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Reduced prefrontal and orbitofrontal gray matter in female adolescents with borderline personality disorder: Is it disorder specific?
NeuroImage 49 (2010) 114–120
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NeuroImage j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / y n i m g
Reduced prefrontal and orbitofrontal gray matter in female adolescents with borderline personality disorder: Is it disorder specific? Romuald Brunner a,⁎,1, Romy Henze a,b,1, Peter Parzer a,1, Jasmin Kramer a, Nina Feigl a, Kira Lutz a, Marco Essig b, Franz Resch a, Bram Stieltjes b a b
Department of Child and Adolescent Psychiatry, Center for Psychosocial Medicine University of Heidelberg, 69115 Heidelberg, Blumenstrasse 8, Germany Department of Radiology, German Cancer Research Center, Heidelberg, Germany
a r t i c l e
i n f o
Article history: Received 22 January 2009 Revised 23 July 2009 Accepted 29 July 2009 Available online 4 August 2009
a b s t r a c t There is evidence that adults with borderline personality disorder (BPD) are characterized by abnormalities in frontolimbic brain areas. In this study we aimed to determine whether brain volume alterations already exist in adolescents with BPD. Sixty female right-handed individuals (age range, 14–18 years), 20 with a DSM-IV diagnosis of borderline personality disorder, 20 patients with a DSM-IV defined current psychiatric disorder and 20 healthy control subjects were included. Groups were matched for age and IQ. Using a 3 T MRI scanner, we collected 1 mm axial sections using a three-dimensional sagittal isotropic Magnetization Prepared Rapid Acquisition Gradient Echo (MPRAGE) sequence. Images were analyzed using voxel-based morphometry (VBM). Voxel-based analysis revealed that adolescents with BPD showed reduced gray matter in the dorsolateral cortex (DLPFC) bilaterally and in the left orbitofrontal cortex (OFC) relative to healthy control subjects. Adolescent clinical control subjects displayed significantly decreased gray matter volume in the right DLPFC in comparison with healthy control subjects. No significant gray matter differences were detected between the BPD group and the clinical control group. No group differences were found in the limbic system or in any white matter structures. The present study indicates that the early morphological changes in BPD are located in the PFC. However, these changes may not be BPD specific since similar changes were found in the clinical control group. Changes in limbic brain volumes and white matter structures might occur over the course of the illness. © 2009 Elsevier Inc. All rights reserved.
Introduction Affective instability, impulsiveness, aggressive and autoaggressive behaviour together with instability of interpersonal relationships and self-image are the core features of borderline personality disorder (American Psychiatric Association, 1994). Borderline personality disorder (BPD) affects 1–2% of the general population and the prevalence rises as high as 15–20% in psychiatric settings (Lieb et al., 2004). BPD manifests itself during late adolescence and early adulthood, causes significant social impairment and yields a lifetime suicide mortality of almost 10% (Skodol et al., 2002a). With regard to an etiological conceptualization, a combination of inherited genetic predispositions and environmental factors are considered to be of fundamental importance (Skodol et al., 2002b). To enhance our understanding of the developmental psychobiology of this disorder, neuroimaging studies at early stages of onset of this severe psychiatric illness are of pivotal importance. Adolescents with BPD provide a unique opportunity to examine abnormal brain ⁎ Corresponding author. Fax: +49 6221 566941. E-mail address: [email protected] (R. Brunner). 1 Contributed equally to this work. 1053-8119/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.neuroimage.2009.07.070
development at the early onset of the disorder which reduces confounding factors associated with the damaging effects of illness or side effects of treatment on brain morphology (Chanen et al., 2008). From a neurobiological perspective, the failure of frontolimbic functions has been linked to the core elements of the psychopathology of BPD, like impulsivity, emotional instability and impulsive aggression (Tebartz van Elst et al., 2003). It has been postulated that emotional dysregulation is the key feature of BPD and predisposes individuals to the emotional disinhibition and impulsive aggression responsible for many of the volatile behaviours seen in patients (Johnson et al., 2003; Linehan, 1993). In this context, it has been suggested that emotional dysregulation in patients with BPD is caused by prefrontal deficits or hyperactivity of the limbic system or a combination of both (Herpertz et al., 2001). Prefrontal deficits lead to a failure to control negative emotions (control-down modulation) and heightened activity in the limbic system leads to disordered emotional behaviour (bottom-up modulation). In recent years, the conceptualization of frontolimbic dysfunction in BPD resulted in a growing number of imaging studies using different imaging methods (for review see Lis et al., 2007). Initial structural magnetic resonance imaging (MRI) studies revealed volume reductions in the frontal lobe (Lyoo et al., 1998), the left
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orbitofrontal cortex (OFC) (Hazlett et al., 2005; Tebartz van Elst et al., 2003), and right parietal cortex (Irle et al., 2005). Very recently, reductions in gray matter volume have also been found in frontal, temporal and parietal cortices in men with BPD (Völlm et al., 2009). In contrast, in other structural MRI studies using both voxel-based morphometry (VBM) (Rüsch et al., 2003) as well as manual tracing (Brambilla et al., 2004), no group differences between patients with BPD and healthy control subjects could be found in the frontal lobe. With regard to limbic structures conflicting results have been reported (Lis et al., 2007). In structural MRI studies (Driessen et al., 2000; Schmahl et al., 2003b; Tebartz van Elst et al., 2003), reduced volumes of the hippocampus in both hemispheres have been found. With regard to the amygdala, in adult patients with BPD compared with healthy controls, three studies found increased amygdala volumes (Driessen et al., 2000; Schmahl et al., 2003b; Tebartz van Elst et al., 2003), while two found decreased amygdala volumes (Brambilla et al., 2004; Rüsch et al., 2003). A recent VBM study found higher relative gray matter concentration in the amygdala compared to a group of healthy control subjects (Minzenberg et al., 2008). Another study revealed that only patients with both BPD and a comorbid diagnosis of major depression demonstrated a larger amygdala volume in both hemispheres compared with those without major depression (Zetzsche et al., 2006). All of the aforementioned studies were carried out with adult subjects, but as pointed out earlier, studies of adolescents with BPD allowed us to examine the early onset of the illness, thus reducing the confounding influence of treatment and knock-on effects of the original dysfunction on dependent brain structures (Chanen et al., 2008). To our knowledge, there has been only one study (Chanen et al., 2008) where volumetric changes in cortical and subcortical structures have been reported in adolescents with BPD using manual tracing of multiple regions of interests (ROIs). Compared with healthy controls, adolescent patients with BPD demonstrated gray matter reduction in the right orbitofrontal cortex. Hippocampal or amygdala volumetric differences could not be detected. In a subsample of 15 female adolescents with BPD of this former sample (Chanen et al., 2008), a decrease in volume of the left anterior cingulate cortex (ACC) (Whittle et al., 2009) as well as a shorter adhesio interthalamica (Takahashi et al., 2009) could be revealed in comparison with healthy controls. There is evidence from activation studies (fMRI) in adult patients with BPD which is also consistent with a morphological basis for functional changes in BPD. These studies revealed predominantly increased activity in the ACC in response to affective pictures (Donegan et al., 2003; Herpertz et al., 2001) and deactivation in response to aversive emotional stimuli (Donegan et al., 2003; Schmahl et al., 2004; Schmahl et al., 2003a). Functional brain imaging studies employing [18F]-deoxyglucose positron emission tomography (FDG-PET) (Soloff et al., 2000) or brain perfusion single photon emission computerized tomography (SPECT) (Goethals et al., 2005) revealed hypometabolism in medial, orbital, and dorsolateral prefrontal cortices. Further support for frontolimbic abnormalities in BPD resulted from challenge studies which found a blunted response to fenfluramine (Siever et al., 1999; Soloff et al., 2003) and m-CPP (metachloropiperazine) in PFC as well as the ACC (New et al., 2007). Thus, there is combined evidence of both structural and functional changes in the BPD brain but all findings together are rather heterogeneous. This observed variability across studies could reflect the use of small samples, an interaction with comorbid psychiatric conditions, patient heterogeneity, or differences in methodology. In the present study VBM was used to examine volumetric MR imaging changes in adolescents with BPD. In line with previous MR imaging studies, we expected volume reductions in limbic and prefrontal brain areas in BPD compared to healthy controls. To test if such changes are specific to BPD, we not only compared BPD patients to healthy controls, but also included a control group of nonBPD clinical patients.
