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Neuroanatomical Correlates of Temperamentin Early Adolescents

SARAH WHITTLE, PH.D., MURAT YUCEL, PH.D., M.A.P.S., ALEX FORNITO, PH.D.,ANNA BARRETT, B.A.(HONS.), STEPHEN J. WOOD, PH.D., DAN I. LUBMAN, PH.D.,

JULIAN SIMMONS, B.SC., CHRISTOS PANTELIS, M.D., AND NICHOLAS B. ALLEN, PH.D.

A B S T R A C T

O b je ctiv e: T emperament re fers to enduring behaviora l characteristics tha t underpin individua l differences in human

behavior, including risk for psychopa thology. R ese arch a ttempting to investiga te the neurobiologica l basis of temperament

represents an important step toward e lucida ting the biologica l mechanisms underlying these individua l differences. In the

present study, we examined the re la tion be twe en four core temperament dimensions and ana tomica lly de fined regions of

the limbic and pre fronta l cortices. Meth o d : W e used a cross-sectiona l design to examine a large sample (N = 153; me an

age 12.6 ye ars, S D 0.4, range 11.4Y13.7) of he a lthy e arly adolescents who were se lected from a larger sample to

maximiz e varia tion in temperament. The ma in outcome me asures were psychome tric me asures of temperament (four

factors: e ffortful control, nega tive a ffectivity, surgency, and a ffilia tiveness) based on the E arly Adolescent T emperament

Q uestionna ire-R evised, and volume tric me asures of a priori bra in regions of interest (anterior cingula te cortex [A C C ],

orbitofronta l cortex, amygda la , and hippocampus). R e s u lts : W e found regiona l bra in volumes to account for sma ll but

significant amounts of the variance in se lf-reported temperament scores. Specifica lly, higher e ffortful control was

associa ted with larger volume of the le ft orbitofronta l cortex and hippocampus. H igher nega tive a ffectivity was associa ted

with sma ller volume of the le ft dorsa l para limbic re la tive to limbic portion of the A C C . H igher a ffilia tiveness was associa ted

with larger volume of the right rostra l/ventra l limbic portion of the A C C . A ffilia tiveness and surgency a lso showed a number

of fema le-specific associa tions, primarily involving the rostra l/ventra l A C C . C o n c lu s io n s : O ur results provide support for a

ne uroa n a tomica l ba sis for indiv idu a l diff erence s in te mpera me nt and ha ve implica tions for understa nding the

neurobiologica l mechanisms underlying the deve lopment of a number of psychia tric disorders. J. Am. A cad. C hild

Adolesc. Psychia try, 2008;47(6):000Y000. K e y W ord s : bra in volume , persona lity, magne tic resonance imaging, anterior

cingula te cortex, risk factor.

Temperament refers to endogenous basic tendenciesof thoughts, emotions, and behaviors. Core tempera-

ment dimensions are observable in infancy, remainrelatively stable across the life span,1 and have beenshown to confer risk for behavioral and mental healthproblems, particularly during adolescence,2 when theonset of such problems is particularly pronounced.3

Many of the neuroanatomical changes associated withadolescent and adult mental illnesses are assumed toexist before illness onset and hence likely to be asso-ciated with putative risk factors4; however, little workhas been conducted to directly test this hypothesis.Thus, investigating the underlying neuroanatomy ofcore temperament dimensions in early adolescencerepresents an important step toward better under-standing the neural mechanisms influencing manyaspects of normal and abnormal adolescent and adultbehavior.

Accepted January 22, 2008.Drs. Whittle, Yucel, Lubman, and Allen and Mr. Simmons are with

ORYGEN Research Centre; Drs. Fornito, Wood, and Pantelis are with theMelbourne Neuropsychiatry Centre, Department of Psychiatry, University ofMelbourne; and Ms. Barrett is with the Department of Psychology, Universityof Melbourne.

This research was supported by ORYGEN Research Centre and the ColonialFoundation. Neuroimaging analysis was facilitated by the NeuropsychiatryImaging Laboratory, MNC, managed by Bridget Soulsby.

The authors thank the Brain Research Institute for support in acquiring theneuroimaging data.

Correspondence to Dr. Nicholas B. Allen, ORYGEN Research Centre, LockedBag 10, Parkville, Victoria 3052, Australia; e-mail: nba@unimelb.edu.au.

0890-8567/08/4706-0000 2008 by the American Academy of Child andAdolescent Psychiatry.

