when ventromedial PFC activity decreases, as the ventromedial PFC activity is inversely related to amygdala activity, leading to dysregulation of the HPA axis (fig. 3)³¹. Similar to the PFC, the hippocampus also allows for modulation of the HPA axis through amygdala inhibition¹⁸. Individuals with PTSD have decreased hippocampal volumes, and while it is unclear whether this reduced size occurs before or after the trauma, individuals with smaller hippocampal volumes are at increased risk of developing PTSD^32,33,34. Since the hippocampus is significant for pattern separation, memory formation, and cognition^35,36, individuals with PTSD have difficulty distinguishing between recalled traumatic memories and similar safe environments, resulting in overgeneralization of traumatic events to benign ones³⁷.

While traumatic memories cannot be removed, they can be altered, and new inhibitory memories can be made to outcompete them^14,38. Many current PTSD therapeutic treatments are focused on extinction, which is the recall of a long-term memory into working memory, allowing the memory to be updated with new information before it can be reconsolidated^14,39. Extinction is achieved through repeated exposure to a conditioned stimulus in the absence of the unconditioned stimulus until the conditioned fear response is effectively reduced¹⁴. For a mouse conditioned to associate an auditory tone with a foot shock, extinction would involve repeatedly exposing the mouse to the auditory tone without the foot shock until the fear response subsides. If an individual with PTSD recalls a traumatic memory and re-experiences it, the memory or their interpretation of the memory can be updated to include added feelings of guilt, shame, and emotional valence³⁸. However, when a recalled memory is updated with new information, exposure therapy can allow for extinction where the memory elicits no adverse consequences, resulting in an adaptive response^14,40,41. However, studies have found that extinction is not always effective, as the fear memory can return following a certain amount of time, a change in contexts, or the reintroduction of the unconditioned stimulus^14,40,41. Therefore, it is important to use extinction in multiple contexts and replace the unconditioned stimulus with non-aversive stimuli^42,43. In addition to behavioral therapy, numerous pharmacologic approaches are being developed to help improve fear-memory extinction training^44,45.

There is still more to learn about the underlying pathophysiological processes of PTSD that create aberrant behavior and dysfunction in the neurocircuits and their connections. Neuroscientists will lead us to a better understanding of these underlying processes and allow us to develop and improve treatments. With COVID-19 causing excessive stress in people’s lives, it is imperative that we better understand PTSD to help those who struggle to adjust to normative life once the pandemic passes.

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Nicole Lookfong is an undergraduate at Penn State Harrisburg majoring in genetics and developmental biology and is a lab technician in Dr. Yuval Silberman’s lab at Penn State College of Medicine. Nicole was mentored by Mariam Melkumyan, one of our Lions Talk Science Editors, to write this article.

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