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Interaction of Parenting Experiences and Brain Structure in the Prediction of Depressive Symptoms in Adolescents

Interaction of Parenting Experiences and Brain Structure in the Prediction of Depressive Symptoms... ORIGINAL ARTICLE Interaction of Parenting Experiences and Brain Structure in the Prediction of Depressive Symptoms in Adolescents Marie B. H. Yap, PhD; Sarah Whittle, PhD; Murat Yücel, PhD; Lisa Sheeber, PhD; Christos Pantelis, MD, MRCPsych, FRANZCP; Julian G. Simmons, BSc; Nicholas B. Allen, PhD Context: Although some evidence suggests that neuro- gulate cortex (ACC); (2) frequency of observed mater- anatomic abnormalities may confer risk for major de- nal aggressive behavior during a mother-adolescent con- pressive disorder, findings are inconsistent. One poten- flict-resolution interaction; and (3) adolescent depressive tial explanation for this is the moderating role of symptoms. environmental context, with individuals differing in their biological sensitivity to context. Results: Boys with smaller right amygdalas reported more depressive symptoms. However, neither hippocampal vol- Objective: To examine the influence of adverse parent- ume nor asymmetry measures of limbic or paralimbic ACC ing as an environmental moderator of the association be- were directly related to level of depressive symptoms. Im- tween brain structure and depressive symptoms. portantly, frequency of maternal aggressive behaviors moderated the associations between both the amygdala Design: Cross-sectional measurement of brain struc- and ACC, and adolescent symptoms. Particularly, in con- ture, adverse parenting, and depressive symptoms in early ditions of low levels of maternal aggressiveness, boys with adolescents. larger right amygdalas, girls with smaller bilateral amyg- dalas, and both boys and girls with smaller left paralim- Setting: General community. bic ACC reported fewer symptoms. Participants: A total of 106 students aged 11 to 13 years Conclusions: These findings help elucidate the com- (55 males [51%]), recruited from primary schools in Mel- plex relationships between brain structure, environmen- bourne, Australia, and their mothers. Selection was based tal factors, and depressive symptoms. Further longitu- on affective temperament, aimed at producing a sample dinal research is required to examine how these factors representing a broad range of risk for major depressive contribute to the onset of case-level disorder, but given disorder. No participant evidenced current or past case- that family context risk factors are modifiable, our find- level depressive, substance use, or eating disorder. ings do suggest the potential utility of targeted early parenting interventions. Main Outcome Measures: (1) Volumetric measures of adolescents’ amygdala, hippocampus, and anterior cin- Arch Gen Psychiatry. 2008;65(12):1377-1385 EUROIMAGING TECH - the observed neuroanatomic abnormali- niques have elucidated ties represent a vulnerability to MDD, un- neuroanatomic corre- derlie symptoms, or are secondary to other Author Affiliations: ORYGEN lates of major depres- pathogenic processes. There is some evi- Research Centre (Drs Yap, 1,2 N sive disorder (MDD), dence that volumes of these structures re- Whittle, Yücel, and Allen and 13,14 with structural abnormalities in the amyg- flect levels of symptoms, and both twin Mr Simmons) and Melbourne Neuropsychiatry Centre dala, hippocampus, and anterior cingu- studies and studies investigating young (Drs Whittle, Yücel, and late cortex (ACC) hypothesized to under- first-episode patients provide support for Pantelis), Department of lie deficits in affective processing and volumetric changes in these structures Psychiatry, and Department of regulation. Findings have been inconsis- being associated with trait or vulnerabil- Psychology (Drs Yap, Whittle, 8,15,16 tent, however, with regard to the direc- ity factors for disorder. Studies of brain and Allen and Mr Simmons), tion of abnormalities (ie, greater vs lesser structure in young healthy individuals with The University of Melbourne, 3,4 volume) with regard to the amygdala, varying levels of depressive symptoms and Melbourne Health 5-7 8-12 hippocampus, and ACC. Although might be particularly useful to help elu- (Drs Whittle, Yücel, and there are likely to be a number of factors cidate these issues. Pantelis), Parkville, Victoria, contributing to these inconsistencies, 2 key Second, environmental moderators may Australia; and Oregon Research Institute, Eugene (Dr Sheeber). issues stand out. First, it is unclear whether have an influence on brain-disorder asso- (REPRINTED) ARCH GEN PSYCHIATRY/ VOL 65 (NO. 12), DEC 2008 WWW. ARCHGENPSYCHIATRY.COM ©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ by a Deepdyve User on 06/28/2021 ciations. That is, certain neuroanatomic features might METHODS be associated with disorder only in the context of par- ticular environmental circumstances. This was demon- PARTICIPANTS strated, for example, in a study of depressed women in whom reduced hippocampal volume, relative to healthy The sample consisted of 106 adolescents (55 males [51%]; 102 controls, was observed only in the subset of depressed self-identified as Australian [96%]; mean [SD] age, 12.5 [0.5] years; women with a history of child abuse. To date, there have range, 11.4-13.6 years) recruited from schools across metropoli- been few other studies investigating the impact of envi- tan Melbourne, Australia. Adolescents were recruited as part of ronmental moderators on brain-disorder associations. a broader adolescent development study (see Yap et al for fur- Diathesis-stress models suggest that individual differences ther details) such that those with particularly high, and particu- in susceptibility to environmental experiences may be due larly low, temperamental risk for mental health problems were 18,19 oversampled, while those with intermediate levels of risk were to phenotypic differences. To the extent that neuroana- undersampled, resulting in a distribution of temperamental risk tomic abnormalities are predisposing factors for psychopatho- that retained the variance associated with the larger screening logic changes, such abnormalities may be conceptualized sample (n = 2453) but was still normally distributed. Using the as biological diatheses that confer heightened risk in the con- Edinburgh Handedness Inventory, we identified 99 students as text of environmental stressors. To this end, it has been pro- right-handed and 7 as left-handed. Participants were screened for posed that genetic influences on hippocampal volume may Axis I disorders by trained research assistants using the Sched- play a causal role in psychopathologic changes by sensitiz- ule for Affective Disorders and Schizophrenia for School-Aged Chil- ing the individual to stressful environmental circumstances. dren, Epidemiologic Version. Ten participants met criteria for Notably, some researchers propose that the effects of bio- a psychiatric diagnosis (past separation anxiety disorder, n = 1; so- logical reactivity to the environment on psychiatric and bio- cial phobia, n = 1; attention-deficit/hyperactivity disorder, n = 1; obsessive-compulsive disorder, n = 2; oppositional defiant disor- medical outcomes are bivalent, giving rise to negative out- der, n = 1; and past oppositional defiant disorder, n = 4). A small comes under adverse conditions and positive outcomes under number of participants reported minimal past cigarette smoking low-stress conditions. 22 (n = 2) or alcohol consumption (n = 6). Informed consent was ob- There is evidence that brain volumes are highly heritable, tained from all participants (adolescent and parent), in accor- and deviant brain structure or function may constitute use- dance with the guidelines of the Human Research Ethics Com- ful intermediate phenotypes for identifying the neurobio- mittee of the University of Melbourne. logical pathways that represent genetic susceptibility to mood disorders. Specifically, brain morphologic characteristics FAMILY INTERACTIONS may serve as useful endophenotypes with which to test the moderating effects of the environment on the link between Procedure biological features and disorder. Although a wide range of environmental factors are Adolescents and their mothers participated in a 20-minute prob- related to risk for mood disorders, a substantial body lem-solving interaction, which was videotaped for coding pur- of research indicates that the family affective climate, in- poses. Topics for the interaction were identified on the basis cluding the nature of parent-child interactions, is a par- of parent and adolescent responses to the Issues Checklist, ticularly important predictor of internalizing problems which comprises 44 topics about which adolescents and par- 25-27 and depression in young people. Specifically, parent- ents may disagree, such as “[adolescent] lying” and “[adoles- ing characterized by high conflict or negativity has been cent] talking back to parents.” Up to 5 Issues Checklist issues rated as conflictual (and recent) by parent and adolescent were found to predict depression in children and adolescents 28-30 chosen for dyads to discuss and resolve during the problem- in prospective studies. solving interaction. This article explores parenting behavior as a devel- opmentally salient environmental moderator of the brain- Observational Coding of Family Interactions depression association in a community sample of young people who vary widely in their depressive symptoms. The affective and verbal content of the interactions were coded We examine the frequency of harsh parenting as a po- with the use of the Living in Familial Environments coding tential moderator of brain volume–depression associa- system. This is an event-based coding system in which new codes tions, specifically the amygdala, hippocampus, and ACC. are entered each time the affect or verbal content of the par- We use an observational measure of harsh maternal be- ticipant changes. The system consists of 10 affect and 27 ver- haviors directed at the target adolescent, derived during bal content codes. The index of aversive parenting was rate per a conflictual mother-adolescent interaction task. We hy- minute of a composite construct of maternal aggressive behav- pothesize that, while there may be direct associations ior, which includes all events with contemptuous, angry, and belligerent affect, as well as disapproving, threatening, or ar- among the volume of selected brain structures, parent- gumentative verbal content with neutral affect. Higher fre- ing, and adolescent depressive symptoms, the interac- quency of negative parental behaviors distinguishes abusive and tion between