DOI: 10.1097/CHI.0b013e31816bffca

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R E C E N T A N D R E L E V A N T LIT E R A T U R E R E VIE W

Although there have been a number of neuroche-mical, neurophysiological, and functional brain imagingstudies of temperament and personality (see Cloninger5

for a review), structural brain imaging research withhealthy control populations has been limited. A handfulof studies have been conducted to examine theneuroanatomical correlates of adult temperament inthe context of Cloninger`s6 biological model,7Y9 and ofpersonality in the context of the five-factor model.10Y13

These studies do provide grounds to suggest a neuro-anatomical basis for individual differences in tempera-ment; however, findings are difficult to integrate asmethodologies have varied widely with respect to thetype of structural measure used (i.e., region of interest[ROI] versus voxel-based morphometry [VBM]), thelocation and extent of brain regions investigated, and theparticular traits measured. Furthermore, although thesestudies indicate that there is indeed a relation betweenvariations in brain structure and core temperament andpersonality dimensions in adults, it is as yet unclearwhether such associations are also observable earlier indevelopment. This is particularly important given themajority of temperament research in other domains hasfocused on the developmental period of childhood andadolescence, based on the assumption that temperamentis more easily observable during this life phase, and isless confounded by experiential-based characteristics.14

The model of temperament Rothbart and collea-gues15,16 may be particularly useful to examine because itis based on neurobiological theory17 and has a develop-mental orientation with a focus on childhood andadolescent temperament. Four core temperament dimen-sions comprise the model. Surgency refers to a tendencyto seek out and enjoy intense experiences, together with alack of shyness and fear, negative affectivity refers toexpressed and felt frustration/anger in response tolimitations. These two dimensions primarily captureindividual differences in reflexive responding (i.e.,reactivity) to affective stimuli and are thought to haveroots in limbic circuits (particularly the amygdala andhippocampus) that have evolved to serve appetitive anddefensive needs.Other research has implicated themedialprefrontal cortex, particularly the portion of the anteriorcingulate cortex (ACC) extending rostrally and ventrallyaround the corpus callosum in such reflexive affectiveresponding.18 These regions have been particularlyimplicated in mood and anxiety disorders, and it has

been suggested that structural abnormalities observed inthese disorders may be trait based or represent predis-posing risk factors.19,20

Affiliativeness refers to the desire for closeness withothers and the tendency to notice and experiencepleasure from low-intensity stimuli. This dimension isthought to have roots in neural systems underlyingsocially directed motivated behavior and separationdistress panic. Recent research points toward the limbicportion of the ACC as a key component of thesesystems21,22; however, whether rostral/ventral or moredorsal portions of the limbic ACC are of greaterimportance is uncertain. It is speculated that thesesystems may be separable from those underlying morebasic reward- and punishment-related approach andavoidance behavior.23

Effortful control refers to the ability to direct attentionand regulate emotion and behavior. It is thought to havedevelopmental roots in a neural system subserving exe-cutive attention, the pivotal circuitry of which is focusedon the anterior cingulate region, particularly that portionthat lies dorsal to the corpus callosum.24 Paralimbic andorbitofrontal cortex (OFC) regions are also suggested asimportant for the regulatory aspects of emotion andbehavior.25,26 Structural changes in these regions havebeen reported in child, adolescent, and adult disordersinvolving deficits in attention (such as attention-deficit/hyperactivity disorder [ADHD]27Y30) and other execu-tive functioning and behavioral regulation (such asschizophrenia,31 autism,32 and substance abuse33).

P U R P O S E O F S T U D Y A N D A P RIO RI H Y P O T H E S E S

This study sought to examine the relation betweenthese core temperament dimensions and brain structurein a large sample of healthy early adolescents. Four keybrain areas were targeted based on the literaturedescribed above (see Whittle et al.4 for a fuller review).We predicted that core temperament dimensions wouldbe distinguishable in terms of their associations withvolumes of predefined brain structures including theamygdala, hippocampus, OFC, and dorsal, rostral,and ventral portions of the limbic and paralimbicACC. Establishing such relations will make animportant contribution to our understanding of theneuroanatomical features that may be associated withrisk for developing a number of psychiatric disordersin adolescence.

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M E T H O D

P articipants

The sample consisted of 72 females and 81 males (mean age 12.6years, SD 0.4; range 11.4Y13.7). There were 139 right-handed and14 left-handed subjects (as established using the EdinburghHandedness Inventory).34 Participants were screened for presentand past case level Axis I disorders by trained research assistants usingthe Schedule for Affective Disorder and Schizophrenia for School-Age Children-Epidemiologic Version (K-SADS-E).35 Overall, 15participants met criteria for a psychiatric diagnosis (past depressivedisorder, n = 1; past separation anxiety disorder, n = 1; social phobia,n = 1; ADHD, n = 1; obsessive compulsive disorder, n = 2; past andcurrent psychotic disorder with hallucinations, n = 2; currentoppositional defiant disorder, n = 1; past oppositional defiantdisorder, n = 6). Informed consent was obtained for all participants(and their parent or guardian) before their inclusion in the study, inaccordance with local ethics committee guidelines.

