Association of Prepubertal and Postpubertal Exposure to Childhood Maltreatment With Adult Amygdala Function

Abstract

Importance: Abnormalities in amygdala response to threatening faces have been observed in anxiety disorders, autism, bipolar disorder, depression, posttraumatic stress disorder, and schizophrenia. Abnormally hyperactive and hypoactive responses have typically been associated with anxiety and inhibition vs risk taking and inappropriate social behaviors. Maltreatment is a major risk factor for most of these disorders and is associated with abnormal amygdala function.

Objective: To identify the type and age of exposure to childhood maltreatment that are associated with hyperactive and hypoactive amygdala responses in young adulthood.

Design, setting, and participants: Data collection for this retrospective cohort study took place from November 8, 2010, to August 23, 2012. Data analyses were conducted from September 20, 2012, to June 27, 2018. Participants were recruited from the urban and suburban Boston vicinity without diagnostic restrictions based on exposure history.

Exposures: The Maltreatment and Abuse Chronology of Exposure (MACE) scale was used to retrospectively assess type and age of exposure to childhood maltreatment.

Main outcomes and measures: Activation and pattern information functional magnetic resonance imaging were used to assess bilateral amygdala response to angry and fearful faces vs neutral faces or shapes, and sensitive exposure periods were identified using cross-validated artificial intelligence predictive analytics (50 averaged randomized iterations with training on 63.3% and testing on 36.7% of the sample).

Results: Of the 202 participants (mean [SD] age, 23.2 [1.7] years; 118 [58.4%] female), 52 (25.7%) reported no exposure to maltreatment and 150 (74.3%) reported exposure to 1 or more maltreatment types. Eight participants (15.1%) with a MACE score of 0 and 51 (34.2%) with a MACE score of 1 or higher had a history of major depression (odds ratio, 2.40; 95% CI, 1.05-6.06; P = .03); 8 unexposed participants (15.1%) and 46 with MACE scores of 1 or higher (30.9%) had a history of 1 or more anxiety disorders (odds ratio, 2.45; 95% CI, 1.03-6.50; P = .03). Retrospective self-report of physical maltreatment between 3 and 6 years of age and peer emotional abuse at 13 and 15 years were associated with amygdala activation to emotional faces vs shapes. Early exposure was associated with blunted response (β = -0.17, P < .001), whereas later exposure was associated with augmented response (β = 0.16, P < .001). Prepubertal vs postpubertal maltreatment was associated with an opposite response on the voxelwise response pattern in clustering stimuli of the same type (eg, mean [SD] emotional ellipse areas for physical maltreatment at age 4 years vs nonverbal emotional abuse at 13 years: 1.41 [1.05] vs 0.25 [0.10], P < .001) and in distinguishing between stimuli of different types (eg, mean [SD] emotional vs neutral faces distance for peer emotional abuse at age 6 years vs 13 years: 1.89 [0.75] vs 0.80 [0.39], P < .001).

Conclusions and relevance: The findings suggest that prepubertal vs postpubertal developmental differences in the association between maltreatment and amygdala response to threatening or salient stimuli exist. Understanding the role of adversity in different sensitive exposure periods and the potential adaptive significance of attenuated vs enhanced amygdala response may help explain why maltreatment may be a risk factor for many different disorders and foster creation of targeted interventions to preempt the emergence of psychopathology in at-risk youths.

