Oxytocin, PTSD, and sexual abuse are associated with attention network intrinsic functional connectivity

https://doi.org/10.1016/j.pscychresns.2021.111345Get rights and content

Highlights

  • PTSD is related to ventral and dorsal neural attention network dysfunction.

  • Childhood sexual (not physical) abuse is related to similar dysfunction to PTSD.

  • Oxytocin administration may mitigate dysfunction related to PTSD and sexual abuse.

Abstract

Childhood maltreatment is linked to Posttraumatic Stress Disorder (PTSD) in adulthood. Neural attention network function contributes to resilience against PTSD following maltreatment; oxytocin administration alters functional connectivity differentially among resilient to PTSD groups. The present study examined intrinsic connectivity between ventral and dorsal neural attention networks (VAN and DAN) to clarify the nature of dysfunction versus resilience in the context of maltreatment-related PTSD, and to explore differential dysfunction related to varied aspects of maltreatment. Oxytocin administration was examined as a factor in these relationships. Resting-state functional connectivity data were collected from 39 adults with maltreatment histories, with and without PTSD, who were randomly assigned to receive oxytocin or placebo. We found that PTSD and sexual abuse (SA) were associated with reduced VAN-DAN connectivity. There were no significant effects with regard to physical abuse. Oxytocin was associated with greater VAN-DAN connectivity strength. These preliminary findings suggest dysfunction within attentional systems in PTSD, as well as following SA. Further, oxytocin may help ameliorate attentional neurocircuitry dysfunction in individuals with PTSD and those with maltreatment histories.

Introduction

Childhood trauma, including maltreatment, is strongly linked to Posttraumatic Stress Disorder (PTSD) in adulthood (Goldstein et al., 2016). A substantial proportion of individuals with childhood physical or sexual abuse histories develop PTSD, and maltreatment is one of the most commonly reported trauma exposures among individuals with PTSD (Goldstein et al., 2016; Kessler et al., 2014). Childhood maltreatment is associated with lasting impairment in part because of the vulnerability of the developing brain (Arnow, 2004; Teicher and Samson, 2016; Teicher, Samson, Anderson, and Ohashi, 2016). Understanding its neural impact and identifying factors that contribute to resilience against PTSD development following maltreatment is necessary to inform intervention efforts. Neural attention network function represents a potential factor contributing to resilience against PTSD following childhood maltreatment.

Altered functional connectivity in brain networks that support attention capacities represents a potential factor differentiating trauma-exposed individuals with and without PTSD (trauma-exposed controls; TEC) (Aupperle, Melrose, Stein, and Paulus, 2012; Block and Liberzon, 2016). Attention is a complex phenomenon orchestrated by several large-scale neural networks, and how their interplay differentiates PTSD and TEC individuals is unclear. The ventral and dorsal attention networks (VAN and DAN, respectively) are involved in the orientation and shifting of attention (Corbetta and Shulman, 2002; Petersen and Posner, 2012; Seeley et al., 2007; Vossel, Geng, and Fink, 2014). VAN is implicated in the alerting aspect of attention and includes cortical regions in the temporoparietal junction and ventral frontal cortex. DAN is implicated in the orienting aspect of attention—specifically, “voluntary” spatial attention allocation. DAN includes cortical regions in the frontal eye fields (the intersection of middle frontal and precentral gyri) and superior, lateral parietal cortex (e.g., close to the intraparietal sulcus). Studies examining VAN and DAN involvement in PTSD-related attentional dysfunction have yielded mixed findings with regard to directionality of VAN and DAN activity in resiliency against PTSD. Some studies have reported decreased VAN and DAN activation to emotional stimuli in PTSD patients versus TEC and non-trauma-exposed controls (NTC) (Blair et al., 2013). Others have reported increased DAN activation (Fani et al., 2012) and/or increased VAN activation (Thomaes et al., 2014) to threat cues in PTSD patients versus TEC during cognitive tasks (Fani et al., 2012). Moreover, some prior work suggests greater PTSD symptom severity is associated with greater DAN activity, but decreased VAN activity, to emotional distractors in a cognitive task (Hayes, LaBar, Petty, McCarthy, and Morey, 2009). Other work suggests greater PTSD symptom severity is associated with greater VAN activation to trauma-relevant stimuli (Morey, Petty, Cooper, LaBar, and McCarthy, 2008), and greater VAN and DAN activation to emotional stimuli during cognitive tasks (White et al., 2015). Attention system functional differences in resiliency against PTSD are apparent even outside the context of emotional stimuli (Block et al., 2019).

Differences observed in task-related activation studies may be driven in part by task demands and other cognitive factors, highlighting the importance of using intrinsic functional connectivity at rest (resting-state functional connectivity; rsFC) to examine large-scale attention networks. Indeed, rsFC varies as a function of PTSD in brain regions associated with attention. Compared to TEC, individuals with PTSD show decreased VAN and DAN rsFC (Kennis, Van Rooij, Van Den Heuvel, Kahn, and Geuze, 2016; Yin et al., 2011) but increased rsFC within visual attention regions (Kennis et al., 2016). Regarding connectivity with other attentional systems, relative to TEC, individuals with PTSD show increased rsFC between VAN, DAN, and salience network, another large-scale neural network involved in attention coordination (Block and Liberzon, 2016).