brain volume and parenting will explain ad- neglectful families from controls and is associated with poorer ditional variance in symptoms. Given research indicating 41,42 cognitive and psychosocial outcomes in children. sex differences in adolescent brain development, brain Video recordings were coded by 2 specially trained research as- correlates of affective processes, sensitivity to distur- sistants blind to participant characteristics (eg, symptom levels) bances in parent-child interactions, and depressive symp- and study hypotheses. Approximately 20% of the interactions were toms, sex differences in the associations between these coded by a second observer to provide an estimate of observer agree- brain structures, parenting, and adolescent depressive ment. The coefficient for the aggressive composite code was 0.77, symptoms were also examined. which reflects good to excellent agreement. (REPRINTED) ARCH GEN PSYCHIATRY/ VOL 65 (NO. 12), DEC 2008 WWW. ARCHGENPSYCHIATRY.COM ©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ by a Deepdyve User on 06/28/2021 NEUROIMAGING Image Acquisition Magnetic resonance imaging was performed on a 3-T scanner (General Electric, Milwaukee, Wisconsin), using a gradient echo volumetric acquisition sequence (repetition time, 36 millisec- onds; echo time, 9 milliseconds; flip angle, 35°; field of view, 20 cm ; pixel matrix, 410 410) to obtain 124 T1-weighted con- tiguous 1.5-mm-thick sections (voxel dimensions, Absent Present 0.4883 0.4883 1.5 mm). Image Preprocessing Image preprocessing was carried out with tools from the FMRIB software library (http://www.fmrib.ox.ac.uk/fsl/). Each 3-di- Figure 1. Example of changes in the location and extent of the limbic (ACC ; highlighted in green) and paralimbic (ACC ; highlighted in blue) mensional image was stripped of all nonbrain tissue, aligned L P anterior cingulate cortices as a function of variations in the cingulate sulcus to the Montreal Neurological Institute 152 average template (CS; green arrow, top row) and paracingulate sulcus (PCS; blue arrow, top (6-parameter rigid body transform with trilinear interpola- row). A PCS is absent at left and present at right. The top 2 images present tion) by means of the Flexible Image Registration Toolbox, parasagittal sections through an individual’s T1-weighted image. The coronal and resampled to 1 mm . This registration served to align each section illustrates the distinction between cases with absent (left) and image axially along the anterior commissure–posterior com- present (right) PCS. Notice that the ACC is buried in the depths of the CS when the PCS is absent and extends over the paracingulate gyrus when the missure plane and sagittally along the interhemispheric fis- PCS is present. The same principle applies throughout consecutive coronal sure without any deformation. sections. Morphometric Analysis Hippocampal tracings included the hippocampus proper, Regions of interest (ROIs) were defined and quantified on the the dendate gyrus, the subiculum, and part of the fimbria and basis of previously published techniques (see the following para- alveus. Boundaries were defined as follows: posterior, section graphs). All ROIs were traced by one of us (S.W.) on each in- with the greatest length of continuous fornix; lateral, tempo- dividual’s images by using the software package ANALYZE ral horn; medial, open end of the hippocampal fissure poste- (Mayo Clinic, Rochester, Minnesota; http://mayoresearch.mayo riorly and the uncal fissure anteriorly; and superior, fimbria and .edu/mayo/research/robb_lab/). Brain tissue was segmented into alveus posteriorly and amygdala anteriorly. gray matter, white matter, and cerebrospinal fluid by means of The boundaries of the ACC have been described in detail an automated algorithm, as implemented in FAST (FMRIB’s [Ox- by Fornito et al. This protocol demarcates limbic (ACC ) and ford Centre for Functional MRI of the Brain] Automated Seg- paralimbic (ACC ) portions of the ACC by taking into ac- mentation Tool. An estimate of whole brain volume was ob- count individual differences in morphologic characteristics of tained by summing gray and white matter pixel counts (ie, whole the cingulate (CS), paracingulate (PCS), and superior rostral brain volume included cerebral gray and white matter, the cer- (SRS) sulci. Tracing was initially performed on contiguous sag- ebellum, and brainstem, but not the ventricles, cisterns, or ce- ittal sections, and the medial borders were edited on coronal rebrospinal fluid). The ACC estimates were based on gray mat- sections. The anterior ACC contained all gray matter in the ter pixel counts contained within the defined ROIs. Amygdala gyrus bound by the callosal sulcus and the CS. The borders of and hippocampal estimates were based on total voxels within the ACC depended on the course of the PCS and SRS. The PCS the defined ROI. was considered present or prominent if it ran parallel to the CS for at least 20 mm or at least 40 mm, respectively. Seg- Amygdala, Hippocampus, and ACC mented sections were considered part of the PCS if they were 10 mm or greater and separated from other segments by 10 mm The guidelines for tracing the amygdala and hippocampus or less. For cases where the PCS was present or prominent, the were adapted from those described by Velakoulis and col- ACC contained all gray matter in the gyrus bound by the CS 47,48 leagues. These structures were traced on contiguous coro- and PCS. For cases where the PCS was either absent or not par- nal sections. The boundaries of the amygdala were defined as allel along the full length of the CS, in those sections in which follows: posterior, first appearance of gray matter above the the PCS was absent the ACC included only the gray matter temporal horn; lateral, temporal stem; and medial, the semilu- on the upper bank of the CS. The SRS was classified either as nar gyrus superiorly and subamygdaloid white matter inferi- continuous with the CS or separate from it. In the former case, orly. Guidelines for marking the anterior boundary of the the inferior part of the ACC region included only gray matter amygdala and the boundary between the amygdala and hippo- on the upper bank of the CS; in the latter case, the inferior part campus differed slightly from those of Velakoulis and col- of the ACC comprised gray matter between the CS and SRS. leagues to maximize reliability. The anterior boundary of the See Figure 1 for illustration. amygdala was identified as the section posterior to the most posterior of either the point where the optic chiasm joins, or the point where the lateral sulcus closes to form the endorhi- ADOLESCENT DEPRESSIVE SYMPTOMS nal sulcus. The protocol of Watson et al was used to separate the amygdala from the hippocampus. This protocol involves The Center for Epidemiological Studies–Depression Scale, Re- using the uncal recess of the temporal horn, the alveus, or the vised has been found to be valid and reliable for adoles- semilunar gyrus as the inferior boundary of the amygdala, cents. In the current sample, the Cronbach  was 0.89 and depending on the visibility of these features. scores ranged from 0 to 55 (mean, 11.58; SD, 9.54). (REPRINTED) ARCH GEN PSYCHIATRY/ VOL 65 (NO. 12), DEC 2008 WWW. ARCHGENPSYCHIATRY.COM ©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ by a Deepdyve User on 06/28/2021 Table 1. Brain Measures and Tests for Sex Differences Full Sample Boys Girls Sex Difference Brain Measure No. Mean (SD) No. Mean (SD) No. Mean (SD) tP Value Left amygdala volume, mm 106 1882.44 (265.51) 55 1935.96 (263.60) 51 1824.73 (257.79) 4.81 .03 Right amygdala volume, mm 106 1844.80 (277.91) 55 1844.80 (277.91) 51 1784.37 (260.36) 1.33 .25 Left hippocampus volume, mm 106 2776.03 (323.50) 55 2820.75 (317.63) 51 2727.80 (325.92) 2.21 .14 Right hippocampus volume, mm 106 2937.24 (354.54) 55 2961.40 (356.48) 51 2911.18 (354.10) 0.53 .47 ACC asymmetry index 104 −315.16 (2386.42) 53 −672.67 (2260.72) 51 56.36 (2477.94) 2.46 .12 ACC asymmetry index 101 370.87 (2259.92) 50 441.78 (2159.52) 51 301.35 (2373.66) 0.10 .76 Maternal aggressive frequency 106 1.30 (0.61) 55 1.31 (0.61) 51 1.29 (0.60) 0.04 .84 Adolescent depressive symptoms, No. 106 11.46 (9.50) 55 12.14 (9.21) 51 10.72 (9.84) 0.58 .45 Abbreviations: ACC , limbic anterior cingulate cortex; ACC , paralimbic anterior cingulate cortex. L P Anterior cingulate cortex data were missing for some participants because of visualization or delineation difficulties. STATISTICAL ANALYSIS ence was in the volume of the left amygdala, with boys having a larger amygdala than girls. Interrater and intrarater reliabilities were assessed by means of the intraclass correlation coefficient (absolute agreement) using AMYGDALA 15 brain images from a separate magnetic resonance imaging database established for this purpose. Intraclass correlation co- efficient values (14 of 16 0.90 and none 0.85) were accept- As summarized in Table 2, in analyses for the left and able for all ROIs. Removing the 8 left-handed participants’ data right amygdala, greater frequency of maternal aggres- from analyses did not change the pattern of results, so we have sive behaviors and the 3-way interaction term reported results from the full set of data. (amygdala parenting sex) were associated with more Given literature suggesting that asymmetry of ACC volume adolescent depressive symptoms. Right amygdala vol- may be important for aspects of executive functioning and affect ume was also negatively associated with depressive symp- regulation, which may in turn have implications for mood dis- toms, although follow-up analyses showed that this was orders, ACC volume asymmetries were also investigated. An asym- significant for boys but not girls. Follow-up analyses on metry index was calculated for the ACC and ACC by using the L P the significant 3-way interaction showed that, in boys, formula left minus right. All brain structural measures were cor- rected for whole-brain size by means of a covariance adjustment only the right amygdala parenting interaction was sig- 54 2 method. Hypotheses were tested with 6 hierarchical linear re- nificant ( = 0.35, t = 2.81, P = .007, f = 0.16). In girls, both gressions, with parenting and adolescent brain structure vari- the left and right amygdala parenting interactions pre- ables used as predictors of adolescent depressive symptoms. For dicted depressive symptoms ( = −0.44, t = −3.82, each regression, adolescent sex, maternal aggressive behavior, and 2 P .001, f = 0.30; and  = −0.46, t = −3.91, P .001, one of the brain structure measures (ie, left or right amygdala vol- f = 0.34, respectively). ume, left or right hippocampal volume, and ACC or ACC asym- L P Significant interactions were interpreted by plotting metry