Anatomical MRI study of borderline personality disorder patients

Psychiatry Research: Neuroimaging 131 (2004) 125 – 133 www.elsevier.com/locate/psychresns

Anatomical MRI study of borderline personality disorder patients Paolo Brambilla a,b,c,d, Paul H. Soloff b, Michela Sala e, Mark A. Nicoletti a,f, Matcheri S. Keshavan b, Jair C. Soares a,f,g,* a

Division of Mood and Anxiety Disorders, Department of Psychiatry, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA b Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA c Department of Pathology and Experimental and Clinical Medicine, Section of Psychiatry, University of Udine, Udine, Italy d Advanced Biotechnology Center, University of Genova, Genova, Italy e Department of Psychiatry, IRCCS S. Matteo, University of Pavia School of Medicine, Pavia, Italy f South Texas Veterans Health Care System, Audie L. Murphy Division, San Antonio, TX, USA g Department of Radiology, University of Texas Health Science Center, San Antonio, TX, USA Received 14 July 2003; received in revised form 20 April 2004; accepted 26 April 2004

Abstract Hippocampal volume reduction has been reported in patients with borderline personality disorder (BPD), and is hypothesized to be associated with traumatic childhood experiences. We extended this investigation to explore additional brain regions and other potential clinical correlates of structural brain changes in BPD. Ten unmedicated BPD subjects and 20 healthy controls were assessed for current and past Axis I and II comorbidities and histories of childhood abuse. All had magnetic resonance imaging (MRI) studies with a 1.5 T GE Signa Imaging System, performing threedimensional-gradient echo imaging (SPGR) with the following parameters: TR=25 ms, TE=5 ms, and slice-thickness=1.5 mm. Compared with healthy controls, BPD subjects had significantly smaller right and left hippocampal volumes, most marked in subjects with childhood abuse, and significantly increased right and left putamen volumes, especially in subjects with substance use disorders. No significant differences between groups were found for caudate, amygdala, temporal lobes, dorsolateral prefrontal cortex and total brain volumes. This study replicated prior findings of diminished hippocampal volumes in subjects with BPD. Also, increased putamen volumes were found in BPD, a finding that has not been previously reported. Early traumatic experiences may play a role in hippocampal atrophy, whereas substance use disorders may contribute to putamen enlargement. D 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Neuroimaging; Personality disorder; Basal ganglia; Hippocampus; Amygdala; Frontal cortex; Temporal cortex; Brain; Magnetic resonance imaging

* Corresponding author. Tel.: +1-210-567-5492; fax: +1-210-567-3759. E-mail address: [email protected] (J.C. Soares). 0925-4927/$ - see front matter D 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.pscychresns.2004.04.003

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1. Introduction Borderline personality disorder (BPD) is a serious mental disorder characterized by affective dysregulation, abnormalities in impulse control, cognitiveperceptual symptoms and unstable interpersonal relationships (Soloff et al., 1994, 2000a; Siever et al., 2002; Skodol et al., 2002a,b). The regulation of mood and impulse, recognition of social signals, control and correction of reward-related and punishment-related behavior, decision making and other higher ‘executive functions’ depend, in part, upon the functional integrity of neural circuits involving the prefrontal cortex and related structures (Rolls, 2000; O’Doherty et al., 2001). The psychopathology of BPD, especially dysregulation of affect, impulse and cognition, suggests that structural brain abnormalities (especially in prefrontal cortex) could contribute to loss of functional connectivity in the neural circuits modulating these functions. Recent studies using magnetic resonance imaging (MRI) have demonstrated volume abnormalities in brain structures related to regulation of emotion and behavior in BPD. Lyoo et al. (1998) reported significantly diminished total frontal lobe volumes in subjects with BPD compared with normal controls. BPD subjects were criteria-defined and free of any current or lifetime comorbid Axis I or II disorders. There were no differences between groups for temporal lobes or lateral ventricles. Unfortunately, Lyoo et al. did not separate gray and white matter or control for total brain size. Specific frontal sub-regions were not measured. Decreased volumes of the hippocampus (Driessen et al., 2000; Rusch et al., 2003; Schmahl et al., 2003; Tebartz van Elst et al., 2003) and the amygdala (Schmahl et al., 2003; Tebartz van Elst et al., 2003) have been reported in BPD patients with early traumatic experiences. A history of childhood traumatic experience is highly prevalent in BPD, with sexual abuse reported by 40 – 70% and physical abuse by 25– 73% of adults with BPD (Zanarini et al., 2000a; Soloff et al., 2002). Reduced hippocampal volume and abnormalities of hypothalamic-pituitary axis (HPA) function are associated with histories of early maltreatment in adolescent females, independent of a diagnosis of BPD (Stein et al.,

