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Limbic Scars: Long-Term Consequences of Childhood Maltreatment Revealed by Functional and Structural Magnetic Resonance Imaging

Published:November 24, 2011DOI:https://doi.org/10.1016/j.biopsych.2011.10.021

      Background

      Childhood maltreatment represents a strong risk factor for the development of depression and posttraumatic stress disorder (PTSD) in later life. In the present study, we investigated the neurobiological underpinnings of this association. Since both depression and PTSD have been associated with increased amygdala responsiveness to negative stimuli as well as reduced hippocampal gray matter volume, we speculated that childhood maltreatment results in similar functional and structural alterations in previously maltreated but healthy adults.

      Methods

      One hundred forty-eight healthy subjects were enrolled via public notices and newspaper announcements and were carefully screened for psychiatric disorders. Amygdala responsiveness was measured by means of functional magnetic resonance imaging and an emotional face-matching paradigm particularly designed to activate the amygdala in response to threat-related faces. Voxel-based morphometry was used to study morphological alterations. Childhood maltreatment was assessed by the 25-item Childhood Trauma Questionnaire (CTQ).

      Results

      We observed a strong association of CTQ scores with amygdala responsiveness to threat-related facial expressions. The morphometric analysis yielded reduced gray matter volumes in the hippocampus, insula, orbitofrontal cortex, anterior cingulate gyrus, and caudate in subjects with high CTQ scores. Both of these associations were not influenced by trait anxiety, depression level, age, intelligence, education, or more recent stressful life events.

      Conclusions

      Childhood maltreatment is associated with remarkable functional and structural changes even decades later in adulthood. These changes strongly resemble findings described in depression and PTSD. Therefore, the present results might suggest that limbic hyperresponsiveness and reduced hippocampal volumes could be mediators between the experiences of adversities during childhood and the development of emotional disorders.