index) were entered in step 1. The three 2-way interaction the simple regression lines for the high (1 SD), aver- terms (parenting  adolescent sex, brain  sex, and age (mean), and low (−1 SD) values of maternal aggres- parenting  brain) were entered in step 2, and the sive frequency. Equations were then used to plot val- parenting brain sex interaction term was entered in step 3. ues of adolescent depressive symptoms at high, average, Interaction terms were computed after centering all continuous variables. Significant sex interactions were followed up with re- and low values of maternal aggressive frequency and at gression analyses for males and females separately (with parent- high (2 SDs) and low (−2 SDs) values of (left or right) ing and the appropriate brain variable entered in step 1 and the amygdala volume. Two-tailed t tests showed that, for boys, interaction entered in step 2). Significant parenting brain and the slopes of the regression lines at low ( = −0.70, 3-way interactions were probed following recommendations by t = −3.95, P .001) and average ( = −0.37, t = −2.99, 55 56 51 51 Aiken and West, with the use of O’Connor’s SPSS macros to P = .004) values of maternal aggressive frequency were sig- compute simple slope analyses. Following Cohen and Cohen’s 2 nificantly different from zero (Figure 2). Hence, while guidelines, f is taken as the index of the effect size of interac- boys with a smaller right amygdala reported more de- tions, whereby an f value of 0.02 is small, 0.15 is medium, and pressive symptoms, in the context of low to average lev- 0.35 is large. Because changes in structural brain asymmetry may result from changes in the size of either or both hemispheres, els of maternal aggressiveness, larger right amygdala was significant main effects or interactions involving asymmetry vari- also associated with fewer symptoms. ables were followed up with 2 hierarchical regressions using left For girls, both the low ( = 0.46, t = 2.69, P = .01) and and right hemisphere ROI volumes as predictors of adolescent high ( = −0.36, t = −2.56, P = .01) maternal aggressive- depressive symptoms (along with sex, parenting, and the 2- and ness slopes were significant for the right amygdala 3-way interactions). (Figure 3). Similarly, both the low ( = 0.56, t = 3.16, P = .003) and high ( = −0.30, t = −2.12, P = .04) mater- RESULTS nal aggressiveness slopes were significant for the left amyg- dala (graph similar to Figure 3, thus not shown). Hence, Table 1 shows means, standard deviations, and sex dif- in girls exposed to high levels of maternal aggressive- ferences in all variables. The only significant sex differ- ness, there was a significant negative association be- (REPRINTED) ARCH GEN PSYCHIATRY/ VOL 65 (NO. 12), DEC 2008 WWW. ARCHGENPSYCHIATRY.COM ©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ by a Deepdyve User on 06/28/2021 Table 2. Summary of 6 Regressions Predicting Adolescent Maternal aggressive frequency Depressive Symptoms With Brain Measures and MAF –1 SD Mean +1 SD Regressions  t Value F R Regression 1 (n=106) Step 1 4.04 0.11 Left amygdala −0.11 −1.11 .27 MAF 0.29 3.19 .003 Step 3: Left amygdala 0.43 3.34 .001 11.18 0.08 MAF sex Regression 2 (n=106) Step 1 5.83 0.15 Right amygdala −0.23 −2.47 .02 MAF 0.29 3.13 .002 Step 3: Right amygdala 0.59 4.75 .001 22.54 0.15 MAF sex Regression 3 (n=106) Step 1 3.60 0.10 0 Left hippocampus −0.02 −.19 .85 MAF 0.30 3.16 .002 –5 Regression 4 (n=106) –2 SDs +2 SDs Step 1 3.59 0.10 Boys’ Right Amygdala Volume Right hippocampus 0.02 .17 .87 MAF 0.30 3.18 .002 Step 2: MAF sex −0.29 −2.11 .04 1.79 0.05 Figure 2. Plots of simple slopes showing the interaction between maternal Regression 5 (n=104) aggressive frequency and the volume of boys’ right amygdala predicting adolescent depressive symptoms (score on the Center for Epidemiological Step 1 3.52 0.10 Studies–Depression Scale). ACC asymmetry −0.08 −.84 .40 MAF 0.30 3.11 .002 Step 2: ACC asymmetry MAF 0.19 1.97 .05 3.80 0.10 Regression 6 (n=101) Maternal aggressive frequency Step 1 4.06 0.11 –1 SD ACC asymmetry 0.10 1.09 .28 Mean +1 SD MAF 0.31 3.23 .002 Step 3: ACC asymmetry −0.29 −2.13 .04 4.54 0.04 MAF sex Abbreviations: ACC , limbic anterior cingulate cortex; ACC , paralimbic L P anterior cingulate cortex; , change; MAF, maternal aggressive frequency. The first step in each model included adolescent sex coded as 1 for male and 0 for female, but it had no significant effects and hence is not shown here. Only significant interactions are shown. Change in F and R values for 15 2-way interactions refer to effects of all 2-way interaction variables in that block, whereas the values for 3-way interactions are specific to the corresponding 3-way interaction variable. The ACC data were missing for some participants because of visualization or delineation difficulties. tween amygdala volume and depressive symptoms. Con- versely, in the context of low maternal aggressiveness, there was a positive association between amygdala vol- ume and depressive symptoms. –5 HIPPOCAMPUS –2 SDs +2 SDs Girls’ Right Amygdala Volume As before, greater frequency of maternal aggressive be- haviors was associated with more adolescent depressive Figure 3. Plots of simple slopes showing the interaction between maternal symptoms. In addition, the parenting sex interaction aggressive frequency and the volume of girls’ right amygdala predicting was significant in the model with the right hippocam- adolescent depressive symptoms (score on the Center for Epidemiological Studies–Depression Scale). pus. Follow-up regressions showed that higher mater- nal aggressive frequency was associated with more de- pressive symptoms for girls ( = 0.49, t = 3.92, P .001). ANTERIOR CINGULATE CORTEX Hippocampal volumes were not associated with depres- sive symptoms either as main effects or in interaction with Again, greater frequency of maternal aggressive behaviors the other variables. was associated with more adolescent symptoms. Neither (REPRINTED) ARCH GEN PSYCHIATRY/ VOL 65 (NO. 12), DEC 2008 WWW. ARCHGENPSYCHIATRY.COM ©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ by a Deepdyve User on 06/28/2021 No. of Adolescent Depressive Symptoms No. of Adolescent Depressive Symptoms AMYGDALA Maternal aggressive frequency The direct association between a smaller right amygdala –1 SD Mean and elevated depressive symptoms in boys is consistent with +1 SD previous findings. The moderation of associations be- tween amygdala volume and symptoms by family context and sex suggests that these factors may help account for null or contradictory findings in previous studies. Our find- ings indicate that, in boys overall, while a larger right amyg- dala is associated with reduced depressive symptoms, among boys with a larger than average right amygdala, low levels of aggressive maternal behavior further reduce the risk for symptoms. In girls, although a smaller amygdala is not di- rectly associated with elevated symptoms, it may engen- der sensitivity to the effects of family affective environ- ment. That is, girls with smaller amygdalas report more symptoms only if their mothers are frequently aggressive toward them. This is consistent with evidence from the de- velopmental literature that girls may be more susceptible 60,61 to the effect of negative family interactions and points 0 toward a potential neurobiological mechanism for this sex difference. Moreover, there are indications in these find- –2 SDs +2 SDs ings that, among girls, smaller amygdala volume is also as- Boys’ Left ACC Volume sociated with especially low levels of depressive symp- toms when paired with low levels of maternal aversiveness. Figure 4. Plots of simple slopes showing the interaction between maternal This suggests that smaller amygdalas might be a neuro- aggressive frequency and the volume of boys’ left paralimbic anterior cingulate cortex (ACC ) region predicting adolescent depressive symptoms anatomic marker of general sensitivity to environmental (score on the Center for Epidemiological Studies–Depression Scale). influences, consistent with the “differential susceptibil- 21,62 ity” hypothesis, which proposes that some individuals (for biological reasons) are more susceptible than others asymmetry measure was significantly associated with to positive as well as negative aspects of the environment. depressive symptoms, but the ACC asymmetry It has been speculated that “sensitivity” might result from parenting sex interaction term was. Follow-up analyses 21,62 increased attention or hyperreactivity to stress. Whether showed that the asymmetry parenting interaction was or how these factors are related to volumetric measures of significant for boys ( = −0.37, t = −2.26, P = .03, f = 0.11) the amygdala is not clear, but it is interesting that the amyg- but not girls ( = 0.06, t = 0.48, P = .63). Further analyses dala has been noted to have distinct functions with regard were conducted to see whether the 3-way interaction to attention to environmentally salient stimuli. effect was driven by the left or right ACC . Only the left Notably, boys and girls benefit differentially from low ACC  parenting interaction was significantly associated levels of aversive parenting—boys with larger right amyg- with depressive symptoms ( = −0.40, t = −2.86, P = .006, dalas vs girls with smaller right and left amygdalas ben- f = 0.16). The plot for the left ACC  parenting interaction efit more. Alternatively, boys with larger right amygda- for boys is shown in Figure 4. Only the slope for low ma- las vs girls with smaller bilateral amygdalas may have a ternal aggressiveness was significantly different from zero greater biological sensitivity to the parenting context (ie, ( = 0.50, t = 2.57, P = .01). Hence, among adolescent boys 50 21 both harmful and helpful aspects of parenting). These exposed to low levels of maternal aggressiveness, there was findings add to the literature suggesting sex differences a significant positive association between the left ACC vol- P 64 in amygdala functioning, although the exact nature of ume and depressive symptoms. these differences remains unclear. It is possible that sex differences in the rate of amygdala development during COMMENT adolescence may contribute to this pattern of find- 65,66 ings. Longitudinal research is required to investigate In a nonclinical sample of early adolescents, there was no the developmental trajectories of these associations. direct relationship between adolescent depressive symp- toms and the volumes of the amygdala, hippocampus, or HIPPOCAMPUS ACC. However, boys with smaller right amygdalas, and ado- lescents whose mothers displayed more frequent aggres- Contrary to expectations, the hippocampus was not as- sive behaviors during a conflict resolution