Sex Differences in Trauma-Related Psychopathology: a Critical Review of Neuroimaging Literature (2014–2017)

Abstract

Purpose of Review Sex differences in the epidemiology and clinical presentation of trauma-related psychopathology have long been documented. Multiple underlying mechanisms have been examined, both psychosocial and biological. Among the most promising biological mechanisms are neural substrates of trauma-related psychopathology that have been uncovered in recent years. Recent Findings Neuroimaging studies of sex-related heterogeneity published over the past 3 years (2014–2017) demonstrate an interaction between sex and type, timing, and load of trauma exposure. These studies suggest that, for males, early trauma exposure may involve a loss of gray matter in the limbic system, including the prefrontal cortex (PFC), amygdala, and hippocampus, and an over-activity and increased connectivity of salience hubs, and particularly dorsal anterior cingulate cortex (dACC). For females, however, early trauma exposure may involve overactive and possibly an enlarged amygdala, as well as decreased connectivity of salience hubs such as the dACC. Underlying mechanisms may include interaction with several endocrine systems and result in differential neural response to naturally occurring and added endocrine ligands, as well as sex-specific genetic and epigenetic risk and resilience factors. This complex interaction between multiple biological systems may be associated with sex-specific behavioral patterns, in turn associated with trauma-related psychopathology. Summary While substantial number of published studies present preliminary evidence for neural mechanisms of sex-specific posttraumatic responses, there is a paucity of research directly designed to examine sex as a biological factor in trauma-related psychopathology. Specific foci for future studies aiming to bridge current gaps in the literature are discussed.

Neurobiological mechanisms underlying sex-related differences in stress-related disorders: Effects of neuroactive steroids on the hippocampus

“…Multiple studies indeed show that childhood adversities, ranging from low birth weight or social status to severe maltreatment or abuse, are associated with chronically-elevated cortisol levels ( Sheridan et al, 2013 ; Frodl and O'Keane, 2013 ; Engert et al, 2010 ; Dahmen et al, 2018 ; Bremner, 2005 ), but lower hippocampal volumes ( Dahmen et al, 2018 ; Samplin et al, 2013 ; Frodl et al, 2017 ; Everaerd et al, 2012 ; Calem et al, 2017 ). While there seem to be no sex differences in MDD effects on hippocampal volumes, effects of childhood adversities are consistently stronger in males ( Samplin et al, 2013 ; Everaerd et al, 2012 ; Calem et al, 2017 ; Helpman et al, 2017 ). Following the idea that smaller hippocampal volumes are not so much a result of chronically elevated cortisol levels, but represent a vulnerability factor for HPA-axis dysregulation due to severe stress, the fact that pre-adolescent girls have larger hippocampi and a larger cortisol response than boys may contribute to this finding ( Whittle et al, 2011 ).…”

Neuroimaging Correlates of Resilience to Traumatic Events—A Comprehensive Review

“…Additionally, there is increasing evidence for a gender-specific pattern of the described structural and functional changes: While male individuals largely present PFC, amygdala and hippocampus gray matter reductions following traumatic exposure, females often present with amygdala hyperactivity. This might not only explain the heterogeneity of study results, but also suggest far-reaching implications for the selection of adequate therapeutic measures (74).…”

More than a feeling: A unified view of stress measurement for population science

“…In a small study employing an acute laboratory stressor, men showed increased activation in the prefrontal cortex while women displayed elevated activity in limbic regions, including the ventral striatum and cingulate (Wang et al, 2007). In terms of structural changes due to stress, childhood trauma may impact the hippocampal volume of males more than females (reviewed in Tiwari and Gonzalez, 2018) and may enlarge amygdala and decrease connectivity of salience hubs such as the dACC in females more than males (Helpman et al, 2017). Animal studies have delineated some of the mechanisms of sex differences.…”