Background
Approximately 10% of individuals exposed to a traumatic event go on to be diagnosed with posttraumatic stress disorder (PTSD), a debilitating psychiatric condition [
1]. Neural differences have been noted among those with PTSD compared with those exposed to trauma but not diagnosed with the disorder [
2,
3]. According to the widely-adopted neurocircuitry model, PTSD is primarily associated with structural and functional changes in the amygdala, medial prefrontal cortex (mPFC), and hippocampus [
4,
5]. Investigation of neural correlates that are associated with greater likelihood of developing PTSD following trauma exposure enriches our understanding of disorder biomarkers and could guide therapeutic targets [
6,
7]. The primary objective of the present study was to investigate subregional hippocampal neural correlates of current and future symptoms in PTSD.
Current theories of PTSD identify hippocampal dysfunction as a key contributor to hallmark symptoms of PTSD including trauma-related intrusions, difficulty voluntarily recollecting trauma details, and overgeneralization of fear [
1,
8,
9]. Moreover, individuals with PTSD demonstrate difficulties with everyday memory [
10], working memory [
11], and episodic memory [
12,
13]. Given the integral role of the hippocampus in PTSD symptoms, memory, and related processes, it is of interest to understand how the role of the hippocampus in the neurocircuitry model differs between individuals with PTSD and a trauma-exposed control (TEC) group, and the functional connectivity within this system to PTSD symptoms.
Resting-state functional connectivity (rsFC) is commonly used to explore patterns of brain system activity in psychiatric conditions, such as PTSD [
7,
14]. rsFC is a powerful tool that assesses correlated activity across brain regions over time during rest, permitting investigation of functional networks independent of a task to characterize abnormal intrinsic brain activity [
7]. Thus, rsFC is a sensitive imaging technique that offers potential to identify imaging biomarkers of PTSD. rsFC studies in PTSD have found group differences in FC using whole-brain analyses [
15], as well as using seed region-of-interest (ROI) analyses [
16‐
18]. For instance, rsFC differences in hippocampal FC between PTSD and controls have been observed based on analyses using the amygdala [
17,
18], the PCC [
16], and the mPFC [
19] as seed regions. However, functional magnetic resonance imaging (fMRI) research has largely focused on the hippocampus as a unitary structure. Given the different structural and functional connectivities of hippocampal subregions [
20‐
22], investigating hippocampal rsFC at a subregional level may further elucidate the functional neurobiology of PTSD.
Anterior and posterior hippocampal subregions have distinct structural and functional connections and contribute to different emotional and cognitive processes (see [
23] for a review). For example, the posterior hippocampus has connections with the pregenual ACC, the PCC, and the precuneus [
21], and makes a greater contribution to the default mode network compared with the anterior hippocampus [
20]. The posterior hippocampus specifically plays an important role in memory retrieval and spatial cognition [
24]. In contrast, the anterior hippocampus is preferentially associated with the amygdala [
22], the hypothalamic-pituitary-adrenal (HPA) axis, and the limbic prefrontal circuitry compared with the posterior hippocampus [
20,
25]. Neuroimaging studies have linked anterior hippocampal activation with emotional memory [
26] and reward-directed behaviour [
27]. Anterior hippocampal-amygdala connections are thought to underlie atypical memory processes in PTSD, including flashbacks, intrusive thoughts, and nightmares [
9], as well as overgeneralization of fear [
28]. In sum, there is evidence to support differential roles of the anterior and posterior hippocampal subregions in memory processes, and PTSD symptoms and associated processes. Thus, here we investigated differential FC with these subregions to provide added insight into hippocampal FC in PTSD compared with TEC.
