Neuroanatomical Correlates of Temperament in Early Adolescents

Neuroanatomical Correlates of Temperament in Early Adolescents ¨ CEL, PH.D., M.A.P.S., ALEX FORNITO, PH.D., SARAH WHITTLE, PH.D., MURAT YU ANNA BARRETT, B.A.(HONS.), STEPHEN J. WOOD, PH.D., DAN I. LUBMAN, PH.D., JULIAN SIMMONS, B.SC.(POST GRAD. DIP.), CHRISTOS PANTELIS, M.D., AND NICHOLAS B. ALLEN, PH.D.

ABSTRACT Objective: Temperament refers to enduring behavioral characteristics that underpin individual differences in human behavior, including risk for psychopathology. Research attempting to investigate the neurobiological basis of temperament represents an important step toward elucidating the biological mechanisms underlying these individual differences. In the present study, we examined the relation between four core temperament dimensions and anatomically defined regions of the limbic and prefrontal cortices. Method: We used a cross-sectional design to examine a large sample (N = 153; mean age 12.6 years, SD 0.4, range 11.4Y13.7) of healthy early adolescents who were selected from a larger sample to maximize variation in temperament. The main outcome measures were psychometric measures of temperament (four factors: effortful control, negative affectivity, surgency, and affiliativeness) based on the Early Adolescent Temperament Questionnaire-Revised, and volumetric measures of a priori brain regions of interest (anterior cingulate cortex [ACC], orbitofrontal cortex, amygdala, and hippocampus). Results: We found regional brain volumes to account for small but significant amounts of the variance in self-reported temperament scores. Specifically, higher effortful control was associated with larger volume of the left orbitofrontal cortex and hippocampus. Higher negative affectivity was associated with smaller volume of the left dorsal paralimbic relative to limbic portion of the ACC. Higher affiliativeness was associated with larger volume of the right rostral/ventral limbic portion of the ACC. Affiliativeness and surgency also showed a number of female-specific associations, primarily involving the rostral/ventral ACC. Conclusions: Our results provide support for a neuroanatomical basis for individual differences in temperament and have implications for understanding the neurobiological mechanisms underlying the development of a number of psychiatric disorders. J. Am. Acad. Child Adolesc. Psychiatry, 2008;47(6):682Y693. Key Words: brain volume, personality, magnetic resonance imaging, anterior cingulate cortex, risk factor.

Temperament refers to endogenous basic tendencies of thoughts, emotions, and behaviors. Core temperament dimensions are observable in infancy, remain relatively stable across the life span,1 and have been shown to confer risk for behavioral and mental health

problems, particularly during adolescence,2 when the onset of such problems is particularly pronounced.3 Many of the neuroanatomical changes associated with adolescent and adult mental illnesses are assumed to exist before illness onset and hence likely to be

Accepted January 22, 2008. Drs. Whittle, Yu¨cel, Lubman, and Allen and Mr. Simmons are with ORYGEN Research Centre, Department of Psychiatry, University of Melbourne; Drs. Fornito, Wood, and Pantelis are with the Melbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne; and Ms. Barrett is with the Department of Psychology, University of Melbourne. This research was supported by ORYGEN Research Centre and grants from the National Health and Medical Research Council (NHMRC) of Australia (I.D. 350241) and the Colonial Foundation. Dr. Whittle was supported by an Australian Postgraduate Award. Dr. Yu¨cel is supported by an NHMRC Clinical Career Development Award (I.D. 509345). Dr. Fornito is supported by an

NHMRC CJ Martin Fellowship. Dr. Wood is supported by an NHMRC Clinical Career Development Award and a NARSAD Young Investigator Award. Neuroimaging analysis was facilitated by the Neuropsychiatry Imaging Laboratory, MNC, managed by Bridget Soulsby. The authors thank the Brain Research Institute for support in acquiring the neuroimaging data. Correspondence to Dr. Nicholas B. Allen, ORYGEN Research Centre, Locked Bag 10, Parkville, Victoria 3052, Australia; e-mail: [email protected]. 0890-8567/08/4706-0682Ó2008 by the American Academy of Child and Adolescent Psychiatry. DOI: 10.1097/CHI.0b013e31816bffca

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NEUROANATOMY OF ADOLESCENT TEMPERAMENT

associated with putative risk factors4; however, little work has been conducted to directly test this hypothesis. Thus, investigating the underlying neuroanatomy of core temperament dimensions in early adolescence represents an important step toward better understanding the neural mechanisms influencing many aspects of normal and abnormal adolescent and adult behavior. RECENT AND RELEVANT LITERATURE REVIEW