Me asures

Participants completed the Early Adolescent TemperamentQuestionnaire-Revised (EATQ-R).36 The questionnaire was com-pleted at two time points (in-school screening and diagnosticassessment 6 months to 1 year postscreening). Confirmatory factoranalysis, performed on item data from the large-school screeningsample, provided good fit for a factor structure reflecting 10temperament subscales, largely consistent with the a priori scalesdescribed by Ellis and Rothbart.37 Items were also used to derive fourhigher order factors: negative affectivity (comprising solely of itemsfrom the Frustration subscale), effortful control (comprising itemsfrom Activation Control, Attention, and Inhibitory Controlsubscales), surgency (comprising fear [reversed-scored], shyness[reversed-scored], and surgency items), and affiliativeness (compris-ing affiliation, pleasure sensitivity, and perceptual sensitivity items).Subsequent analyses of EATQ-R data obtained from the diagnosticassessment were based on the factor solutions derived from theschool screening sample data. The four factors showed good internalconsistencies for both school screening and diagnostic assessmentadministrations, with Cronbach " values being .82 and .78,respectively, for negative affectivity, .82 and .83, respectively, foreffortful control, .82 and .81, respectively, for surgency, and .77 and.76, respectively, for affiliativeness.

Correlations between the two self-report measurements weremoderately high for all of the temperament scales, ranging from 0.42to 0.66, consistent with the conceptualization of temperament as arelatively stable trait. To increase reliability, the mean of the twomeasurements was used for all of the analyses.

Parents also completed the parent-report version of the EATQ-Rduring the diagnostic assessment, which comprises all but twosubscales (Pleasure and Perceptual Sensitivity) of the adolescent-report EATQ-R. Parent and adolescent convergence was found to bemoderate on all of the scales, ranging from 0.33 to 0.56, providingsupport for the validity of the adolescent`s self-report.

S e lection Procedure

Participant screening was conducted in a large sample of 2,479sixth grade students from 97 schools in metropolitan Melbourne,Australia. Selection was based on temperament and aimed atmaximizing the range of risk and resiliency for later onset of

psychopathology in recruited participants. To this end, we aimed toascertain a sample of adolescents who were representative of the rangeof scores across each higher order temperament dimension measuredby the EATQ-R. Equal numbers of adolescents were recruited acrossthe following ranges of scores on each of the four higher order factorsof the EATQ-R: 0 to 1 SDs above and below the mean, 1 to 2 SDsabove and below the mean, 2 to 2.5 SDs above and below the mean,and >2.5 SDs above and below themean.This resulted in selection of425 (16%) adolescents showing even variation across each of thehigher order traits of interest, with some emphasis in the distributionat the tails. Of the selected adolescents, 245 agreed to participate inone or more intensive phases of research, and of these, 153 agreed toundergo magnetic resonance imaging. No differences betweenparticipants who agreed to undergo magnetic resonance imagingand those who were selected but declined were observed ontemperament (negative affectivity (t[412] = 0.58, p = .56; effortfulcontrol (t[412] = 0.32, p = .75; surgency (t[412] = 0.56, p = .58;affiliativeness (t[412] =j0.71, p = .48), or sex ( 2 1 = 0.54, p = .46).

Image Acquisition

Magnetic resonance imaging scans were performed on a 3-Tscanner at the Brain Research Institute, Austin AQ1and RepatriationMedical Centre, Melbourne, Australia, using a gradient echovolumetric acquisition sequence (repetition time = 36 milliseconds;echo time = 9 milliseconds; flip angle = 35-, field of view = 20 cm2,pixel matrix = 410 ! 410) to obtain 124 T1-weighted contiguous2-mm thick slices (voxel dimensions = 0.4883! 0.4883! 2.0mm).

Image Preprocessing

Images were transferred to an SGI/Linux workstation formorphometric analysis. Image preprocessing was carried out usingtools from the Functional Magnetic Resonance Imaging of the Brain(FMRIB) software library (http://www.frmib.ox.ac.uk/fsl ). Each

F ig . 1 Example of region-of-interest boundaries as a function of sulcalvariability in the anterior cingulated cortex (ACC) region. The vertical blackline represents the posterior border of the dorsal ACC region. The vertical redline represents the border between the dorsal and rostral and the rostral andventral ACC subregions. Limbic cortex is highlighted in green, andparalimbic cortex is highlighted in blue.

Fig

14/c

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three-dimensional scan was stripped of all nonbrain tissue,38

resampled to 1 mm3, and aligned to the MNI 152 average template(six-parameter rigid body transform with trilinear interpolation)using FLIRT.39 This registration served to align each image axiallyalong the AC-PCAQ2 plane and sagittally along the interhemisphericfissure without any deformation.

Morphome tric Ana lysis

ROIs were defined and quantified based on previous techniquesdeveloped and published by the Melbourne Neuropsychiatry Centre(see below). All of the ROIs were traced using the software packageANALYZE (Mayo Clinic, Rochester, MN; http://www.mayo.edu/bir). Brain tissue was segmented into gray matter, white matter, andCSF using an automated algorithm, as implemented inAQ3 FAST.40 Anestimate of whole brain volume was obtained by summing gray and

whitematter pixel counts (i.e., whole brain volume included cerebralgray and white matter, the cerebellum, and brainstem, but not theventricles, cisterns, or CSF). ACC and OFC estimates were based ongray matter pixel counts contained within the defined ROIs.Amygdala and hippocampal estimates were based on total voxelswithin the defined ROIs.