      Key Words

      Childhood maltreatment is highly prevalent in Western countries with estimations of about 30% to 40% of the adult population having experienced at least some form of maltreatment during childhood (
      • Scher C.D.
      • Forde D.R.
      • McQuaid J.R.
      • Stein M.B.
      Prevalence and demographic correlates of childhood maltreatment in an adult community sample.
      ). Maltreatment includes a spectrum of sexual, physical, and emotional forms of abuse, as well as emotional or physical neglect. Epidemiologic studies have shown that childhood maltreatment is a strong risk factor for developing major depression in later life (
      • Gilbert R.
      • Widom C.S.
      • Browne K.
      • Fergusson D.
      • Webb E.
      • Janson S.
      Burden and consequences of child maltreatment in high-income countries.
      ), one of the most debilitating diseases worldwide, with up to 30% of all maltreated children fulfilling DSM-IV criteria for major depression in their late 20s (
      • Widom C.S.
      • DuMont K.
      • Czaja S.J.
      A prospective investigation of major depressive disorder and comorbidity in abused and neglected children grown up.
      ). Furthermore, childhood maltreatment increases the susceptibility for developing posttraumatic stress disorder (PTSD) after experiencing further traumata in later life (
      • Gilbert R.
      • Widom C.S.
      • Browne K.
      • Fergusson D.
      • Webb E.
      • Janson S.
      Burden and consequences of child maltreatment in high-income countries.
      ). To understand the underpinnings of the relationship between maltreatment and such emotional disorders, a considerable body of research investigated the neurobiological consequences of childhood maltreatment, which could thereby help to identify potential risk markers for depression and PTSD. In endocrinological studies, it was repeatedly shown that childhood maltreatment causes lasting changes in the hypothalamic-pituitary-adrenal axis responsiveness to stress and could thereby increase the risk for developing depression (
      • Heim C.M.
      • Newport D.J.
      • Mletzko T.C.
      • Miller A.H.
      • Nemeroff C.B.
      The link between childhood trauma and depression: Insights from HPA axis studies in humans.
      ,
      • Heim C.M.
      • Newport D.J.
      • Heit S.
      • Graham Y.P.
      • Wilcox M.
      • Bonsall R.
      • et al.
      Pituitary-adrenal and autonomic responses to stress in women after sexual and physical abuse in childhood.
      ). Studies using neuroimaging techniques revealed notable structural changes in maltreated children as morphologic correlates for impaired brain development, including smaller brain volume and corpus callosum atrophy (
      • De Bellis M.D.
      • Keshavan M.S.
      • Clark D.B.
      • Casey B.J.
      • Giedd J.N.
      • Boring A.M.
      • et al.
      A.E. Bennett Research Award. Developmental traumatology. Part II: Brain development.
      ). More recent studies have focused on the association of childhood maltreatment and hippocampal volumes. The hippocampus is highly susceptible for stress and involved in the regulation of the hypothalamic-pituitary-adrenal axis. Furthermore, several studies have shown that depression and PTSD are associated with smaller hippocampal volumes (
      • MacQueen G.M.
      • Frodl T.
      The hippocampus in major depression: Evidence for the convergence of the bench and bedside in psychiatric research?.
      ,
      • Kasai K.
      • Yamasue H.
      • Gilbertson M.W.
      • Shenton M.E.
      • Rauch S.L.
      • Pitman R.K.
      Evidence for acquired pregenual anterior cingulate gray matter loss from a twin study of combat-related posttraumatic stress disorder.
      ), which seem to be apparent also in subjects at risk for depression or PTSD (
      • Chen M.C.
      • Hamilton J.P.
      • Gotlib I.H.
      Decreased hippocampal volume in healthy girls at risk of depression.
      ,
      • Amico F.
      • Meisenzahl E.
      • Koutsouleris N.
      • Reiser M.
      • Möller H.J.
      • Frodl T.
      Structural MRI correlates for vulnerability and resilience to major depressive disorder.
      ,
      • Gilbertson M.W.
      • Shenton M.E.
      • Ciszewski A.
      • Kasai K.
      • Lasko N.B.
      • Orr S.P.
      • Pitman R.K.
      Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma.
      ). Accordingly, it was demonstrated that patients suffering from depression show even smaller hippocampal volumes if they experienced emotional neglect (
      • Frodl T.
      • Reinhold E.
      • Koutsouleris N.
      • Reiser M.
      • Meisenzahl E.M.
      Interaction of childhood stress with hippocampus and prefrontal cortex volume reduction in major depression.
      ) and physical or sexual abuse as a child (
      • Vythilingam M.
      • Heim C.M.
      • Newport J.
      • Miller A.H.
      • Anderson E.
      • Bronen R.
      • et al.
      Childhood trauma associated with smaller hippocampal volume in women with major depression.
      ).
      A second imaging finding that has been frequently described in both depression (
      • Siegle G.J.
      • Thompson W.K.
      • Carter C.S.
      • Steinhauer S.R.
      • Thase M.E.
      Increased amygdala and decreased dorsolateral prefrontal BOLD responses in unipolar depression: Related and independent features.
      ,
      • Sheline Y.I.
      • Barch D.M.
      • Donnelly J.M.
      • Ollinger J.M.
      • Snyder A.Z.
      • Mintun M.A.
      Increased amygdala response to masked emotional faces in depressed subjects resolves with antidepressant treatment: An fMRI study.
      ,
      • Victor T.A.
      • Furey M.L.
      • Fromm S.J.
      • Öhman A.
      • Drevets W.C.
      Relationship between amygdala responses to masked faces and mood state and treatment in major depressive disorder.
      ,
      • Suslow T.
      • Konrad C.
      • Kugel H.
      • Rumstadt D.
      • Zwitserlood P.
      • Schöning S.
      • et al.
      Automatic mood-congruent amygdala responses to masked facial expressions in major depression.
      ,
      • Stuhrmann A.
      • Suslow T.
      • Dannlowski U.
      Facial emotion processing in major depression: A systematic review of neuroimaging findings.
      ) and PTSD (
      • Shin L.M.
      • Wright C.I.
      • Cannistraro Pa
      • Wedig M.M.
      • McMullin K.
      • Martis B.
      • et al.
      A functional magnetic resonance imaging study of amygdala and medial prefrontal cortex responses to overtly presented fearful faces in posttraumatic stress disorder.
      ,
      • Rauch S.L.
      • Whalen P.J.
      • Shin L.M.
      • McInerney S.C.
      • Macklin M.L.
      • Lasko N.B.
      • et al.
      Exaggerated amygdala response to masked facial stimuli in posttraumatic stress disorder: A functional MRI study.
      ,
      • Francati V.
      • Vermetten E.
      • Bremner J.D.
      Functional neuroimaging studies in posttraumatic stress disorder: Review of current methods and findings.
      ) is amygdala hyperresponsiveness to emotionally negative stimuli. The amygdala is a central structure in limbic emotion processing circuits (
      • Davis M.
      • Whalen P.J.
      The amygdala: Vigilance and emotion.
      ), critically involved in the rapid processing particularly of threat-related stimuli (
      • Costafreda S.G.
      • Brammer M.J.
      • David A.S.
      • Fu C.H.Y.
      Predictors of amygdala activation during the processing of emotional stimuli: A meta-analysis of 385 PET and fMRI studies.
      ), and amygdala hyperactivity has been implicated in the pathogenesis of major depression, probably by causing negatively biased emotion processing (
      • Dannlowski U.
      • Ohrmann P.
      • Bauer J.
      • Kugel H.
      • Arolt V.
      • Heindel W.
      • et al.
      Amygdala reactivity to masked negative faces is associated with automatic judgmental bias in major depression: A 3 T fMRI study.
      ,
      • Hamilton J.P.
      • Gotlib I.H.
      Neural substrates of increased memory sensitivity for negative stimuli in major depression.
      ). One recent study reported a positive correlation of childhood maltreatment and right amygdala responsiveness to sad facial expression in a subsample of depressed patients (n = 20), driven by the physical abuse scale (26; but see [
      • Hsu D.T.
      • Langenecker S.A.
      • Kennedy S.E.
      • Zubieta J.-K.
      • Heitzeg M.M.
      fMRI BOLD responses to negative stimuli in the prefrontal cortex are dependent on levels of recent negative life stress in major depressive disorder.
      ,
      • Taylor S.E.
      • Eisenberger N.I.
      • Saxbe D.
      • Lehman B.J.
      • Lieberman M.D.
      Neural responses to emotional stimuli are associated with childhood family stress.
      ] for conflicting findings). Therefore, the authors suggested that the association of childhood maltreatment and depression could be mediated by amygdala hyperresponsiveness.
      However, the majority of imaging studies describing maltreatment-related functional and structural changes investigated patients already affected by major depression or PTSD. Thus, it is difficult to infer whether limbic alterations following childhood maltreatment are only evident in subjects who eventually develop emotional disorders in later life or if these changes are detectable consequences of maltreatment in subjects without any history of psychiatric disorders and accordingly constitute promising vulnerability markers. To the best of our knowledge, only one recent study provided evidence of an association between early-life adversity and smaller hippocampal volumes in healthy adolescents (
      • Rao U.
      • Chen L.-A.
      • Bidesi A.S.
      • Shad M.U.
      • Thomas M.A.
      • Hammen C.L.
      Hippocampal changes associated with early-life adversity and vulnerability to depression.
      ). Furthermore, the study data suggest that small hippocampal volumes, indeed, could mediate the association of early-life adversity and the onset of depression (
      • Rao U.
      • Chen L.-A.
      • Bidesi A.S.
      • Shad M.U.
      • Thomas M.A.
      • Hammen C.L.
      Hippocampal changes associated with early-life adversity and vulnerability to depression.
      ).
      In the present study, we sought to further clarify the role of childhood maltreatment on functional (amygdala responsiveness to aversive stimuli) and structural (hippocampus gray matter volume) imaging markers associated with depression and PTSD in a large sample of healthy adults carefully screened for psychiatric conditions. We employed a robust amygdala activation paradigm and high-resolution structural images for morphometric analyses. We hypothesized that healthy adults having experienced maltreatment as children would show amygdala hyperresponsiveness to negative facial expressions and reduced hippocampal volumes.