Although there have been a number of neurochemical, neurophysiological, and functional brain imaging studies of temperament and personality (see Cloninger5 for a review), structural brain imaging research with healthy control populations has been limited. A handful of studies have been conducted to examine the neuroanatomical correlates of adult temperament in the context of Cloninger`s6 biological model,7Y9 and of personality in the context of the five-factor model.10Y13 These studies do provide grounds to suggest a neuroanatomical basis for individual differences in temperament; however, findings are difficult to integrate as methodologies have varied widely with respect to the type of structural measure used (i.e., region of interest [ROI] versus voxel-based morphometry [VBM]), the location and extent of brain regions investigated, and the particular traits measured. Furthermore, although these studies indicate that there is indeed a relation between variations in brain structure and core temperament and personality dimensions in adults, it is as yet unclear whether such associations are also observable earlier in development. This is particularly important given the majority of temperament research in other domains has focused on the developmental period of childhood and adolescence, based on the assumption that temperament is more easily observable during this life phase, and is less confounded by experiential-based characteristics.14 The model of temperament developed by Rothbart and colleagues15,16 may be particularly useful to examine because it is based on neurobiological theory17 and has a developmental orientation with a focus on childhood and adolescent temperament. Four core temperament dimensions comprise the model. Surgency refers to a tendency to seek out and enjoy intense experiences, together with a lack of shyness and fear, negative affectivity refers to expressed and felt frustration/anger in response to limitations. These two dimensions primarily capture individual differences in reflexive responding (i.e.,

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reactivity) to affective stimuli and are thought to have roots in limbic circuits (particularly the amygdala and hippocampus) that have evolved to serve appetitive and defensive needs. Other research has implicated the medial prefrontal cortex, particularly the portion of the anterior cingulate cortex (ACC) extending rostrally and ventrally around the corpus callosum in such reflexive affective responding.18 These regions have been particularly implicated in mood and anxiety disorders, and it has been suggested that structural abnormalities observed in these disorders may be trait based or represent predisposing risk factors.19,20 Affiliativeness refers to the desire for closeness with others and the tendency to notice and experience pleasure from low-intensity stimuli. This dimension is thought to have roots in neural systems underlying socially directed motivated behavior and separation distress panic. Recent research points toward the limbic portion of the ACC as a key component of these systems21,22; however, whether rostral/ventral or more dorsal portions of the limbic ACC are of greater importance is uncertain. It is speculated that these systems may be separable from those underlying more basic reward- and punishment-related approach and avoidance behavior.23 Effortful control refers to the ability to direct attention and regulate emotion and behavior. It is thought to have developmental roots in a neural system subserving executive attention, the pivotal circuitry of which is focused on the anterior cingulate region, particularly that portion that lies dorsal to the corpus callosum.24 Paralimbic and orbitofrontal cortex (OFC) regions are also suggested as important for the regulatory aspects of emotion and behavior.25,26 Structural changes in these regions have been reported in child, adolescent, and adult disorders involving deficits in attention (such as attention-deficit/ hyperactivity disorder [ADHD]27Y30) and other executive functioning and behavioral regulation (such as schizophrenia,31 autism,32 and substance abuse33). PURPOSE OF STUDY AND A PRIORI HYPOTHESES

This study sought to examine the relation between these core temperament dimensions and brain structure in a large sample of healthy early adolescents. Four key brain areas were targeted based on the literature described above (see Whittle et al.4 for a fuller review). We predicted that core temperament dimensions would

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WHITTLE ET AL.