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Methods and materials Participants and recruitment Participants were right-handed female adolescents between 14 and 18 years of age. Excluded were patients with a lifetime diagnosis of schizophrenia, schizoaffective disorder, bipolar disorder, pervasive developmental disorder, alcohol/drug dependence, or significant neurological disease, a body mass index ≤ 16.0 and individuals with an IQ ≤ 85. The adolescents comprised three groups: 20 patients with a DSM-IV defined diagnosis of BPD (borderline personality disorder group), 20 patients with mixed psychiatric diagnoses who did not fulfill more than one of the nine DSM-IV diagnostic criteria of BPD (clinical control subjects) and healthy volunteers with no current psychiatric disorder and who had never received a psychiatric diagnosis or undergone any psychological or psychiatric treatment in their lifetime (healthy control subjects). Patient subjects were consecutively recruited at the Department of Child and Adolescent Psychiatry at the University of Heidelberg. Patients were informed about the study by their attending physician. Healthy control subjects were recruited through advertisements in public schools. After assessment of handedness and confirmation of diagnosis, patients were included in the study. As with subjects with BPD, clinical control subjects and healthy control subjects were interviewed using a structured clinical interview to determine comorbid psychiatric disorders and the presence or absence of a psychiatric disorder respectively. In addition, the adolescents of both control groups were interviewed using the BPD section of a structured clinical interview for personality disorders. Patients without a diagnosis of BPD and healthy comparison subjects who fulfilled the inclusion criteria for the clinical or healthy control group were matched with patients with BPD for age and school type. From 159 patients admitted to the clinic during the recruitment period, 64 fulfilled the inclusion criteria and agreed to participate in the study. Four of the participants dropped out, one missed the appointment, and three where excluded from the MRI scan due to metallic objects on their body. The study was approved by the Ethics Committee of the Faculty of Medicine, University of Heidelberg. After the study procedures were fully explained and before participation, all adolescent subjects and their legal guardians gave written informed consent and assent, respectively. Measures Borderline personality diagnoses were assessed using the German version (Fydrich et al., 1997) of the BPD section of the Structured Clinical Interview for DSM-IV Axis II Personality Disorders (SCID-II) (First et al., 1997). Comorbid psychiatric disorders and confirmation of the absence of a psychiatric disorder in the healthy control group were assessed with the German version (Delmo et al., 2000) of the Schedule for Affective Disorders and Schizophrenia for School-Age Children—Present Version (K-SADS-P), a semistructured diagnostic clinical interview (Kaufman et al., 2000). The German version (Delmo et al., 2000) of the Children's Global Assessment Scale (C-GAS) (Shaffer et al., 1983) was used to measure the overall psychosocial functioning of the participants. All interviews were conducted by trained graduate-level clinicians. Uncertain ratings were discussed in a consensus conference of research staff led by child and adolescent psychiatrists with extensive clinical experience in treatment of and research on adolescents with BPD. The BPD section of the SCID-II interview was tape-recorded for reassessment. For a randomly selected sample of 30 participants (16 with and 14 without a diagnosis of BPD), the BPD diagnosis was reassessed by a second rater. The interrater-reliability of the BPD diagnosis was found to be sufficient (Cohen's Kappa = .94).
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Handedness was assessed by the Edinburgh Handedness Inventory (Oldfield, 1971). IQ was measured by the German version (Dahl, 1986) of the Wechsler Abbreviated Scale of Intelligence (Wechsler, 1999). The extent of depressive symptoms was assessed with the German version (Beck, 1995) of the Beck Depression Inventory. The degree of symptoms of anxiety was obtained using the German version of the Beck Anxiety Inventory (Beck and Steer, 1990). Dissociative symptoms were assessed with the German version (Brunner et al., 1999) of the Adolescent Dissociative Experiences Scale (Armstrong et al., 1997). To measure the degree of problems in emotion regulation the German version (Tausch, 1996) of the Emotion Control Questionnaire (Roger and Najarian, 1989) was used. Impulsiveness was measured using the German version of the Barrett Impulsiveness Scale, version 11 (Patton et al., 1995). The extent of traumatic life experiences was determined using the pertinent section of the German version (Steil and Füchsel, 2005) of the Clinician Administered PTSD Scale, Child and Adolescent Version (Nader et al., 1996) that assesses the occurrence of a number of traumatic life events. Magnetic resonance imaging procedures For the volumetric assessment a three-dimensional sagittal isotropic Magnetization Prepared Rapid Acquisition Gradient Echo (MPRAGE) sequence was obtained using a 3 T scanner (Tim Trio, Siemens, Erlangen, Germany) using a 12 channel standard head coil (flip angle 9°, repetition time 2300 ms, echo time 2.98 s, field of view 256 mm, matrix size 256 × 256 pixels, slice thickness 1 mm). One hundred and sixty slices with an isotropic voxel size of 1 × 1 × 1 mm were acquired. Beside the 3D sequence an axial T2 weighted FLAIR (repetition time 9000 ms, echo time 129 ms) sequence was performed. Both sequences were reviewed by an experienced neuroradiologist to exclude clinically significant abnormalities. Data analysis Volumetric data were analyzed with SPM5 (Statistical Parametric Mapping, Wellcome Trust Center for Neuroimaging, London, United Kingdom) using the VBM5 toolbox (http:www.fil.ion.ucl.ac.uk/spm). The procedure of data analysis has been described in more detail elsewhere (Ashburner and Friston, 2000; Good et al., 2001). After the manual setting of the origin (anterior commissure) using the display tool, images were segmented into gray and white matter as well as cerebrospinal fluid. In SPM5, the method of brain tissue segmentation is partly based on an implementation of a Gaussian Hidden Markov Random Field approach. This procedure removes isolated voxels that are unlikely to be members of the tissue class to which they have been assigned initially, thereby minimising noise effects. In the preprocessing step of spatial normalisation, some brain regions are expanded and others contracted. Modulation involves scaling by the amount of contraction, so that the total amount of gray matter in the modulated gray matter remains unchanged in comparison with the original images. In the current study, images were corrected for non-linear warping only. Images were smoothed using a Gaussian kernel of 10 mm full width at half-maximum (FWHM). Statistical analysis Demographic and psychometric characteristics of the participants were compared using chi-square tests for categorical variables and analysis of variance (ANOVA) for continuous variables. For pairwise post-hoc comparisons of the groups, p-values were corrected with Sidak's method to compensate for multiple testing. Statistical analyses were performed using the statistical software program Stata, version 10 (StataCorp, 2007). For volumetric data, t-tests were calculated to compare three groups: patients with borderline personality disorder, healthy con-
trols and a clinical control group. Images were thresholded at an absolute level of .1 and therefore only voxels which exceeded the threshold were included. Whole brain analyses were generated separately for gray and white matter and corrected for multiple comparisons. When performing multiple comparisons, uncorrected data possess a high rate of false positives. In SPM5, there are two ways to correct for this. A more conservative correction is provided by the control of the Family Wise Error (FWE) rate using either the Bonferroni criterion or the Gaussian field theory (Ashburner and Friston, 2000). A less conservative correction is provided by the False Discovery Rate (FDR) method. While FWE controls for the chance of any false positives, FDR controls only the expected proportion of false positives among suprathreshold voxels. A FDR threshold is determined from the observed p-value distribution, and hence adapts to the size of the effect in the data. An extent threshold for voxel clusters of at least k = 50 voxels and a significance threshold of p b .05 was chosen. In a second step, a regression analysis with the individual results of Beck Depression Inventory as well as the subscales and the total score of the Barrett Impulsiveness Scale as covariates was calculated. All cerebral regions were specified using the MAsks for Region of INterest Analysis (MARINA; http:www.bion.de/index.php?title=MARINA and lang=eng). Results Demographic and psychometric data As shown in Table 1, the BPD group and both control samples were matched for age and school type and there was no significant between-group difference in either age (F(2,57) = 2.02, p = .141) or IQ (F(2,57) = 1.70, p = .193). Adolescents with a diagnosis of BPD displayed significant functional impairment (C-GAS) compared to the clinical control group (t38 = 5.45, p b .001). As shown in Table 2, for all psychometric ratings, patients with BPD scored significantly higher compared to both the clinical and the healthy control groups. Current comorbid psychiatric diagnoses of the BPD group included mood disorders (N = 9), anxiety disorders (N = 9), substance abuse (N = 9), eating disorders (N = 7), and conduct disorders (N = 2). Current psychiatric diagnoses of the clinical control group included mood disorders (N = 4), anxiety disorders (N = 4), eating disorders (N = 6), somatoform disorders (N = 3), adjustment disorders (N = 6), conduct disorders (N = 1), and attention/deficit and hyperactivity
Table 1 Demographic information in female right-handed adolescents with borderline personality disorder, clinical control subjects and healthy control subjects. Characteristics
Borderline personality disorder (N = 20)
Clinical controls (N = 20)
Healthy controls (N = 20)
Age, mean ± SD, y IQ, mean ± SD School type, % Gymnasium Realschule Hauptschule Clinical setting Inpatient Day clinic Outpatient C-GAS
16.7 ± 1.6 107.1 ± 10.7
16.0 ± 1.3 114.0 ± 8.4
16.8 ± 1.2 111.0 ± 15.7
9 (45.0) 4 (20.0) 7 (35.0)
13 (65.0) 5 (25.0) 2 (10.0)
10 (50.0) 5 (25.0) 5 (25.0) NA
10 (50.0) 2 (10.0) 8 (40.0) 47.5 (8.2)
7 (35.0) 0 13 (65.0) 61.9 (9.3)
NA
IQ was measured using the Wechsler Abbreviated Scale of Intelligence (Wechsler, 1999). School type: Gymnasium, eight years of school after 4 years of elementary school, terminating with the general qualification for university entrance. Realschule, six years of school after 4 years of elementary school, terminating with a secondary-school level-I certificate. Hauptschule, nine years of elementary school. Abbreviations: C-GAS, Children's Global Assessment Scale.