Limited prior research has investigated subregional hippocampal rsFC in PTSD. Chen and Etkin [
20] compared anterior and posterior hippocampal rsFC between patients with Generalized Anxiety Disorder, PTSD, and non-traumatized controls. Compared with both the anxiety and control groups, connectivity to the PTSD group was diminished between the posterior hippocampus and brain regions part of the default mode network (associated with self-related cognitive processes) [
29,
30], including the PCC and pregenual ACC. The PTSD and GAD groups differed from controls in their anterior hippocampal connectivity to the dorsal ACC/pre-supplementary motor area. Chen and Etkin [
20] acknowledged the lack of a TEC group as a limitation: a TEC group is important to elucidating abnormal connectivity differences among individuals exposed to trauma who develop PTSD compared with those who do not. A recent study by Lazarov, Zhu, Suarez-Jimenez, Rutherford, and Neria [
31] compared rsFC of the anterior and posterior hippocampus with brain regions within the salience and default-mode networks in PTSD patients and TECs. No between-group differences were evident when the hippocampus was treated as a homogenous structure. However, when investigating the anterior and posterior subregions separately, decreased rsFC was observed between the anterior hippocampus and the precuneus within the PTSD group compared with TEC. These recent studies [
20,
31] highlight the importance of investigating subregional hippocampal rsFC.
rsFC can be used to predict PTSD symptoms measured by the Clinician Administered PTSD Scale (CAPS), a well-validated measure of PTSD symptom severity [
32]. For instance, PCC/precuneus connectivity with the amygdala in PTSD patients is positively associated with CAPS scores and predictive of future symptoms 6 weeks later [
33]. PCC connectivity with the right hippocampus, right amygdala, left mPFC, and left superior temporal gyrus are negatively correlated with CAPS scores [
19,
34]. Moreover, the strength of the connectivity between the PCC and amygdala predicted PTSD symptom severity 1 to 6 months following the traumatic event [
19]. Investigating relationships between FC and PTSD symptom severity can help identify possible biomarkers of PTSD or identify individuals with a greater predisposition for the disorder [
19]. The hippocampus is a central structure in the neurocircuitry model of PTSD [
4] and abnormal hippocampal connectivity is proposed to underlie key symptoms in PTSD [
9]. Thus, subregional hippocampal rsFC may be predictive of PTSD symptom severity and could be a biomarker of the disorder; however this has not previously been investigated directly.
In sum, current theories of PTSD identify hippocampal dysfunction as a key contributor to hallmark symptoms of PTSD [
1,
8,
9]. To our knowledge, only one study [
31] has used subregional hippocampal seed regions to compare rsFC between PTSD and TEC groups. This level of analysis provides a more nuanced understanding of hippocampal connectivity. Moreover, given the integral role of the hippocampus in PTSD symptoms, subregional hippocampal rsFC is a likely predictor of PTSD symptom severity; however, no studies to date have investigated this association. The present study first compared subregional hippocampal rsFC with brain regions part of the neurocircuitry model between PTSD and TEC groups. A priori hypotheses were made based on previous rsFC research in PTSD and neuroanatomical connectivity. It was hypothesized that the PTSD and TEC groups would differ in rsFC between the anterior hippocampus and the amygdala and mPFC and between the posterior hippocampus and PCC. Secondly, the present study builds on existing literature by investigating the associations between subregional hippocampal rsFC and current PTSD symptoms, as well as the ability of subregional hippocampal rsFC to predict future symptoms. Given that the anterior and posterior hippocampal subregions contribute to different emotional and cognitive processes it was expected that these regions would differentially predict PTSD symptoms. Based on the literature reviewed above, we predicted that greater functional connectivity of the anterior hippocampus and lower connectivity of the posterior hippocampus would predict greater symptom severity.
Discussion
The present study provides empirical support for distinct rsFC among hippocampal subregions when investigating PTSD pathophysiology and its relation with PTSD symptoms. Comparing rsFC between groups we found greater rsFC between the posterior hippocampus and bilateral PCC in the PTSD group compared to the TEC group, which may reflect a biomarker of PTSD pathophysiology or of resilience in the TEC group. This relation on the left was also predictive of symptom severity 4 months post-scan.