1997; DeBellis et al., 1999; Vythilingam et al., 2002), and in patients with posttraumatic stress disorder (Bremner et al., 1995; Gurvits et al., 1996; Bremner et al., 1997; Gilbertson et al., 2002). Stress is related to hyper-glucocorticoid levels (Sala et al., in press), which have been associated with decreased hippocampal volume in animal studies (Sapolsky et al., 1990; Kaufman et al., 2000). We conducted a preliminary study to examine the hypothesis of hippocampal and amygdala volume reduction in BPD associated with histories of childhood abuse, and to investigate the potential involvement of other sub-regions important in the regulation of emotion and impulsive behavior, including the dorsolateral prefrontal cortex (DLPFC), temporal lobes and basal ganglia (De La Fuente et al., 1997; Soloff et al., 2000b; Laakso et al., 2002; Soderstrom et al., 2002).

2. Methods 2.1. Subjects Ten BPD outpatients diagnosed by the Diagnostic Interview for Borderline Patients (DIB, scorez7) (Gunderson et al., 1981) and meeting the DSM IIIR criteria for BPD were studied. Axis II and Axis I disorders were determined, respectively, by the International Personality Disorders Examination (IPDE; Loranger et al., 1987) and the Structured Clinical Interview for DSM III-R (SCID; Spitzer et al., 1988). Childhood abuse was assessed by the means of a 19-item abuse history questionnaire (Soloff et al., 2002). The 24-item Hamilton Depression Rating Scale (HRDS; Hamilton, 1960) was used to rate current depressive symptoms and was administered within a week prior to the MRI study. All patients were medication free for at least 2 months before their participation in the study. In Table 1, details on demographical and clinical variables are reported. Twenty control subjects were recruited. They were physically healthy individuals with no past or current history of any DSM-IV Axis I or Axis II disorders, no current medical problems, no history of substance/ alcohol abuse, and no history of psychiatric disorders among first-degree relatives.

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Table 1 Demographical and clinical variables for borderline personality disorder patients Sex/age

Psychopharmacological

Comorbidity

history

Axis I

Axis II

MDE: recur./cur. AN: past MDE: single past MDE: cur. None MDE: recur. Dysthymia: cur. MDE: single past Panic D/O: past Dysthymia: cur.

None None APD APD None

F/18

AD 1985 – 1988, HAL in 1993, VPA in Jan. 2000 FLX, TRZ, BDZ in 1996 Lithium 2 m in 1987 Drug-naı¨ve Probable prior long treatment with AD FLX, Paroxetine, BDZ 1990 – 2000 Drug-naı¨ve

F/25

Drug-naı¨ve

M/21 F/25

Venlafaxine 1 m. in 1999 Drug-naı¨ve

MDE: single past Dysthymia: cur. Dysthymia: cur. MDE: recur.