R. Brunner et al. / NeuroImage 49 (2010) 114–120 Table 2 Mean and standard deviations of psychometric measures in female right-handed adolescents with borderline personality disorder, clinical control subjects and healthy control subjects. Measures
Borderline personality disorder (N = 20)
Clinical controls (N = 20)
Healthy controls (N = 20)
p
BDIa BAIa A-DESa BISa ECQ subscales Rehearsala Emotional inhibitiona Benign controla Aggression controla CAPS-CAa
27.3 ± 12.7 24.3 ± 10.6 3.0 ± 1.4 70.6 ± 13.7
10.5 ± 8.5 12.5 ± 10.2 1.4 ± 1.2 59.0 ± 8.9
3.7 ± 4.3 12.0 ± 16.4 1.1 ± .9 55.4 ± 9.9
b.001 .005 b.001 b.001
23.2 ± 5.7 30.8 ± 4.4 13.3 ± 3.0 27.0 ± 4.8 27.2 ± 13.8
18.8 ± 5.6 25.9 ± 5.4 10.3 ± 1.6 21.4 ± 3.4 17.1 ± 11.3
17.4 ± 3.5 26.2 ± 4.1 11.1 ± 2.4 23.7 ± 3.1 14.3 ± 8.4
.002 .002 .001 b.001 .002
Abbreviations: BDI, Beck Depression Inventory; BAI, Beck Anxiety Inventory; A-DES, Adolescent Dissociative Experiences Scale; ECQ, Emotion Control Questionnaire, rehearsal: tendency to mentally rehearse emotional events, emotional inhibition: tendency not to express emotions, aggression control: inhibition of feelings of anger, benign control: index of impulsivity ; BIS, Barrett Impulsiveness Scale; CAPS-CA, Clinician Administered PTSD Scale, Child and Adolescent Version. a Pairwise post-hoc comparisons of groups: BPD N clinical controls, BPD N healthy controls, clinical controls = healthy controls.
disorders (N = 1). Patients from both groups could receive more than one psychiatric diagnosis concurrently. None of the patients received medical treatment that was started before the current admission to our hospital thus excluding long term medical treatment. Of the patients receiving medical treatment, nine patients in the BPD group were taking psychopharmacological medication at the time of the scan. Of the nine patients, seven patients were taking antidepressants (six patients were taking selective serotonin re-uptake inhibitors (SSRIs), one patient was taking a tricyclic antidepressant, and one patient was taking two kinds of psychotropic medication (SSRI and tricyclic antidepressant) concurrently. Of the five patients in the clinical control group who took medication at the time of scanning, three patients were taking antidepressants (two patients were taking selective serotonin reuptake inhibitors (SSRIs), one patient was taking a tricyclic antidepressant), one patient was taking a neuroleptic drug (olanzapin) and one patient was taking an antiepileptic drug (valproic acid). Imaging findings Using FWE as a more conservative correction for multiple comparisons (pcorrected b .05), adolescent patients with borderline personality disorder showed volume decreases in the dorsolateral frontal gyrus bilaterally and the left orbitofrontal gyrus compared to healthy control subjects (Table 3, Fig. 1). Applying the more liberal correction with FDR (pcorrected b .05), the volume changes extended to further frontal areas (the opercular part of the left inferior frontal gyrus and the precentral gyrus bilaterally) as well as parietal (the left
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inferior parietal gyrus) and temporal regions (the superior temporal gyrus bilaterally and the left middle temporal gyrus) but most interestingly not in the parts that constitute the hippocampus or amygdala. FWE-corrected volume decreases in the right dorsolateral frontal gyrus were found in clinical control subjects compared with healthy control subjects (Table 3, Fig. 2). When comparing patients with a diagnosis of BPD with clinical control subjects, no volume differences were found using either FWE or FDR corrections for multiple comparisons. No volume alterations in limbic structures and no volume differences in white matter were found in any comparison between the three groups. Comparisons between subgroups of BPD patients with and without psychotropic medication as well as with and without substance abuse did not reveal any significant differences in brain morphology (tested with pcorrected b .05 and FWE / FDR). The scores for the Beck Depression Inventory, the total score of the Barrett Impulsiveness Scale and the scores of the subscales of the Emotion Control Questionnaire did not explain any additional variance and there were no significant associations between the gray matter volumes and the scores with correction for multiple comparisons in any group (tested with pcorrected b .05 and FWE / FDR). Discussion Voxel-based morphometry revealed that adolescent patients with BPD displayed a significantly decreased gray matter volume in the DLPFC bilaterally and in the left OFC compared with healthy subjects. In addition, adolescent patients from the clinical control group demonstrated significantly decreased gray matter volume in the right DLPFC in comparison with the control group of healthy subjects. No significant gray matter reductions were detected between the BPD group and the clinical control group. Furthermore no group differences were found in limbic areas or any white matter structures. Our study results are in accordance with Chanen et al. (2008) who reported orbitofrontal deficits and no differences in either the amygdala or the hippocampus in comparison with healthy adolescent subjects using manual ROI tracing. Discrepancies between both studies exist with regard to the hemispheric lateralization of the OFC alterations. In contrast to the left-side gray matter reductions observed in the OFC in our study, Chanen et al. (2008) found rightsided reductions in the OFC. Another novel finding compared to this earlier study is our observation of bilateral gray matter reduction in the DLPFC, which was not included in this previous study. Our findings are consistent with other structural MRI studies performed in adults with BPD (Hazlett et al., 2005; Lyoo et al., 1998; Tebartz van Elst et al., 2003) as well as the majority of functional brain imaging studies, which reveal hypometabolism in the DLPFC (Goethals et al., 2005; Soloff et al., 2000). Gray matter deficits in prefrontal areas are in accordance with several MR imaging studies of adult BPD (Hazlett et al., 2005; Lyoo et al., 1998; Tebartz van Elst et al., 2003; Völlm et al., 2009). However, some of these studies found additional changes well beyond the frontal lobe e.g. in the limbic system. Thus, the absence of structural differences in limbic structures
Table 3 Areas of reduced regional gray matter volume in adolescent patients with and without borderline personality disorder relative to healthy control subjects. pFWE-corr
t
Z score
x
y
z
Patients with borderline personality disorder vs. healthy control subjects Dorsolateral prefrontal cortex Right 164 Dorsolateral prefrontal cortex Left 71 Orbitofrontal cortex Left 51
Regions
Hemisphere
Extent threshold in voxels
.004 .002 .002
6.55 5.92 6.11
5.32 4.95 5.07
22 − 18 −9
68 55 58
20 31 − 22
Clinical control subjects vs. healthy control subjects Dorsolateral prefrontal cortex Right
.004
6.58
4.60
20
37
46
120
Only regions with pFWE-corr. b .05 (FWE-corr = family wise error corrected) and extent threshold of at least 50 voxels are reported. x, y, z: Coordinates from the stereotaxic atlas of Talairach and Tournoux (1988).
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Fig. 1. Gray matter volume reductions in patients with borderline personality disorder relative to healthy control subjects. Volume differences were found in the dorsolateral prefrontal regions bilaterally and in the left orbitofrontal regions (pFWE-corr. b .05, extent threshold of at least 50 voxels).
in our study is in contrast to studies in adults with BPD (Driessen et al., 2000; Schmahl et al., 2003b; Tebartz van Elst et al., 2003) in this respect. Since all these studies were performed in adults, it may be postulated that these differences may be related to the duration of disease and prolonged medication. Also, differences in methodology may have influenced the results. In a VBM study of adult patients with BPD (Rüsch et al., 2003), only changes in the left amygdala were reported. In contrast to our study and Chanen et al.'s (2008), no frontal alterations were found in this sample. Our study differs from this study in terms of included sample as well as methodological approach. Especially, the reported results in this study are uncorrected as opposed to the correction for multiple comparisons applied in our study that in our opinion strongly fortify the results of our study. Again, in an adult sample, duration of disease and medication may also have confounded the results, especially when searching for the origin of morphological changes of BPD. The first two independent volumetric studies in an adolescent BPD sample using different methods (ROI vs. VBM) showed changes in the frontal lobe exclusively. Our findings that are in accordance with
Chanen et al.'s (2008) indicate that volumetric changes might first become apparent in the prefrontal cortex and suggest a role for the PFC early in the course of this disorder. Very recently, a further study (Whittle et al., 2009) of a subpopulation of the initial study from Chanen et al. (2008) indicates a volume reduction of the left ACC. This finding is in conflict with our results. Even with liberal correction for multiple comparisons, this area is not significantly changed in our study. Thus, we feel that the differences in the prefrontal lobe are central in the early phase of BPD. However, further studies using the same evaluation methods should be performed to clarify this topic. Volume differences in the limbic system as revealed in former studies in samples of adult patients with BPD may be due to the course of illness since there is evidence that the duration of illness and side effects of medication may play a role in the development of volume differences in these brain areas (Weinberger and McClure, 2002). Taking these findings together, the present study in adolescent BPD provides further evidence that PFC alterations occur early in the development of the disorder, whereas volume changes in limbic structures might become apparent as a function of the course and/or
Fig. 2. Gray matter volume reductions in clinical control subjects relative to healthy control subjects. Volume differences were found in the dorsolateral part of the right superior frontal gyrus (pFWE-corr. b .05, extent threshold of at least 50 voxels).