Amygda la and H ippocampus

The guidelines for tracing the amygdala and hippocampus wereadapted from those described by Velakoulis and colleagues.41,42

Differences in method, which were adopted in efforts to maximizereliability for the current dataset, relate to marking the anteriorboundary of the amygdala and the boundary between the amygdalaand hippocampus. The anterior boundary of the amygdala wasidentified as the section posterior to the most posterior of either thepoint where the optic chiasm joins or the point where the lateralsulcus closes to form the endorhinal sulcus. The Watson et al.43

protocol was used to separate the amygdala from the hippocampus.

A C C

The boundaries of the ACC have been described in detail byFornito et al.44 This protocol defines separate limbic (ACCL) andparalimbic (ACCP) regions by taking into account individualdifferences in morphology of the cingulate, paracingulate, andsuperior rostral sulci. The protocol further divides the ACC intodorsal, rostral, and ventral regions based on evidence of functionalheterogeneity.45 The method results in six ACC subregions: dorsalACCL (d-ACCL), dorsal ACCP (d-ACCP), rostral ACCL (r-ACCL),rostral ACCP (r-ACCP), ventral ACCL (v-ACCL), and ventral ACCP(v-ACCP). See F1Figure 1 for an example parcellation.

O F C

The boundaries of the OFC were based on a previously publishedmethod.46 A line through the AC-PC was used to define the superiorboundary of the OFC. The posterior boundary was marked by acoronal plane passing through the most posterior aspect of theolfactory sulcus in each hemisphere. All of the images were manuallyedited to eliminate subcortical tissue and artifacts related to the eyesockets and nasal bones.

T A B L E 1Exploratory Factor Analysis of Anterior Cingulate Cortex ROI

Volumes: Promax Rotated Loadings

ROI 1 2 3 4 5

Left r-ACCL jjjj0.771 j0.018 0.118 0.117 0.183Left r-ACCP 0.733 0.007 0.213 0.093 j0.099Left v-ACCL jjjj0.750 j0.083 0.344 0.420 j0.030Left v-ACCP 0.683 j0.090 0.031 0.482 0.242Left d-ACCL 0.019 0.066 0.075 j0.007 0.886Left d-ACCP 0.234 0.017 0.230 0.124 jjjj0.727Right r-ACCL j0.016 0.336 j0.349 0.475 j0.178Right r-ACCP 0.052 j0.274 0.660 j0.181 j0.096Right v-ACCL j0.052 j0.032 j0.185 0.933 j0.068Right v-ACCP j0.061 0.233 0.974 j0.128 j0.017Right d-ACCL 0.166 0.932 0.273 0.083 0.098Right d-ACCP 0.143 jjjj0.854 0.085 0.168 0.026

Note: ROI volumes with primary loadings are in bold type.ROI = region of interest; ACCL = anterior cingulate cortex (limbic);ACCP = anterior cingulate cortex (paralimbic); d = dorsal; r = rostral;v = ventral.

T A B L E 2ROI Volume Predictors of Early Adolescent Temperament Questionnaire-Revised Temperament Factors Used in Initial Hypothesis-Driven and

Secondary Exploratory Regression Analyses

Temperament Hypothesized Predictors Exploratory Predictors

Negative affectivity Amygdala, hippocampus, right r/v(ACCL),right r/v(ACCP), left r/v(ACCLjACCP)

d(ACCLjACCP), OFC

Effortful control d(ACCL j ACCP), OFC Amygdala, hippocampus, right r/v(ACCL),right r/v(ACCP), left r/v(ACCLjACCP)

Surgency Amygdala, hippocampus, right r/v(ACCL),right r/v(ACCP), left r/v(ACCLjACCP)

d(ACCLjACCP), OFC

Affiliativeness Right r/v(ACCL), right r/v(ACCP),left r/v(ACCLjACCP),d(ACCLjACCP)

Amygdala, hippocampus, OFC

Note: Regions are bilateral unless otherwise indicated; positive values for d(ACCLjACCP) and r/v(ACCLjACCP) variables indicate largerACCL relative to ACCP volumes of dorsal and rostral/ventral regions, respectively. ROI = region of interest; ACCL = anterior cingulate cortex(limbic); ACCP = anterior cingulate cortex (paralimbic); d = dorsal; r/v = rostral + ventral; OFC = orbitofrontal cortex.

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S ta tistica l Ana lysis

Intra- and interrater reliabilities were calculated for each raw ROIvolume. Intraclass correlation coefficients (most >0.9 and none <0.8)were deemed acceptable for all of the ROIs. All of the ROI volumeswere corrected for whole brain volume using a covarianceapproach.47

Preliminary inter-ROI volume bivariate Pearson`s correlationsrevealed that there were a number of significant within-hemispherecorrelations between ACC ROI volumes. Factor analysis withpromax rotation (an oblique rotation was used because regional brainstructures are likely related to varying degrees)48 was performed onall of the ACC ROI volumes. This analysis yielded five factors withan eigenvalue cutoff of 1, and which explained approximately 75%of the structure variance (T1 Table 1). The five factors were found to betheoretically interpretable, and thus the ACC subregion ROIvolumes were subsequently combined (added) as indicated byprimary factor loadings. Specifically, the factor analysis showed aclear distinction between dorsal regions and rostral/ventral regions(within hemispheres), which is consistent with research indicating aprimary functional distinction between these two regions (cognitiveand affective, respectively).45 ACCL and ACCP subregions tended toload inversely within factors, which is consistent with previous workshowing an inverse relation between the size of these adjacentstructures,25,44 and is likely due to the influence of local sulcalmorphology. The right rostral/ventral region did not follow thispattern, but rather the ACCL and ACCP regions comprised twoseparate factors, suggesting that these regions may be functionallydistinct. The combined ROI volumes were used in subsequentanalyses to reduce both type I error and issues associated withmulticollinearity.