      Methods and Materials

      Subjects

      One hundred forty-eight right-handed healthy subjects participated in the present study. Subjects responded to local newspaper ads and public notices with no direct reference to childhood maltreatment as a key variable in the study. All subjects were thoroughly investigated by experienced psychologists and were free from any lifetime history of psychiatric disorders according to DSM-IV criteria (
      American Psychiatric Association
      Diagnostic and Statistical Manual of Mental Disorders.
      ), as diagnosed with the Structured Clinical Interview for DSM-IV interview (
      • Wittchen H.-U.
      • Wunderlich U.
      • Gruschwitz S.
      • Zaudig M.
      SKID-I Strukturiertes Klinisches Interview für DSM-IV.
      ). Exclusion criteria were scores ≥ 10 on the Beck Depression Inventory (
      • Beck A.T.
      • Steer R.A.
      Beck Depression Inventory: Manual.
      ), any neurological abnormalities, history of seizures, head trauma or unconsciousness, intake of any psychotropic medication, and the usual magnetic resonance imaging contraindications. Two subjects had to be excluded for anatomical abnormalities (abnormally enlarged ventricles) discovered in the structural magnetic resonance imaging images, checked by visual inspection, and identified as extreme outliers in the check data quality function of the VBM8-Toolbox (version 419; http://dbm.neuro.uni-jena.de/vbm). The Childhood Trauma Questionnaire (CTQ) was administered to assess maltreatment during childhood. The CTQ is a 25-item retrospective self-report questionnaire designed to assess five types of negative childhood experiences (
      • Bernstein D.P.
      • Fink L.
      • Handelsman L.
      • Foote J.
      • Lovejoy M.
      • Wenzel K.
      • et al.
      Initial reliability and validity of a new retrospective measure of child abuse and neglect.
      ). The reliability was high in the present sample (Cronbach's α = .93). Furthermore, the Perceived Stress Scale (PSS) and the List of Threatening Experiences Questionnaire (LTE-Q) were administered. The PSS is a measure of the degree to which situations in the subject's life are appraised as stressful and how unpredictable, uncontrollable, and overloaded respondents find their lives during the past month (
      • Cohen S.
      • Kamarck T.
      • Mermelstein R.
      A global measure of perceived stress.
      ). The LTE-Q assesses 12 different stressful life events that could have occurred during the last 12 months (
      • Brugha T.S.
      • Cragg D.
      The List of Threatening Experiences: The reliability and validity of a brief life events questionnaire.
      ). Trait anxiety was measured with the State-Trait Anxiety Inventory (trait version). Neuroticism and harm avoidance were measured with the NEO Five Factor Inventory (
      • Costa P.T.
      • McCrae R.R.
      Revised NEO Personality Inventory (NEO-PI-RTM) and NEO Five Factor Inventory (NEO-FFI): Professional Manual.
      ) and the Tridimensional Personality Questionnaire (
      • Weyers P.
      • Krebs H.
      • Janke W.
      Reliability and construct validity of the German version of Cloninger's Tridimensional Personality Questionnaire.
      ). Verbal intelligence was estimated by the Mehrfachwahl-Wortschatz-Intelligenztest (multiple choice vocabulary intelligence test) (
      • Lehrl S.
      Mehrfachwahl-Wortschatz-Intelligenztest MWT-B.
      ). Table 1 lists sociodemographic, questionnaire, and behavioral data of study participants. The study was approved by the Ethics Committee of the University of Münster. After complete description of the study to the participants, written informed consent was obtained. Participants received a financial compensation of 30 €.
      Table 1Sociodemographic, Questionnaire, and Behavioral Data of Study Participants
      Age33.8 ± 10.4 (20–57)
      Education Years15.6 ± 2.1 (10–21)
      Sex (M/F)75/70
      Verbal Intelligence
      Assessed with the Mehrfachwahl-Wortschatz-Intelligenztest (38).
      117.0 ± 12.3 (93–145)
      BDI1.6 ± 1.9 (0–9)
      STAI-T31.4 ± 6.6 (20–53)
      CTQ Score33.4 ± 10.0 (25–74)
      CTQ Emotional Neglect8.8 ± 4.1 (5–25)
      CTQ Emotional Abuse7.2 ± 3.4 (5–23)
      CTQ Physical Abuse5.7 ± 2.1 (5–20)
      CTQ Physical Neglect6.4 ± 1.9 (5–13)
      CTQ Sexual Abuse5.2 ± 1.0 (5–14)
      PSS18.6 ± 6.6 (5–35)
      LTE-Q1.1 ± 1.3 (0–7)
      % Correct Faces99.3 ± 2.0 (91.7–100)
      % Correct Shapes98.6 ± 2.3 (86.7–100)
      Mean RT Faces (milliseconds)1032.4 ± 170.4 (668.3–1579.0)
      Mean RT Shapes (milliseconds)861.8 ± 148.0 (559.0–1449.6)
      n = 145 representing the final sample included in the morphometry analysis; mean ± SE (range).
      BDI, Beck Depression Inventory; CTQ, Childhood Trauma Questionnaire; F, female; LTE-Q, List of Threatening Experiences Questionnaire; M, male; PSS, Perceived Stress Scale; RT, reaction time; STAI-T, State-Trait Anxiety Inventory-Trait version.
      a Assessed with the Mehrfachwahl-Wortschatz-Intelligenztest (
      • Lehrl S.
      Mehrfachwahl-Wortschatz-Intelligenztest MWT-B.
      ).

      Face-Matching Paradigm

      For the functional magnetic resonance imaging (fMRI) study, a robust paradigm for eliciting amygdala responses to fearful and angry faces was used. The paradigm has already been employed in numerous previous imaging studies to investigate amygdala responsiveness (e.g., [
      • Hariri A.R.
      • Mattay V.S.
      • Tessitore A.
      • Kolachana B.
      • Fera F.
      • Goldman D.
      • et al.
      Serotonin transporter genetic variation and the response of the human amygdala.
      ,
      • Pezawas L.
      • Meyer-Lindenberg A.
      • Drabant E.M.
      • Verchinski B.A.
      • Muñoz K.E.
      • Kolachana B.S.
      • et al.
      5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: A genetic susceptibility mechanism for depression.
      ,
      • Dannlowski U.
      • Kugel H.
      • Franke F.
      • Stuhrmann A.
      • Hohoff C.
      • Zwanzger P.
      • et al.
      Neuropeptide-S (NPS) receptor genotype modulates basolateral amygdala responsiveness to aversive stimuli.
      ]). The task consisted of four blocks of a face-processing task alternating with five blocks of a sensorimotor control task. During the face-processing task, participants viewed a trio of faces (all three expressing either anger or fear) from the Ekman and Friesen (
      • Ekman P.
      • Friesen W.V.
      Pictures of Facial Affect.
      ) stimulus set. Subjects were instructed to selected one of two faces (bottom) that was identical to a target face (top). Each face-processing block consisted of six images, balanced for gender and emotion (angry or fearful). During the sensorimotor control blocks, participants viewed a trio of geometric shapes (circles and ellipses) and selected one of two shapes (bottom) that were identical to a target shape (top). Each sensorimotor control block consisted of six different shape trios. All blocks were preceded by an instruction (match faces or match shapes in German) that lasted 2 seconds. In the face-processing blocks, each of the six face trios was presented for 4 seconds with a variable interstimulus interval of 2 seconds to 6 seconds (mean, 4 seconds), for a total block length of 48 seconds. In the sensorimotor control blocks, each of the six shape trios was presented for 4 seconds with a fixed interstimulus interval of 2 seconds, for a total block length of 36 seconds. Total task time was 390 seconds. Participant performance (accuracy and reaction time) was recorded.