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severity of the disorder. This explanation for the missing volume differences in limbic structures is supported by former studies in children and adolescents with stress-related psychiatric disorders (De Bellis et al., 1999). White matter alterations may also occur later in the course of the illness. Alterations may be the result of exposure to medication or related either to pathological processes associated with the illness or to adaptive processes within the brain. Furthermore, the plasticity of these neural structures has to be considered. In this respect, follow-up imaging studies of adolescent BPD would be of particular importance. Our finding of prefrontal deficits in both clinical groups may indicate that these changes are not BPD specific but rather imply a general biological vulnerability to the development of psychiatric disturbances. For instance, deficits in PFC areas are shared with other psychiatric disorders like depression (Koolschijn et al., 2009; Serene et al., 2007) and anxiety disorder (Bremner, 2004). Thus, it may be hypothesized that BPD could be a frontal deficit spectrum disease that shares frontal deficits with other disorders. Our findings of prefrontal deficits may be less of an endophenotypic pattern for a specific diagnosis, but may instead represent a pattern that reflects dysfunctioning of cognitive abilities (like attention, working memory, declarative memory) which impairs the capacity to control emotions. The main contributing disorders in our clinical control group were mood disorders (N = 4), anxiety disorders (N = 4) and eating disorders (N = 6) and adjustment disorders (N = 6). Further studies of these disorders with observations beginning at their onset and comparison with clinical control groups are needed to clarify the question of disorder specificity. Longitudinal studies of BPD could further elucidate the effect of disease duration on brain maturation. It may well be that over the time course of the disease the pattern of changes in brain morphology is unique for BPD. This longitudinal development should then be compared to longitudinal developments in other disorders. There are several limitations of the present study. The limited sample size may preclude the possibility of detecting volume differences with smaller effect sizes. Furthermore, since we aimed to examine a homogeneous sample and because both gender and handedness are known to be potential confounders for brain structures (Annett, 2002), we restricted the study to right-handed females. This selection implicates that the findings cannot be generalized to male patients and patients with different hemispheric lateralization. Comorbid psychiatric diagnoses, especially mood and anxiety disorders might be a potential confounding factor (Zetzsche et al., 2006). Given that it is rare to find patients with BPD who do not have comorbid diagnoses, such a sample would not allow the generalizability of the results. Inclusion of larger samples of patients with BPD might enable investigations into subtypes of this group (e.g., patients with a high extent of impulsivity vs. patients with anxiety or depressive symptoms). Comorbid personality disorders have not been assessed in this present study and might be another possible confounding factor. Although the validity of the diagnosis of BPD for adolescents has been discussed controversially and this may pose a further limitation, recent studies have revealed that the diagnosis of BPD in adolescent inpatients can reliably be assessed and has good concurrent validity (Levy et al., 1999; Miller et al., 2008) and show similar stability in comparison to adult BPD (Chanen et al., 2004). The strength of this study is in the use of a sample of adolescent patients who were at early stages of the illness. This may reduce the effect of illness duration on brain development. The consecutive recruitment guarantees a sample which is typical for a population treated in a hospital setting for child and adolescent psychiatry. Moreover, our clinic is—despite its status as a university clinic—a primary care center serving adolescents with psychiatric disturbances from a large catchment area; therefore we can expect that our sample is representative of adolescent psychiatric patients. A further methodological advantage lies in the use of automated analysis
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methods like VBM which can effectively yield information on the entire brain and provide a means of identifying areas of cerebral abnormality in a user-independent way. Even after the most rigid correction for re-testing, the changes found in the prefrontal brain regions remained significant thus fortifying the conclusion that the initial morphological changes in BPD are located there. In conclusion, our present findings suggest a possible biological precondition in the PFC in the development of BPD. However, this precondition may not be BPD specific, since our clinical control group disorder similar changes. This issue of disease specificity should be clarified in further studies. VBM revealed no differences in limbic or white matter structures. Further longitudinal neuroimaging studies are needed in adolescents with BPD to enhance our understanding of how prefrontal dysfunction contributes to the pathophysiology of BPD in both adolescents and adults. Diffusion tensor imaging studies should investigate whether subtle aberrations in the integrity of cerebral white matter tracts, especially those connected to frontolimbic structures, exist in patients with BPD. Acknowledgment We gratefully acknowledge the participating adolescents. References American Psychiatric Association, 1994. Diagnostic and Statistical Manual of Mental Disorders. DSM-IV4 ed. APA, Washington, DC. Annett, M., 2002. Handedness and Brain Asymmetry: The Right Shift Theory. Psychology Press, Hove. Armstrong, J.G., Putnam, F.W., Carlson, E.B., Libero, D.Z., Smith, S.R., 1997. Development and validation of a measure of adolescent dissociation: the adolescent dissociative experiences scale. J. of Nerv. Ment. Dis. 185, 491–497. Ashburner, J., Friston, K.J., 2000. Voxel-based morphometry—the methods. NeuroImage 11, 805–821. Beck, A.T., 1995. Beck-Depressions-Inventar (BDI). Dt. Bearbeitung von M. Hautzinger, M. Bailer, H. Worall, F. Keller. Hogrefe, Göttingen. Beck, A.T., Steer, R.A., 1990. Manual for the Beck Anxiety Inventory. Psychological Cooperation, San Antonio, TX. Brambilla, P., Soloff, P.H., Sala, M., Nicoletti, M.A., Keshavan, M.S., Soares, J.C., 2004. Anatomical MRI study of borderline personality disorder patients. Psychiatry Res. 131, 125–133. Bremner, J.D., 2004. Brain imaging in anxiety disorders. Expert Reviews of Neurotherapeutics 4, 275–284. Brunner, R., Resch, F., Parzer, P., Koch, E., 1999. Heidelberger Dissoziations-Inventar (HDI). Swets Test Services, Frankfurt/Main. Chanen, A.M., Jackson, H.J., McGorry, P.D., Allot, K.A., Clarkson, V., Yuen, H.P., 2004. Twoyear stability of personality disorder in older adolescent outpatients. J. Pers. Disord. 18, 526–541. Chanen, A.M., Velakoulis, D., Carison, K., Gaunson, K., Wood, S.J., Yuen, H.P., Yucel, M., Jackson, H.J., McGorry, P.D., Pantelis, C., 2008. Orbitofrontal, amygdala and hippocampal volumes in teenagers with first-presentation borderline personality disorder. Psychiatry Res. 163, 116–125. Dahl, G., 1986. Reduzierter Wechsler-Intelligenztest (WIP). Hogrefe, Göttingen, Bern. De Bellis, M.D., Keshavan, M.S., Clark, D.B., Casey, B.J., Giedd, J.N., Boring, A.M., Frustaci, K., Ryan, N.D., 1999. Developmental traumatology part II: brain development. Biol. Psychiatry 45, 1271–1284. Delmo, C., Weiffenbach, O., Gabriel, M., Poustka, F., 2000. Kiddie-Sads-Present and Lifetime Version (K-SADS-PL). 3. Auflage der Deutsche Forschungsversion. Klinik für Psychiatrie und Psychotherapie des Kindes-und Jugendalters der Universität Frankfurt, Frankfurt am Main. Donegan, N.H., Sanislow, C.A., Blumberg, H.P., Fulbright, R.K., Lacadie, C., Skudlarski, P., Gore, J.C., Olson, I.R., McGlashan, T.H., Wexler, B.E., 2003. Amygdala hyperreactivity in borderline personality disorder: implications for emotional dysregulation. Biol. Psychiatry 54, 1284–1293. Driessen, M., Herrmann, J., Stahl, K., Zwaan, M., Meier, S., Hill, A., Osterheider, M., Petersen, D., 2000. Magnetic resonance imaging volumes of the hippocampus and the amygdala in women with borderline personality disorder and early traumatization. Arch. Gen. Psychiatry 57, 1115–1122. First, M.B., Gibbon, M., Spitzer, R.L., Williams, J.B.W., Benjamin, L.S., 1997. Structured Clinical Interview for DSM-IV Axis II Personality Disorders. SCID-II) American Psychiatric Press, Washington DC. Fydrich, T., Renneberg, B., Schmitz, B., Wittchen, H.-U., 1997. Strukturiertes Klinisches Interview für DSM-IV: Achse II: Persönlichkeitsstörungen (SKID-II). Hogrefe, Göttingen. Goethals, I., Audenaert, K., Jacobs, F., Van den Eynde, F., Bernagie, K., Kolindou, A., Vervaet, M., Dierckx, R., Van Heeringen, C., 2005. Brain perfusion SPECT in impulsivity-related personality disorders. Behav. Brain Res. 157, 187–192.