interaction, re- sociated with depressive symptoms, either directly or in ported more depressive symptoms. In addition, significant interaction with the parenting environment. Previous interaction effects showed that amygdala volume and ACC studies of hippocampal volume involving pediatric and asymmetry were associated with depressive symptoms in early-onset MDD samples have been mixed, with some 7,59 the context of certain levels of maternal aggressiveness, sug- showing no alterations and others finding smaller hip- 67-69 gesting that these structures may represent markers of bio- pocampal volumes. Because the participants in the cur- logical sensitivity to the parenting context. rent study were not experiencing case-level disorders, our (REPRINTED) ARCH GEN PSYCHIATRY/ VOL 65 (NO. 12), DEC 2008 WWW. ARCHGENPSYCHIATRY.COM ©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ by a Deepdyve User on 06/28/2021 No. of Adolescent Depressive Symptoms findings suggest that hippocampal volume is not asso- young people at risk for a number of psychopathologic ciated with levels of depressive symptoms that are be- changes may prove to be beneficial. low threshold for clinical diagnosis. This is in line with the neurotoxicity hypothesis of trauma or pathogenic en- LIMITATIONS vironments on the hippocampus, suggesting that hip- pocampal neurodegeneration may result from severe stress The cross-sectional design of the study precludes us from associated with prolonged or recurrent psychopatho- drawing strong conclusions regarding the causality of re- logic features, or exposure to trauma. It is possible that lationships. That is, whether changes in regional brain vol- adverse parenting as measured in this study is not a se- ume and maternal aggressive behaviors result from, or rep- vere enough stressor to produce neurotoxic effects on the resent early predictors of, adolescent depressive problems hippocampus. Alternatively, if hippocampal volume loss remains unclear. Furthermore, the marked brain reorga- is an indication of an early phase of MDD or an MDD nization and sex differences in brain development occur- subtype, our findings may indicate that these partici- 79,80 ring during adolescence may complicate the interpre- pants are not at risk for developing such psychopatho- tation of findings. Finally, given the genetic contribution logic characteristics. to brain structure, risk for psychopathologic changes, and the family environment, family history of psychopatho- ANTERIOR CINGULATE CORTEX logic characteristics may covary with some of the relation- ships examined herein. Longitudinal assessment of parent- The finding for paralimbic ACC volume asymmetry sug- ing, brain structure, and depressive symptoms or disorder, gested that boys with a smaller left than right ACC were as well as assessment of family history of psychopatho- more sensitive to the effects of maternal aggressiveness, logic features, is needed to resolve these issues. and this appeared to be driven by a reduction in left ACC A further limitation of the study concerns the gener- volume specifically. In these individuals, low maternal alizability of results because selection was biased to overs- aggressiveness was associated with fewer depressive symp- ample adolescents with “extreme” temperaments. Fur- toms. The lateralization of our finding is consistent with ther research will be required to assess the association research showing predominantly left lateralized ACC volu- between brain structure, parenting, and depressive symp- metric abnormalities in MDD. Furthermore, previous re- toms in representative adolescent population samples. An- search has indicated that a reduced leftward asymmetry other issue relevant to generalizability is that only 1 type of the PCS (which is associated with reduced size of the of environmental stressor, the maternal-child relation- left ACC ) characterizes those (particularly males) ex- ship, was examined. Although this relationship is of par- periencing or at risk for a range of psychopathologic ticular relevance to depressive symptoms in adoles- 71-73 changes. Moreover, there is evidence that individu- cence, the patterns of results may not be generalizable als with smaller left ACC perform poorly on tasks of ex- to other important environmental factors such as, for ex- ecutive functioning and are temperamentally prone to ample, experiences of abuse. It is also important to ac- the experience of high negative affect. The present re- knowledge that laboratory-based interactions likely dif- sult suggests that this structural brain feature is not nec- fer from those that occur in day-to-day interactions. essarily associated with adverse outcomes, but rather may Nevertheless, laboratory-based family interactions have be associated with sensitivity to environmental factors, good predictive and convergent validity with other mea- such that it may be related to positive outcomes given sures of these processes as well as with depressive syn- 21,62 favorable environmental circumstances. dromes, suggesting that they capture valid and impor- The significance of the male specificity of our finding 82,83 tant information regarding family interactions. for the ACC requires further investigation; however, we Finally, a large number of analyses were conducted, speculate that this result may reflect a sensitivity engen- raising the possibility of type 1 error. Our goal was to dered by the testosterone-mediated developmental lag of discover plausible patterns of interaction between envi- the male left hemisphere, which has been suggested to ronmental and biological factors, and thereby inform fu- increase the sensitivity of this hemisphere to environ- ture more detailed research. The presentation of analy- mental input. ses in the current article ensures that the reader is aware Because subthreshold depressive symptoms are an early of the full range of analyses that were performed; how- sign of a number of disorders other than MDD (eg, schizo- ever, because of the risk of type 1 error, we emphasize 77 78 phrenia and bipolar disorder ), the results of this study the need for replication. may also have implications for understanding the etiol- ogy of these disorders. In particular, our findings may CONCLUSIONS provide insight into the role of the family environment in the etiologic path by which ACC structure is associ- ated with schizophrenia. Bipolar disorders, on the other Our findings suggest that structural features of the amyg- hand, may have a distinct neuroanatomic profile, par- dala and ACC are phenotypic markers of sensitivity to ticularly with regard to the course of changes in struc- the parenting environment in a nonclinical sample of ado- ture of the amygdala and hippocampus over the course lescents with no history of MDD. Marked sex differ- of the disorder. Longitudinal work is crucial to inves- ences in the nature of the reported associations and in- tigate these complex associations. teractions were found. The findings suggest that taking In any case, the present results suggest that early in- environmental factors into consideration when examin- terventions that target aversive parenting in families of ing brain/disorder associations may facilitate a clearer un- (REPRINTED) ARCH GEN PSYCHIATRY/ VOL 65 (NO. 12), DEC 2008 WWW. ARCHGENPSYCHIATRY.COM ©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ by a Deepdyve User on 06/28/2021 12. Ballmaier M, Toga AW, Blanton RE, Sowell ER, Lavretsky H, Peterson J, Pham derstanding of the nature of these associations. Low lev- D, Kumar A. Anterior cingulate, gyrus rectus, and orbitofrontal abnormalities in els of aversive parenting may have protective effects for elderly depressed patients: an MRI-based parcellation of the prefrontal cortex. adolescents with a heightened biological sensitivity to the Am J Psychiatry. 2004;161(1):99-108. parenting context. Because these family context risk fac- 13. MacMillan S, Szeszko PR, Moore GJ, Madden R, Lorch E, Ivey J, Banerjee SP, tors are modifiable, these findings suggest the poten- Rosenberg DR. Increased amygdala:hippocampal volume ratios associated with severity of anxiety in pediatric major depression. J Child Adolesc Psychopharmacol. tial of targeted parenting interventions with families of 2003;13(1):65-73. at-risk adolescents. 14. Chen CH, Ridler K, Suckling J, Williams S, Fu CH, Merlo-Pich E, Bullmore E. Brain imaging correlates of depressive symptom severity and predictors of symp- tom improvement after antidepressant treatment. Biol Psychiatry. 2007;62 Submitted for Publication: January 22, 2008; final re- (5):407-414. vision received May 4, 2008; accepted June 9, 2008. 15. Frodl T, Meisenzahl EM, Zetzsche T, Born C, Groll C, Jäger M, Leinsinger G, Bot- tlender R, Hahn K, Möller HJ. Hippocampal changes in patients with a first epi- Correspondence: Nicholas B. Allen, PhD, ORYGEN Re- sode of major depression. Am J Psychiatry. 2002;159(7):1112-1118. search Centre, Locked Bag 10, Parkville, Victoria 3052, 16. Botteron KN, Raichle ME, Heath AC, Price A, Sternhell KE, Singer TM, Todd R. Australia (nba@unimelb.edu.au). An epidemiological twin study of prefrontal neuromorphometry in early onset Financial Disclosure: None reported. depression [abstract]. Biol Psychiatry. 1999;45(8)(suppl 1):59S. Funding/Support: This research was supported by grants 17. Vythilingam M, Heim C, Newport J, Miller AH. Childhood trauma associated with smaller hippocampal volume in women with major depression. Am J Psychiatry. from the Colonial Foundation and the National Health 2002;159(12):2072-2080. and Medical Research Council (NHMRC) (program grant 18. Caspi A, Moffitt TE. Gene-environment interactions in psychiatry: joining forces 350241). Dr Yap is supported by an NHMRC Centre for with neuroscience. Nat Rev Neurosci. 2006;7(7):583-590. Clinical Research Excellence Postdoctoral Fellowship. Dr 19. Jaffee SR, Caspi A, Moffitt TE, Dodge KA, Rutter M, Taylor A, Tully LA. Nature x Whittle is supported by an Australian Research Council nurture: genetic vulnerabilities interact with physical maltreatment to promote conduct problems. Dev Psychopathol. 2005;17(1):67-84. Postdoctoral Fellowship. Dr Yücel is supported by an 20. de Geus EJ, van’t Ent D, Wolfensberger S, Heutink P, Hoogendijk WJ, Boomsma NHMRC Clinical Career Development Award (ID DI, Veltman DJ. Intrapair differences in hippocampal volume in monozygotic twins 509345). discordant for the risk for anxiety and depression. Biol Psychiatry. 2007;61 Additional Contributions: Neuroimaging analysis was (9):1062-1071. facilitated by the Neuropsychiatry Imaging Laboratory 21. Boyce WT, Ellis BJ. Biological sensitivity to context, I: an evolutionary– developmental theory of the origins and functions of stress reactivity. 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Interaction of Parenting Experiences and Brain Structure in the Prediction of Depressive Symptoms in Adolescents