      fMRI Methods

      Images were projected to the rear end of the scanner (Sharp XG-PC10XE with additional high-frequency shielding; Osaka, Japan). T2* functional data were acquired at a 3T scanner (Gyroscan Intera 3T, Philips Medical Systems, Best, The Netherlands), using a single-shot echo planar sequence with parameters selected to minimize distortion in the region of central interest, while retaining adequate signal-to-noise ratio and T2* sensitivity. Volumes consisting of 34 slices were acquired (matrix 64 × 64, resolution 3.6 × 3.6 × 3.6 mm; repetition time = 2.1 seconds, echo time = 30 milliseconds, flip angle = 90°). The slices were tilted 25° from the anterior commissure/posterior commissure line to minimize dropout artifacts in the orbitofrontal and mediotemporal regions.
      Functional imaging data were realigned and unwarped, spatially normalized to standard Montreal Neurological Institute space and smoothed (Gaussian kernel, 6 mm full-width at half maximum) using Statistical Parametric Mapping (SPM8, http://www.fil.ion.ucl.ac.uk/spm). Twenty-two subjects did not receive functional scans for technical reasons. For the fMRI analysis, 10 further subjects had to be excluded due to excessive head movement (exclusion criterion > 2 mm and/or 2°), leaving n = 114 complete datasets for fMRI analyses. However, including these subjects would not weaken (but slightly strengthen) the reported fMRI results.
      Onsets and durations of the two experimental conditions (faces and shapes) were modeled with a canonical hemodynamic response function in the context of the general linear model and the model was corrected for serial correlations. For each participant, one contrast image was generated in each individual fixed-effects first-level analysis comparing activation in response to fear-relevant faces with the shapes baseline. The resulting contrast images were then entered into second-level random-effects group analyses, regressing CTQ scores on brain activation.

      fMRI Data Analysis

      We tested our main hypothesis of amygdala responsiveness modulation by childhood maltreatment via regressing CTQ scores on amygdala responsiveness to aversive facial expressions. A statistical threshold of p < .05, family wise error (FWE) corrected for the bilateral amygdala was used. The amygdala was defined according to Tzourio-Mazoyer et al. (
      • Tzourio-Mazoyer N.
      • Landeau B.
      • Papathanassiou D.
      • Crivello F.
      • Etard O.
      • Delcroix N.
      • et al.
      Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain.
      ) and the amygdala mask was created by means of the WFU PickAtlas (
      • Maldjian J.A.
      • Laurienti P.J.
      • Kraft R.A.
      • Burdette J.H.
      An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets.
      ). In a second step, the mean contrast values of the significant cluster from this analysis were extracted for each participant and further analyzed with PASW Statistics 18 (IBM, Armonk, New York). We conducted a multiple regression model predicting amygdala responsiveness by CTQ scores, age, gender, total education time (years), verbal intelligence, trait anxiety, and depression level, as well as PSS scores and LTE-Q scores. Furthermore, each of the five CTQ subscales was separately correlated with amygdala responsiveness to explore which maltreatment type was the strongest predictor. Additionally, we conducted a nonparametric correlation of CTQ and amygdala responsiveness.

      Voxel-Based Morphometry

      T1-weighted high-resolution anatomical images were acquired with a three-dimensional (3D) fast gradient echo sequence (turbo field echo), repetition time = 7.4 milliseconds, echo time = 3.4 milliseconds, flip angle = 9°, two signal averages, inversion prepulse every 814.5 milliseconds, acquired over a field of view of 256 (feet-head [FH]) × 204 (anterior-posterior [AP]) × 160 (right-left [RL]) mm, phase encoding in AP and RL direction, reconstructed to cubic voxels of .5 mm × .5 mm × .5 mm. The VBM8 Toolbox was used for preprocessing the structural images with default parameters. Images were bias-corrected, tissue classified, and normalized to Montreal Neurological Institute space using linear (12-parameter affine) and nonlinear transformations, within a unified model (
      • Ashburner J.
      • Friston K.J.
      Unified segmentation.
      ) including high-dimensional DARTEL normalization. Gray matter (GM) and white matter (WM) segments were modulated only by the nonlinear components to preserve actual GM and WM values locally (modulated GM and WM volumes).
      Homogeneity of gray matter images was checked using the covariance structure of each image with all other images, as implemented in the check data quality function. As described above, two extreme outliers showing anatomical abnormalities were identified and excluded. One further subject had to be excluded because of an incomplete T1 scan. The remaining n = 145 images were clear of such problems. The modulated gray matter images were smoothed with a Gaussian kernel of 8 mm FWHW. Group statistics were calculated with second-level models using SPM8. We used the same analysis strategy as in the fMRI analysis, starting with a voxel-wise regression restricted to the bilateral hippocampus as defined by Tzourio-Mazoyer et al. (
      • Tzourio-Mazoyer N.
      • Landeau B.
      • Papathanassiou D.
      • Crivello F.
      • Etard O.
      • Delcroix N.
      • et al.
      Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain.
      ) with a rigorous FWE-correction for multiple comparisons. Again, values of the significant cluster from this analysis were extracted for all subjects and further processed as described above using the same regression model and nonparametric statistics.
      Given several previous reports of childhood trauma affecting the structure of other brain regions, including the prefrontal cortex (
      • Frodl T.
      • Reinhold E.
      • Koutsouleris N.
      • Reiser M.
      • Meisenzahl E.M.
      Interaction of childhood stress with hippocampus and prefrontal cortex volume reduction in major depression.
      ,
      • van Harmelen A.-L.
      • van Tol M.-J.
      • van der Wee N.J.A.
      • Veltman D.J.
      • Aleman A.
      • Spinhoven P.
      • et al.
      Reduced medial prefrontal cortex volume in adults reporting childhood emotional maltreatment.
      ) and visual areas (
      • Tomoda A.
      • Navalta C.P.
      • Polcari A.M.
      • Sadato N.
      • Teicher M.H.
      Childhood sexual abuse is associated with reduced gray matter volume in visual cortex of young women.
      ), a supplementary whole-brain analysis correlating CTQ scores with the gray matter images was also performed at p < .001 (uncorrected), with a cluster threshold of k = 50 voxels (see Table 2 for results). The anatomical labeling for the whole-brain data was performed by means of the AAL-Toolbox (
      • Tzourio-Mazoyer N.
      • Landeau B.
      • Papathanassiou D.
      • Crivello F.
      • Etard O.
      • Delcroix N.
      • et al.
      Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain.
      ), and the Brodmann areas (BA) were identified with the Talairach Daemon atlas (http://www.talairach.org).
      Table 2Results of a Whole-Brain Regression Analysis of CTQ Scores on Gray Matter Volumes Conducted at p < .001, Uncorrected, k = 50 Voxels
      Anatomical RegionBASideCluster SizexyzZ-Scorep Value (Uncorrected)
      Insula, Hippocampus, STG, Putamen13,38,21,47,22R109538−16−114.54<.00001
      SFG, MidFG9R2022033344.38<.00001
      SMG, Rolandic Operculum, Postcentral Gyrus1–4,6,40, 43R78756−25314.30<.00001
      Precentral Gyrus, IFG, MidFG9,6,8R216509374.20.00001
      STG, SMG, MTG, Rolandic Operculum, Heschl's Gyrus21,22,13,40–42L1769−46−30194.20.00001
      Cuneus, Precuneus, SOG, SPG7,18,19,31L634−8−70314.05.00003
      Precuneus, SPG5,7R13310−48583.88.00005
      SOG, MOG19,7L59−26−85343.81.00007
      Insula, IFG (Orbital Part), SFG (Orbital Part)47R542220−143.63.00014
      IFG (Orbital Part), Insula47,38L57−4415−93.63.00014
      SFG (Medial Part), ACC10,31,9R/L214463133.44.00029
      Caudate, Putamen, Olfactory GyrusR1141218−83.42.00031
      ACC, anterior cingulate cortex; BA, Brodmann area; CTQ, Childhood Trauma Questionnaire; IFG, inferior frontal gyrus; L, left; MidFG, middle frontal gyrus; MOG, middle occipital gyrus; MTG, middle temporal gyrus; R, right; SFG, superior frontal gyrus; SMG, supramarginal gyrus; SOG, superior occipital gyrus; SPG, superior parietal gyrus; STG, superior temporal gyrus.