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NeuroImage j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / y n i m g
Reduced prefrontal and orbitofrontal gray matter in female adolescents with borderline personality disorder: Is it disorder specific? Romuald Brunner a,⁎,1, Romy Henze a,b,1, Peter Parzer a,1, Jasmin Kramer a, Nina Feigl a, Kira Lutz a, Marco Essig b, Franz Resch a, Bram Stieltjes b a b
Department of Child and Adolescent Psychiatry, Center for Psychosocial Medicine University of Heidelberg, 69115 Heidelberg, Blumenstrasse 8, Germany Department of Radiology, German Cancer Research Center, Heidelberg, Germany
a r t i c l e
i n f o
Article history: Received 22 January 2009 Revised 23 July 2009 Accepted 29 July 2009 Available online 4 August 2009
a b s t r a c t There is evidence that adults with borderline personality disorder (BPD) are characterized by abnormalities in frontolimbic brain areas. In this study we aimed to determine whether brain volume alterations already exist in adolescents with BPD. Sixty female right-handed individuals (age range, 14–18 years), 20 with a DSM-IV diagnosis of borderline personality disorder, 20 patients with a DSM-IV defined current psychiatric disorder and 20 healthy control subjects were included. Groups were matched for age and IQ. Using a 3 T MRI scanner, we collected 1 mm axial sections using a three-dimensional sagittal isotropic Magnetization Prepared Rapid Acquisition Gradient Echo (MPRAGE) sequence. Images were analyzed using voxel-based morphometry (VBM). Voxel-based analysis revealed that adolescents with BPD showed reduced gray matter in the dorsolateral cortex (DLPFC) bilaterally and in the left orbitofrontal cortex (OFC) relative to healthy control subjects. Adolescent clinical control subjects displayed significantly decreased gray matter volume in the right DLPFC in comparison with healthy control subjects. No significant gray matter differences were detected between the BPD group and the clinical control group. No group differences were found in the limbic system or in any white matter structures. The present study indicates that the early morphological changes in BPD are located in the PFC. However, these changes may not be BPD specific since similar changes were found in the clinical control group. Changes in limbic brain volumes and white matter structures might occur over the course of the illness. © 2009 Elsevier Inc. All rights reserved.
Introduction Affective instability, impulsiveness, aggressive and autoaggressive behaviour together with instability of interpersonal relationships and self-image are the core features of borderline personality disorder (American Psychiatric Association, 1994). Borderline personality disorder (BPD) affects 1–2% of the general population and the prevalence rises as high as 15–20% in psychiatric settings (Lieb et al., 2004). BPD manifests itself during late adolescence and early adulthood, causes significant social impairment and yields a lifetime suicide mortality of almost 10% (Skodol et al., 2002a). With regard to an etiological conceptualization, a combination of inherited genetic predispositions and environmental factors are considered to be of fundamental importance (Skodol et al., 2002b). To enhance our understanding of the developmental psychobiology of this disorder, neuroimaging studies at early stages of onset of this severe psychiatric illness are of pivotal importance. Adolescents with BPD provide a unique opportunity to examine abnormal brain ⁎ Corresponding author. Fax: +49 6221 566941. E-mail address: [email protected] (R. Brunner). 1 Contributed equally to this work. 1053-8119/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.neuroimage.2009.07.070
development at the early onset of the disorder which reduces confounding factors associated with the damaging effects of illness or side effects of treatment on brain morphology (Chanen et al., 2008). From a neurobiological perspective, the failure of frontolimbic functions has been linked to the core elements of the psychopathology of BPD, like impulsivity, emotional instability and impulsive aggression (Tebartz van Elst et al., 2003). It has been postulated that emotional dysregulation is the key feature of BPD and predisposes individuals to the emotional disinhibition and impulsive aggression responsible for many of the volatile behaviours seen in patients (Johnson et al., 2003; Linehan, 1993). In this context, it has been suggested that emotional dysregulation in patients with BPD is caused by prefrontal deficits or hyperactivity of the limbic system or a combination of both (Herpertz et al., 2001). Prefrontal deficits lead to a failure to control negative emotions (control-down modulation) and heightened activity in the limbic system leads to disordered emotional behaviour (bottom-up modulation). In recent years, the conceptualization of frontolimbic dysfunction in BPD resulted in a growing number of imaging studies using different imaging methods (for review see Lis et al., 2007). Initial structural magnetic resonance imaging (MRI) studies revealed volume reductions in the frontal lobe (Lyoo et al., 1998), the left
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orbitofrontal cortex (OFC) (Hazlett et al., 2005; Tebartz van Elst et al., 2003), and right parietal cortex (Irle et al., 2005). Very recently, reductions in gray matter volume have also been found in frontal, temporal and parietal cortices in men with BPD (Völlm et al., 2009). In contrast, in other structural MRI studies using both voxel-based morphometry (VBM) (Rüsch et al., 2003) as well as manual tracing (Brambilla et al., 2004), no group differences between patients with BPD and healthy control subjects could be found in the frontal lobe. With regard to limbic structures conflicting results have been reported (Lis et al., 2007). In structural MRI studies (Driessen et al., 2000; Schmahl et al., 2003b; Tebartz van Elst et al., 2003), reduced volumes of the hippocampus in both hemispheres have been found. With regard to the amygdala, in adult patients with BPD compared with healthy controls, three studies found increased amygdala volumes (Driessen et al., 2000; Schmahl et al., 2003b; Tebartz van Elst et al., 2003), while two found decreased amygdala volumes (Brambilla et al., 2004; Rüsch et al., 2003). A recent VBM study found higher relative gray matter concentration in the amygdala compared to a group of healthy control subjects (Minzenberg et al., 2008). Another study revealed that only patients with both BPD and a comorbid diagnosis of major depression demonstrated a larger amygdala volume in both hemispheres compared with those without major depression (Zetzsche et al., 2006). All of the aforementioned studies were carried out with adult subjects, but as pointed out earlier, studies of adolescents with BPD allowed us to examine the early onset of the illness, thus reducing the confounding influence of treatment and knock-on effects of the original dysfunction on dependent brain structures (Chanen et al., 2008). To our knowledge, there has been only one study (Chanen et al., 2008) where volumetric changes in cortical and subcortical structures have been reported in adolescents with BPD using manual tracing of multiple regions of interests (ROIs). Compared with healthy controls, adolescent patients with BPD demonstrated gray matter reduction in the right orbitofrontal cortex. Hippocampal or amygdala volumetric differences could not be detected. In a subsample of 15 female adolescents with BPD of this former sample (Chanen et al., 2008), a decrease in volume of the left anterior cingulate cortex (ACC) (Whittle et al., 2009) as well as a shorter adhesio interthalamica (Takahashi et al., 2009) could be revealed in comparison with healthy controls. There is evidence from activation studies (fMRI) in adult patients with BPD which is also consistent with a morphological basis for functional changes in BPD. These studies revealed predominantly increased activity in the ACC in response to affective pictures (Donegan et al., 2003; Herpertz et al., 2001) and deactivation in response to aversive emotional stimuli (Donegan et al., 2003; Schmahl et al., 2004; Schmahl et al., 2003a). Functional brain imaging studies employing [18F]-deoxyglucose positron emission tomography (FDG-PET) (Soloff et al., 2000) or brain perfusion single photon emission computerized tomography (SPECT) (Goethals et al., 2005) revealed hypometabolism in medial, orbital, and dorsolateral prefrontal cortices. Further support for frontolimbic abnormalities in BPD resulted from challenge studies which found a blunted response to fenfluramine (Siever et al., 1999; Soloff et al., 2003) and m-CPP (metachloropiperazine) in PFC as well as the ACC (New et al., 2007). Thus, there is combined evidence of both structural and functional changes in the BPD brain but all findings together are rather heterogeneous. This observed variability across studies could reflect the use of small samples, an interaction with comorbid psychiatric conditions, patient heterogeneity, or differences in methodology. In the present study VBM was used to examine volumetric MR imaging changes in adolescents with BPD. In line with previous MR imaging studies, we expected volume reductions in limbic and prefrontal brain areas in BPD compared to healthy controls. To test if such changes are specific to BPD, we not only compared BPD patients to healthy controls, but also included a control group of nonBPD clinical patients.