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ORIGINAL ARTICLE Interaction of Parenting Experiences and Brain Structure in the Prediction of Depressive Symptoms in Adolescents Marie B. H. Yap, PhD; Sarah Whittle, PhD; Murat Yücel, PhD; Lisa Sheeber, PhD; Christos Pantelis, MD, MRCPsych, FRANZCP; Julian G. Simmons, BSc; Nicholas B. Allen, PhD Context: Although some evidence suggests that neuro- gulate cortex (ACC); (2) frequency of observed mater- anatomic abnormalities may confer risk for major de- nal aggressive behavior during a mother-adolescent con- pressive disorder, findings are inconsistent. One poten- flict-resolution interaction; and (3) adolescent depressive tial explanation for this is the moderating role of symptoms. environmental context, with individuals differing in their biological sensitivity to context. Results: Boys with smaller right amygdalas reported more depressive symptoms. However, neither hippocampal vol- Objective: To examine the influence of adverse parent- ume nor asymmetry measures of limbic or paralimbic ACC ing as an environmental moderator of the association be- were directly related to level of depressive symptoms. Im- tween brain structure and depressive symptoms. portantly, frequency of maternal aggressive behaviors moderated the associations between both the amygdala Design: Cross-sectional measurement of brain struc- and ACC, and adolescent symptoms. Particularly, in con- ture, adverse parenting, and depressive symptoms in early ditions of low levels of maternal aggressiveness, boys with adolescents. larger right amygdalas, girls with smaller bilateral amyg- dalas, and both boys and girls with smaller left paralim- Setting: General community. bic ACC reported fewer symptoms. Participants: A total of 106 students aged 11 to 13 years Conclusions: These findings help elucidate the com- (55 males [51%]), recruited from primary schools in Mel- plex relationships between brain structure, environmen- bourne, Australia, and their mothers. Selection was based tal factors, and depressive symptoms. Further longitu- on affective temperament, aimed at producing a sample dinal research is required to examine how these factors representing a broad range of risk for major depressive contribute to the onset of case-level disorder, but given disorder. No participant evidenced current or past case- that family context risk factors are modifiable, our find- level depressive, substance use, or eating disorder. ings do suggest the potential utility of targeted early parenting interventions. Main Outcome Measures: (1) Volumetric measures of adolescents’ amygdala, hippocampus, and anterior cin- Arch Gen Psychiatry. 2008;65(12):1377-1385 EUROIMAGING TECH - the observed neuroanatomic abnormali- niques have elucidated ties represent a vulnerability to MDD, un- neuroanatomic corre- derlie symptoms, or are secondary to other Author Affiliations: ORYGEN lates of major depres- pathogenic processes. There is some evi- Research Centre (Drs Yap, 1,2 N sive disorder (MDD), dence that volumes of these structures re- Whittle, Yücel, and Allen and 13,14 with structural abnormalities in the amyg- flect levels of symptoms, and both twin Mr Simmons) and Melbourne Neuropsychiatry Centre dala, hippocampus, and anterior cingu- studies and studies investigating young (Drs Whittle, Yücel, and late cortex (ACC) hypothesized to under- first-episode patients provide support for Pantelis), Department of lie deficits in affective processing and volumetric changes in these structures Psychiatry, and Department of regulation. Findings have been inconsis- being associated with trait or vulnerabil- Psychology (Drs Yap, Whittle, 8,15,16 tent, however, with regard to the direc- ity factors for disorder. Studies of brain and Allen and Mr Simmons), tion of abnormalities (ie, greater vs lesser structure in young healthy individuals with The University of Melbourne, 3,4 volume) with regard to the amygdala, varying levels of depressive symptoms and Melbourne Health 5-7 8-12 hippocampus, and ACC. Although might be particularly useful to help elu- (Drs Whittle, Yücel, and there are likely to be a number of factors cidate these issues. Pantelis), Parkville, Victoria, contributing to these inconsistencies, 2 key Second, environmental moderators may Australia; and Oregon Research Institute, Eugene (Dr Sheeber). issues stand out. First, it is unclear whether have an influence on brain-disorder asso- (REPRINTED) ARCH GEN PSYCHIATRY/ VOL 65 (NO. 12), DEC 2008 WWW. ARCHGENPSYCHIATRY.COM ©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ by a Deepdyve User on 06/28/2021 ciations. That is, certain neuroanatomic features might METHODS be associated with disorder only in the context of par- ticular environmental circumstances. This was demon- PARTICIPANTS strated, for example, in a study of depressed women in whom reduced hippocampal volume, relative to healthy The sample consisted of 106 adolescents (55 males [51%]; 102 controls, was observed only in the subset of depressed self-identified as Australian [96%]; mean [SD] age, 12.5 [0.5] years; women with a history of child abuse. To date, there have range, 11.4-13.6 years) recruited from schools across metropoli- been few other studies investigating the impact of envi- tan Melbourne, Australia. Adolescents were recruited as part of ronmental moderators on brain-disorder associations. a broader adolescent development study (see Yap et al for fur- Diathesis-stress models suggest that individual differences ther details) such that those with particularly high, and particu- in susceptibility to environmental experiences may be due larly low, temperamental risk for mental health problems were 18,19 oversampled, while those with intermediate levels of risk were to phenotypic differences. To the extent that neuroana- undersampled, resulting in a distribution of temperamental risk tomic abnormalities are predisposing factors for psychopatho- that retained the variance associated with the larger screening logic changes, such abnormalities may be conceptualized sample (n = 2453) but was still normally distributed. Using the as biological diatheses that confer heightened risk in the con- Edinburgh Handedness Inventory, we identified 99 students as text of environmental stressors. To this end, it has been pro- right-handed and 7 as left-handed. Participants were screened for posed that genetic influences on hippocampal volume may Axis I disorders by trained research assistants using the Sched- play a causal role in psychopathologic changes by sensitiz- ule for Affective Disorders and Schizophrenia for School-Aged Chil- ing the individual to stressful environmental circumstances. dren, Epidemiologic Version. Ten participants met criteria for Notably, some researchers propose that the effects of bio- a psychiatric diagnosis (past separation anxiety disorder, n = 1; so- logical reactivity to the environment on psychiatric and bio- cial phobia, n = 1; attention-deficit/hyperactivity disorder, n = 1; obsessive-compulsive disorder, n = 2; oppositional defiant disor- medical outcomes are bivalent, giving rise to negative out- der, n = 1; and past oppositional defiant disorder, n = 4). A small comes under adverse conditions and positive outcomes under number of participants reported minimal past cigarette smoking low-stress conditions. 22 (n = 2) or alcohol consumption (n = 6). Informed consent was ob- There is evidence that brain volumes are highly heritable, tained from all participants (adolescent and parent), in accor- and deviant brain structure or function may constitute use- dance with the guidelines of the Human Research Ethics Com- ful intermediate phenotypes for identifying the neurobio- mittee of the University of Melbourne. logical pathways that represent genetic susceptibility to mood disorders. Specifically, brain morphologic characteristics FAMILY INTERACTIONS may serve as useful endophenotypes with which to test the moderating effects of the environment on the link between Procedure biological features and disorder. Although a wide range of environmental factors are Adolescents and their mothers participated in a 20-minute prob- related to risk for mood disorders, a substantial body lem-solving interaction, which was videotaped for coding pur- of research indicates that the family affective climate, in- poses. Topics for the interaction were identified on the basis cluding the nature of parent-child interactions, is a par- of parent and adolescent responses to the Issues Checklist, ticularly important predictor of internalizing problems which comprises 44 topics about which adolescents and par- 25-27 and depression in young people. Specifically, parent- ents may disagree, such as “[adolescent] lying” and “[adoles- ing characterized by high conflict or negativity has been cent] talking back to parents.” Up to 5 Issues Checklist issues rated as conflictual (and recent) by parent and adolescent were found to predict depression in children and adolescents 28-30 chosen for dyads to discuss and resolve during the problem- in prospective studies. solving interaction. This article explores parenting behavior as a devel- opmentally salient environmental moderator of the brain- Observational Coding of Family Interactions depression association in a community sample of young people who vary widely in their depressive symptoms. The affective and verbal content of the interactions were coded We examine the frequency of harsh parenting as a po- with the use of the Living in Familial Environments coding tential moderator of brain volume–depression associa- system. This is an event-based coding system in which new codes tions, specifically the amygdala, hippocampus, and ACC. are entered each time the affect or verbal content of the par- We use an observational measure of harsh maternal be- ticipant changes. The system consists of 10 affect and 27 ver- haviors directed at the target adolescent, derived during bal content codes. The index of aversive parenting was rate per a conflictual mother-adolescent interaction task. We hy- minute of a composite construct of maternal aggressive behav- pothesize that, while there may be direct associations ior, which includes all events with contemptuous, angry, and belligerent affect, as well as disapproving, threatening, or ar- among the volume of selected brain structures, parent- gumentative verbal content with neutral affect. Higher fre- ing, and adolescent depressive symptoms, the interac- quency of negative parental behaviors distinguishes abusive and tion between brain volume and parenting will explain ad- neglectful