      Results

      Behavioral Results

      Table 1 lists mean reaction times and mean percent correct responses for the two experimental conditions (faces and shapes). There was no significant association of CTQ scores and any behavioral measure.

      fMRI Results

      The regression analysis conducted with SPM8 yielded a strong positive association of CTQ scores and right amygdala responsiveness to fearful/angry faces (x = 26, y = −2, z = −12; t = 5.43, df = 112, puncorrected < .0001; pFWE-corrected = .001; r = .46, cluster size k = 64) (Figure 1) . These results also survived a FWE correction for the entire brain (pFWE-corrected = .008).
      Figure thumbnail gr1
      Figure 1Childhood maltreatment (Childhood Trauma Questionnaire [CTQ] scores) is positively associated with right amygdala responsiveness to negative facial expressions. Left: Coronal view (y = −2) depicting amygdala responsiveness modulated by CTQ scores. For display reasons, the statistical threshold was set to p < 01, uncorrected. Color bar, correlation coefficient r. Right: Scatter plot depicting the positive correlation (r = .456, p < .0001) of the mean cluster activation values (left panel) and CTQ scores. fMRI, functional magnetic resonance imaging.
      In the subsequent multiple regression analysis predicting the mean activation of the significant cluster by CTQ score, Beck Depression Inventory, State-Trait Anxiety Inventory trait, PSS, LTE-Q, age, gender, verbal intelligence, and total education time, the strong effect of CTQ remained practically unchanged (β = .49, t = 5.31, df = 104, p < .0001). Except for a significant (negative) association of total education time and amygdala responsiveness (β = −.22, t = −2.36, df = 104, p = .02), no other predictor had any significant effect (all ps > .20). Thus, the association of childhood maltreatment and limbic hyperresponsiveness was not confounded by recent stressful life events, current levels of subclinical depression and anxiety symptoms, verbal intelligence, or sociodemographic factors. Also a nonparametric correlation of CTQ scores and amygdala responsiveness (Spearman's rho) was highly significant rs = .29, p = .002. There was no significant association of amygdala responsiveness with neuroticism or harm avoidance (ps > .13).
      From all five subscales, emotional abuse (r = .47, p < .0001) and emotional neglect (r = .37, p < .0001) were the strongest predictors for amygdala responsiveness, followed by physical abuse (r = .34, p = .0002), physical neglect (r = .29, p = .002), and sexual abuse (r = .27, p = .004).
      There was no anatomical area in the entire brain showing a negative association with CTQ scores, even at a lenient threshold (p < .005, uncorrected).

      Voxel-Based Morphometry Results

      The region of interest analysis of the bilateral hippocampus revealed a significant negative association of hippocampal gray matter volume and CTQ scores only in the right hippocampus (x = 38, y = −15, z = −12; t = 4.69, df = 143, puncorrected < .0001; pFWE-corrected = .001; r = −.37, cluster size k = 102) (Figure 2) . Again, using FWE correction for the entire brain, this peak still reached significance (pFWE-corrected = .048).
      Figure thumbnail gr2
      Figure 2Childhood maltreatment (Childhood Trauma Questionnaire [CTQ] scores) is negatively associated with right hippocampal gray matter volume. Left: Sagittal view (x = 38) depicting gray matter volumes correlating with CTQ scores. For display reasons, the statistical threshold was set to p < .01, uncorrected. Color bar, negative correlation coefficient −r. Right: Scatter plot depicting the negative correlation (r = −.365, p < .0001) of the cluster values (left panel) and CTQ scores.
      In the multiple regression analysis, the association of CTQ and hippocampal volume remained highly significant (β = −.33, t = −3.89, df = 135, p = .0002). A marginally significant negative association of LTE-Q scores and hippocampal gray matter volumes emerged (β = −.14, t = −1.78, df = 135, p = .078), but no other predictor had any significant effect (all ps > .20). Again, nonparametric correlation of CTQ scores and hippocampal volume yielded comparable results, rs = −.29, p = .006. There was no significant association of hippocampus morphometry with neuroticism or harm avoidance (ps > .5).
      All CTQ subscales showed very similar associations with hippocampal volume. Physical neglect was the strongest predictor (r = −.32, p < .0001), followed by emotional abuse (r = −.32, p < .0001), sexual abuse (r = −.31, p = .0001), physical abuse (r = −.30, p = .0003), and emotional neglect (r = −.24, p = .003).
      The whole-brain results are listed in Table 2. Notably, areas in the prefrontal cortex emerged showing gray matter volume reductions in dorsomedial and also ventromedial parts, including the anterior cingulate gyrus. There were no brain areas revealing positive associations with CTQ scores at the exploratory threshold.