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Methods and materials Participants and recruitment Participants were right-handed female adolescents between 14 and 18 years of age. Excluded were patients with a lifetime diagnosis of schizophrenia, schizoaffective disorder, bipolar disorder, pervasive developmental disorder, alcohol/drug dependence, or significant neurological disease, a body mass index ≤ 16.0 and individuals with an IQ ≤ 85. The adolescents comprised three groups: 20 patients with a DSM-IV defined diagnosis of BPD (borderline personality disorder group), 20 patients with mixed psychiatric diagnoses who did not fulfill more than one of the nine DSM-IV diagnostic criteria of BPD (clinical control subjects) and healthy volunteers with no current psychiatric disorder and who had never received a psychiatric diagnosis or undergone any psychological or psychiatric treatment in their lifetime (healthy control subjects). Patient subjects were consecutively recruited at the Department of Child and Adolescent Psychiatry at the University of Heidelberg. Patients were informed about the study by their attending physician. Healthy control subjects were recruited through advertisements in public schools. After assessment of handedness and confirmation of diagnosis, patients were included in the study. As with subjects with BPD, clinical control subjects and healthy control subjects were interviewed using a structured clinical interview to determine comorbid psychiatric disorders and the presence or absence of a psychiatric disorder respectively. In addition, the adolescents of both control groups were interviewed using the BPD section of a structured clinical interview for personality disorders. Patients without a diagnosis of BPD and healthy comparison subjects who fulfilled the inclusion criteria for the clinical or healthy control group were matched with patients with BPD for age and school type. From 159 patients admitted to the clinic during the recruitment period, 64 fulfilled the inclusion criteria and agreed to participate in the study. Four of the participants dropped out, one missed the appointment, and three where excluded from the MRI scan due to metallic objects on their body. The study was approved by the Ethics Committee of the Faculty of Medicine, University of Heidelberg. After the study procedures were fully explained and before participation, all adolescent subjects and their legal guardians gave written informed consent and assent, respectively. Measures Borderline personality diagnoses were assessed using the German version (Fydrich et al., 1997) of the BPD section of the Structured Clinical Interview for DSM-IV Axis II Personality Disorders (SCID-II) (First et al., 1997). Comorbid psychiatric disorders and confirmation of the absence of a psychiatric disorder in the healthy control group were assessed with the German version (Delmo et al., 2000) of the Schedule for Affective Disorders and Schizophrenia for School-Age Children—Present Version (K-SADS-P), a semistructured diagnostic clinical interview (Kaufman et al., 2000). The German version (Delmo et al., 2000) of the Children's Global Assessment Scale (C-GAS) (Shaffer et al., 1983) was used to measure the overall psychosocial functioning of the participants. All interviews were conducted by trained graduate-level clinicians. Uncertain ratings were discussed in a consensus conference of research staff led by child and adolescent psychiatrists with extensive clinical experience in treatment of and research on adolescents with BPD. The BPD section of the SCID-II interview was tape-recorded for reassessment. For a randomly selected sample of 30 participants (16 with and 14 without a diagnosis of BPD), the BPD diagnosis was reassessed by a second rater. The interrater-reliability of the BPD diagnosis was found to be sufficient (Cohen's Kappa = .94).
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Handedness was assessed by the Edinburgh Handedness Inventory (Oldfield, 1971). IQ was measured by the German version (Dahl, 1986) of the Wechsler Abbreviated Scale of Intelligence (Wechsler, 1999). The extent of depressive symptoms was assessed with the German version (Beck, 1995) of the Beck Depression Inventory. The degree of symptoms of anxiety was obtained using the German version of the Beck Anxiety Inventory (Beck and Steer, 1990). Dissociative symptoms were assessed with the German version (Brunner et al., 1999) of the Adolescent Dissociative Experiences Scale (Armstrong et al., 1997). To measure the degree of problems in emotion regulation the German version (Tausch, 1996) of the Emotion Control Questionnaire (Roger and Najarian, 1989) was used. Impulsiveness was measured using the German version of the Barrett Impulsiveness Scale, version 11 (Patton et al., 1995). The extent of traumatic life experiences was determined using the pertinent section of the German version (Steil and Füchsel, 2005) of the Clinician Administered PTSD Scale, Child and Adolescent Version (Nader et al., 1996) that assesses the occurrence of a number of traumatic life events. Magnetic resonance imaging procedures For the volumetric assessment a three-dimensional sagittal isotropic Magnetization Prepared Rapid Acquisition Gradient Echo (MPRAGE) sequence was obtained using a 3 T scanner (Tim Trio, Siemens, Erlangen, Germany) using a 12 channel standard head coil (flip angle 9°, repetition time 2300 ms, echo time 2.98 s, field of view 256 mm, matrix size 256 × 256 pixels, slice thickness 1 mm). One hundred and sixty slices with an isotropic voxel size of 1 × 1 × 1 mm were acquired. Beside the 3D sequence an axial T2 weighted FLAIR (repetition time 9000 ms, echo time 129 ms) sequence was performed. Both sequences were reviewed by an experienced neuroradiologist to exclude clinically significant abnormalities. Data analysis Volumetric data were analyzed with SPM5 (Statistical Parametric Mapping, Wellcome Trust Center for Neuroimaging, London, United Kingdom) using the VBM5 toolbox (http:www.fil.ion.ucl.ac.uk/spm). The procedure of data analysis has been described in more detail elsewhere (Ashburner and Friston, 2000; Good et al., 2001). After the manual setting of the origin (anterior commissure) using the display tool, images were segmented into gray and white matter as well as cerebrospinal fluid. In SPM5, the method of brain tissue segmentation is partly based on an implementation of a Gaussian Hidden Markov Random Field approach. This procedure removes isolated voxels that are unlikely to be members of the tissue class to which they have been assigned initially, thereby minimising noise effects. In the preprocessing step of spatial normalisation, some brain regions are expanded and others contracted. Modulation involves scaling by the amount of contraction, so that the total amount of gray matter in the modulated gray matter remains unchanged in comparison with the original images. In the current study, images were corrected for non-linear warping only. Images were smoothed using a Gaussian kernel of 10 mm full width at half-maximum (FWHM). Statistical analysis Demographic and psychometric characteristics of the participants were compared using chi-square tests for categorical variables and analysis of variance (ANOVA) for continuous variables. For pairwise post-hoc comparisons of the groups, p-values were corrected with Sidak's method to compensate for multiple testing. Statistical analyses were performed using the statistical software program Stata, version 10 (StataCorp, 2007). For volumetric data, t-tests were calculated to compare three groups: patients with borderline personality disorder, healthy con-
trols and a clinical control group. Images were thresholded at an absolute level of .1 and therefore only voxels which exceeded the threshold were included. Whole brain analyses were generated separately for gray and white matter and corrected for multiple comparisons. When performing multiple comparisons, uncorrected data possess a high rate of false positives. In SPM5, there are two ways to correct for this. A more conservative correction is provided by the control of the Family Wise Error (FWE) rate using either the Bonferroni criterion or the Gaussian field theory (Ashburner and Friston, 2000). A less conservative correction is provided by the False Discovery Rate (FDR) method. While FWE controls for the chance of any false positives, FDR controls only the expected proportion of false positives among suprathreshold voxels. A FDR threshold is determined from the observed p-value distribution, and hence adapts to the size of the effect in the data. An extent threshold for voxel clusters of at least k = 50 voxels and a significance threshold of p b .05 was chosen. In a second step, a regression analysis with the individual results of Beck Depression Inventory as well as the subscales and the total score of the Barrett Impulsiveness Scale as covariates was calculated. All cerebral regions were specified using the MAsks for Region of INterest Analysis (MARINA; http:www.bion.de/index.php?title=MARINA and lang=eng). Results Demographic and psychometric data As shown in Table 1, the BPD group and both control samples were matched for age and school type and there was no significant between-group difference in either age (F(2,57) = 2.02, p = .141) or IQ (F(2,57) = 1.70, p = .193). Adolescents with a diagnosis of BPD displayed significant functional impairment (C-GAS) compared to the clinical control group (t38 = 5.45, p b .001). As shown in Table 2, for all psychometric ratings, patients with BPD scored significantly higher compared to both the clinical and the healthy control groups. Current comorbid psychiatric diagnoses of the BPD group included mood disorders (N = 9), anxiety disorders (N = 9), substance abuse (N = 9), eating disorders (N = 7), and conduct disorders (N = 2). Current psychiatric diagnoses of the clinical control group included mood disorders (N = 4), anxiety disorders (N = 4), eating disorders (N = 6), somatoform disorders (N = 3), adjustment disorders (N = 6), conduct disorders (N = 1), and attention/deficit and hyperactivity
Table 1 Demographic information in female right-handed adolescents with borderline personality disorder, clinical control subjects and healthy control subjects. Characteristics
Borderline personality disorder (N = 20)
Clinical controls (N = 20)
Healthy controls (N = 20)
Age, mean ± SD, y IQ, mean ± SD School type, % Gymnasium Realschule Hauptschule Clinical setting Inpatient Day clinic Outpatient C-GAS
16.7 ± 1.6 107.1 ± 10.7
16.0 ± 1.3 114.0 ± 8.4
16.8 ± 1.2 111.0 ± 15.7
9 (45.0) 4 (20.0) 7 (35.0)
13 (65.0) 5 (25.0) 2 (10.0)
10 (50.0) 5 (25.0) 5 (25.0) NA
10 (50.0) 2 (10.0) 8 (40.0) 47.5 (8.2)
7 (35.0) 0 13 (65.0) 61.9 (9.3)
NA
IQ was measured using the Wechsler Abbreviated Scale of Intelligence (Wechsler, 1999). School type: Gymnasium, eight years of school after 4 years of elementary school, terminating with the general qualification for university entrance. Realschule, six years of school after 4 years of elementary school, terminating with a secondary-school level-I certificate. Hauptschule, nine years of elementary school. Abbreviations: C-GAS, Children's Global Assessment Scale.