families from controls and is associated with poorer ditional variance in symptoms. Given research indicating 41,42 cognitive and psychosocial outcomes in children. sex differences in adolescent brain development, brain Video recordings were coded by 2 specially trained research as- correlates of affective processes, sensitivity to distur- sistants blind to participant characteristics (eg, symptom levels) bances in parent-child interactions, and depressive symp- and study hypotheses. Approximately 20% of the interactions were toms, sex differences in the associations between these coded by a second observer to provide an estimate of observer agree- brain structures, parenting, and adolescent depressive ment. The coefficient for the aggressive composite code was 0.77, symptoms were also examined. which reflects good to excellent agreement. (REPRINTED) ARCH GEN PSYCHIATRY/ VOL 65 (NO. 12), DEC 2008 WWW. ARCHGENPSYCHIATRY.COM ©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ by a Deepdyve User on 06/28/2021 NEUROIMAGING Image Acquisition Magnetic resonance imaging was performed on a 3-T scanner (General Electric, Milwaukee, Wisconsin), using a gradient echo volumetric acquisition sequence (repetition time, 36 millisec- onds; echo time, 9 milliseconds; flip angle, 35°; field of view, 20 cm ; pixel matrix, 410 410) to obtain 124 T1-weighted con- tiguous 1.5-mm-thick sections (voxel dimensions, Absent Present 0.4883 0.4883 1.5 mm). Image Preprocessing Image preprocessing was carried out with tools from the FMRIB software library (http://www.fmrib.ox.ac.uk/fsl/). Each 3-di- Figure 1. Example of changes in the location and extent of the limbic (ACC ; highlighted in green) and paralimbic (ACC ; highlighted in blue) mensional image was stripped of all nonbrain tissue, aligned L P anterior cingulate cortices as a function of variations in the cingulate sulcus to the Montreal Neurological Institute 152 average template (CS; green arrow, top row) and paracingulate sulcus (PCS; blue arrow, top (6-parameter rigid body transform with trilinear interpola- row). A PCS is absent at left and present at right. The top 2 images present tion) by means of the Flexible Image Registration Toolbox, parasagittal sections through an individual’s T1-weighted image. The coronal and resampled to 1 mm . This registration served to align each section illustrates the distinction between cases with absent (left) and image axially along the anterior commissure–posterior com- present (right) PCS. Notice that the ACC is buried in the depths of the CS when the PCS is absent and extends over the paracingulate gyrus when the missure plane and sagittally along the interhemispheric fis- PCS is present. The same principle applies throughout consecutive coronal sure without any deformation. sections. Morphometric Analysis Hippocampal tracings included the hippocampus proper, Regions of interest (ROIs) were defined and quantified on the the dendate gyrus, the subiculum, and part of the fimbria and basis of previously published techniques (see the following para- alveus. Boundaries were defined as follows: posterior, section graphs). All ROIs were traced by one of us (S.W.) on each in- with the greatest length of continuous fornix; lateral, tempo- dividual’s images by using the software package ANALYZE ral horn; medial, open end of the hippocampal fissure poste- (Mayo Clinic, Rochester, Minnesota; http://mayoresearch.mayo riorly and the uncal fissure anteriorly; and superior, fimbria and .edu/mayo/research/robb_lab/). Brain tissue was segmented into alveus posteriorly and amygdala anteriorly. gray matter, white matter, and cerebrospinal fluid by means of The boundaries of the ACC have been described in detail an automated algorithm, as implemented in FAST (FMRIB’s [Ox- by Fornito et al. This protocol demarcates limbic (ACC ) and ford Centre for Functional MRI of the Brain] Automated Seg- paralimbic (ACC ) portions of the ACC by taking into ac- mentation Tool. An estimate of whole brain volume was ob- count individual differences in morphologic characteristics of tained by summing gray and white matter pixel counts (ie, whole the cingulate (CS), paracingulate (PCS), and superior rostral brain volume included cerebral gray and white matter, the cer- (SRS) sulci. Tracing was initially performed on contiguous sag- ebellum, and brainstem, but not the ventricles, cisterns, or ce- ittal sections, and the medial borders were edited on coronal rebrospinal fluid). The ACC estimates were based on gray mat- sections. The anterior ACC contained all gray matter in the ter pixel counts contained within the defined ROIs. Amygdala gyrus bound by the callosal sulcus and the CS. The borders of and hippocampal estimates were based on total voxels within the ACC depended on the course of the PCS and SRS. The PCS the defined ROI. was considered present or prominent if it ran parallel to the CS for at least 20 mm or at least 40 mm, respectively. Seg- Amygdala, Hippocampus, and ACC mented sections were considered part of the PCS if they were 10 mm or greater and separated from other segments by 10 mm The guidelines for tracing the amygdala and hippocampus or less. For cases where the PCS was present or prominent, the were adapted from those described by Velakoulis and col- ACC contained all gray matter in the gyrus bound by the CS 47,48 leagues. These structures were traced on contiguous coro- and PCS. For cases where the PCS was either absent or not par- nal sections. The boundaries of the amygdala were defined as allel along the full length of the CS, in those sections in which follows: posterior, first appearance of gray matter above the the PCS was absent the ACC included only the gray matter temporal horn; lateral, temporal stem; and medial, the semilu- on the upper bank of the CS. The SRS was classified either as nar gyrus superiorly and subamygdaloid white matter inferi- continuous with the CS or separate from it. In the former case, orly. Guidelines for marking the anterior boundary of the the inferior part of the ACC region included only gray matter amygdala and the boundary between the amygdala and hippo- on the upper bank of the CS; in the latter case, the inferior part campus differed slightly from those of Velakoulis and col- of the ACC comprised gray matter between the CS and SRS. leagues to maximize reliability. The anterior boundary of the See Figure 1 for illustration. amygdala was identified as the section posterior to the most posterior of either the point where the optic chiasm joins, or the point where the lateral sulcus closes to form the endorhi- ADOLESCENT DEPRESSIVE SYMPTOMS nal sulcus. The protocol of Watson et al was used to separate the amygdala from the hippocampus. This protocol involves The Center for Epidemiological Studies–Depression Scale, Re- using the uncal recess of the temporal horn, the alveus, or the vised has been found to be valid and reliable for adoles- semilunar gyrus as the inferior boundary of the amygdala, cents. In the current sample, the Cronbach  was 0.89 and depending on the visibility of these features. scores ranged from 0 to 55 (mean, 11.58; SD, 9.54). (REPRINTED) ARCH GEN PSYCHIATRY/ VOL 65 (NO. 12), DEC 2008 WWW. ARCHGENPSYCHIATRY.COM ©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ by a Deepdyve User on 06/28/2021 Table 1. Brain Measures and Tests for Sex Differences Full Sample Boys Girls Sex Difference Brain Measure No. Mean (SD) No. Mean (SD) No. Mean (SD) tP Value Left amygdala volume, mm 106 1882.44 (265.51) 55 1935.96 (263.60) 51 1824.73 (257.79) 4.81 .03 Right amygdala volume, mm 106 1844.80 (277.91) 55 1844.80 (277.91) 51 1784.37 (260.36) 1.33 .25 Left hippocampus volume, mm 106 2776.03 (323.50) 55 2820.75 (317.63) 51 2727.80 (325.92) 2.21 .14 Right hippocampus volume, mm 106 2937.24 (354.54) 55 2961.40 (356.48) 51 2911.18 (354.10) 0.53 .47 ACC asymmetry index 104 −315.16 (2386.42) 53 −672.67 (2260.72) 51 56.36 (2477.94) 2.46 .12 ACC asymmetry index 101 370.87 (2259.92) 50 441.78 (2159.52) 51 301.35 (2373.66) 0.10 .76 Maternal aggressive frequency 106 1.30 (0.61) 55 1.31 (0.61) 51 1.29 (0.60) 0.04 .84 Adolescent depressive symptoms, No. 106 11.46 (9.50) 55 12.14 (9.21) 51 10.72 (9.84) 0.58 .45 Abbreviations: ACC , limbic anterior cingulate cortex; ACC , paralimbic anterior cingulate cortex. L P Anterior cingulate cortex data were missing for some participants because of visualization or delineation difficulties. STATISTICAL ANALYSIS ence was in the volume of the left amygdala, with boys having a larger amygdala than girls. Interrater and intrarater reliabilities were assessed by means of the intraclass correlation coefficient (absolute agreement) using AMYGDALA 15 brain images from a separate magnetic resonance imaging database established for this purpose. Intraclass correlation co- efficient values (14 of 16 0.90 and none 0.85) were accept- As summarized in Table 2, in analyses for the left and able for all ROIs. Removing the 8 left-handed participants’ data right amygdala, greater frequency of maternal aggres- from analyses did not change the pattern of results, so we have sive behaviors and the 3-way interaction term reported results from the full set of data. (amygdala parenting sex) were associated with more Given literature suggesting that asymmetry of ACC volume adolescent depressive symptoms. Right amygdala vol- may be important for aspects of executive functioning and affect ume was also negatively associated with depressive symp- regulation, which may in turn have implications for mood dis- toms, although follow-up analyses showed that this was orders, ACC volume asymmetries were also investigated. An asym- significant for boys but not girls. Follow-up analyses on metry index was calculated for the ACC and ACC by using the L P the significant 3-way interaction showed that, in boys, formula left minus right. All brain structural measures were cor- rected for whole-brain size by means of a covariance adjustment only the right amygdala parenting interaction was sig- 54 2 method. Hypotheses were tested with 6 hierarchical linear re- nificant ( = 0.35, t = 2.81, P = .007, f = 0.16). In girls, both gressions, with parenting and adolescent brain structure vari- the left and right amygdala parenting interactions pre- ables used as predictors of adolescent depressive symptoms. For dicted depressive symptoms ( = −0.44, t = −3.82, each regression, adolescent sex, maternal aggressive behavior, and 2 P .001, f = 0.30; and  = −0.46, t = −3.91, P .001, one of the brain structure measures (ie, left or right amygdala vol- f = 0.34, respectively). ume, left or right hippocampal volume, and ACC or ACC asym- L P Significant interactions were interpreted by plotting metry index) were entered in step 1. The three 2-way