      Discussion

      The present data suggest a robust effect of childhood maltreatment on two separate neuroimaging markers previously associated with depression and PTSD—amygdala responsiveness to negative facial expressions and reduced hippocampal volumes. These associations were demonstrated in a large sample of healthy subjects without any history of psychiatric disorders and they were not confounded by age, verbal intelligence, education, current depression and trait anxiety levels, level of perceived stress during the past month, or stressful life events during the year before participation.
      Common to all neurobiological theories of emotion is the notion that the amygdala plays a key role in a neural circuit processing emotional valence and generating rapid affective responses (
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      ). In human imaging studies, high amygdala responsiveness to negative stimuli has been shown to be associated with trait anxiety (
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      ), depression level (
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      Amygdala reactivity to masked negative faces is associated with automatic judgmental bias in major depression: A 3 T fMRI study.
      ,
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      • Arolt V.
      • Heindel W.
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      Amygdala reactivity predicts automatic negative evaluations for facial emotions.
      ). Several studies reported amygdala hyperresponsiveness to negative stimuli in acutely depressed patients (
      • Siegle G.J.
      • Thompson W.K.
      • Carter C.S.
      • Steinhauer S.R.
      • Thase M.E.
      Increased amygdala and decreased dorsolateral prefrontal BOLD responses in unipolar depression: Related and independent features.
      ,
      • Sheline Y.I.
      • Barch D.M.
      • Donnelly J.M.
      • Ollinger J.M.
      • Snyder A.Z.
      • Mintun M.A.
      Increased amygdala response to masked emotional faces in depressed subjects resolves with antidepressant treatment: An fMRI study.
      ,
      • Victor T.A.
      • Furey M.L.
      • Fromm S.J.
      • Öhman A.
      • Drevets W.C.
      Relationship between amygdala responses to masked faces and mood state and treatment in major depressive disorder.
      ,
      • Suslow T.
      • Konrad C.
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      Automatic mood-congruent amygdala responses to masked facial expressions in major depression.
      ,
      • Stuhrmann A.
      • Suslow T.
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      Facial emotion processing in major depression: A systematic review of neuroimaging findings.
      ,
      • Abler B.
      • Erk S.
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      • Walter H.
      Anticipation of aversive stimuli activates extended amygdala in unipolar depression.
      ,
      • Kessler H.
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      • Buchheim A.
      • Münte T.F.
      • Stasch M.
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      Individualized and clinically derived stimuli activate limbic structures in depression: An fMRI Study.
      ,
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      • Thase M.E.
      • Stenger V.A.
      • Carter C.S.
      Can't shake that feeling: Event-related fMRI assessment of sustained amygdala activity in response to emotional information in depressed individuals.
      ,
      • Yang T.T.
      • Simmons A.N.
      • Matthews S.C.
      • Tapert S.F.
      • Frank G.K.
      • Max J.E.
      • et al.
      Adolescents with major depression demonstrate increased amygdala activation.
      ,
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      • Monkul E.S.
      • Najt P.
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      Amygdala hyperactivation in untreated depressed individuals.
      ). However, due to the lack of longitudinal studies, it is not clear whether amygdala hyperresponsiveness represents a feature of current major depression or a risk factor for depression onset. On the one hand, pharmaco-fMRI studies in healthy subjects, as well as in depressed patients, suggest that antidepressant medication reduces amygdala responsiveness to aversive stimuli (
      • Sheline Y.I.
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      ,
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      • Harmer C.J.
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      ), even within less than a day after application of a single dose (
      • Rawlings N.B.
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      A single dose of mirtazapine modulates neural responses to emotional faces in healthy people.
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      ). On the other hand, amygdala hyperresponsiveness to negative stimuli has been described in healthy subjects at risk for depression (
      • Wolfensberger S.P.A.
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      ,
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      Neural correlates of automatic mood regulation in girls at high risk for depression [published online ahead of print September 5].
      ) and also in remitted patients (
      • Victor T.A.
      • Furey M.L.
      • Fromm S.J.
      • Öhman A.
      • Drevets W.C.
      Relationship between amygdala responses to masked faces and mood state and treatment in major depressive disorder.
      ). Since childhood maltreatment is a strong risk factor for depression, the present data further suggest that also unaffected risk populations show stronger amygdala responsiveness to negative stimuli, which might nourish speculations that the increased risk could be mediated by limbic hyperresponsiveness. Our findings are in line with a previous study investigating the relationship of childhood maltreatment and amygdala responsiveness to negative facial expressions (
      • Grant M.M.
      • Cannistraci C.
      • Hollon S.D.
      • Gore J.C.
      • Shelton R.C.
      Childhood trauma history differentiates amygdala response to sad faces within MDD.
      ) but contradict results reported by Taylor et al. (
      • Taylor S.E.
      • Eisenberger N.I.
      • Saxbe D.
      • Lehman B.J.
      • Lieberman M.D.
      Neural responses to emotional stimuli are associated with childhood family stress.
      ). Differences regarding the fMRI task and different assessment tools for adverse childhood experiences could explain these discrepant findings.
      Also, smaller hippocampus volumes are a frequent imaging finding in major depression (
      • MacQueen G.M.
      • Frodl T.
      The hippocampus in major depression: Evidence for the convergence of the bench and bedside in psychiatric research?.
      ). Since this has already been demonstrated in subjects at risk for depression (
      • Chen M.C.
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      • Gotlib I.H.
      Decreased hippocampal volume in healthy girls at risk of depression.
      ,
      • Amico F.
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      Structural MRI correlates for vulnerability and resilience to major depressive disorder.
      ,
      • Rao U.
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      Hippocampal changes associated with early-life adversity and vulnerability to depression.
      ), it was argued that reduced hippocampal volumes could be rather a risk factor for than a feature of depression (
      • Amico F.
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      • Möller H.J.