be distinguishable in terms of their associations with volumes of predefined brain structures including the amygdala, hippocampus, OFC, and dorsal, rostral, and ventral portions of the limbic and paralimbic ACC. Establishing such relations will make an important contribution to our understanding of the neuroanatomical features that may be associated with risk for developing a number of psychiatric disorders in adolescence. METHOD Participants The sample consisted of 72 females and 81 males (mean age 12.6 years, SD 0.4; range 11.4Y13.7). There were 139 right-handed and 14 left-handed subjects (as established using the Edinburgh Handedness Inventory).34 Participants were screened for present and past case level Axis I disorders by trained research assistants using the Schedule for Affective Disorder and Schizophrenia for SchoolAge Children-Epidemiologic Version (K-SADS-E).35 Overall, 15 participants met criteria for a psychiatric diagnosis (past depressive disorder, n = 1; past separation anxiety disorder, n = 1; social phobia, n = 1; ADHD, n = 1; obsessive compulsive disorder, n = 2; past and current psychotic disorder with hallucinations, n = 2; current oppositional defiant disorder, n = 1; past oppositional defiant disorder, n = 6). Informed consent was obtained for all participants (and their parent or guardian) before their inclusion in the study, in accordance with local ethics committee guidelines. Measures Participants completed the Early Adolescent Temperament Questionnaire-Revised (EATQ-R).36 The questionnaire was completed at two time points (in-school screening and diagnostic assessment 6 months to 1 year postscreening). Confirmatory factor analysis, performed on item data from the large-school screening sample, provided good fit for a factor structure reflecting 10 temperament subscales, largely consistent with the a priori scales described by Ellis and Rothbart.37 Items were also used to derive four higher order factors: negative affectivity (comprising solely of items from the Frustration subscale), effortful control (comprising items from Activation Control, Attention, and Inhibitory Control subscales), surgency (comprising fear [reversed-scored], shyness [reversed-scored], and surgency items), and affiliativeness (comprising affiliation, pleasure sensitivity, and perceptual sensitivity items). Subsequent analyses of EATQ-R data obtained from the diagnostic assessment were based on the factor solutions derived from the school screening sample data. The four factors showed good internal consistencies for both school screening and diagnostic assessment administrations, with Cronbach " values being .82 and .78, respectively, for negative affectivity, .82 and .83, respectively, for effortful control, .82 and .81, respectively, for surgency, and .77 and .76, respectively, for affiliativeness. Correlations between the two self-report measurements were moderately high for all of the temperament scales, ranging from 0.42 to 0.66, consistent with the conceptualization of temperament as a relatively stable trait. To increase reliability, the mean of the two measurements was used for all of the analyses.

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Parents also completed the parent-report version of the EATQ-R during the diagnostic assessment, which comprises all but two subscales (Pleasure and Perceptual Sensitivity) of the adolescentreport EATQ-R. Parent and adolescent convergence was found to be moderate on all of the scales, ranging from 0.33 to 0.56, providing support for the validity of the adolescent`s self-report. Selection Procedure Participant screening was conducted in a large sample of 2,479 sixth grade students from 97 schools in metropolitan Melbourne, Australia. Selection was based on temperament and aimed at maximizing the range of risk and resiliency for later onset of psychopathology in recruited participants. To this end, we aimed to ascertain a sample of adolescents who were representative of the range of scores across each higher order temperament dimension measured by the EATQ-R. Equal numbers of adolescents were recruited across the following ranges of scores on each of the four higher order factors of the EATQ-R: 0 to 1 SDs above and below the mean, 1 to 2 SDs above and below the mean, 2 to 2.5 SDs above and below the mean, and >2.5 SDs above and below the mean. This resulted in selection of 425 (16%) adolescents showing even variation across each of the higher order traits of interest, with some emphasis in the distribution at the tails. Of the selected adolescents, 245 agreed to participate in one or more intensive phases of research, and of these, 153 agreed to undergo magnetic resonance imaging. No differences between participants who agreed to undergo magnetic resonance imaging and those who were selected but declined were observed on temperament (negative affectivity (t[412] = 0.58, p = .56; effortful control (t[412] = 0.32, p = .75; surgency (t[412] = 0.56, p = .58; affiliativeness (t[412] = j0.71, p = .48), or sex (21 = 0.54, p = .46). Image Acquisition Magnetic resonance imaging scans were performed on a 3-T scanner at the Brain Research Institute, Austin and Repatriation

Fig. 1 Example of region-of-interest boundaries as a function of sulcal variability in the anterior cingulated cortex (ACC) region. The vertical black line represents the posterior border of the dorsal ACC region. The vertical red line represents the border between the dorsal and rostral and the rostral and ventral ACC subregions. Limbic cortex is highlighted in green, and paralimbic cortex is highlighted in blue.

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TABLE 1 Exploratory Factor Analysis of Anterior Cingulate Cortex ROI Volumes: Promax Rotated Loadings ROI Left r-ACCL Left r-ACCP Left v-ACCL Left v-ACCP Left d-ACCL Left d-ACCP Right r-ACCL Right r-ACCP Right v-ACCL Right v-ACCP Right d-ACCL Right d-ACCP

1 j0.771 0.733 j0.750 0.683 0.019 0.234 j0.016 0.052 j0.052 j0.061 0.166 0.143

2

3

4

5

j0.018 0.118 0.117 0.183 0.007 0.213 0.093 j0.099 j0.083 0.344 0.420 j0.030 j0.090 0.031 0.482 0.242 0.066 0.075 j0.007 0.886 0.017 0.230 0.124 j0.727 0.336 j0.349 0.475 j0.178 j0.274 0.660 j0.181 j0.096 j0.032 j0.185 0.933 j0.068 0.233 0.974 j0.128 j0.017 0.932 0.273 0.083 0.098 j0.854 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. Medical Centre, Melbourne, Australia, using a gradient echo volumetric 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 contiguous 1.5-mm thick slices (voxel dimensions = 0.4883  0.4883  1.5 mm).