Figure 1.. Representational Similarity Analysis

A, The degree of similarity (ie, correlation) was calculated among every pair of stimuli (eg, emotional faces and shapes) in their pattern of voxel response, controlling for block effects by partialing out the degree of correlation observed among each pair of stimuli in cerebrospinal fluid and global white matter. B, A correlational matrix was derived for each research participant from the partial correlations among all pairs of stimuli and transformed into a dissimilarity matrix by subtracting the correlation coefficient from 1. C, The dissimilarity matrix was converted into its corresponding best-fitting euclidean 2-dimensional representation using multidimensional scaling with all representations fixed to have the same axis dimensions. On the basis of the 2-dimensional representation, we calculated the minimum spanning ellipses area for each stimulus category as well as the d′ value reflecting the discriminability among clusters as defined by the mean euclidean distance among ellipse centroids divided by the SD derived from the euclidean distances of each stimulus in a cluster from the category cluster centroid. The size of the minimum spanning ellipse is indicative of the degree of similarity among items within the same category. The smaller the ellipse, the more similar the pattern of voxel response among each stimulus within the category. The d′ distance indicates how different the pattern of voxelwise responses are between stimuli from different categories. D, Random forest regression with conditional inference trees was used to delineate the type and timing of exposure to maltreatment that was most closely associated with the ellipse area and d′ euclidean distance between 2 ellipses. EN indicates emotional neglect; NVEA, nonverbal emotional abuse; Peer_E, peer emotional bullying; Peer_P, peer physical bullying; Phys, parental physical abuse; PN, physical neglect; PVA, parental verbal abuse; SexA, sexual abuse; WIPV, witnessing interparental violence; and WSIB, witnessing violence toward siblings.

Figure 2.. Sensitive Period Analyses

Random forest regression with conditional inference trees indicating the importance of 10 types of childhood maltreatment across ages on different aspects of bilateral amygdala response during an emotional face matching task. Mean importance is defined as the increase in mean square error of the fit following permutation of each variable. A, Blood oxygenation level–dependent functional magnetic resonance imaging activation to emotional faces vs shapes. B, Minimal spanning emotional ellipse area from representational similarities analysis and multidimensional scaling. C, Discriminability in pattern of voxel response between emotional and neutral faces based on d′ euclidean distance from representational similarities analysis and multidimensional scaling. EN indicates emotional neglect; NVEA, nonverbal emotional abuse; Peer_E, peer emotional bullying; Peer_P, peer physical bullying; Phys, parental physical abuse; PN, physical neglect; PVA, parental verbal abuse; SexA, sexual abuse; WIPV, witnessing interparental violence; and Wsib, witnessing violence toward siblings. ^aP < .05. ^bP < .01. ^cP < .001.

Figure 3.. Maltreatment at Peak Predictive Ages and Bilateral Amygdala Response to Emotional Faces vs Shapes

A, Severity of exposure to prepubertal maltreatment defined as the sum of parental physical abuse at 3 to 4 years of age and peer physical bullying at 6 years of age. B, Severity of exposure to postpubertal emotional maltreatment defined as the sum of peer emotional abuse at 13 and 15 years of age. ^aAll clusters in the glass brain are corrected for false display rate across the bilateral amygdala region of interest (P < .05). ^bCombined severity of parental physical maltreatment at 3 and 4 years of age and peer physical bullying at age 6 years. ^cCombined severity of peer emotional bullying at 13 and 15 years of age.

Figure 4.. Multidimensional Scaling of Amygdala Response Based on Type and Timing of Maltreatment

Comparison of multidimensional scaling patterns of voxelwise response to emotional faces, neutral faces, and shapes in groups of individuals with and without exposure to a particular type of maltreatment during a specific developmental phase. The ellipse area is indicative of the homogeneity of voxelwise response to stimuli within the same category, with smaller ellipses corresponding to more similar response patterns. Differences in d′ distance are indicative of heterogeneity of response to stimuli from different categories, with larger distances reflected in more separation and less overlap between category ellipses. A, Differences in the ellipse area associated with exposure to parental physical maltreatment at 4 years of age. B, Differences in the ellipse area associated with exposure to parental nonverbal emotional abuse at 13 years of age. C, Differences in d′ euclidean distance between emotional and neutral faces associated with exposure to peer emotional bullying at 6 years of age. D, Differences in d′ euclidean distance between emotional and neutral faces associated with exposure to peer emotional bullying at 13 years of age. The x-axis and y-axis are scaled the same for each plot and range from −0.9 to 1.5 for the x-axis and −1.0 to 1.2 for the y-axis.