Hierarchical linear regressions were carried out to investigate thevariance in temperament explained by regional brain volumes. Foreach EATQ-R temperament factor, sex was entered as a predictor ina first block, followed by stepwise entry of hypothesized ROIvolumes in a second block (T2 Table 2). Because of noted sex differencesin both temperament49 and brain structure,50 sex differences weretested via stepwise entry of interaction terms in a final block.Significant interactions were followed up by separate regressions for

males and females, forcing all of the implicated ROIs into one block.In a secondary exploratory analysis, regressions were run with theremaining ROI predictors (i.e., those with weaker theoretical links totemperament; Table 2). The procedure for these analyses wasidentical to that described for the hypothesized ROI volumes. Theuse of stepwise entry reflected our desire to explore the differentialimportance of brain regions to temperament and also to uncovernovel findings that may guide future research.

Note that the entry of age in the initial step of regression modelsdid not result in any significant effects of age on temperament, nordid it affect the significance of any other neuroanatomical predictors.Because of the low age range in the sample and the lack of a priorihypotheses concerning age, the presented results stem from analysesthat exclude this variable as a predictor.

R E S U L T S

E ffortful C ontrol

Effortful control was significantly predicted by sex(females > males) and larger volume of the left OFC( T3Table 3). Exploratory analyses revealed that effortfulcontrol was also significantly predicted by larger volumeof the left hippocampus.

N ega tive A ffectivity

Exploratory analysis revealed that negative affectivitywas significantly predicted by smaller volume of the leftd(ACCP) relative to the left d(ACCL) ( T4Table 4).

Affiliativeness was significantly predicted by sex(females > males), larger volume of the right r/v(ACCL), and an interaction between sex and left r/v(ACCL-ACCP; T5Table 5). Follow-up regressions, withright r/v(ACCL) and left r/v(ACCL-ACCP) as predictorswere performed for males and females separately. Theregression was significant for females (F 2,71 = 3.46, p <.05, R 2 = 0.09) but not males (F 2,78 = 2.07, p = not

T A B L E 3Summary of Hierarchical Linear Regression Analysis PredictingEarly Adolescent Temperament Questionnaire-Revised Effortful

Control With ROI Volumes

Variable

Step 1 Step 2

B SE B $ B SE B $

Hypothesis drivenSex 3.61 1.43 0.20* 4.42 1.45 0.25**Left OFC 0.00 0.00 0.17*&R 2 0.041 0.027&F 6.38* 4.24*

ExploratorySex 3.44 1.45 0.19* 4.14 1.45 0.23**Left hippocampus 0.01 0.00 0.21*&R 2 0.037 0.042&F 5.60* 6.51*

Note: ROI = region of interest; OFC = orbitofrontal cortex.*p < .05; **p < .01.

T A B L E 4Summary of Hierarchical Linear Regression Analysis PredictingEarly Adolescent Temperament Questionnaire-Revised Negative

Affectivity With Exploratory ROI Volumes

Variable(Hypothesis Driven)

Step 1 Step 2

B SE B $ B SE B $

Sex j1.57 0.90 j0.14 j0.17 0.89j0.15Leftd(ACCLjACCP)

0.00 0.00 0.18*

&R 2 0.020 0.031&F 3.07 4.94*

Note: d(ACCLjACCP) = dorsal limbic relative to paralimbicACC volume. ROI = region of interest; ACC = anterior cingulatecortex.

*p < .05; **p < .01.

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significant, R 2 = 0.05). Analyses showed that smal-ler volumes of the left r/v(ACCL) relative to the leftr/v(ACCP) significantly predict higher affiliativenessscores for females ($ = j.27, p = .022), but not formales ($ = .19, p = .868).

Surgency

Surgency was significantly predicted by interactionsbetween sex and the right r/v(ACCL) and sex and theright amygdala (T6 Table 6). Follow-up regressions, withright r/v(ACCL) and right amygdala forced as predictors,were performed formales and females separately.Neitherright r-ACCL volume nor right amygdala volumesignificantly predicted surgency for males ($ = .11, p =.332 and $ = j.11, p = .339) or females ($ = j.19, p =.115 and $ = .20, p = .094). Although the regression wasnot significant for males (F 2,80 = 1.03, p = .364, R 2 =0.03), it trended toward significance for females (F 2,71 =3.01, p = .056, R 2 = 0.08).