Morphometric Analysis ROIs were defined and quantified based on previous techniques developed and published by the Melbourne Neuropsychiatry Centre (see below). All of the ROIs were traced using the software package ANALYZE (Mayo Clinic, Rochester, MN; http://www.mayo.edu/ bir). Brain tissue was segmented into gray matter, white matter, and CSF using an automated algorithm, as implemented in FAST (FMRIB’s automated segmentation tool).40 An estimate of whole brain volume was obtained by summing gray and white matter pixel counts (i.e., whole brain volume included cerebral gray and white matter, the cerebellum, and brainstem, but not the ventricles, cisterns, or CSF). ACC and OFC estimates were based on gray matter pixel counts contained within the defined ROIs. Amygdala and hippocampal estimates were based on total voxels within the defined ROIs. Amygdala and Hippocampus The guidelines for tracing the amygdala and hippocampus were adapted from those described by Velakoulis and colleagues.41,42 Differences in method, which were adopted in efforts to maximize reliability for the current dataset, relate to marking the anterior boundary of the amygdala and the boundary between the amygdala and hippocampus. The anterior boundary of the 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 endorhinal sulcus. The Watson et al.43 protocol was used to separate the amygdala from the hippocampus.

Image Preprocessing

ACC

Images were transferred to an SGI/Linux workstation for morphometric analysis. Image preprocessing was carried out using tools from the Functional Magnetic Resonance Imaging of the Brain (FMRIB) software library (http://www.frmib.ox.ac.uk/fsl ). Each 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 axially along the anterior commissure-posterior commissure plane and sagittally along the interhemispheric fissure without any deformation.

The boundaries of the ACC have been described in detail by Fornito et al.44 This protocol defines separate limbic (ACCL) and paralimbic (ACCP) regions by taking into account individual differences in morphology of the cingulate, paracingulate, and superior rostral sulci. The protocol further divides the ACC into dorsal, rostral, and ventral regions based on evidence of functional heterogeneity.45 The method results in six ACC subregions: dorsal ACCL (d-ACCL), dorsal ACCP (d-ACCP), rostral ACCL (r-ACCL), rostral ACCP (r-ACCP), ventral ACCL (v-ACCL), and ventral ACCP (v-ACCP). See Figure 1 for an example parcellation.

TABLE 2 ROI Volume Predictors of Early Adolescent Temperament Questionnaire-Revised Temperament Factors Used in Initial Hypothesis-Driven and Secondary Exploratory Regression Analyses Temperament Negative affectivity Effortful control Surgency Affiliativeness

Hypothesized Predictors Amygdala, hippocampus, right r/v(ACCL), right r/v(ACCP), left r/v(ACCLjACCP) d(ACCL j ACCP), OFC Amygdala, hippocampus, right r/v(ACCL), right r/v(ACCP), left r/v(ACCLjACCP) Right r/v(ACCL), right r/v(ACCP), left r/v(ACCLjACCP),d(ACCLjACCP)

Exploratory Predictors d(ACCLjACCP), OFC Amygdala, hippocampus, right r/v(ACCL), right r/v(ACCP), left r/v(ACCLjACCP) d(ACCLjACCP), OFC Amygdala, hippocampus, OFC

Note: Regions are bilateral unless otherwise indicated; positive values for d(ACCLjACCP) and r/v(ACCLjACCP) variables indicate larger ACCL 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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TABLE 3 Summary of Hierarchical Linear Regression Analysis Predicting Early Adolescent Temperament Questionnaire-Revised Effortful Control With ROI Volumes Step 1 Step 2 Variable

B

SE B

$

B

$

SE B

Hypothesis driven Sex 3.61 1.43 0.20* 4.42 1.45 Left OFC 0.00 0.00 $R 2 0.041 0.027 $F 6.38* 4.24* Exploratory Sex 3.44 1.45 0.19* 4.14 1.45 Left hippocampus 0.01 0.00 $R 2 0.037 0.042 $F 5.60* 6.51*