Further analyses revealed lower FC between the anterior hippocampus and the bilateral PCC and FC between the posterior hippocampus and the left PCC and right mPFC in the PTSD sample that was associated with greater symptoms 4 months following the resting-state scan. In the TEC group, lower FC between the anterior hippocampus and the bilateral mPFC and PCC were associated with greater current PTSD symptom severity and lower FC between the anterior hippocampus and the right amygdala was associated with higher symptoms 4 months later. Notably, the left-head – right PCC and right-tail – right-mFPC predictors of CAPS scores 4 months post scan were also significantly greater in the PTSD than TEC group. These findings may reflect meaningful differential relations to symptoms reflective of pathophysiology. However, caution is warranted given their exploratory nature and the observation of greater variability and mean FCs in the PTSD group that may reflect psychometric sensitivity. Regardless, these relations warrant further investigation.
The correlation analyses extend previous research by demonstrating that PTSD symptoms were preferentially associated with anterior hippocampal rsFC. This finding is consistent with research that suggests the anterior hippocampus plays a greater role in PTSD symptoms and associated processes compared to the posterior hippocampus. Specifically, anterior hippocampal-amygdala FC is hypothesized to underlie the hallmark intrusion symptoms in PTSD, including intrusive thoughts, flashbacks, and nightmares [
9], as well as overgeneralization of fear [
28]. Moreover, anterior hippocampal FC is preferentially involved in emotional memory [
26] and reward-directed behaviour [
27], which may contribute to avoidance, a maladaptive behaviour that maintains PTSD symptoms. Specifically, it is proposed that following trauma exposure individuals with PTSD overconsolidate the traumatic memory, which is easily reactivated by trauma reminders and accompanied by conditioned emotional arousal. This leads to hypervigilance towards trauma-related cues and subsequent avoidance of trauma-related memories and reminders to minimize associated distress [
48]. The avoidance could be conceptualized as a form of negative reinforcement that is rewarding for individuals with PTSD. Future research is warranted to investigate anterior hippocampal FC as a predictor of PTSD symptoms and its relationship with avoidance.
With respect to the group contrasts, the PTSD group revealed greater FC between the posterior hippocampus and PCC compared to TEC participants. Posterior hippocampal FC with the cingulate, precuneus, and visual cortices has been linked to spatial processing, including spatial memory and navigation [
22]. There is preliminary support for greater impairment in PTSD compared to TEC samples on visuospatial copying tasks [
49] and in constructing a cognitive map of a virtual environment [
50]. The abnormal FC between the posterior hippocampus and PCC in PTSD compared to the TEC group may reflect differences in these processes and is a future direction for task-based imaging research. Moreover, the PCC and hippocampus are part of the default mode network, which is associated with self-referential thought processes and autobiographical memory [
29]. Lower FC within the default mode network is more frequently observed across psychiatric and neurological conditions, with some variation across its subnetworks [
30]. Hippocampal-PCC connectivity is associated with memory functions and the current enhanced FC may reflect a unique role of this subnetwork in PTSD. Previous research that has investigated differences in the default mode network between PTSD and TEC samples also support group differences in this network [
16,
17]. Group rsFC differences between the hippocampus and PCC may reflect group differences in integration and contextualization of memories, which may contribute to threat hypersensitivity evident in PTSD [
16]. Previous research comparing rsFC between individuals with PTSD and trauma-naïve controls has found there to be less hippocampal-PCC rsFC in the PTSD group compared to controls [
16,
20]. This discrepancy from the greater FC observed here may be attributable to differences in data preprocessing, sample characteristics and a trauma-exposed versus trauma-naïve control group. These distinctions highlight the need for more consistent methodology across imaging studies and further assessment of moderating factors in PTSD research. Moreover, research is warranted comparing FC between individuals with PTSD, trauma-naïve controls, and TEC samples to characterize normal trauma-related changes in FC and FC specific to PTSD [
3].
