Elsevier

Journal of Psychiatric Research

Volume 94, November 2017, Pages 15-22
Journal of Psychiatric Research

Resting-state functional connectivity of anterior and posterior hippocampus in posttraumatic stress disorder

https://doi.org/10.1016/j.jpsychires.2017.06.003Get rights and content

Highlights

  • PTSD is characterized by lack of anterior-posterior connectivity differentiation.

  • PTSD is associated with lower negative posterior hippocampus-precuneus connectivity.

  • No findings emerge when examining the hippocampus as a whole.

  • In PTSD age is associated with normalized posterior hippocampus connectivity.

Abstract

Posttraumatic stress disorder (PTSD) has been associated with altered resting-state functional connectivity (rs-FC) of several brain regions within the salience (SN) and default-mode (DMN) networks, including the hippocampus. However, most rs-FC studies have not focused primarily on the hippocampus, nor have they appreciated its structural heterogeneity, despite clear evidence for a dissociation between posterior and anterior hippocampal connectivity. Here, we examine rs-FC of anterior and posterior hippocampus with key regions in the SN (amygdala, insula, and dorsal anterior cingulate cortex/pre-supplementary motor area) and DMN (ventromedial prefrontal cortex, posterior cingulate cortex, and precuneus) previously implicated in PTSD, using a seed-based approach. Resting-state magnetic resonance images were obtained from 48 PTSD patients and 34 trauma-exposed healthy participants (TEHC). Results indicated no group differences when examining the hippocampus as a whole. However, examining the anterior and posterior hippocampus revealed a loss of anterior to posterior connectivity differentiation in PTSD patients. The PTSD group also demonstrated lower negative connectivity of the posterior hippocampus-precuneus pathway compared with the TEHC group. Finally, as differences in anterior and posterior hippocampus connectivity have been also related to age, we performed a secondary analysis exploring the association between age and posterior- and anterior-hippocampus connectivity in both groups. Results showed that among PTSD patients, increased age had the effect of normalizing posterior hippocampus-precuneus and hippocampus-posterior cingulate cortex connectivity, whereas no such effect was noted for the control group. These findings highlight the need for PTSD connectivity research to consider sub-parts of the hippocampus and to account for age-related connectivity differences.

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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