0.25** 0.17*

0.23** 0.21*

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

RESULTS

The boundaries of the OFC were based on a previously published method.46 A line through the AC-PC was used to define the superior boundary of the OFC. The posterior boundary was marked by a coronal plane passing through the most posterior aspect of the olfactory sulcus in each hemisphere. All of the images were manually edited to eliminate subcortical tissue and artifacts related to the eye sockets and nasal bones. Statistical Analysis Intra- and interrater reliabilities were calculated for each raw ROI volume. Intraclass correlation coefficients (most >0.9 and none <0.8) were deemed acceptable for all of the ROIs. All of the ROI volumes were corrected for whole brain volume using a covariance approach.47 Preliminary inter-ROI volume bivariate Pearson`s correlations revealed that there were a number of significant within-hemisphere correlations between ACC ROI volumes. Factor analysis with promax rotation (an oblique rotation was used because regional brain structures are likely related to varying degrees)48 was performed on all of the ACC ROI volumes. This analysis yielded five factors with an eigenvalue cutoff of 1, and which explained approximately 75% of the structure variance (Table 1). The five factors were found to be theoretically interpretable, and thus the ACC subregion ROI volumes were subsequently combined (added) as indicated by primary factor loadings. Specifically, the factor analysis showed a clear distinction between dorsal regions and rostral/ventral regions (within hemispheres), which is consistent with research indicating a primary functional distinction between these two regions (cognitive and affective, respectively).45 ACCL and ACCP subregions tended to load inversely within factors, which is consistent with previous work showing an inverse relation between the size of these adjacent structures,25,44 and is likely due to the influence of local sulcal morphology. The right rostral/ventral region did not follow this pattern, but rather the ACCL and ACCP regions comprised two separate factors, suggesting that these regions may be functionally distinct. The combined ROI volumes were used in subsequent analyses to reduce both type I error and issues associated with multicollinearity.

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Hierarchical linear regressions were carried out to investigate the variance in temperament explained by regional brain volumes. For each EATQ-R temperament factor, sex was entered as a predictor in a first block, followed by stepwise entry of hypothesized ROI volumes in a second block (Table 2). Because of noted sex differences in both temperament49 and brain structure,50 sex differences were tested 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 the remaining ROI predictors (i.e., those with weaker theoretical links to temperament; Table 2). The procedure for these analyses was identical to that described for the hypothesized ROI volumes. The use of stepwise entry reflected our desire to explore the differential importance of brain regions to temperament and also to uncover novel findings that may guide future research. Note that the entry of age in the initial step of regression models did not result in any significant effects of age on temperament, nor did it affect the significance of any other neuroanatomical predictors. Because of the low age range in the sample and the lack of a priori hypotheses concerning age, the presented results stem from analyses that exclude this variable as a predictor.

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Effortful Control

Effortful control was significantly predicted by sex (females > males) and larger volume of the left OFC (Table 3). Exploratory analyses revealed that effortful control was also significantly predicted by larger volume of the left hippocampus. Negative Affectivity

Exploratory analysis revealed that negative affectivity was significantly predicted by smaller volume of the left d(ACCP) relative to the left d(ACCL) (Table 4). Affiliativeness was significantly predicted by sex (females > males), larger volume of the right TABLE 4 Summary of Hierarchical Linear Regression Analysis Predicting Early Adolescent Temperament Questionnaire-Revised Negative Affectivity With Exploratory ROI Volumes Step 1 Step 2 Variable (Hypothesis Driven) B SE B $ B SE B $ Sex Left d(ACCLjACCP) $R 2 $F

j1.57 0.90

0.020 3.07

j0.14 j0.17 0.89 j0.15 0.00 0.00 0.18* 0.031 4.94*

Note: d(ACCLjACCP) = dorsal limbic relative to paralimbic ACC volume. ROI = region of interest; ACC = anterior cingulate cortex. *p < .05; **p < .01.

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TABLE 5 Summary of Hierarchical Linear Regression Analysis Predicting Early Adolescent Temperament Questionnaire-Revised Affiliativeness With ROI Volumes Step 1

Step 2

Step 3

Variable (Hypothesis Driven)

B

SE B

$

B

SE B

$

B

SE B

$

Sex Right r/v(ACCL) Left r/v(ACCLjACCP)  sex $R 2 $F

2.36

1.22

0.16

2.62 0.00

1.20 0.00

0.18* 0.20*

2.91 0.00 0.00

1.19 0.00 0.00

0.20* 0.18* j0.18* 0.031 4.88*

0.025 3.76

0.039 5.97*

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.