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      Structural MRI correlates for vulnerability and resilience to major depressive disorder.
      ). There is evidence that smaller hippocampus volume could act as a mediator for the relation between childhood maltreatment and depression (
      • Rao U.
      • Chen L.-A.
      • Bidesi A.S.
      • Shad M.U.
      • Thomas M.A.
      • Hammen C.L.
      Hippocampal changes associated with early-life adversity and vulnerability to depression.
      ). The same holds for PTSD, since smaller hippocampus volumes were associated with increased risk for developing PTSD after combat exposure (
      • Gilbertson M.W.
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      • Ciszewski A.
      • Kasai K.
      • Lasko N.B.
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      Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma.
      ). The hippocampus is a highly susceptible structure for the detrimental effects of stress, considering the high expression of glucocorticoid receptors. Since childhood trauma is associated with sensitization of the neuroendocrine stress response (
      • Heim C.M.
      • Newport D.J.
      • Mletzko T.C.
      • Miller A.H.
      • Nemeroff C.B.
      The link between childhood trauma and depression: Insights from HPA axis studies in humans.
      ), it seems plausible to conclude that the hippocampus, as one of the most plastic structures in the brain, would show structural abnormalities resulting from repeated maltreatment experiences during childhood. Our morphometric results provide support for this hypothesis, and furthermore, this is the first evidence that these maltreatment-associated hippocampal volume reductions persist into adulthood, even in healthy subjects.
      Regarding etiological specificity, it might be the case that childhood maltreatment generally increases the susceptibility for stress in later life with amygdala hyperresponsiveness and hippocampal atrophy representing two different aspects of this vulnerability. Therefore, it could be just a matter of which kind of stress occurs during later life, e.g., acute and traumatizing events could result in the onset of PTSD and/or more subtle but chronic stress could rather result in the development of depression. Ultimately, using such neuroimaging markers could be clinically useful to estimate individual risks for developing depression or PTSD.
      Our morphometric finding regarding medial prefrontal cortex volume reductions in maltreated subjects stands in line with a previous study reporting a similar association (
      • van Harmelen A.-L.
      • van Tol M.-J.
      • van der Wee N.J.A.
      • Veltman D.J.
      • Aleman A.
      • Spinhoven P.
      • et al.
      Reduced medial prefrontal cortex volume in adults reporting childhood emotional maltreatment.
      ). The medial prefrontal cortex is critically involved in emotion regulation processes and has dense connections with the amygdala. Volume reduction in this area as a sign for inhibition of growth or structural damage could be associated with lasting deficits in emotion processing and emotion regulation and therefore increase the risk for depression. Further, gray matter volume decreases associated with maltreatment were found in the bilateral insula, anterior cingulate gyrus, orbitofrontal cortex, and caudate—again mirroring results previously obtained in major depression compared with healthy control subjects (
      • Slavich G.M.
      • Way B.M.
      • Eisenberger N.I.
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      Neural sensitivity to social rejection is associated with inflammatory responses to social stress.
      ,
      • Gilbert A.M.
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      • Keshavan M.
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      Grey matter volume reductions in the emotion network of patients with depression and coronary artery disease.
      ,
      • Arnone D.
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      • Ebmeier K.P.
      • Munafò M.R.
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      Magnetic resonance imaging studies in unipolar depression: Systematic review and meta-regression analyses.
      ,
      • Koolschijn P.C.M.P.
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      • Hulshoff Pol H.E.
      • Kahn R.S.
      Brain volume abnormalities in major depressive disorder: A meta-analysis of magnetic resonance imaging studies.
      ).
      Our data might shed a new light on several previous imaging studies in major depression and PTSD. Since childhood maltreatment is strongly associated with these disorders, it seems very likely that most neuroimaging studies comparing patients and control subjects regarding functional or structural abnormalities were confounded by this variable. Thus, it might well be that some of the neurobiological findings previously reported in depression and PTSD could actually be attributed to differences regarding maltreatment experiences as a child. Future studies should address this issue by including measures of childhood maltreatment in samples of patients and control subjects.
      Both neuroimaging measures showed their association with childhood maltreatment lateralized to the right. Laterality has already been described previously, e.g., associations of hippocampus morphometry and maltreatment measures have been reported predominantly left-sided in subjects suffering from depression or PTSD (
      • Vythilingam M.
      • Heim C.
      • Newport J.
      • Miller A.H.
      • Anderson E.
      • Bronen R.
      • et al.
      Childhood trauma associated with smaller hippocampal volume in women with major depression.
      ,
      • Bremner J.D.
      • Randall P.
      • Vermetten E.
      • Staib L.
      • Bronen R.
      • Mazure C.
      • et al.
      Magnetic resonance imaging-based measurement of hippocampal volume in posttraumatic stress disorder related to childhood physical and sexual abuse–a preliminary report.
      ,
      • Stein M.B.
      • Koverola C.
      • Hanna C.
      • Torchia M.G.
      • McClarty B.
      Hippocampal volume in women victimized by childhood sexual abuse.
      ,
      • Frodl T.
      • Reinhold E.
      • Koutsouleris N.
      • Reiser M.
      • Meisenzahl E.M.
      Interaction of childhood stress with hippocampus and prefrontal cortex volume reduction in major depression.
      ) but rather right-sided in borderline personality disorders (
      • Brambilla P.
      • Soloff P.H.
      • Sala M.
      • Nicoletti M.A.
      • Keshavan M.S.
      • Soares J.C.
      Anatomical MRI study of borderline personality disorder patients.
      ,
      • Schmahl C.G.
      • Vermetten E.
      • Elzinga B.M.
      • Bremner J.D.
      Magnetic resonance imaging of hippocampal and amygdala volume in women with childhood abuse and borderline personality disorder.
      ,
      • Weniger G.
      • Lange C.
      • Sachsse U.
      • Irle E.
      Reduced amygdala and hippocampus size in trauma-exposed women with borderline personality disorder and without posttraumatic stress disorder.
      ,
      • Driessen M.
      • Beblo T.
      • Mertens M.
      • Piefke M.
      • Rullkoetter N.
      • Silva-Saavedra A.
      • et al.
      Posttraumatic stress disorder and fMRI activation patterns of traumatic memory in patients with borderline personality disorder.
