Neurobiology of PTSD


Fear is the basis of all evolutionary progress, and neuroscientists have been investigating how different brain regions can give rise to various fear mental illnesses. Some of the fear disorders include generalized anxiety, phobias, social phobias, agoraphobia, panic disorders, and PTSD. Until recently, PTSD was bundled with the other anxiety disorders, but in the latest DSM edition (DSM 5), PTSD was categorized on its own due to its altered neurobiological mechanism involving fear extinction and learning. But a more general model of PTSD can seen from Mowrer's two-factor step model. This model suggests that fear acquisition is learned through classical conditioning, and the maladaptive behaviors/ associated patterns are learned through operant conditioning. In case of PTSD, a child with domestic violence learns that home is associated with danger, and reduces their fear by generating the avoidance behavior of staying away. 

The diagram above shows these two steps: first the classical conditioning to learn an associated fear, and second, to avoid it for negative reinforcement. This is also known as the avoidance theory, which suggests avoiding an unwanted physiological or mental experience gives relief and reinforces the action of seeking avoidance behaviors. For example, in the first step, a veteran may learn to associate a conditioned stimulus such as a doorknob opening with an unconditioned stimulus of getting ready for action, which he has learned from his prior experience in the army. He may start to avoid being in the room alone, perhaps even avoid being around other things that trigger the anxiety. In this manner, the veteran starts to negative reinforce his avoidance behaviors. Each time, the person avoids the fear stimulus (CS), they also avoid the fear response, and thus find relief. The relief is enough for the brain to learn avoidance behaviors that may actually be more dangerous than the fear stimulus itself. This is the basic principle of fear acquisition in fear disorders. But it is more applicable to PTSD than any of the other disorders. 

PTSD and Mechanism

PTSD is defined through three main criteria: hyperarousal, hypervigilance, and avoidance. A person who has been through a life-threatening life event will naturally develop PTSD-like symptoms. Evolutionarily, our fear circuits are useful for us as they reinforce safety and reduce our chance of getting into any difficult situations. But when our fear circuits in the brain are overly active and impaired due to severe life-threatening situations, we may be at risk of getting a PTSD diagnosis. The general neurobiology of PTSD is that our autonomic nervous system disproportionally activates our fight or flight system/ sympathetic nervous system. We may see a stick as a snake or view airplanes as bomber aircraft, or a german shepherd as a savage beast. Regardless of what our association may be, our SNS activates irregularly and signals our brain to constantly be on the lookout for danger. Our SNS starts to upregulate our amygdala which is the almond-shaped region in the brain responsible for fear learning and appraisal of the enviornemnt. Activation of the amygdala has a negative impact on 1. our hippocampus, which is responsible for the consolidation of memories, 2. our prefrontal cortex, which is responsible for decision making and emotional regulation, and 3. our anterior cingulate cortex, which is responsible for reward predictions and goal orientation. All of these functions are very important to our regular life, so inhibition of these brain regions can produce debilitating responses. 

Alongside this, the HPA axis is working to increase cortisol, which is responsible for the physiological and mental stress during the episode. The hypothalamus secretes corticotrophin-releasing factor to the anterior pituitary, which then secretes an adrenocorticotrophic hormone to adrenal glands located in the kidneys. Finally, the adrenal glands secrete cortisol. Cortisol is necessary for daily functioning, but high levels of it can actually damage our hippocampus and memory consolidation. This is why PTSD patients have an unclear image of their traumatic experience. It is also why eyewitnesses in courts can be fallacious if the event is severe enough. Patients with PTSD often have high cortisol levels alongside higher amygdala activation. When this circuitry is impaired, our high cortisol levels lead to a poor appraisal of the environment. The individual starts to feel like they are out of control of themselves and the environment. The amygdala dysregulates the prefrontal cortex pathway, which leads to reduced rationality, and higher emotional distress. Now, we know why PTSD patients learn avoidance behaviors. It isn't just to get away from the environment, it is also to avoid this poor physiological response, which may lead to panic attacks at times. The combination and interaction of hyperarousal, hypervigilance and avoidance may be the most evidence-based theory for PTSD at the moment. Avoidance isn't simply a mental act, rather it is governed by physiological symptoms and operant conditioning. 