not significant for males (F2,80 = 1.03, p = .364, R 2 = 0.03), it trended toward significance for females (F2,71 = 3.01, p = .056, R 2 = 0.08). Because the surgency dimension is conceptually bipolar in nature, with surgency (the tendency to seek out and enjoy intense experiences) at one pole and shyness and fear at the opposite pole, analyses (with right r/v(ACCL) and right amygdala as predictors) were performed separately for 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 significant relations for females only. That is, females high in fear had larger volumes of the right r/v(ACCL) ($ = .25, p = .037), and females high in shyness had smaller volumes of the right amygdala ($ = j.25, p = .036).

r/v(ACCL), and an interaction between sex and left r/ v(ACCL-ACCP; Table 5). Follow-up regressions, with right r/v(ACCL) and left r/v(ACCL-ACCP) as predictors were performed for males and females separately. The regression was significant for females (F2,71 = 3.46, p < .05, R 2 = 0.09) but not males (F2,78 = 2.07, p = not significant, R 2 = 0.05). Analyses showed that smaller volumes of the left r/v(ACCL) relative to the left r/ v(ACCP) significantly predict higher affiliativeness scores for females ($ = j.27, p = .022), but not for males ($ = .19, p = .868). Surgency

Surgency was significantly predicted by interactions between sex and the right r/v(ACCL) and sex and the right amygdala (Table 6). Follow-up regressions, with right r/v(ACCL) and right amygdala forced as predictors, were performed for males and females separately. Neither right r-ACCL volume nor right amygdala volume significantly 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 was

DISCUSSION

In the present study, analyses revealed that anatomically defined regional brain volumes account for small

TABLE 6 Summary of Hierarchical Linear Regression Analysis Predicting Early Adolescent Temperament Questionnaire-Revised Surgency With ROI Volumes Step 1 Step 2 Step 3 Variable (Hypothesis Driven) Sex Right r/v(ACCL)  sex Right amygdala  sex $R 2 $F

B

SE B

$

B

SE B

$

B

SE B

$

j1.52

1.55

j0.08

j1.78 0.00

1.53 0.00

j0.10 j0.19*

j1.32 j0.00 0.01

1.53 0.00 0.01 0.028 4.24*

j0.07 j0.18* 0.17*

0.007 0.96

0.036 5.43*

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

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WHITTLE ET AL.

but significant proportions of variance in core temperament dimensions. Variance estimates ranged from approximately 3% to 13%; values similar in magnitude to most estimates of neuroanatomical contributions to measures of intelligence and other cognitive abilities.51 In summary, higher temperamental effortful control was associated with larger volume of the OFC and hippocampus in the left hemisphere, whereas higher negative affectivity was associated with smaller volume of the left dorsal ACCP relative to ACCL, and higher affiliativeness was associated with larger volume of the right rostral/ventral ACCL. Sex differences emerged in the neuroanatomical predictors of affiliativeness and surgency, with a number of associations being more pronounced for females. Figure 2 provides a pictorial representation of the results. It can be seen that associations were found for all temperament dimensions, and although there was some degree of specificity, there was also some overlap in the specific regions associated with temperament factors. This is consistent with the argument that human temperament is complex and interactive, which is likely reflected in underlying neurobiology.37 Although we did not obtain behavioral measures per se, the particular regions associated with specific temperament dimensions are largely consistent with previous brain imaging investigations of the processes and behaviors that are captured in the descriptions of these temperaments, as discussed below. Hence, our findings offer support for the notion that measures of brain volume in limbic and prefrontal cortices have behavioral significance.

Effortful Control

The positive relation between effortful control and volume of the left OFC is consistent with both functional imaging and lesion studies showing this region to be crucial for attentional processes and the inhibition of behavior in both cognitive and affective domains.52Y54 Furthermore, studies showing greater OFC activity in adults compared to children/adolescents during tasks that tap into these functions suggest that OFC may be particularly important for the development of behavioral regulation during the adolescent period.55 Thus, our results suggest a structural correlate of individual differences in behavioral and emotional self-regulation, and the development of these skills during adolescence.

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Fig. 2 A pictorial representation of the associations obtained between region of interest (ROI) volumes and the effortful control (A), negative affectivity (B), affiliativeness (C), and surgency (D) temperament dimensions of the Early Adolescent Temperament Questionnaire-Revised. Green labeling indicates a positive relation between the ROI volume and temperament; red labeling indicates a negative relation. Associations found for females but not males are indicated. Note that for surgency, the negative relation indicated for the rostral/ ventral limbic anterior cingulated cortex (ACC) actually reflects a positive relation with the fear subscale, and the positive relation indicated for the right amygdala actually reflects a negative relation with the shyness subscale. For ACC limbic volume and ACC paralimbic volume (ACCLjACCP) variables, a positive relation indicates a larger ACCL relative to ACCP, whereas a negative relation indicates a larger ACCP relative to ACCL.

