Resting-state functional connectivity of anterior and posterior hippocampus in posttraumatic stress disorder
Introduction
Elucidating neural abnormalities associated with posttraumatic stress disorder (PTSD) is considered a crucial stepping stone toward identifying reliable novel targets for treatment (Patel et al., 2012). The hippocampus is one brain area considered to play an important role in PTSD due to its involvement in memory functions (Brohawn et al., 2010) and fear-related learning processes (Corcoran et al., 2005, Quirk and Mueller, 2008). Research has demonstrated reduced hippocampal volume in PTSD (O'Doherty et al., 2015), which are associated with persistent re-experiencing of the traumatic event (Brewin et al., 2010) and poor treatment response (Rubin et al., 2016). However, task-based functional neuroimaging studies have been less consistent, with some showing reduced or impaired hippocampal activation in PTSD (Etkin and Wager, 2007), while others reporting abnormal hyperactivation (Patel et al., 2012).
Recently, investigations of PTSD-related differences using resting-state functional connectivity (rs-FC) have begun to emerge. Extant PTSD rs-FC studies have primarily focused on key node regions within the salience network (SN) and the default mode network (DMN). SN nodes include the amygdala (Brown et al., 2014, Rabinak et al., 2011, Sripada et al., 2012a), anterior insula (Sripada et al., 2012b), and dorsal anterior cingulate cortex (dACC; (Kennis et al., 2015, Sripada et al., 2012b, Yin et al., 2011), and more specifically the dACC/pre-supplementary motor area (pre-SMA (Chen and Etkin, 2013, Shirer et al., 2012, Sripada et al., 2012b);). DMN nodes include the hippocampus, ventromedial prefrontal cortex (vmPFC), posterior cingulate cortex (PCC), and the precuneus (Bluhm et al., 2009, DiGangi et al., 2016, Koch et al., 2016, Reuveni et al., 2016). Evidence for altered connectivity between the hippocampus and different SN nodes is mixed at best (Koch et al., 2016), with some reporting reduced connectivity in PTSD (Chen and Etkin, 2013, Sripada et al., 2012a, Sripada et al., 2012b) while others finding no such evidence (Brown et al., 2014, Chen and Etkin, 2013, Rabinak et al., 2011). Research focusing on DMN nodes found reduced hippocampal connectivity with the PCC (Bluhm et al., 2009, Sripada et al., 2012b) and precuneus (Bluhm et al., 2009, Chen and Etkin, 2013) in PTSD patients compared with healthy controls, as well as a positive correlation between the strength of within-DMN connectivity and PTSD and acute stress disorder (ASD) symptom severity (Birn et al., 2014, Cisler et al., 2013, Kennis et al., 2015, Lanius et al., 2010, Sripada et al., 2012b). However, more recent studies comparing within-DMN functional connectivity of PTSD patients and trauma-exposed healthy controls (TEHCs) did not find any evidence for group differences in connectivity (DiGangi et al., 2016, Reuveni et al., 2016).
Though nearly all PTSD seed-based rs-FC studies involving the hippocampus investigated it as a singular structure, research has increasingly recognized three functionally discrete subparts along its longitudinal axis based on gene expression and anatomical connectivity (Chen and Etkin, 2013, Fanselow and Dong, 2010, Zarei et al., 2013). Anterior-posterior hippocampal resting-state connectivity differences have been reported in healthy participants for different brain regions such as the pregenual ACC (pgACC), PCC, precuneus, PFC, and thalamus (Chen and Etkin, 2013, Zarei et al., 2013). Moreover, functional differences between anterior and posterior hippocampus were also found, with the posterior part primarily involved in memory and cognitive functions, and the anterior region in emotion and affect (Fanselow and Dong, 2010, Poppenk et al., 2013, Small et al., 2011). In PTSD, one previous study has shown that compared with healthy controls, PTSD patients demonstrate lower connectivity between the posterior hippocampus and the pgACC, PCC, and precuneus. Connectivity of the anterior hippocampus with dACC/pre-SMA was shown to be reduced in PTSD patients (combined with generalized anxiety disorder (GAD) patients), compared with healthy participants. However, as acknowledged by the authors, this study did not include trauma-exposed healthy participants, which might have yielded different results (Chen and Etkin, 2013).