Because the surgency dimension is conceptually bipolarin nature, with surgency (the tendency to seek out and

enjoy intense experiences) at one pole and shyness and fearat the opposite pole, analyses (with right r/v(ACCL) andright amygdala as predictors) were performed separatelyfor each subscale to aid interpretation of these results.These analyses showed significant sex ! right r/v(ACCL)($ = .22, p = .008) and sex ! right amygdala ($ = j.20,p = .018) interactions for fear and shyness, respectively.Follow-up sex-specific regressions showed significantrelations for females only. That is, females high in fearhad larger volumes of the right r/v(ACCL) ($ = .25, p =.037), and females high in shyness had smaller volumesof the right amygdala ($ = j.25, p = .036).

DIS C U S SIO N

In the present study, analyses revealed that anatomi-cally defined regional brain volumes account for smallbut significant proportions of variance in core tempera-ment dimensions. Variance estimates ranged fromapproximately 3% to 13%; values similar in magnitudeto most estimates of neuroanatomical contributions to

T A B L E 6Summary of Hierarchical Linear Regression Analysis Predicting Early Adolescent Temperament Questionnaire-Revised Surgency

With ROI VolumesAQ4(a) Variable(Hypothesis Driven)

Step 1 Step 2 Step 3

B SE B $ B SE B $ B SE B $

Sex j1.52 1.55 j0.08 j1.78 1.53 j0.10 j1.32 1.53 j0.07Right r/v(ACCL) ! sex 0.00 0.00 j0.19* j0.00 0.00 j0.18*Right amygdala ! sex 0.01 0.01 0.17*&R 2 0.007 0.036 0.028&F 0.96 5.43* 4.24*

Note: ROI = region of interest; ACC = anterior cingulate cortex; r/v(ACCL) = rostral/ventral limbic ACC.*p < .05; **p < .01.

T A B L E 5Summary of Hierarchical Linear Regression Analysis Predicting Early Adolescent Temperament Questionnaire-Revised Affiliativeness

With ROI VolumesAQ4

(a) Variable (Hypothesis Driven)

Step 1 Step 2 Step 3

B SE B $ B SE B $ B SE B $

Sex 2.36 1.22 0.16 2.62 1.20 0.18* 2.91 1.19 0.20*Right r/v(ACCL) 0.00 0.00 0.20* 0.00 0.00 0.18*Left r/v(ACCLjACCP) ! sex 0.00 0.00 j0.18*&R 2 0.025 0.039 0.031&F 3.76 5.97* 4.88*

Note: ROI = region of interest; ACC = anterior cingulate cortex; r/v(ACCL) = rostral/ventral limbic ACC volume; r/v(ACCLjACCP) =rostral/ventral limbic relative to paralimbic ACC volume.

*p < .05; **p < .01.

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measures of intelligence and other cognitive abilities.51

In summary, higher temperamental effortful control wasassociated with larger volume of the OFC andhippocampus in the left hemisphere, whereas highernegative affectivity was associated with smaller volumeof the left dorsal ACCP relative to ACCL, and higheraffiliativeness was associated with larger volume of theright rostral/ventral ACCL. Sex differences emerged inthe neuroanatomical predictors of affiliativeness andsurgency, with a number of associations being morepronounced for females.

F2 Figure 2 provides a pictorial representation of theresults. It can be seen that associations were found for alltemperament dimensions, and although there was somedegree of specificity, there was also some overlap in thespecific regions associated with temperament factors.This is consistent with the argument that humantemperament is complex and interactive, which is likelyreflected in underlying neurobiology.37 Althoughwe didnot obtain behavioral measures per se, the particularregions associated with specific temperament dimen-sions are largely consistent with previous brain imaginginvestigations of the processes and behaviors that arecaptured in the descriptions of these temperaments, asdiscussed below. Hence, our findings offer support forthe notion that measures of brain volume in limbic andprefrontal cortices have behavioral significance.

E ffortful C ontrol

The positive relation between effortful control andvolume of the left OFC is consistent with bothfunctional imaging and lesion studies showing thisregion to be crucial for attentional processes and theinhibition of behavior in both cognitive and affectivedomains.52Y54 Furthermore, studies showing greaterOFC activity in adults compared to children/adolescentsduring tasks that tap into these functions suggest thatOFC may be particularly important for the develop-ment of behavioral regulation during the adolescentperiod.55 Thus, our results suggest a structural correlateof individual differences in behavioral and emotionalself-regulation, and the development of these skillsduring adolescence.

Although hippocampal volume was hypothesized tobe associated with reactive aspects of temperamentcaptured in dimensions such as negative affectivity andsurgency, the present finding of a positive associationwith effortful control is consistent with arguments

F ig . 2 A pictorial representation of the associations obtained between regionof interest (ROI) volumes and the effortful control (A), negative affectivity (B),affiliativeness (C), and surgency (D) temperament dimensions of the EarlyAdolescent Temperament Questionnaire-Revised. Green labeling indicates apositive relation between the ROI volume and temperament; red labelingindicates a negative relation. Associations found for females but not males areindicated. Note that for surgency, the negative relation indicated for the rostral/ventral limbic anterior cingulated cortex (ACC) actually reflects a positiverelation with the fear subscale, and the positive relation indicated for the rightamygdala actually reflects a negative relation with the shyness subscale. ForACC limbic volume and ACC paralimbic volume (ACCLjACCP) variables, apositive relation indicates a larger ACCL relative to ACCP, whereas a negativerelation indicates a larger ACCP relative to ACCL.