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NEUROANATOMY OF ADOLESCENT TEMPERAMENT

Although hippocampal volume was hypothesized to be associated with reactive aspects of temperament captured in dimensions such as negative affectivity and surgency, the present finding of a positive association with effortful control is consistent with arguments implicating the hippocampus in inhibitory aspects of behavior.56 Such views posit that hippocampal hyperfunction underlies a decreased tendency for approachrelated actions and cognitions, which may result in increased anxious affect. Indeed, there is some evidence of an association between high temperamental effortful control and anxiety; childhood effortful control has been reliably shown as a prospective outcome of early fearful, inhibited behavior57 and also as a predictor of later development of avoidance behaviors and anxiety.58 Thus, the present result suggests a possible temperament-related neuroanatomical basis for this proposed hippocampal function. No support was found for the predicted relation between effortful control and dorsal ACC structure. Rather, this brain region was associated with negative affectivity (discussed below). It is possible that a relation between effortful control and dorsal ACC structure may emerge later in development, when executive functions are more developed. There is evidence that effortful control and negative affectivity are inversely related36 and often co-occur in associations with behavior.58 Thus, another possibility is that previous findings suggestive of dorsal ACC involvement in effortful control may in fact reflect the contribution of comorbid negative affective temperament. Negative Affectivity

Decreased volume of the left dorsal ACCP relative to ACCL was found to predict higher negative affectivity. To our knowledge, no previous neuroanatomical study has used such a fine-grained ROI approach to ACC parcellation to examine behavioral phenomena, and, thus, direct comparison with past neuroanatomical research is not possible. Research has shown the absence of the paracingulate sulcus in the left hemisphere, which is associated with decreased size of the left ACCP relative to ACCL, to characterize patients with disorders such as schizophrenia31 and autism,59 and it has been suggested that this morphometric abnormality may be associated with deficits in executive functioning.60,61 Our results, however, suggest that this morphometric feature, at least in the dorsal part of the ACC, may be specifically related

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to individual differences in the ability to effectively regulate negative emotions, namely, anger and frustration. This is consistent with a number of functional imaging studies in both adults and children suggesting that the dorsal ACC has an important role in effortful downregulation of negative affect.62,63 Thus, our results suggest that larger volume of the ACCP relative to ACCL specifically in the left dorsal region may contribute to individual differences in the ability to effectively regulate negative emotions such as anger and frustration. Affiliativeness

Volume of the right rostral/ventral ACCL was found to predict scores on the higher order factor affiliativeness. This finding is consistent with literature implicating the ACCL in affiliative behavior, both in terms of social cognition,64 as well as distress behaviors directed at maintaining affiliative relations (e.g., mother distress while listening to infant cries,65 distress associated with social exclusion66). Affiliativeness was also associated with reduced volume of the left rostral/ventral ACCL relative to ACCP, but this association was only apparent in females. Increased left lateralized activity in this region has been associated with the experience of sad mood.67 Furthermore, greater activity in this region during negative affective experience has been reported in females compared to males.68 Given that affiliative traits have been linked with depressed mood69 and that females tend to score higher both on measures of affiliation49 (in the present sample, females scored higher than males on affiliativeness) and negative affective experience,70 our result is consistent with this functional brain imaging research. Thus, our results suggest a possible temperament-related structural basis for the role of this brain region in negative affective processing, particularly in females. Surgency

Low surgency (i.e., high fear and shyness) was associated with increased volume of the right rostral/ ventral ACCL and reduced volume of the right amygdala in females only. The former association is consistent with a previous finding of a positive correlation between size of total right ACCL surface area and Cloninger`s harm avoidance,9 which reflects behavioral avoidance, fear, and worry. Our finding regarding the right amygdala is consistent with a previous study reporting a negative relation between gray matter density in this

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WHITTLE ET AL.

structure and neuroticism.11 This finding is also consistent with other research indicating a key role for the amygdala in regulating arousal and vigilance and responding to signals of fear.71 The lateralization of our findings is consistent with theory suggesting that the right limbic system has a predominant role in the stress response via its key roles in monitoring sensory inputs for alerting signals and mediating stimulus-triggered reactions (including autonomic reactions to affective stimuli).72 It is of note that distinct neuroanatomical correlates were found for negative affectivity (frustration) and fear because these two aspects of temperament are often included in a single dimension describing the propensity to experience negative emotions. Although there may be more general neural systems contributing to different aspects of negative emotion, there is some research supporting separable neural systems.17 Our findings add to this research and suggest that a distinction between frustration and fear may be neurobiologically supported.

