Samantha Goldberg, University of Michigan, Department of Psychology
“Hippocampal Activity in Extinction Recall Related to Stress Exposure”
Many individuals experience traumatic events and other stressful events, but very few develop Post-Traumatic Stress Disorder. Many studies focus on individuals with the disorder when looking at differences in learning and memory, but there is little knowledge of how healthy individuals may differ in these areas in relation to stressful event exposure. We aimed to examine relationships between stressful event exposure, subclinical PTSD symptoms, and neural activity during fear extinction recall task in healthy individuals to better understand how stress may be related to deficits in fear learning. Twenty-one healthy participants, with and without exposure to a traumatic event, went through a fear learning paradigm. Participants were conditioned (light paired with an aversive noise) in one context, followed by extinction in another, to establish danger and safety contexts. The next day, the extinguished conditioned stimulus was presented again, while participants were in a fMRI scanner, to test extinction recall. There were no differences in hippocampal activity related to trauma exposure. However, across all participants, lower hippocampal activity during extinction recall was associated with exposure to more types of stressful events. Our findings support the inclusion of healthy individuals and measures of overall stressful event exposure in research examining fear learning.
In the U.S., an estimated 80% of the population experiences one or more traumatic events in their lifetime, but less than 10% of those exposed to a traumatic event develop Post Traumatic Stress Disorder (PTSD) (Breslau, 2009). The disparity between traumatic event exposure and development of PTSD brings about questions regarding what factors contribute to development of PTSD following traumatic event exposure. There is a large amount of research focused on both structural and functional differences in brain areas primarily involved in memory and emotion in people with PTSD, compared to trauma-exposed controls, and/or non-trauma exposed controls (Carrion et al., 2009; Gilbertson et al., 2002; Gurvits et al., 1996; Logue et al., 2017; Milad et al., 2009; Woon, Sood, & Hedges, 2010).
Structural differences have been identified in multiple brain regions in people with PTSD, particularly the hippocampus (Gurvits et al., 1996; Logue et al., 2017; Woon, Sood, & Hedges, 2010; Xie et al, 2017). There are also findings of lowered hippocampal volume in trauma-exposed groups without PTSD, compared to non-trauma-exposed groups (Woon, et al., 2010). Longitudinal imaging work in soldiers has also found stress-induced reductions in hippocampal volume, even in those who had not developed PTSD (Admon, et al., 2012). There is a definite connection between brain volume and brain function (Qing & Gong, 2016), so these findings bring up questions regarding differences in hippocampal function in people who have experienced a criteria A traumatic event, compared to those who have not.
Evidence suggests that hippocampal function during learning and memory tasks is associated with PTSD symptoms. For instance, lower hippocampal activation during retrieval on a verbal declarative memory task has been correlated with greater avoidance symptoms in PTSD (Carrión et al., 2009). There is also evidence to support that, even without PTSD diagnosis, there are differences in performance on various tasks and neural activity related to exposure to stressful and/or traumatic events. For example, performance on a hippocampal dependent memory task has been found to be related to stressful event exposure in healthy trauma-exposed individuals (John & Duval, 2018).
Hippocampal dysfunction has also been associated with contextual memory (Acheson, et al., 2011). Specifically, people with PTSD experience fear in safe environments (e.g. A lion in a zoo is not threatening). This deficit can be seen in fear learning and extinction paradigms, particularly extinction recall tasks. During these tasks, there is evidence that better extinction recall performance is associated with greater hippocampal activation (Milad et al., 2010). Studies specifically investigating early extinction found positive correlations between symptom severity and patterns of brain activity during these tasks (Sripada, Garfinkel, & Liberzon, 2013). However, it remains unclear how hippocampal activity during extinction recall, which has been found to be poorer in those with PTSD (Milad et al., 2010), would interact with symptom severity. Animal studies have also found that stressful event exposure, such as maternal separation, is related to poorer extinction recall (Cowan, Callaghan, & Richardson, 2013). However, there is a lack of research looking at these relationships in healthy human populations.
