Abnormal Structure of Fear Circuitry in Pediatric Post-Traumatic Stress Disorder

Abstract

Structural brain studies of adult post-traumatic stress disorder (PTSD) show reduced gray matter volume (GMV) in fear regulatory areas including the ventromedial prefrontal cortex (vmPFC) and hippocampus. Surprisingly, neither finding has been reported in pediatric PTSD. One possibility is that they represent age-dependent effects that are not fully apparent until adulthood. In addition, lowerresolution MRI and image processing in prior studies may have limited detection of such differences. Here we examine fear circuitry GMV, including age-related differences, using higher-resolution MRI in pediatric PTSD vs healthy youth. In a cross-sectional design, 3 T anatomical brain MRI was acquired in 27 medication-free youth with PTSD and 27 healthy non-traumatized youth of comparable age, sex, and IQ. Voxel-based morphometry was used to compare GMV in a priori regions including the medial prefrontal cortex and amygdala/hippocampus. Compared with healthy youth, PTSD youth had reduced GMV but no age-related differences in anterior vmPFC (BA 10/11, Z ¼ 4.5), which inversely correlated with PTSD duration. In contrast, although there was no overall group difference in hippocampal volume, a group  age interaction (Z ¼ 3.6) was present in the right anterior hippocampus. Here, age positively predicted hippocampal volume in healthy youth but negatively predicted volume in PTSD youth. Within the PTSD group, re-experiencing symptoms inversely correlated with subgenual anterior cingulate cortex (sgACC, Z ¼ 3.7) and right anterior hippocampus (Z ¼ 3.5) GMV. Pediatric PTSD is associated with abnormal structure of the vmPFC and age-related differences in the hippocampus, regions important in the extinction and contextual gating of fear. Reduced anterior vmPFC volume may confer impaired recovery from illness, consistent with its role in the allocation of attentional resources. In contrast, individual differences in sgACC volume were associated with re-experiencing symptoms, consistent with the role of the sgACC in fear extinction. The negative relationship between age and hippocampal volume in youth with PTSD may suggest an ongoing neurotoxic process over development, which further contributes to illness expression. Future studies employing a longitudinal design would be merited to further explore these possibilities.

Prefrontal–Amygdala Dysregulation to Threat in Pediatric Posttraumatic Stress Disorder

“…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). Fear extinction and putatively safety signaling are mediated by differential signaling between the amygdala, vmPFC, and dACC (Senn et al, 2014).…”

“…Participant recruitment has been previously described (Keding and Herringa, 2015) and is summarized in detail in Supplementary Information. Participant data were excluded after data collection for excessive head motion during the scan, resulting in at least 20% of volumes being censored (n = 2 healthy, n = 1 PTSD), failure to respond to at least 75% of trials during the scan (n = 1 PTSD), or terminating the scan early (n = 1 healthy).…”

“…Finally, prior studies have examined youth with a wide range of PTSS and it remains unclear whether similar abnormalities are present in more severe PTSD. Our prior structural brain analysis in this sample of youth with severe PTSD revealed both overall group differences and potential developmental abnormalities in fear circuit structure, namely decreased vmPFC volume and age-related decline in hippocampus volume (Keding and Herringa, 2015). Thus, we aimed to extend this analysis in the current study to functional brain abnormalities in pediatric PTSD, including age-related effects and functional connectivity analyses.…”

Forming competing fear learning and extinction memories in adolescence makes fear difficult to inhibit

“…However, adolescents do not show significant PFC-amygdala interactions during fear learning and extinction (Tzschoppe et al 2014), suggesting a cross-species lack of vmPFC-amygdala connectivity during extinction in adolescence. Further, in clinical populations, adolescents with anxiety disorders (generalized anxiety disorder and/or social phobia) show decreased resting-state vmPFC-amygdala functional connectivity (Roy et al 2013;Hamm et al 2014) and youth with posttraumatic stress disorder (PTSD) have reduced vmPFC gray matter volume (Keding and Herringa 2015), which was linked to reexperiencing symptoms. It therefore appears that structural and functional changes in the adolescent vmPFC and amygdala in both rodents and humans are related to altered fear extinction, anxiety, and re-experiencing symptoms of PTSD.…”

Maternal and pediatric health and disease: integrating biopsychosocial models and epigenetics

“…Of particular importance in child health, unfavorable birth outcomes and psychosocial deprivation early in life have been associated with adverse health and developmental outcomes and changes in brain architecture (99,100). Moreover, maternal psychological stress or depression during pregnancy, which more often occurs in individuals with low SES, can have profound adverse effects across generations.…”