Hippocampus Dysfunction

One of the most useful findings from the neuroscience of PTSD is that our hippocampal volume usually decreases with prolonged stress and more traumatic episodes. HIppocampus is often seen as the region for consolidating memory, but it is also important in other regions including salience, reward prediction, and fear learning. Our memories define ourselves, our possessions, and our value in the world. When our memories of events become unclear, our brain starts to create its own story to fill in the gaps of the experience. Our top-down processes are actually more predominant than the bottom-up ones. So regardless of the quality of the sensory input, if our circuitry is predetermined to view things as threatening, it will affect the way we behave and respond to certain events. This is the very pinnacle approach of PTSD research. Researchers are able to induce fear in participants with a small sensory input and measure their hyperactivity symptoms. If PTSD was only triggered by severe stimuli, it would've been ethically impossible for researchers to learn about the neurobiology of PTSD. But, because of the way our fear circuits work and affect our physiological symptoms, researchers can start to take a look at the various factors leading to hyperarousal and poor symptomatology. 

Regulatory Regions are altered in PTSD group

So far we have only talked about the limbic structures that play a role in fear learning. To recap, the amygdala is an important subcortical structure involved with detecting threat signals and upregulating the HPA axis. Normally, the hippocampus has a regulatory role on amygdala thus it can reduce the stress response based on contextual cues. The exact mechanism of how hippocampus stores fear related memory is unknown, but it most likely has to do him gene specific gene expressions in hippocampal neurons. Thus the hippocampus can regulate the amygdala according to the genetic instructions following previous episodes. In case of PTSD, hippocampal regulation over amygdala is dampened, thus leading to lower inhibition and heightened stress response. Another key structure involved in amygdala regulation is the vmPFC, ventromedial prefrontal cortex. This region is involved in fear extinction, and learning safety after the removal of stressful stimulus. High trauma is thought to interfere with the regulation of fear extinction and make it harder for people to learn safety. Several fMRI studies have shown that individuals who have PTSD tend to have reduced vmPFC activation when engaging in emotionally taxing tasks, as compared to individuals who don't have PTSD (Jovanovic et al, 2013)- Link to paper here

Whereas the vmPFC is involved in fear extinction, the dlPFC and insula are involved in attention and salience involving fear learning. Functional connectivity between dlPFC and hippocampus, as well as insula and hippocampus is thought to underlie appropriate learning during a traumatic event. Individuals with PTSD may have altered connections between the salient network, which can then have downstream effects on how well the amygdala and limbic structures are regulated. Furthermore, it may lead to inability to contextualize fear and learn fear extinction in safe situations. More research needs to done on what these alterations entail and how attention control plays a role in the PTSD model. 

Another region of interest is the dACC, the dorsal anterior cingulate cortex which is associated with executive functioning and cognitive control. It facilitates rationale thinking and useful decision making during our day to day stressful encounters. The the classic PTSD model is that individuals have higher emotional dysregulation due to lower cognitive control, so the dACC might have diminished powers in regulating emotions. Research at Detroit Trauma Project (website here: ) is also looking at whether glutamate release at the dACC is altered in individuals with trauma exposure. A decrease in glutamate might reduce excitability of neurons in the dACC, and reduce cognitive control, leading to poor emotional processing in events of stress. 

Overall, the dACC and vmPFC tend to show altered functional activation (to emotionally taxing tasks) in people with PTSD, while the salient regions tend to have altered connectivity with hippocampus, leading to inability to contextualize fear and learn safety. All these brain regions are very interconnected, so isolating their function based on anatomy may not be sufficient. A better approach could be to see how multiple regions are changed following trauma, and which of those are associated with different clusters of PTSD (such as avoidance, hyperarousal, numbing, intrusive thoughts,). In general, finding neural signatures of PTSD symptoms before they worsen can allow us to help us identify and treat at risk population. 

Fear Potentiated Startle

I work as a Research Assistant at Dr. Jovanovic's lab, and we have been studying PTSD for a long time. Tanja Jovanovic, my PI, has written several papers on the fear acquisition and its correlation with PTSD scales. Most of the information on here comes from her papers or from the research I have done in the lab. Below, I have attached some useful papers that further enhance the understanding of fear acquisition and inhibition. 