Age-related anterior and posterior connectivity differences have been noted in previous research. An association between increased age and reduced functional connectivity within the DMN has been found in healthy participants for the posterior but not for the anterior hippocampus (Damoiseaux et al., 2016). Blum et al. (2014) examining connectivity dominance within the hippocampus reported somewhat contradictory results. They found a relative increase in rs-FC of the posterior hippocampus to neocortex areas in older adults, with several brain areas, including the precuneus, identified as demonstrating an age-related shift in connectivity from anterior to posterior hippocampus (Blum et al., 2014). Finally, while numerous neuroimaging studies have examined the hippocampus in PTSD, age-related differences were seldom addressed. The only few neuroimaging studies addressing age mainly focused on volumetric differences between PTSD patients and healthy controls in older adults (Golier et al., 2005, Yehuda et al., 2007). No studies to date have explored the effects of age on hippocampal rs-FC among PTSD patients.
Aiming to address gaps in the above-reviewed research on hippocampal connectivity, we recorded rs-FC of the hippocampus with core pre-defined nodes of the SN (i.e., anterior insula, dACC/pre-SMA, and amygdala) and DMN (i.e., PCC, precuneus, and vmPFC) previously identified as aberrant in PTSD connectivity research (Sripada et al., 2012b). Our primary goal was to examine whether PTSD patients and TEHC participants differ in functional connectivity of the anterior and posterior parts of the hippocampus with these brain regions, in an attempt to clarify mixed results from previous studies. In addition, as research has demonstrated age differences in hippocampal connectivity, we conducted a secondary analysis of specific pathways found to differ between groups in the main analysis by exploring within-group associations between age and rs-FC.
Section snippets
Participants
Fifty-three patients with PTSD and 36 TEHC participants were recruited for participation in the study via online advertisement and fliers. PTSD and TEHC participants were matched on age, sex, trauma type, and race/ethnicity. All participants met DSM-IV-TR (American Psychiatric Association, 2000) criterion A for a traumatic event. A psychiatrist determined medical exclusion criteria by conducting a medical history and physical examination. An independent clinical evaluator administered the
Demographic and clinical characteristics
Participants’ demographic and clinical characteristics are presented in Table 1. As expected, significant differences between groups were noted for PTSD symptom severity (p < 0.001). Groups differed also in their years of education (p < 0.001) and depressive symptom severity (P < 0.001), but not on age (p = 0.67), sex (p = 0.45), ethnicity (p = 0.70), duration since trauma (p = 0.96) or trauma type (p = 0.40).
Functional connectivity analysis
ROI-to-ROI connectivity analysis was performed on a priori defined ROIs (see Fig. 1,
Discussion
This study examined whether PTSD patients and TEHC participants exhibit different resting-state functional connectivity patterns between anterior and posterior hippocampus and key brain regions of the SN (i.e., amygdala, dACC/pre-SMA, and anterior insula) and the DMN (i.e., precuneus, PCC, and vmPFC) previously implicated in PTSD. A differential rs-FC pattern emerged for the PTSD and TEHC groups regarding anterior and posterior hippocampal connectivity with the precuneus and PCC. In TEHC
Conclusions
The present study provides evidence for the importance of referring to the anterior and posterior parts of the hippocampus as distinct regions with different roles when examining resting-state connectivity in PTSD. While we found no differences in rs-FC between subjects with PTSD and TEHCs when examining the hippocampus as a whole, examining the anterior and the posterior hippocampus revealed a pathologic loss of anterior to posterior connectivity differentiation in PTSD patients. In addition,
Conflicts of interest
The authors declare that there are no conflicts of interest.
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2022, Neurobiology of StressCitation Excerpt :More specifically, we found PTSD-related decreased connectivity between hippocampus and angular gyrus, a region encompassed by the lateral parietal node of the DMN, compared to HCs (Table 2; Fig. 1). These results are consistent with previous studies of RSFC in PTSD finding reduced hippocampal-lateral parietal connectivity (Chen and Etkin, 2013; Lazarov et al., 2017). Furthermore, previous research has reported decreases in hippocampal-lateral parietal connectivity in females but not in males (Helpman et al., 2021), highlighting the importance of examining PTSD-related differences in RSFC in one gender at a time.
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2021, Neurobiology of StressCitation Excerpt :We also found sex-dependent, opposite patterns of within DMN connectivity (HIP-precuneus) for individuals with and without PTSD. HIP-precuneus connectivity has been previously found to differentiate controls from PTSD (Lazarov et al., 2017), and has been associated with memory problems and cognitive impairment (Apple et al., 2018; Xue et al., 2019). Within DMN connectivity has also previously been implicated in sex-specific, opposite association with pubertal maturation (Ernst et al., 2019), suggesting the involvement of sex hormones in the onset of this disparity.
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This work reflects equal contribution of the first two authors.