R. Brunner et al. / NeuroImage 49 (2010) 114–120 Table 2 Mean and standard deviations of psychometric measures in female right-handed adolescents with borderline personality disorder, clinical control subjects and healthy control subjects. Measures
Borderline personality disorder (N = 20)
Clinical controls (N = 20)
Healthy controls (N = 20)
p
BDIa BAIa A-DESa BISa ECQ subscales Rehearsala Emotional inhibitiona Benign controla Aggression controla CAPS-CAa
27.3 ± 12.7 24.3 ± 10.6 3.0 ± 1.4 70.6 ± 13.7
10.5 ± 8.5 12.5 ± 10.2 1.4 ± 1.2 59.0 ± 8.9
3.7 ± 4.3 12.0 ± 16.4 1.1 ± .9 55.4 ± 9.9
b.001 .005 b.001 b.001
23.2 ± 5.7 30.8 ± 4.4 13.3 ± 3.0 27.0 ± 4.8 27.2 ± 13.8
18.8 ± 5.6 25.9 ± 5.4 10.3 ± 1.6 21.4 ± 3.4 17.1 ± 11.3
17.4 ± 3.5 26.2 ± 4.1 11.1 ± 2.4 23.7 ± 3.1 14.3 ± 8.4
.002 .002 .001 b.001 .002
Abbreviations: BDI, Beck Depression Inventory; BAI, Beck Anxiety Inventory; A-DES, Adolescent Dissociative Experiences Scale; ECQ, Emotion Control Questionnaire, rehearsal: tendency to mentally rehearse emotional events, emotional inhibition: tendency not to express emotions, aggression control: inhibition of feelings of anger, benign control: index of impulsivity ; BIS, Barrett Impulsiveness Scale; CAPS-CA, Clinician Administered PTSD Scale, Child and Adolescent Version. a Pairwise post-hoc comparisons of groups: BPD N clinical controls, BPD N healthy controls, clinical controls = healthy controls.
disorders (N = 1). Patients from both groups could receive more than one psychiatric diagnosis concurrently. None of the patients received medical treatment that was started before the current admission to our hospital thus excluding long term medical treatment. Of the patients receiving medical treatment, nine patients in the BPD group were taking psychopharmacological medication at the time of the scan. Of the nine patients, seven patients were taking antidepressants (six patients were taking selective serotonin re-uptake inhibitors (SSRIs), one patient was taking a tricyclic antidepressant, and one patient was taking two kinds of psychotropic medication (SSRI and tricyclic antidepressant) concurrently. Of the five patients in the clinical control group who took medication at the time of scanning, three patients were taking antidepressants (two patients were taking selective serotonin reuptake inhibitors (SSRIs), one patient was taking a tricyclic antidepressant), one patient was taking a neuroleptic drug (olanzapin) and one patient was taking an antiepileptic drug (valproic acid). Imaging findings Using FWE as a more conservative correction for multiple comparisons (pcorrected b .05), adolescent patients with borderline personality disorder showed volume decreases in the dorsolateral frontal gyrus bilaterally and the left orbitofrontal gyrus compared to healthy control subjects (Table 3, Fig. 1). Applying the more liberal correction with FDR (pcorrected b .05), the volume changes extended to further frontal areas (the opercular part of the left inferior frontal gyrus and the precentral gyrus bilaterally) as well as parietal (the left
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inferior parietal gyrus) and temporal regions (the superior temporal gyrus bilaterally and the left middle temporal gyrus) but most interestingly not in the parts that constitute the hippocampus or amygdala. FWE-corrected volume decreases in the right dorsolateral frontal gyrus were found in clinical control subjects compared with healthy control subjects (Table 3, Fig. 2). When comparing patients with a diagnosis of BPD with clinical control subjects, no volume differences were found using either FWE or FDR corrections for multiple comparisons. No volume alterations in limbic structures and no volume differences in white matter were found in any comparison between the three groups. Comparisons between subgroups of BPD patients with and without psychotropic medication as well as with and without substance abuse did not reveal any significant differences in brain morphology (tested with pcorrected b .05 and FWE / FDR). The scores for the Beck Depression Inventory, the total score of the Barrett Impulsiveness Scale and the scores of the subscales of the Emotion Control Questionnaire did not explain any additional variance and there were no significant associations between the gray matter volumes and the scores with correction for multiple comparisons in any group (tested with pcorrected b .05 and FWE / FDR). Discussion Voxel-based morphometry revealed that adolescent patients with BPD displayed a significantly decreased gray matter volume in the DLPFC bilaterally and in the left OFC compared with healthy subjects. In addition, adolescent patients from the clinical control group demonstrated significantly decreased gray matter volume in the right DLPFC in comparison with the control group of healthy subjects. No significant gray matter reductions were detected between the BPD group and the clinical control group. Furthermore no group differences were found in limbic areas or any white matter structures. Our study results are in accordance with Chanen et al. (2008) who reported orbitofrontal deficits and no differences in either the amygdala or the hippocampus in comparison with healthy adolescent subjects using manual ROI tracing. Discrepancies between both studies exist with regard to the hemispheric lateralization of the OFC alterations. In contrast to the left-side gray matter reductions observed in the OFC in our study, Chanen et al. (2008) found rightsided reductions in the OFC. Another novel finding compared to this earlier study is our observation of bilateral gray matter reduction in the DLPFC, which was not included in this previous study. Our findings are consistent with other structural MRI studies performed in adults with BPD (Hazlett et al., 2005; Lyoo et al., 1998; Tebartz van Elst et al., 2003) as well as the majority of functional brain imaging studies, which reveal hypometabolism in the DLPFC (Goethals et al., 2005; Soloff et al., 2000). Gray matter deficits in prefrontal areas are in accordance with several MR imaging studies of adult BPD (Hazlett et al., 2005; Lyoo et al., 1998; Tebartz van Elst et al., 2003; Völlm et al., 2009). However, some of these studies found additional changes well beyond the frontal lobe e.g. in the limbic system. Thus, the absence of structural differences in limbic structures
Table 3 Areas of reduced regional gray matter volume in adolescent patients with and without borderline personality disorder relative to healthy control subjects. pFWE-corr
t
Z score
x
y
z
Patients with borderline personality disorder vs. healthy control subjects Dorsolateral prefrontal cortex Right 164 Dorsolateral prefrontal cortex Left 71 Orbitofrontal cortex Left 51
Regions
Hemisphere
Extent threshold in voxels
.004 .002 .002
6.55 5.92 6.11
5.32 4.95 5.07
22 − 18 −9
68 55 58
20 31 − 22
Clinical control subjects vs. healthy control subjects Dorsolateral prefrontal cortex Right
.004
6.58
4.60
20
37
46
120
Only regions with pFWE-corr. b .05 (FWE-corr = family wise error corrected) and extent threshold of at least 50 voxels are reported. x, y, z: Coordinates from the stereotaxic atlas of Talairach and Tournoux (1988).
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Fig. 1. Gray matter volume reductions in patients with borderline personality disorder relative to healthy control subjects. Volume differences were found in the dorsolateral prefrontal regions bilaterally and in the left orbitofrontal regions (pFWE-corr. b .05, extent threshold of at least 50 voxels).
in our study is in contrast to studies in adults with BPD (Driessen et al., 2000; Schmahl et al., 2003b; Tebartz van Elst et al., 2003) in this respect. Since all these studies were performed in adults, it may be postulated that these differences may be related to the duration of disease and prolonged medication. Also, differences in methodology may have influenced the results. In a VBM study of adult patients with BPD (Rüsch et al., 2003), only changes in the left amygdala were reported. In contrast to our study and Chanen et al.'s (2008), no frontal alterations were found in this sample. Our study differs from this study in terms of included sample as well as methodological approach. Especially, the reported results in this study are uncorrected as opposed to the correction for multiple comparisons applied in our study that in our opinion strongly fortify the results of our study. Again, in an adult sample, duration of disease and medication may also have confounded the results, especially when searching for the origin of morphological changes of BPD. The first two independent volumetric studies in an adolescent BPD sample using different methods (ROI vs. VBM) showed changes in the frontal lobe exclusively. Our findings that are in accordance with
Chanen et al.'s (2008) indicate that volumetric changes might first become apparent in the prefrontal cortex and suggest a role for the PFC early in the course of this disorder. Very recently, a further study (Whittle et al., 2009) of a subpopulation of the initial study from Chanen et al. (2008) indicates a volume reduction of the left ACC. This finding is in conflict with our results. Even with liberal correction for multiple comparisons, this area is not significantly changed in our study. Thus, we feel that the differences in the prefrontal lobe are central in the early phase of BPD. However, further studies using the same evaluation methods should be performed to clarify this topic. Volume differences in the limbic system as revealed in former studies in samples of adult patients with BPD may be due to the course of illness since there is evidence that the duration of illness and side effects of medication may play a role in the development of volume differences in these brain areas (Weinberger and McClure, 2002). Taking these findings together, the present study in adolescent BPD provides further evidence that PFC alterations occur early in the development of the disorder, whereas volume changes in limbic structures might become apparent as a function of the course and/or
Fig. 2. Gray matter volume reductions in clinical control subjects relative to healthy control subjects. Volume differences were found in the dorsolateral part of the right superior frontal gyrus (pFWE-corr. b .05, extent threshold of at least 50 voxels).