interaction the simple regression lines for the high (1 SD), aver- terms (parenting  adolescent sex, brain  sex, and age (mean), and low (−1 SD) values of maternal aggres- parenting  brain) were entered in step 2, and the sive frequency. Equations were then used to plot val- parenting brain sex interaction term was entered in step 3. ues of adolescent depressive symptoms at high, average, Interaction terms were computed after centering all continuous variables. Significant sex interactions were followed up with re- and low values of maternal aggressive frequency and at gression analyses for males and females separately (with parent- high (2 SDs) and low (−2 SDs) values of (left or right) ing and the appropriate brain variable entered in step 1 and the amygdala volume. Two-tailed t tests showed that, for boys, interaction entered in step 2). Significant parenting brain and the slopes of the regression lines at low ( = −0.70, 3-way interactions were probed following recommendations by t = −3.95, P .001) and average ( = −0.37, t = −2.99, 55 56 51 51 Aiken and West, with the use of O’Connor’s SPSS macros to P = .004) values of maternal aggressive frequency were sig- compute simple slope analyses. Following Cohen and Cohen’s 2 nificantly different from zero (Figure 2). Hence, while guidelines, f is taken as the index of the effect size of interac- boys with a smaller right amygdala reported more de- tions, whereby an f value of 0.02 is small, 0.15 is medium, and pressive symptoms, in the context of low to average lev- 0.35 is large. Because changes in structural brain asymmetry may result from changes in the size of either or both hemispheres, els of maternal aggressiveness, larger right amygdala was significant main effects or interactions involving asymmetry vari- also associated with fewer symptoms. ables were followed up with 2 hierarchical regressions using left For girls, both the low ( = 0.46, t = 2.69, P = .01) and and right hemisphere ROI volumes as predictors of adolescent high ( = −0.36, t = −2.56, P = .01) maternal aggressive- depressive symptoms (along with sex, parenting, and the 2- and ness slopes were significant for the right amygdala 3-way interactions). (Figure 3). Similarly, both the low ( = 0.56, t = 3.16, P = .003) and high ( = −0.30, t = −2.12, P = .04) mater- RESULTS nal aggressiveness slopes were significant for the left amyg- dala (graph similar to Figure 3, thus not shown). Hence, Table 1 shows means, standard deviations, and sex dif- in girls exposed to high levels of maternal aggressive- ferences in all variables. The only significant sex differ- ness, there was a significant negative association be- (REPRINTED) ARCH GEN PSYCHIATRY/ VOL 65 (NO. 12), DEC 2008 WWW. ARCHGENPSYCHIATRY.COM ©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ by a Deepdyve User on 06/28/2021 Table 2. Summary of 6 Regressions Predicting Adolescent Maternal aggressive frequency Depressive Symptoms With Brain Measures and MAF –1 SD Mean +1 SD Regressions  t Value F R Regression 1 (n=106) Step 1 4.04 0.11 Left amygdala −0.11 −1.11 .27 MAF 0.29 3.19 .003 Step 3: Left amygdala 0.43 3.34 .001 11.18 0.08 MAF sex Regression 2 (n=106) Step 1 5.83 0.15 Right amygdala −0.23 −2.47 .02 MAF 0.29 3.13 .002 Step 3: Right amygdala 0.59 4.75 .001 22.54 0.15 MAF sex Regression 3 (n=106) Step 1 3.60 0.10 0 Left hippocampus −0.02 −.19 .85 MAF 0.30 3.16 .002 –5 Regression 4 (n=106) –2 SDs +2 SDs Step 1 3.59 0.10 Boys’ Right Amygdala Volume Right hippocampus 0.02 .17 .87 MAF 0.30 3.18 .002 Step 2: MAF sex −0.29 −2.11 .04 1.79 0.05 Figure 2. Plots of simple slopes showing the interaction between maternal Regression 5 (n=104) aggressive frequency and the volume of boys’ right amygdala predicting adolescent depressive symptoms (score on the Center for Epidemiological Step 1 3.52 0.10 Studies–Depression Scale). ACC asymmetry −0.08 −.84 .40 MAF 0.30 3.11 .002 Step 2: ACC asymmetry MAF 0.19 1.97 .05 3.80 0.10 Regression 6 (n=101) Maternal aggressive frequency Step 1 4.06 0.11 –1 SD ACC asymmetry 0.10 1.09 .28 Mean +1 SD MAF 0.31 3.23 .002 Step 3: ACC asymmetry −0.29 −2.13 .04 4.54 0.04 MAF sex Abbreviations: ACC , limbic anterior cingulate cortex; ACC , paralimbic L P anterior cingulate cortex; , change; MAF, maternal aggressive frequency. The first step in each model included adolescent sex coded as 1 for male and 0 for female, but it had no significant effects and hence is not shown here. Only significant interactions are shown. Change in F and R values for 15 2-way interactions refer to effects of all 2-way interaction variables in that block, whereas the values for 3-way interactions are specific to the corresponding 3-way interaction variable. The ACC data were missing for some participants because of visualization or delineation difficulties. tween amygdala volume and depressive symptoms. Con- versely, in the context of low maternal aggressiveness, there was a positive association between amygdala vol- ume and depressive symptoms. –5 HIPPOCAMPUS –2 SDs +2 SDs Girls’ Right Amygdala Volume As before, greater frequency of maternal aggressive be- haviors was associated with more adolescent depressive Figure 3. Plots of simple slopes showing the interaction between maternal symptoms. In addition, the parenting sex interaction aggressive frequency and the volume of girls’ right amygdala predicting was significant in the model with the right hippocam- adolescent depressive symptoms (score on the Center for Epidemiological Studies–Depression Scale). pus. Follow-up regressions showed that higher mater- nal aggressive frequency was associated with more de- pressive symptoms for girls ( = 0.49, t = 3.92, P .001). ANTERIOR CINGULATE CORTEX Hippocampal volumes were not associated with depres- sive symptoms either as main effects or in interaction with Again, greater frequency of maternal aggressive behaviors the other variables. was associated with more adolescent symptoms. Neither (REPRINTED) ARCH GEN PSYCHIATRY/ VOL 65 (NO. 12), DEC 2008 WWW. ARCHGENPSYCHIATRY.COM ©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ by a Deepdyve User on 06/28/2021 No. of Adolescent Depressive Symptoms No. of Adolescent Depressive Symptoms AMYGDALA Maternal aggressive frequency The direct association between a smaller right amygdala –1 SD Mean and elevated depressive symptoms in boys is consistent with +1 SD previous findings. The moderation of associations be- tween amygdala volume and symptoms by family context and sex suggests that these factors may help account for null or contradictory findings in previous studies. Our find- ings indicate that, in boys overall, while a larger right amyg- dala is associated with reduced depressive symptoms, among boys with a larger than average right amygdala, low levels of aggressive maternal behavior further reduce the risk for symptoms. In girls, although a smaller amygdala is not di- rectly associated with elevated symptoms, it may engen- der sensitivity to the effects of family affective environ- ment. That is, girls with smaller amygdalas report more symptoms only if their mothers are frequently aggressive toward them. This is consistent with evidence from the de- velopmental literature that girls may be more susceptible 60,61 to the effect of negative family interactions and points 0 toward a potential neurobiological mechanism for this sex difference. Moreover, there are indications in these find- –2 SDs +2 SDs ings that, among girls, smaller amygdala volume is also as- Boys’ Left ACC Volume sociated with especially low levels of depressive symp- toms when paired with low levels of maternal aversiveness. Figure 4. Plots of simple slopes showing the interaction between maternal This suggests that smaller amygdalas might be a neuro- aggressive frequency and the volume of boys’ left paralimbic anterior cingulate cortex (ACC ) region predicting adolescent depressive symptoms anatomic marker of general sensitivity to environmental (score on the Center for Epidemiological Studies–Depression Scale). influences, consistent with the “differential susceptibil- 21,62 ity” hypothesis, which proposes that some individuals (for biological reasons) are more susceptible than others asymmetry measure was significantly associated with to positive as well as negative aspects of the environment. depressive symptoms, but the ACC asymmetry It has been speculated that “sensitivity” might result from parenting sex interaction term was. Follow-up analyses 21,62 increased attention or hyperreactivity to stress. Whether showed that the asymmetry parenting interaction was or how these factors are related to volumetric measures of significant for boys ( = −0.37, t = −2.26, P = .03, f = 0.11) the amygdala is not clear, but it is interesting that the amyg- but not girls ( = 0.06, t = 0.48, P = .63). Further analyses dala has been noted to have distinct functions with regard were conducted to see whether the 3-way interaction to attention to environmentally salient stimuli. effect was driven by the left or right ACC . Only the left Notably, boys and girls benefit differentially from low ACC  parenting interaction was significantly associated levels of aversive parenting—boys with larger right amyg- with depressive symptoms ( = −0.40, t = −2.86, P = .006, dalas vs girls with smaller right and left amygdalas ben- f = 0.16). The plot for the left ACC  parenting interaction efit more. Alternatively, boys with larger right amygda- for boys is shown in Figure 4. Only the slope for low ma- las vs girls with smaller bilateral amygdalas may have a ternal aggressiveness was significantly different from zero greater biological sensitivity to the parenting context (ie, ( = 0.50, t = 2.57, P = .01). Hence, among adolescent boys 50 21 both harmful and helpful aspects of parenting). These exposed to low levels of maternal aggressiveness, there was findings add to the literature suggesting sex differences a significant positive association between the left ACC vol- P 64 in amygdala functioning, although the exact nature of ume and depressive symptoms. these differences remains unclear. It is possible that sex differences in the rate of amygdala development during COMMENT adolescence may contribute to this pattern of find- 65,66 ings. Longitudinal research is required to investigate In a nonclinical sample of early adolescents, there was no the developmental trajectories of these associations. direct relationship between adolescent depressive symp- toms and the volumes of the amygdala, hippocampus, or HIPPOCAMPUS ACC. However, boys with smaller right amygdalas, and ado- lescents whose mothers displayed more frequent aggres- Contrary to expectations, the hippocampus was not as- sive behaviors during a conflict resolution interaction, re- sociated with depressive symptoms, either