Few studies to date have investigated differential functional connectivity in individuals with PTSD specifically related to childhood maltreatment, compared to TEC. Previous literature suggests the potential for maltreatment to exert lasting deleterious effects on a variety of neural systems, including brain regions involved in attention (Teicher and Samson, 2016). Attentional systems are among the latest to develop in childhood, and therefore may be particularly susceptible to influence from adverse experiences (Rubia, 2013; Shaw et al., 2008). Indeed, reduced DAN activation during response-control tasks has been reported as a function of childhood maltreatment severity (Blair et al., 2019), and individuals with maltreatment histories show lower functional connectivity in VAN and DAN regions compared to individuals without maltreatment histories during sustained attention tasks (Hart et al., 2017; Lim et al., 2016). Further, differential forms of maltreatment—such as different types of abuse—may be associated with varied patterns of attention network dysfunction. For example, reduced cerebral blood flow to DAN regions has been reported among individuals with sexual abuse (SA)-related PTSD compared to TEC with SA histories during response-control tasks (Bremner et al., 2004). Among depressed adults, childhood physical abuse (PA) history was associated with greater VAN-DAN rsFC (Yu et al., 2019). However, rsFC between VAN and DAN as a function of varied aspects of childhood maltreatment (i.e., PA versus SA) has not been examined in the context of susceptibility to PTSD specifically.

Given the interpersonal nature of childhood maltreatment, an important factor to consider is the role of the social and affiliative hormone oxytocin in resilience against PTSD. The oxytocin system is involved in stress response and is subject to alteration following psychosocial trauma (Donadon, Martin-Santos, and Osório, 2018; Sippel et al., 2017). Intranasal oxytocin has been proposed as a potential PTSD treatment agent and a possible preventive agent following trauma exposure (Yoon and Kim, 2019) given that oxytocin administration is associated with differences in functional connectivity of regions associated with salience and emotional processing (Frijling, 2017; Koch et al., 2016). Previous studies have found that effects of oxytocin administration on fearful face processing and working memory were more pronounced in individuals with PTSD versus TEC (Flanagan et al., 2018, 2019). Further examination of differential neural attention network responsiveness to oxytocin between TEC and PTSD individuals is essential to both understanding the role of oxytocin in resilience against psychopathology, and enhancing precision of oxytocin as a potential PTSD treatment agent.

The present study examined rsFC between VAN and DAN as a function of PTSD versus TEC, childhood maltreatment type (PA versus SA), and oxytocin administration (versus placebo). Oxytocin was administered in a randomized, double-blind, between-subjects design. Childhood maltreatment was determined retrospectively. Given that VAN and DAN are thought to work synergistically in a “push-pull” manner to flexibly control attentional processes (Vossel et al., 2014), and that compromised attentional shifting is often reported in PTSD (Block and Liberzon, 2016), we hypothesized that individuals with PTSD would show reduced VAN-DAN rsFC. Given that oxytocin has the potential to ameliorate dysfunctional connectivity associated with PTSD (Flanagan et al., 2018; Frijling, 2017; Koch et al., 2016), we hypothesized that oxytocin administration would ameliorate this reduced connectivity. Further, based on existing literature, we hypothesized that individuals with high childhood SA levels would show reduced VAN-DAN rsFC (Bremner et al., 2004), and that individuals with high childhood PA levels would show increased VAN-DAN rsFC (Yu et al., 2019). We hypothesized that oxytocin administration would reduce connectivity differences between groups with high versus low SA or PA.

Section snippets

Participants

Participants were 39 individuals (59% female) recruited via local media advertisements. Childhood trauma-related inclusion criteria included: (1) scores ranging from moderate-severe (>3) on one or more items in the five trauma domains of the Childhood Trauma Questionnaire (CTQ (Bernstein et al., 2003), and (2) meeting Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) Criterion A related to childhood trauma (i.e., exposure to an event prior to age 18 that involved actual or

Results

Table 2 presents sample demographics. PTSD and TEC groups were matched on age, sex, education, and smoking status (smoker vs. non-smoker), ps = 0.438–0.905. Head motion did not significantly differ between PTSD and TEC groups (p = .319). Five participants in the PTSD group endorsed secondary psychiatric diagnoses, including Alcohol Use Disorder (n = 1), Panic Disorder (n = 1), Major Depression (n = 1), Dysthymia (n = 1), and Pre-Menstrual Dysphoric Disorder (n = 1). PTSD diagnosis occurred

Discussion

The present study examined rsFC between VAN and DAN as a function of PTSD, childhood maltreatment type, and oxytocin. Overall, PTSD and high childhood SA levels were associated with reduced VAN-DAN connectivity strength. There were no significant effects, however, with regard to PA. Overall, oxytocin administration was associated with greater VAN-DAN connectivity strength.

Analyses examined VAN-DAN connectivity. VAN and DAN are hypothesized to work synergistically to flexibly control attentional

Contributors

KIC conceptualized this secondary analysis of existing data and wrote the manuscript. JCF contributed to the conduct of the original project and assisted with manuscript writing. BV assisted with analysis. JA assisted with analysis and manuscript writing. MMSM and KTB contributed to the development and conduct of the original project. SEB contributed to the development and conduct of the original project and assisted with manuscript writing. JEJ contributed to the development and conduct of the

Disclosures

The authors report no direct biomedical financial interests or potential conflicts of interest in the development of this manuscript. Dr. Moran-Santa Maria is affiliated with Teva Pharmaceuticals. As noted in Acknowledgments, several grants supported the authors involved in this work, and the development of the overall project from which these data were obtained.

Acknowledgments

The overall project was supported by a NIMH grant (R21MH099619) to Dr. Moran-Santa Maria (Principal Investigator); Dr. Joseph was also supported by this grant as a Co-Investigator. The following authors’ efforts in the development of this manuscript were supported by grant funding: Dr. Crum (NIMH T32 MH018869–31; NIDA U54DA016511); Dr. Flanagan (NIAAA K23AA023845); Dr. Back (NIDA K02DA039229).

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