      ). However, such laterality results should be treated with care, since it might well be the case that findings on one side exceed the significance threshold, while results on the other side just stay below and the actual laterality difference would not be significant. In our case, at a more lenient threshold of p < .005 (uncorrected), both amygdala responsiveness and hippocampus morphometry showed significant associations with CTQ scores also on the left side, which were not apparent at our rigorously corrected threshold.
      For amygdala responsiveness, the strongest associations were found with the emotional abuse and emotional neglect subscales. While these results parallel a study of Teicher et al. (
      • Teicher M.H.
      • Samson J.A.
      • Polcari A.M.
      • McGreenery C.E.
      Sticks, stones, and hurtful words: Relative effects of various forms of childhood maltreatment.
      ) showing that emotional abuse has similar effects on psychiatric symptoms compared with sexual abuse and even larger effects compared with physical abuse, these results should be treated with care since all subscales showed significant effects in the same direction and had comparable effect sizes. Furthermore, the physical and sexual abuse subscales were those with the smallest variance and our sample was still not large enough to detect significant differences between different forms of maltreatment. Additionally, it may be the case that there are differential responses related to different types of abuse (e.g., effects of verbal abuse on superior temporal gyrus [
      • Tomoda A.
      • Sheu Y.-S.
      • Rabi K.
      • Suzuki H.
      • Navalta C.P.
      • Polcari A.
      • Teicher M.H.
      Exposure to parental verbal abuse is associated with increased gray matter volume in superior temporal gyrus.
      ] and arcuate fasciculus [
      • Choi J.
      • Jeong B.
      • Rohan M.L.
      • Polcari A.M.
      • Teicher M.H.
      Preliminary evidence for white matter tract abnormalities in young adults exposed to parental verbal abuse.
      ] versus sexual abuse on occipital regions [47]). It may also be the case that there are sensitive periods when specific brain regions are most vulnerable (
      • Vythilingam M.
      • Heim C.M.
      • Newport J.
      • Miller A.H.
      • Anderson E.
      • Bronen R.
      • et al.
      Childhood trauma associated with smaller hippocampal volume in women with major depression.
      ,
      • Siegle G.J.
      • Thompson W.K.
      • Carter C.S.
      • Steinhauer S.R.
      • Thase M.E.
      Increased amygdala and decreased dorsolateral prefrontal BOLD responses in unipolar depression: Related and independent features.
      ), and one type of abuse may seem more important than another, as it may be more likely to occur at a specific age (e.g., neglect and physical abuse may tend to occur at younger ages than sexual abuse), which cannot be investigated with the present study design (
      • Rao H.
      • Betancourt L.
      • Giannetta J.M.
      • Brodsky N.L.
      • Korczykowski M.
      • Avants B.B.
      • et al.
      Early parental care is important for hippocampal maturation: Evidence from brain morphology in humans.
      ,
      • Andersen S.L.
      • Tomoda A.
      • Vincow E.S.
      • Valente E.
      • Polcari A.
      • Teicher M.H.
      Preliminary evidence for sensitive periods in the effect of childhood sexual abuse on regional brain development.
      ).
      Some limitations must be acknowledged. The assessment of traumatic experiences during childhood was performed retrospectively by means of a self-report measure, which could be problematic. Subjects with high amygdala responsiveness and/or low hippocampus volumes could have a negative recall bias and a better memory for negative events during childhood. While we do not think that this constitutes a major problem in the present study since we could partial out the effects of more recent life stress as well as depression and anxiety levels, only prospective studies could definitely rule out this possibility. Furthermore, future studies should also address genetic effects (e.g., serotonin-transporter-linked polymorphic region or brain-derived neurotrophic factor Valine66Methionine) on the association of childhood maltreatment and neuroimaging measures, which seem to play a moderating role in terms of gene-environment interactions (
      • Gatt J.M.
      • Nemeroff C.B.
      • Dobson-Stone C.
      • Paul R.
      • Bryant R.
      • Schofield P.R.
      • et al.
      Interactions between BDNF Val66Met polymorphism and early life stress predict brain and arousal pathways to syndromal depression and anxiety.
      ,
      • Frodl T.
      • Reinhold E.
      • Koutsouleris N.
      • Donohoe G.
      • Bondy B.
      • Reiser M.
      • et al.
      Childhood stress, serotonin transporter gene and brain structures in major depression.
      ,
      • Joffe R.T.
      • Gatt J.M.
      • Kemp A.H.
      • Grieve S.M.
      • Dobson-Stone C.
      • Kuan S.A.
      • et al.
      Brain derived neurotrophic factor Val66Met polymorphism, the five factor model of personality and hippocampal volume: Implications for depressive illness.
      ).
      In sum, this is the first evidence that childhood maltreatment is associated with amygdala hyperresponsiveness to negative stimuli as well as lower hippocampal volumes in healthy adults without any history of psychiatric disorders. These neurobiological traits could therefore be a marker of an increased vulnerability for emotional disorders.
      The study was supported by Grants of Innovative Medizinische Forschung of the Medical Faculty of Münster ( DA120309 to UD, DA111107 to UD, and DA211012 to UD), German Research Foundation ( SU 222/5-1 to TS), and Rolf-Dierichs-Stiftung ( ZUW80037 to UD).
      We thank Ahmad Hariri for providing the face-matching paradigm. We further thank Mrs. Nina Nagelmann for her skillful technical support during the functional magnetic resonance imaging sessions.
      Professor Volker Arolt, M.D., Ph.D., is a member of advisory boards and/or gave presentations for the following companies: Astra-Zeneca, Janssen-Organon, Lilly, Lundbeck, Servier, Pfizer, and Wyeth. He chairs the committee for the Wyeth Research Award Depression and Anxiety, now the Deutsche Gesellschaft für Psychiatrie, Psychotherapie und Nervenheilkunde (DGPPN)/Pfizer Clinical Neuroscience Award. Professor Katharina Domschke, M.A., M.D., Ph.D., is on the speakers' board of Pfizer, Lilly, and Bristol-Myers Squibb and has received funding by Astra-Zeneca. Professor Peter Zwanzger, M.D., has received speaker fees from Pfizer, Servier, Lilly, Astra-Zeneca, and Bristol-Myers Squibb, is on the advisory board of Pfizer, is a consultant for Ironwood Pharmaceuticals, and has received funding from Astra-Zeneca. These affiliations have no relevance to the work covered in the manuscript. All other authors report no biomedical financial interests or potential conflicts of interest.

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      Linked Article

      • Child Abuse and Psychiatric Illness
        Biological PsychiatryVol. 71Issue 4
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          Child abuse is a nonspecific risk factor associated with an increased risk for a range of psychiatric and substance use disorders. The paper in this issue by Dannlowski et al. (1) adds to a growing body of literature on the mechanisms by which adverse early experiences confer vulnerability to psychiatric illness. The paper by Nikulina et al. (2) delineate further genetic and other factors that account for individual differences in the outcomes of adults who were abused as children.
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