directly or in ported more depressive symptoms. In addition, significant interaction with the parenting environment. Previous interaction effects showed that amygdala volume and ACC studies of hippocampal volume involving pediatric and asymmetry were associated with depressive symptoms in early-onset MDD samples have been mixed, with some 7,59 the context of certain levels of maternal aggressiveness, sug- showing no alterations and others finding smaller hip- 67-69 gesting that these structures may represent markers of bio- pocampal volumes. Because the participants in the cur- logical sensitivity to the parenting context. rent study were not experiencing case-level disorders, our (REPRINTED) ARCH GEN PSYCHIATRY/ VOL 65 (NO. 12), DEC 2008 WWW. ARCHGENPSYCHIATRY.COM ©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ by a Deepdyve User on 06/28/2021 No. of Adolescent Depressive Symptoms findings suggest that hippocampal volume is not asso- young people at risk for a number of psychopathologic ciated with levels of depressive symptoms that are be- changes may prove to be beneficial. low threshold for clinical diagnosis. This is in line with the neurotoxicity hypothesis of trauma or pathogenic en- LIMITATIONS vironments on the hippocampus, suggesting that hip- pocampal neurodegeneration may result from severe stress The cross-sectional design of the study precludes us from associated with prolonged or recurrent psychopatho- drawing strong conclusions regarding the causality of re- logic features, or exposure to trauma. It is possible that lationships. That is, whether changes in regional brain vol- adverse parenting as measured in this study is not a se- ume and maternal aggressive behaviors result from, or rep- vere enough stressor to produce neurotoxic effects on the resent early predictors of, adolescent depressive problems hippocampus. Alternatively, if hippocampal volume loss remains unclear. Furthermore, the marked brain reorga- is an indication of an early phase of MDD or an MDD nization and sex differences in brain development occur- subtype, our findings may indicate that these partici- 79,80 ring during adolescence may complicate the interpre- pants are not at risk for developing such psychopatho- tation of findings. Finally, given the genetic contribution logic characteristics. to brain structure, risk for psychopathologic changes, and the family environment, family history of psychopatho- ANTERIOR CINGULATE CORTEX logic characteristics may covary with some of the relation- ships examined herein. Longitudinal assessment of parent- The finding for paralimbic ACC volume asymmetry sug- ing, brain structure, and depressive symptoms or disorder, gested that boys with a smaller left than right ACC were as well as assessment of family history of psychopatho- more sensitive to the effects of maternal aggressiveness, logic features, is needed to resolve these issues. and this appeared to be driven by a reduction in left ACC A further limitation of the study concerns the gener- volume specifically. In these individuals, low maternal alizability of results because selection was biased to overs- aggressiveness was associated with fewer depressive symp- ample adolescents with “extreme” temperaments. Fur- toms. The lateralization of our finding is consistent with ther research will be required to assess the association research showing predominantly left lateralized ACC volu- between brain structure, parenting, and depressive symp- metric abnormalities in MDD. Furthermore, previous re- toms in representative adolescent population samples. An- search has indicated that a reduced leftward asymmetry other issue relevant to generalizability is that only 1 type of the PCS (which is associated with reduced size of the of environmental stressor, the maternal-child relation- left ACC ) characterizes those (particularly males) ex- ship, was examined. Although this relationship is of par- periencing or at risk for a range of psychopathologic ticular relevance to depressive symptoms in adoles- 71-73 changes. Moreover, there is evidence that individu- cence, the patterns of results may not be generalizable als with smaller left ACC perform poorly on tasks of ex- to other important environmental factors such as, for ex- ecutive functioning and are temperamentally prone to ample, experiences of abuse. It is also important to ac- the experience of high negative affect. The present re- knowledge that laboratory-based interactions likely dif- sult suggests that this structural brain feature is not nec- fer from those that occur in day-to-day interactions. essarily associated with adverse outcomes, but rather may Nevertheless, laboratory-based family interactions have be associated with sensitivity to environmental factors, good predictive and convergent validity with other mea- such that it may be related to positive outcomes given sures of these processes as well as with depressive syn- 21,62 favorable environmental circumstances. dromes, suggesting that they capture valid and impor- The significance of the male specificity of our finding 82,83 tant information regarding family interactions. for the ACC requires further investigation; however, we Finally, a large number of analyses were conducted, speculate that this result may reflect a sensitivity engen- raising the possibility of type 1 error. Our goal was to dered by the testosterone-mediated developmental lag of discover plausible patterns of interaction between envi- the male left hemisphere, which has been suggested to ronmental and biological factors, and thereby inform fu- increase the sensitivity of this hemisphere to environ- ture more detailed research. The presentation of analy- mental input. ses in the current article ensures that the reader is aware Because subthreshold depressive symptoms are an early of the full range of analyses that were performed; how- sign of a number of disorders other than MDD (eg, schizo- ever, because of the risk of type 1 error, we emphasize 77 78 phrenia and bipolar disorder ), the results of this study the need for replication. may also have implications for understanding the etiol- ogy of these disorders. In particular, our findings may CONCLUSIONS provide insight into the role of the family environment in the etiologic path by which ACC structure is associ- ated with schizophrenia. Bipolar disorders, on the other Our findings suggest that structural features of the amyg- hand, may have a distinct neuroanatomic profile, par- dala and ACC are phenotypic markers of sensitivity to ticularly with regard to the course of changes in struc- the parenting environment in a nonclinical sample of ado- ture of the amygdala and hippocampus over the course lescents with no history of MDD. Marked sex differ- of the disorder. Longitudinal work is crucial to inves- ences in the nature of the reported associations and in- tigate these complex associations. teractions were found. The findings suggest that taking In any case, the present results suggest that early in- environmental factors into consideration when examin- terventions that target aversive parenting in families of ing brain/disorder associations may facilitate a clearer un- (REPRINTED) ARCH GEN PSYCHIATRY/ VOL 65 (NO. 12), DEC 2008 WWW. ARCHGENPSYCHIATRY.COM ©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ by a Deepdyve User on 06/28/2021 12. Ballmaier M, Toga AW, Blanton RE, Sowell ER, Lavretsky H, Peterson J, Pham derstanding of the nature of these associations. Low lev- D, Kumar A. Anterior cingulate, gyrus rectus, and orbitofrontal abnormalities in els of aversive parenting may have protective effects for elderly depressed patients: an MRI-based parcellation of the prefrontal cortex. adolescents with a heightened biological sensitivity to the Am J Psychiatry. 2004;161(1):99-108. parenting context. Because these family context risk fac- 13. MacMillan S, Szeszko PR, Moore GJ, Madden R, Lorch E, Ivey J, Banerjee SP, tors are modifiable, these findings suggest the poten- Rosenberg DR. Increased amygdala:hippocampal volume ratios associated with severity of anxiety in pediatric major depression. J Child Adolesc Psychopharmacol. tial of targeted parenting interventions with families of 2003;13(1):65-73. at-risk adolescents. 14. Chen CH, Ridler K, Suckling J, Williams S, Fu CH, Merlo-Pich E, Bullmore E. Brain imaging correlates of depressive symptom severity and predictors of symp- tom improvement after antidepressant treatment. Biol Psychiatry. 2007;62 Submitted for Publication: January 22, 2008; final re- (5):407-414. vision received May 4, 2008; accepted June 9, 2008. 15. Frodl T, Meisenzahl EM, Zetzsche T, Born C, Groll C, Jäger M, Leinsinger G, Bot- tlender R, Hahn K, Möller HJ. Hippocampal changes in patients with a first epi- Correspondence: Nicholas B. Allen, PhD, ORYGEN Re- sode of major depression. Am J Psychiatry. 2002;159(7):1112-1118. search Centre, Locked Bag 10, Parkville, Victoria 3052, 16. Botteron KN, Raichle ME, Heath AC, Price A, Sternhell KE, Singer TM, Todd R. Australia (nba@unimelb.edu.au). An epidemiological twin study of prefrontal neuromorphometry in early onset Financial Disclosure: None reported. depression [abstract]. Biol Psychiatry. 1999;45(8)(suppl 1):59S. Funding/Support: This research was supported by grants 17. Vythilingam M, Heim C, Newport J, Miller AH. Childhood trauma associated with smaller hippocampal volume in women with major depression. Am J Psychiatry. from the Colonial Foundation and the National Health 2002;159(12):2072-2080. and Medical Research Council (NHMRC) (program grant 18. Caspi A, Moffitt TE. Gene-environment interactions in psychiatry: joining forces 350241). Dr Yap is supported by an NHMRC Centre for with neuroscience. Nat Rev Neurosci. 2006;7(7):583-590. Clinical Research Excellence Postdoctoral Fellowship. Dr 19. Jaffee SR, Caspi A, Moffitt TE, Dodge KA, Rutter M, Taylor A, Tully LA. Nature x Whittle is supported by an Australian Research Council nurture: genetic vulnerabilities interact with physical maltreatment to promote conduct problems. Dev Psychopathol. 2005;17(1):67-84. Postdoctoral Fellowship. Dr Yücel is supported by an 20. de Geus EJ, van’t Ent D, Wolfensberger S, Heutink P, Hoogendijk WJ, Boomsma NHMRC Clinical Career Development Award (ID DI, Veltman DJ. Intrapair differences in hippocampal volume in monozygotic twins 509345). discordant for the risk for anxiety and depression. Biol Psychiatry. 2007;61 Additional Contributions: Neuroimaging analysis was (9):1062-1071. facilitated by the Neuropsychiatry Imaging Laboratory 21. Boyce WT, Ellis BJ. Biological sensitivity to context, I: an evolutionary– developmental theory of the origins and functions of stress reactivity. 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