Fear potentiated startle refers to a relative increase in the acoustic startle response to a previously neutral stimulus through classical conditioning paradigms. Our lab has a startle booth, where we have participants go through an acquisition, habituation, and extinction task. Before entering the booth, the participant is set up with EMG, EDA, and EKG electrodes. The EMG electrodes measure the orbicularis oculi muscle activity, indicating eye blinking. The EDA electrodes measure the galvanic skin response, indicating the production of sweat in the participant's hand. Finally, the EKG measures heart rate. All these measures are associated with the autonomic SNS, so our expectation is that the readings for these measures will indicate the severity of a person's fear acquisition and extinction. Predicting PTSD relies on two things: 1. how efficiently a person is able to discriminate between fear and safety, and 2. how quickly they are able to extinguish the fear through habituation. The startle paradigm of classical conditioning goes as follows. The participant sees two different types of shapes, one with a loud sound and an air blast following it, and one that doesn't have a loud sound and the air blast. The UCS is the loud sound followed by the airblast and the CS is the type of shape on the screen. the basic hypothesis is the faster the participant learns to physiologically discriminate between the shape that has the airblast and the shape that doesn't, the less likely they are to develop PTSD. Subjective readings and interviews are often useful, but this paradigm allows us to measure their fear response more accurately. If their startle response during acquisition indicates large discrimination between the two shapes, then we can predict their fear circuitry is not abnormal and that they are likely to have lower PTSD ratings. However, if they continue to blink to the shape that doesn't have an airblast, even after a couple of trials, then we know that this person is likely to have a poor physiological response to acoustic startles. After the participant goes through acquisition, we have them go through extinction, where there is no air blast following either shape. Here, we are trying to figure out how well the participant is able to habituate and learn safety in response to the shapes. If the participant continues to show physiological signs of fear when the airblast is off, it indicates poor fear learning. We are also interested in the difference between their highest fear response and their end habitual response. This showcases the efficacy of their safety learning. Finally, we measure their discrimination rates between the two shapes, solidifying the findings of their ability to discriminate and learn safety. With the EMG, EDA, and EKG sensors, we are able to collect their response and match their readings to the startle paradigm. We have to account for limitations during the startle, as the participants can fall asleep, blink excessively, chew on gum, or play with the sensors. Nonetheless, the startle paradigm provides a great way to measure their SNS response and study fear learning on a large scale. The larger picture is to determine predictive biomarkers of PTSD so that we can get resources to potential PTSD patients before they spiral into worse conditions. In that regard, fear-potentiated startle has shown good results in determining the severity of PTSD ratings.

Research papers by Tanja Jovanovic on Startle Paradigm and PTSD: 

How the Neurocircuitry and Genetics of Fear Inhibition May Inform Our Understanding of PTSD

Impaired safety signal learning may be a biomarker of PTSD

PTSD Treatments

The current treatments for PTSD include exposure therapy, cognitive restructuring therapy, CBT, and mindfulness-based stress reduction therapy.  Exposure therapy is difficult because it requires the participant to stick with the schedule of exposure to threatening stimuli. Of course, the therapist will make sure the stimuli aren't dangerous, but the patient will have to overcome their initial fear to inhibit the fear response. Cognitive restructuring and CBT refer to changing perceptions about oneself and their thoughts through questioning one's beliefs and attitudes. This is often useful if the patient has generalized their fear to everything around them. Mindfulness therapy can be extremely beneficial as it allows the patient to accept their flashbacks of PTSD and avoid catastrophizing the mental and physical feelings. Otherwise, having a strong support group through friends and a routine of physical exercise has also proven to improve PTSD symptoms. 

Some of the more pharmacological interventions include antidepressants such as SSRIs and SSNI. However, relapse chances increase drastically when the medication is stopped. Beta-blockers have also been shown to reduce the more physiological symptoms of PTSD, reducing their hyperactivity and hypervigilance. Beta-blockers work by inhibiting the SNS response, thus reducing the chance of the patient relapsing into flashbacks. Finally, rTMS or Repetitive transcranial magnetic stimulation in the dorsal lateral prefrontal cortex has also shown improvement in the patient's ability to regulate their episodes. It is worth noting, that a combination of medication and therapy yields to greatest results. 

Further Resources

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