Childhood Maltreatment and Combat Posttraumatic Stress Differentially Predict Fear-Related Fronto-Subcortical Connectivity

Abstract

Background Adult post-traumatic stress disorder (PTSD) has been characterized by altered fear network connectivity. Childhood trauma is a major risk factor for adult PTSD, yet its contribution to fear network connectivity in PTSD remains unexplored. We examined, within a single model, the contribution of childhood maltreatment, combat exposure, and combat-related post-traumatic stress symptoms (PTSS) to resting-state connectivity (rs-FC) of the amygdala and hippocampus in military veterans. Methods Medication-free male veterans (n=27, average 26.6 years) with a range of PTSS completed resting-state fMRI. Measures including the Clinician-Administered PTSD Scale (CAPS), Childhood Trauma Questionnaire (CTQ), and Combat Exposure Scale (CES) were used to predict rs-FC using multi-linear regression. Fear network seeds included the amygdala and hippocampus. Results Amygdala: CTQ predicted lower connectivity to ventromedial prefrontal cortex (vmPFC), but greater anticorrelation with dorsal/lateral PFC. CAPS positively predicted connectivity to insula, and loss of anticorrelation with dorsomedial/dorsolateral (dm/dl)PFC. Hippocampus CTQ predicted lower connectivity to vmPFC, but greater anticorrelation with dm/dlPFC. CES predicted greater anticorrelation, while CAPS predicted less anticorrelation with dmPFC. Conclusions Childhood trauma, combat exposure, and PTSS differentially predict fear network rs-FC. Childhood maltreatment may weaken ventral prefrontal-subcortical circuitry important in automatic fear regulation, but, in a compensatory manner, may also strengthen dorsal prefrontal-subcortical pathways involved in more effortful emotion regulation. PTSD symptoms, in turn, appear to emerge with the loss of connectivity in the latter pathway. These findings suggest potential mechanisms by which developmental trauma exposure leads to adult PTSD, and which brain mechanisms are associated with the emergence of PTSD symptoms.

Prefrontal–Amygdala Dysregulation to Threat in Pediatric Posttraumatic Stress Disorder

“…Interestingly, this effect appears to be driven by greater connectivity in PTSD youth at younger ages, similar to older healthy youth, but lower connectivity in older PTSD youth, similar to younger healthy youth. This may indicate early compensatory development of amygdala-vmPFC connectivity mirroring findings in a maternally deprived sample (Gee et al, 2013a), but also suggest developmental weakening of amygdalavmPFC connectivity mirroring the effects of childhood maltreatment experiences by late adolescence and early adulthood (Birn et al, 2014;Herringa et al, 2013). Although the exact significance of this apparent developmental shift remains unclear, our prior structural brain study in this sample revealed an inverse relationship between gray matter volume in a similar region of the vmPFC and re-experiencing symptoms (Keding and Herringa, 2015).…”

“…The dmPFC is important in the conscious appraisal of threat and subsequent regulation of emotional responses (Kalisch and Gerlicher, 2014), and is capable of modulating the amygdala based on threat context (Robinson et al, 2012). Furthermore, successful downregulation of negative emotion is associated with amygdala-dmPFC connectivity (Lee et al, 2012), and both anxiety (Kim et al, 2011) and PTSD (Birn et al, 2014) symptoms in adults have been associated with the relative loss of intrinsic amygdala-dmPFC anticorrelation. Our results are consistent with this and suggest that the ability of the dmPFC to modulate amygdala-dependent responses to threat may be compromised in pediatric PTSD, a notion supported by the relationship between dmPFC activation, amygdala-dmPFC connectivity, and PTSD severity.…”

“…These structural changes are paralleled by age-related decreases in amygdala activation and changes in medial prefrontal-amygdala connectivity (Gee et al, 2013b;Vink et al, 2014). Childhood stress may shift these trajectories by increasing amygdala activation, eg (McCrory et al, 2011;Swartz et al, 2015), spurring early development of prefrontal-amygdala connectivity following maternal deprivation (Gee et al, 2013a), or weakening prefrontal-amygdala connectivity following maltreatment experiences (Birn et al, 2014;Herringa et al, 2013). However, it remains unknown whether development of fear circuit function is altered in pediatric PTSD.…”

The Dissociative Subtype of Posttraumatic Stress Disorder: Unique Resting-State Functional Connectivity of Basolateral and Centromedial Amygdala Complexes

“…Emotional undermodulation consists of reliving traumatic experiences with related hyperarousal, characteristic of non-dissociative PTSD patients (PTSD − DS). This behavioral response is associated with decreased activation of PFC regions and ACC, thereby decreasing top-down inhibition of the amygdala and leading to hyperactivation of the limbic system (Lanius et al, 2010b;2012;Shin et al, 2005;Shin and Liberzon, 2010; also see Birn et al, 2014;Stevens et al, 2013;Yan et al, 2014).…”

Childhood trauma and distress tolerance in a trauma-exposed acute-care psychiatric inpatient sample.

“…Childhood trauma (CT) is a promising potential etiological factor underlying DT. CT has been shown to impair stress reactivity and emotion regulation in self-report (e.g., Banducci et al, 2014) and laboratory designs (e.g., Birn et al, 2014; Hagan et al, 2014). DT may be one mechanism by which CT conveys risk for psychopathology in adulthood.…”