R. Brunner et al. / NeuroImage 49 (2010) 114–120
severity of the disorder. This explanation for the missing volume differences in limbic structures is supported by former studies in children and adolescents with stress-related psychiatric disorders (De Bellis et al., 1999). White matter alterations may also occur later in the course of the illness. Alterations may be the result of exposure to medication or related either to pathological processes associated with the illness or to adaptive processes within the brain. Furthermore, the plasticity of these neural structures has to be considered. In this respect, follow-up imaging studies of adolescent BPD would be of particular importance. Our finding of prefrontal deficits in both clinical groups may indicate that these changes are not BPD specific but rather imply a general biological vulnerability to the development of psychiatric disturbances. For instance, deficits in PFC areas are shared with other psychiatric disorders like depression (Koolschijn et al., 2009; Serene et al., 2007) and anxiety disorder (Bremner, 2004). Thus, it may be hypothesized that BPD could be a frontal deficit spectrum disease that shares frontal deficits with other disorders. Our findings of prefrontal deficits may be less of an endophenotypic pattern for a specific diagnosis, but may instead represent a pattern that reflects dysfunctioning of cognitive abilities (like attention, working memory, declarative memory) which impairs the capacity to control emotions. The main contributing disorders in our clinical control group were mood disorders (N = 4), anxiety disorders (N = 4) and eating disorders (N = 6) and adjustment disorders (N = 6). Further studies of these disorders with observations beginning at their onset and comparison with clinical control groups are needed to clarify the question of disorder specificity. Longitudinal studies of BPD could further elucidate the effect of disease duration on brain maturation. It may well be that over the time course of the disease the pattern of changes in brain morphology is unique for BPD. This longitudinal development should then be compared to longitudinal developments in other disorders. There are several limitations of the present study. The limited sample size may preclude the possibility of detecting volume differences with smaller effect sizes. Furthermore, since we aimed to examine a homogeneous sample and because both gender and handedness are known to be potential confounders for brain structures (Annett, 2002), we restricted the study to right-handed females. This selection implicates that the findings cannot be generalized to male patients and patients with different hemispheric lateralization. Comorbid psychiatric diagnoses, especially mood and anxiety disorders might be a potential confounding factor (Zetzsche et al., 2006). Given that it is rare to find patients with BPD who do not have comorbid diagnoses, such a sample would not allow the generalizability of the results. Inclusion of larger samples of patients with BPD might enable investigations into subtypes of this group (e.g., patients with a high extent of impulsivity vs. patients with anxiety or depressive symptoms). Comorbid personality disorders have not been assessed in this present study and might be another possible confounding factor. Although the validity of the diagnosis of BPD for adolescents has been discussed controversially and this may pose a further limitation, recent studies have revealed that the diagnosis of BPD in adolescent inpatients can reliably be assessed and has good concurrent validity (Levy et al., 1999; Miller et al., 2008) and show similar stability in comparison to adult BPD (Chanen et al., 2004). The strength of this study is in the use of a sample of adolescent patients who were at early stages of the illness. This may reduce the effect of illness duration on brain development. The consecutive recruitment guarantees a sample which is typical for a population treated in a hospital setting for child and adolescent psychiatry. Moreover, our clinic is—despite its status as a university clinic—a primary care center serving adolescents with psychiatric disturbances from a large catchment area; therefore we can expect that our sample is representative of adolescent psychiatric patients. A further methodological advantage lies in the use of automated analysis
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methods like VBM which can effectively yield information on the entire brain and provide a means of identifying areas of cerebral abnormality in a user-independent way. Even after the most rigid correction for re-testing, the changes found in the prefrontal brain regions remained significant thus fortifying the conclusion that the initial morphological changes in BPD are located there. In conclusion, our present findings suggest a possible biological precondition in the PFC in the development of BPD. However, this precondition may not be BPD specific, since our clinical control group disorder similar changes. This issue of disease specificity should be clarified in further studies. VBM revealed no differences in limbic or white matter structures. Further longitudinal neuroimaging studies are needed in adolescents with BPD to enhance our understanding of how prefrontal dysfunction contributes to the pathophysiology of BPD in both adolescents and adults. Diffusion tensor imaging studies should investigate whether subtle aberrations in the integrity of cerebral white matter tracts, especially those connected to frontolimbic structures, exist in patients with BPD. Acknowledgment We gratefully acknowledge the participating adolescents. References American Psychiatric Association, 1994. Diagnostic and Statistical Manual of Mental Disorders. DSM-IV4 ed. APA, Washington, DC. Annett, M., 2002. Handedness and Brain Asymmetry: The Right Shift Theory. Psychology Press, Hove. Armstrong, J.G., Putnam, F.W., Carlson, E.B., Libero, D.Z., Smith, S.R., 1997. Development and validation of a measure of adolescent dissociation: the adolescent dissociative experiences scale. J. of Nerv. Ment. Dis. 185, 491–497. Ashburner, J., Friston, K.J., 2000. Voxel-based morphometry—the methods. NeuroImage 11, 805–821. Beck, A.T., 1995. Beck-Depressions-Inventar (BDI). Dt. Bearbeitung von M. Hautzinger, M. Bailer, H. Worall, F. Keller. Hogrefe, Göttingen. Beck, A.T., Steer, R.A., 1990. Manual for the Beck Anxiety Inventory. Psychological Cooperation, San Antonio, TX. Brambilla, P., Soloff, P.H., Sala, M., Nicoletti, M.A., Keshavan, M.S., Soares, J.C., 2004. Anatomical MRI study of borderline personality disorder patients. Psychiatry Res. 131, 125–133. Bremner, J.D., 2004. Brain imaging in anxiety disorders. Expert Reviews of Neurotherapeutics 4, 275–284. Brunner, R., Resch, F., Parzer, P., Koch, E., 1999. Heidelberger Dissoziations-Inventar (HDI). Swets Test Services, Frankfurt/Main. Chanen, A.M., Jackson, H.J., McGorry, P.D., Allot, K.A., Clarkson, V., Yuen, H.P., 2004. Twoyear stability of personality disorder in older adolescent outpatients. J. Pers. Disord. 18, 526–541. Chanen, A.M., Velakoulis, D., Carison, K., Gaunson, K., Wood, S.J., Yuen, H.P., Yucel, M., Jackson, H.J., McGorry, P.D., Pantelis, C., 2008. Orbitofrontal, amygdala and hippocampal volumes in teenagers with first-presentation borderline personality disorder. Psychiatry Res. 163, 116–125. Dahl, G., 1986. Reduzierter Wechsler-Intelligenztest (WIP). Hogrefe, Göttingen, Bern. De Bellis, M.D., Keshavan, M.S., Clark, D.B., Casey, B.J., Giedd, J.N., Boring, A.M., Frustaci, K., Ryan, N.D., 1999. Developmental traumatology part II: brain development. Biol. Psychiatry 45, 1271–1284. Delmo, C., Weiffenbach, O., Gabriel, M., Poustka, F., 2000. Kiddie-Sads-Present and Lifetime Version (K-SADS-PL). 3. Auflage der Deutsche Forschungsversion. Klinik für Psychiatrie und Psychotherapie des Kindes-und Jugendalters der Universität Frankfurt, Frankfurt am Main. Donegan, N.H., Sanislow, C.A., Blumberg, H.P., Fulbright, R.K., Lacadie, C., Skudlarski, P., Gore, J.C., Olson, I.R., McGlashan, T.H., Wexler, B.E., 2003. Amygdala hyperreactivity in borderline personality disorder: implications for emotional dysregulation. Biol. Psychiatry 54, 1284–1293. Driessen, M., Herrmann, J., Stahl, K., Zwaan, M., Meier, S., Hill, A., Osterheider, M., Petersen, D., 2000. Magnetic resonance imaging volumes of the hippocampus and the amygdala in women with borderline personality disorder and early traumatization. Arch. Gen. Psychiatry 57, 1115–1122. First, M.B., Gibbon, M., Spitzer, R.L., Williams, J.B.W., Benjamin, L.S., 1997. Structured Clinical Interview for DSM-IV Axis II Personality Disorders. SCID-II) American Psychiatric Press, Washington DC. Fydrich, T., Renneberg, B., Schmitz, B., Wittchen, H.-U., 1997. Strukturiertes Klinisches Interview für DSM-IV: Achse II: Persönlichkeitsstörungen (SKID-II). Hogrefe, Göttingen. Goethals, I., Audenaert, K., Jacobs, F., Van den Eynde, F., Bernagie, K., Kolindou, A., Vervaet, M., Dierckx, R., Van Heeringen, C., 2005. Brain perfusion SPECT in impulsivity-related personality disorders. Behav. Brain Res. 157, 187–192.
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