Implications for Psychopathology

A key set of findings in temperament research has been the establishment of prospective links with psychopathology.2 That is, individuals scoring at extreme ends of certain temperament dimensions have been shown to exhibit higher risk for developing certain mental disorders. Thus, examining the neuroanatomical bases of temperament in currently healthy individuals may provide some insight into the developmental characteristics of those at risk before the emergence of these problems and as such may help to tease out those characteristics of brain structure that are more likely to be a cause, as opposed to a consequence, of mental illness. Our findings suggest that some of the volumetric deficits reported in mental illnesses may partially stem from or relate to individual differences in temperamental risk factors. Prospective research investigating the link between these temperaments, brain structure, and development of these disorders will be an important step in testing this possibility. High negative affectivity has been identified as a generalized risk factor for adolescent maladaptive problems.2 Although findings of decreased size of the left ACCP relative to ACCL in a number of disorders have been related to deficits in executive functioning (as described above), our findings suggest that these volu-

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metric deficits may be partly associated with individual differences in the ability to regulate negative affects. Low effortful control has been found to confer particular risk for externalizing problems and substance use in adolescence.2,73 OFC dysfunction has been reported in child and adult studies of related disorders such as ADHD and substance abuse, and there is some evidence that reduced OFC volume may represent a preexisting vulnerability for such disorders.29,33 Our results are consistent with these two lines of research, suggesting that reduced OFC volume may be associated with a temperament-based risk factor for these aforementioned disorders. We suggest that the structural correlates of temperament that were found to be specific to females may have implications for the sex differences in the prevalence of mood and anxiety disorders.74 Interestingly, this cluster of temperaments showing brain structural associations specific to females (affiliativeness, fear, and shyness) appears to map closely onto a personality dimension that is sometimes referred to as sociotropy, interpersonal sensitivity, or interpersonal dependency, and has been particularly implicated in risk for mood and anxiety disorders,69 especially in females.75 The brain regions showing female-specific associations with temperament have been implicated in mood and anxiety disorders. Hyperactivity in right limbic regions including the right ACCL and amygdala has been suggested to underlie stress-related autonomical and neuroendocrine responses associated with mood and anxiety disorders.76,77 A common finding in mood disorder research is left lateralized volume decreases in the rostral/ventral cingulate region78; findings that this volumetric abnormality persists into remission have prompted suggestions that it may represent a trait/risk marker for these disorders.79 Although these neuroimaging findings are typically not restricted to females, it is of note that most of these studies contain all female patients or a high proportion of female patients. Thus, our results suggest a possible neuroanatomical basis for this cluster of temperaments that may render females more susceptible to mood and anxiety disorders. Limitations and Future Directions

Although the large size of the sample proved adequate for detecting significant small effects, performing analyses for sex groups separately resulted in a loss of power and may have prevented some true effects from

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NEUROANATOMY OF ADOLESCENT TEMPERAMENT

reaching significance. Thus, further research with larger sample sizes is required to corroborate these findings. Because little research has investigated the relation between neuroanatomy and behavior/disorder in adolescents, our hypotheses and interpretation of results are largely based on previously reported adult data. However, given that substantial maturational changes occur within the brain during the adolescent period,80 and this is likely to affect both brain volume and behavior, it is not clear whether the degree or nature of the brainYbehavior relation reported here will be the same in adulthood as in adolescence. Furthermore, pubertal status, although not reliably measured in the present sample, likely influences brainYbehavior relations in adolescents, although there has been little research examining this link in humans. These issues represent limitations of the present study, and they highlight the importance and need for further neuroanatomical research examining behavior during the adolescent period. It is assumed that brain volume does have functional relevance, but the interpretation of a volumetric finding is never straightforward81 and ideally would require examination of the underlying cellular properties of the brain tissue. Future research using functional imaging techniques would be useful to complement the present findings and aid interpretation of results. It is possible that the functioning of other parts of the brain than those examined here contribute to temperamental variance. For example, the dorsolateral prefrontal cortex is a likely contributor to individual differences in effortful control due to its role in executive functioning and its strong connections with the ACCP.82 The marked anatomical variability of the prefrontal cortex, however, has made it difficult to establish protocols to parcellate the prefrontal cortex into reliable and functionally meaningful subregions. The development of such protocols would provide a means for testing structureYfunction relations in this area. Summary and Conclusions

Anatomically defined regional brain volumes were found to account for approximately 3% to 13% of the variance in temperament scores, suggesting that individual differences in brain structure are associated with normal and relatively stable behavioral tendencies. Significant sex effects pointed toward a greater contribution of some brain regions to affiliative and fearful

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