Two of the hypothesized group differences in rsFC, those between the anterior hippocampus and the amygdala and the posterior hippocampus and the mPFC, were unsupported in the present study. One possibility is that the subregional hippocampal-amygdala rsFC group differences were too subtle to detect with the current design or they may not have been present within this sample. Consistent with the latter, a previous rsFC study also failed to find hypothesized group differences in hippocampal-amygdala activity [
51]. Moreover, as reported in Table
2, the FCs between anterior hippocampal ROIs with the amygdalae had the highest mean FC coefficients within each group and were comparable across groups. This finding may reflect that the functional connectivity between the hippocampal head and amygdala may remain robust and intact in PTSD under resting conditions or that this FC is similarly high in both trauma-exposed samples (PTSD and TEC); future comparison to a non-traumatized group will be valuable to assess these possibilities. Of note, a recent meta-analysis of task-based brain activation, revealed hippocampal and amygdala hyperactivity in PTSD in comparison to trauma-naïve samples but not TEC samples [
2]. Interestingly, decreased connectivity between these regions was strongly associated with PTSD symptoms in the current TEC sample.
In contrast to the lack of group differences in hippocampal-mPFC rsFC in the present sample, Jin et al. [
15] found weaker connectivity between the mPFC and the hippocampus in their PTSD group compared to trauma-naïve controls. Group FC differences are suggested to be a function of the type of comparison group (i.e., trauma-naïve controls versus TEC) [
3]. It is possible that changes in hippocampal-mPFC FC are normal following exposure to trauma-related stress and do not differentiate individuals with PTSD from those exposed to trauma who did not develop PTSD. It is also possible that the mPFC ROI we used was too liberal to detect group differences or that group differences were not present in this sample. These are notable negative findings that require further investigation and replication.
Interpretations of the present study findings should be considered in light of the study’s limitations. Firstly, although the ROIs were selected based on a priori hypotheses and the PTSD imaging literature, the small sample size constrains the positive predictive value of the findings. To address reproducibility concerns, we propose future pre-registration of larger-scale, collaborative replications [
52,
53]. In addition, the sample was heterogeneous in the types of trauma exposure and time since trauma. In light of evidence that longer resting-state imaging time frames of 9–13 min may improve the test-retest reliability of the scans and FC estimates [
54], future replication studies should consider using longer resting-state durations. Of note, post-hoc assessment of the potential relationship between time since trauma and CAPS scores failed to reveal any relations (data not shown). Future research with larger samples should investigate whether the associations found in this study are potentially moderated by type of trauma, time since trauma, and cumulative trauma load. Nonetheless, the current findings are valuable in demonstrating that there are common FC differences that distinguish PTSD and TEC samples. Consistent with previous studies investigating rsFC in PTSD (e.g., [
16,
20]), participants had psychological comorbidities and were using antidepressant medication. It is unclear how medication use and psychological comorbidities affect rsFC. However, it is unlikely that the FC differences observed in the present study were solely attributable to medication use and psychological comorbidities given these confounds were present in both the PTSD and TEC groups. Depression scores significantly differed between groups and thus depression symptoms could be influencing the group differences found in the study; however, recruiting individuals with no depression affects generalizability and statistically covarying for depression can inappropriately remove true-score variance shared with diagnostic status [
55]. Nonetheless, future neuroimaging research in PTSD is required to investigate the effects of medication use and comorbid symptoms on rsFC. Given heterogeneity of the mPFC and amygdala, another future direction could be to assess the potential of more nuanced rsFC between subregional hippocampal, amygdalar, and functionally distinct mPFC subregions, and their relations with PTSD symptoms. This work may also yield further insight into different symptom profiles. For instance, Nicholson et al. [
56] observed differential rsFC between amygdala subregions among those with and without the dissociative subtype of PTSD.