Participants first came for an initial evaluation, which included a clinical interview, and then later came to the lab on two consecutive days. During day one, participants completed a fear conditioning and extinction paradigm. Participants were fear conditioned with one of two contexts, “library” and “office,” with two cues (pink and blue light) as conditioned stimuli (CS). A 500 ms white noise was used as the unconditioned stimulus (US). During fear conditioning, one context (office or library, counterbalanced) was shown for 2-7 seconds, followed by the CS for an additional 2-7 seconds, with each period controlled to last a total of 9 seconds. For CS+, the US was delivered during 10 of 16 trials (60%) to coincide with CS offset. The CS- was presented 16 times, but never followed by the US. A fixation cross was used as the inter-trial interval, jittered for 4-12 seconds. Extinction followed the Conditioning in the other context. Participants were shown 16 presentations of the CS+E in the absence of the US, interleaved with 16 CS- presentations.
On day 2, participants completed the extinction recall phase for the fear learning task. SCR measured fear reactivity, and fMRI examined hippocampal activity related to fear learning and extinction recall. During extinction recall, the extinction context from day 1 were presented again. Participants were shown interleaved CS+E and CS- stimuli (8 presentations each), and rated how likely they were to hear a loud noise for both the CS+ and CS-.
Clinical Administered PTSD Scale for DSM-5. The Clinician Administered PTSD Scale for DSM-5 (CAPS-5;Weathers et al., 2013) was utilized during the clinical interview prior to confirmation of participants’ inclusion in the study. For participants who had experienced a traumatic event, we measured symptoms related to that experience. For participants who had not experienced a traumatic event, we looked at symptoms related to the most stressful event they had experienced.
Life Events Checklist for DSM-5. Participants completed the Life Events Checklist for DSM-5 (LEC-5) (LEC-5;Weathers et al., 2013) during their clinical interview. The LEC-5 assesses how many different types of stressful life events (i.e. natural disaster, car accident, physical assault, sexual assault, etc.) participants have been exposed to.
Functional Neuroimaging. Scanning was performed using a GE 3-T Discovery MR750 Series MRI (GE Healthcare). T1-weighted anatomic images were acquired with a 3D MPRAGE sequence (FOV = 256 x 256 mm, slice thickness = 1 mm, 0 mm gap). Axial slices aligned with the AC-PC plane were used for slice localization, transformation, and coregistration. Functional scans consisted of gradient echo blood oxygen level dependent (BOLD) scans (TR/TE = 2000/30 ms, flip angle = 90°, FOV = 192 x 192 mm, slice thickness = 3 mm). Data was analyzed using Statistical Parametric Mapping (SPM12) for MATLAB. Images were slice-time corrected, realigned and coregistered to the structural images, normalized to the Montreal Neurological Institute (MNI) standard brain, and smoothed. fMRI data was collected only during extinction recall.
Chi-squared tests of independence showed that there were no significant differences between groups in race, X 2 (2) = 0, p =1 or gender, X 2 (1) = 0.4033, p = 0.525. Both the TE and NTE groups had 7 caucasian participants (70%), 1 African-American participant (10%), and 2 Asian participants (20%). The TE group had 7 female participants (70%) and 3 male participants (30%), while the NTE group had 9 female participants (81.8%) and 2 male participants (18.2%). A two-sample t-test found no significant difference in age between the groups, t (18.972)= -0.257, p = 0.800).
CAPS scores across the entire sample ranged from 0 to 17 (M = 3.62, SD = 5.07).The TE group had significantly higher CAPS scores (M = 6.40, SD = 6.10) than the NTE group (M = 1.09, SD = 1.81; t (10.45) = -2.65, p = 0.012). LEC-5 scores ranged from 1 to 15 (M = 5.24, SD =3.71) The TE group had statistically higher LEC-5 scores (M = 7.20, SD = 4.42) than the NTE group (M = 3.46, SD = 1.64), t (11.22) = -2.53, p = 0.014. There was also a significant positive relationship between LEC-5 score and CAPS score, r (9) = 0.57 , p = 0.007 (Figure 2).