Fig

24/c

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implicating the hippocampus in inhibitory aspects ofbehavior.56 Such views posit that hippocampal hyper-function underlies a decreased tendency for approach-related actions and cognitions, which may result inincreased anxious affect. Indeed, there is some evidenceof an association between high temperamental effortfulcontrol and anxiety; childhood effortful control has beenreliably shown as a prospective outcome of early fearful,inhibited behavior57 and also as a predictor of laterdevelopment of avoidance behaviors and anxiety.58

Thus, the present result suggests a possible tempera-ment-related neuroanatomical basis for this proposedhippocampal function.

No support was found for the predicted relationbetween effortful control and dorsal ACC structure.Rather, this brain region was associated with negativeaffectivity (discussed below). It is possible that a relationbetween effortful control and dorsal ACC structuremayemerge later in development, when executive functionsare more developed. There is evidence that effortfulcontrol and negative affectivity are inversely related36

and often co-occur in associations with behavior.58

Thus, another possibility is that previous findingssuggestive of dorsal ACC involvement in effortfulcontrol may in fact reflect the contribution of comorbidnegative affective temperament.

N ega tive A ffectivity

Decreased volume of the left dorsal ACCP relative toACCL was found to predict higher negative affectivity.To our knowledge, no previous neuroanatomical studyhas used such a fine-grained ROI approach to ACCparcellation to examine behavioral phenomena, and,thus, direct comparison with past neuroanatomicalresearch is not possible. Research has shown the absenceof the paracingulate sulcus in the left hemisphere, whichis associated with decreased size of the left ACCP relativeto ACCL, to characterize patients with disorders such asschizophrenia31 and autism,59 and it has been suggestedthat this morphometric abnormality may be associatedwith deficits in executive functioning.60,61 Our results,however, suggest that thismorphometric feature, at leastin the dorsal part of the ACC,may be specifically relatedto individual differences in the ability to effectivelyregulate negative emotions, namely, anger and frustra-tion. This is consistent with a number of functionalimaging studies in both adults and children suggestingthat the dorsal ACC has an important role in effortful

downregulation of negative affect.62,63 Thus, our resultssuggest that larger volume of the ACCP relative to ACCL

specifically in the left dorsal region may contribute toindividual differences in the ability to effectively regulatenegative emotions such as anger and frustration.

A ffilia tiveness

Volume of the right rostral/ventral ACCL was foundto predict scores on the higher order factor affiliative-ness. This finding is consistent with literature implicat-ing the ACCL in affiliative behavior, both in terms ofsocial cognition,64 as well as distress behaviors directedat maintaining affiliative relations (e.g., mother distresswhile listening to infant cries,65 distress associated withsocial exclusion66).

Affiliativeness was also associated with reduced volumeof the left rostral/ventral ACCL relative to ACCP, but thisassociation was only apparent in females. Increased leftlateralized activity in this region has been associated withthe experience of sad mood.67 Furthermore, greateractivity in this region during negative affective experiencehas been reported in females compared tomales.68Giventhat affiliative traits have been linked with depressedmood69 and that females tend to score higher both onmeasures of affiliation49 (in the present sample, femalesscored higher than males on affiliativeness) and negativeaffective experience,70 our result is consistent with thisfunctional brain imaging research. Thus, our resultssuggest a possible temperament-related structural basisfor the role of this brain region in negative affectiveprocessing, particularly in females.

Surgency

Low surgency (i.e., high fear and shyness) wasassociated with increased volume of the right rostral/ventral ACCL and reduced volume of the right amygdalain females only. The former association is consistentwith a previous finding of a positive correlation betweensize of total right ACCL surface area and Cloninger`sharm avoidance,9 which reflects behavioral avoidance,fear, and worry. Our finding regarding the rightamygdala is consistent with a previous study reportinga negative relation between gray matter density in thisstructure and neuroticism.11 This finding is alsoconsistent with other research indicating a key role forthe amygdala in regulating arousal and vigilance andresponding to signals of fear.71 The lateralization of ourfindings is consistent with theory suggesting that the

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right limbic system has a predominant role in the stressresponse via its key roles in monitoring sensory inputsfor alerting signals and mediating stimulus-triggeredreactions (including autonomic reactions to affectivestimuli).72

It is of note that distinct neuroanatomical correlateswere found for negative affectivity (frustration) and fearbecause these two aspects of temperament are oftenincluded in a single dimension describing the propensityto experience negative emotions. Although theremay bemore general neural systems contributing to differentaspects of negative emotion, there is some researchsupporting separable neural systems.17 Our findings addto this research and suggest that a distinction betweenfrustration and fearmay be neurobiologically supported.

Implica tions for Psychopa thology

A key set of findings in temperament research has beenthe establishment of prospective links with psycho-pathology.2 That is, individuals scoring at extreme endsof certain temperament dimensions have been shown toexhibit higher risk for developing certain mentaldisorders. Thus, examining the neuroanatomical basesof temperament in currently healthy individuals mayprovide some insight into the developmental character-istics of those at risk before the emergence of theseproblems and as such may help to tease out thosecharacteristics of brain structure that aremore likely to bea cause, as opposed to a consequence, of mental illness.

Our findings suggest that some of the volumetricdeficits reported in mental illnesses may partially stemfrom or relate to individual differences in tempera-mental risk factors. Prospective research investigatingthe link between these temperaments, brain structure,and development of these disorders will be an importantstep in testing this possibility.

High negative affectivity has been identified as ageneralized risk factor for adolescent maladaptive pro-blems.2 Although findings of decreased size of the leftACCP relative to ACCL in a number of disorders havebeen related to deficits in executive functioning (asdescribed above), our findings suggest that these volu-metric deficits may be partly associated with individualdifferences in the ability to regulate negative affects.

Low effortful control has been found to conferparticular risk for externalizing problems and substanceuse in adolescence.2,73 OFC dysfunction has beenreported in child and adult studies of related disorders

such as ADHD and substance abuse, and there is someevidence that reduced OFC volume may represent apreexisting vulnerability for such disorders.29,33 Ourresults are consistent with these two lines of research,suggesting that reduced OFC volume may be associatedwith a temperament-based risk factor for these afore-mentioned disorders.

We suggest that the structural correlates of tempera-ment that were found to be specific to females may haveimplications for the sex differences in the prevalence ofmood and anxiety disorders.74 Interestingly, this clusterof temperaments showing brain structural associationsspecific to females (affiliativeness, fear, and shyness)appears tomap closely onto a personality dimension thatis sometimes referred to as sociotropy, interpersonalsensitivity, or interpersonal dependency, and has beenparticularly implicated in risk for mood and anxietydisorders,69 especially in females.75

The brain regions showing female-specific associa-tions with temperament have been implicated in moodand anxiety disorders. Hyperactivity in right limbicregions including the rightACCL and amygdala has beensuggested to underlie stress-related autonomical andneuroendocrine responses associated with mood andanxiety disorders.76,77 A common finding in mooddisorder research is left lateralized volume decreases inthe rostral/ventral cingulate region78; findings that thisvolumetric abnormality persists into remission haveprompted suggestions that it may represent a trait/riskmarker for these disorders.79 Although these neuroima-ging findings are typically not restricted to females, it is ofnote thatmost of these studies contain all female patientsor a high proportion of female patients.Thus, our resultssuggest a possible neuroanatomical basis for this clusterof temperaments that may render females more sus-ceptible to mood and anxiety disorders.

Limita tions and F uture D irections

Although the large size of the sample proved adequatefor detecting significant small effects, performinganalyses for sex groups separately resulted in a loss ofpower and may have prevented some true effects fromreaching significance. Thus, further research with largersample sizes is required to corroborate these findings.

Because little research has investigated the relationbetween neuroanatomy and behavior/disorder in ado-lescents, our hypotheses and interpretation of results arelargely based on previously reported adult data.

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However, given that substantial maturational changesoccur within the brain during the adolescent period,80

and this is likely to affect both brain volume andbehavior, it is not clear whether the degree or nature ofthe brainYbehavior relation reported here will be thesame in adulthood as in adolescence. Furthermore,pubertal status, although not reliably measured in thepresent sample, likely influences brainYbehavior rela-tions in adolescents, although there has been littleresearch examining this link in humans. These issuesrepresent limitations of the present study, and theyhighlight the importance and need for further neuroa-natomical research examining behavior during theadolescent period.It is assumed that brain volume does have functional

relevance, but the interpretation of a volumetric findingis never straightforward81 and ideally would requireexamination of the underlying cellular properties of thebrain tissue. Future research using functional imagingtechniques would be useful to complement the presentfindings and aid interpretation of results.It is possible that the functioning of other parts of the

brain than those examined here contribute to tempera-mental variance. For example, the dorsolateral prefrontalcortex is a likely contributor to individual differences ineffortful control due to its role in executive functioningand its strong connections with the ACCP.

82 Themarked anatomical variability of the prefrontal cortex,however, has made it difficult to establish protocols toparcellate the prefrontal cortex into reliable andfunctionally meaningful subregions. The developmentof such protocols would provide a means for testingstructureYfunction relations in this area.

S u m m ary a n d C o n c lu s io n s

Anatomically defined regional brain volumes werefound to account for approximately 3% to 13% of thevariance in temperament scores, suggesting that indivi-dual differences in brain structure are associated withnormal and relatively stable behavioral tendencies.Significant sex effects pointed toward a greater con-tribution of some brain regions to affiliative and fearfultemperaments in females. These results are an importantstep toward a better understanding of sex differences inrisk for certain psychopathologies.

Disclosure: The authors report no conflicts of interest.

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