When participants were presented with the CS+ in the safe context, 24 hours after initial extinction, there were no differences in hippocampal activation between groups. A regression of CAPS scores with activation in the hippocampus during presentation of the CS+E compared to baseline showed no relationship between hippocampus activation and severity of PTSD symptoms, meaning that hippocampal activation during the CS+E presentation was not related to greater severity of PTSD symptoms. When looking at a regression of LEC-5 scores and BOLD signal during the CS+E, there was a significant negative relationship between bilateral hippocampal activity and the number of types of stressful events participants had been exposed to (Right hippocampus: 15, -28, -4; p < 0.001, FWE SVC; Left hippocampus: -12, -34, -1; p < 0.004, FWE SVC). We found that activation in the right hippocampus during CS+, compared to baseline, was negatively correlated with LEC-5 score, r (9) = -0.97, p < 0.001 (Figure 3). Activation in the left hippocampus during CS+, compared to baseline, was negatively correlated with LEC-5 score r (9) = -0.91, p < 0.001 (Figure 4).
The purpose of this study was to explore questions regarding relationships between hippocampal activation during extinction recall, stressful event exposure, and any present PTSD symptoms in a healthy population, with and without criteria A trauma exposure. Our results indicate that increased exposure to different types of stressful events is related to less hippocampal activity during extinction recall. Exposure to stress, therefore, appears to be associated with poorer ability to retrieve extinction memory, as this is a hippocampal-dependent process (Garfinkel et al., 2014). Our findings are consistent with animal research, which has demonstrated that prolonged stress has negative impacts on extinction learning and recall (Chocyk, 2014; Remmes, 2016). These findings suggest that this relationship may be extended to healthy humans.
The relationship between LEC-5 and CAPS scores suggests that stressful event exposure is associated with emotions and/or behaviors often associated with PTSD, even in healthy populations. The significant difference in CAPS score between groups brings up questions surrounding resilience towards the development of PTSD after exposure to a traumatic event. Symptoms are significantly higher in the TE group, but are still subclinical, so what factors may contribute to this group’s resilience to PTSD? Prior studies have found differences in hippocampal activity in those with PTSD when compared to healthy populations (Carrión et al., 2009; Milad et. al., 2009), and our study found no difference in hippocampal activation between TEs and NTEs. Perhaps hippocampal activation is an important risk or resilience factor for the development of PTSD, such that those who have experienced a traumatic event but have similar patterns of activation to those who have not have some level of resilience towards PTSD.
The lack of a PTSD group made it difficult to look at symptoms in relation to hippocampal activity, meaning that there could be a relationship between CAPS score and hippocampal activity during extinction recall, as originally hypothesized, but this study was unable to fully investigate this. It is possible that further recruitment of healthy individuals, particularly those who have experienced a trauma, will allow for a greater variation in CAPS scores, highlighting any relationship between symptoms and hippocampal activity during the extinction recall task.
This study begins to fill a gap in previous literature surrounding stressful event exposure and fear learning in healthy individuals. The strength of the LEC-5 and hippocampal activity regression provides impressive evidence that, even in healthy individuals, neural activity may differ as a function of stress exposure. This builds upon previous animal research (Cowan et al., 2013) and findings of structural differences related to stress exposure (Admon et al., 2012). Lowered hippocampal activity during the extinction recall task may point to increased fear in a safe context for those who have experienced multiple types of stressful events, suggesting that, even without PTSD or trauma exposure, individuals exhibit deficits related to stressful events. These findings provide solid evidence for the need of further research related to fear learning in healthy populations and exposure to stressful events, regardless of trauma exposure history.
This research implies both that healthy individuals experience deficits related to stressful event exposure, and that trauma-exposed individuals without PTSD still experience increased distress compared to non-trauma-exposed individuals. This may suggest that healthcare providers should assess for stressful and traumatic event exposure, and that those without a mental health diagnosis related to these events may still benefit from some form of therapeutic intervention. Trauma and distress surrounding trauma are not a black and white issue- some events are not considered traumatic, but are very distressing, and some individuals may not meet criteria for PTSD, but may still experience considerable symptoms. Policy around mental healthcare should take this into consideration when determining coverage of mental health services.
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