F/31 F/24 M/45 M/36 F/24 M/43

Substance abuse

APD None None None None

Childhood

Suicide

HDRS

abuse

attempts

score

None

Sexual

2

19

Cannabis: past Alcohol: past/cur. Alcohol: cur. Alcohol: cur. Inhalant: past Alcohol: past

Physical None Physical Sexual

2 5 0 2

10 20 9 15

None

2

7

Alcohol+sedatives: cur.; Cannabis: past Alcohol+cannabis: past None None

Sexual

1

16

None

1

8

None Physical

0 0

20 4

BPD=borderline personality disorder; F=female, M=male; AD=antidepressants, HAL=haloperidol, VPA=valproate, FLX=fluoxetine, TRZ=trazodone, BDZ=benzodiazepines; MDE=major depressive episode; AN=anorexia nervosa; Recur.=recurrent; Cur.=current; ASPD=antisocial personality disorder; HDRS=Hamilton Depression Rating Scale 24-items. All BPD patients had been unmedicated at the time of participation in the study for at least 2 months.

All subjects provided signed informed consent as required by the Institutional Review Board of the University of Pittsburgh. 2.2. MRI acquisition MRI scans were acquired with a 1.5 T GE Signa Imaging System running version Signa 5.4.3 software (General Electric Medical Systems, Milwaukee, WI). A T1-weighted sagittal scout image was obtained for graphic prescription of the coronal and axial images. Three-dimensional gradient echo imaging (Spoiled Gradient Recalled Acquisition, SPGR) was performed in the coronal plane (TR=25 ms, TE=5 ms, nutation angle=40j, FOV=24 cm, slice thickness=1.5 mm, NEX=1, matrix size=256192) to obtain 124 images covering the entire brain. Additionally, a double echo spin echo sequence was used to obtain T2 and proton density images in the axial plane to screen for neuroradiological abnormalities. Anatomical measurements were conducted on a PC workstation (Dell Dimension, Pentium II 400, Windows NT 4.0) using the semi-automated software Scion Image Beta-3b for Windows (Scion Corporation, Inc., Frederick, MD). Volumetric measurements

for hippocampus, amygdala, temporal lobe, DLPFC, putamen, caudate, total brain and intracranium (ICV) were obtained manually in the coronal plane by welltrained evaluators blind to group assignment and to subjects’ identity. The intraclass correlation coefficients (ICCs), which were calculated by having two raters trace 10 training scans, were >0.90 for all measurements. The values for gray matter, white matter and cerebrospinal fluid (CSF) were obtained from a histogram, as per the method previously reported (Keshavan et al., 1995). 2.3. Anatomical landmarks The anatomical landmarks for hippocampus, amygdala, temporal lobe, caudate, putamen, total brain and intracranium have previously been reported elsewhere (Brambilla et al., 2001a,b, 2003). We report here our method for measurement of DLPFC. 2.3.1. DLPFC The tracing was started where the genu of the corpus callosum was formed, constituting the posterior limit. The anterior limit was marked by moving anteriorly nine slices. The superior and inferior bor-

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ders were the superior frontal sulcus and the superior temporal sulcus, respectively. 2.4. Statistical analyses All analyses were conducted using the SPSS for Windows software, version 8.0 (SPSS Inc., Chicago), and two-tailed statistical significance level was set at P<0.05. All the MRI volumetric measures were found to be normally distributed, as determined by the Shapiro – Wilks test. Analysis of covariance (ANCOVA) with age, gender and ICV as covariates was performed to compare the volumes of the anatomical structures between BPD patients and healthy controls. Partial correlation analyses were used to examine the effects of HDRS scores on the anatomical volumes.

3. Results BPD patients and healthy controls did not significantly differ in age (BPD: 29.2F9.3 years; control: 34.9F8.1 years, t=1.74, d.f.=28, P=0.09), gender (BPD: four males, six females; control: 14 males, six females, v2=2.5, d.f.=1, P=0.11), or years of education (BPD: 14.90F2.31 years; control: 13.30F1.77 years, t=1.92, d.f.=28, P=0.07). Six BPD patients had current comorbid major depressive episodes or dysthymic disorder, four BPD subjects had current comorbid substance use disorders, and six BPD individuals had a history of childhood abuse (three with histories of sexual and three with physical abuse). Seven patients had histories of medically significant suicide attempts; three were non-attempters. Compared with healthy controls, BPD patients had significantly smaller right and left hippocampal volumes, with age, gender and ICV as covariates ( F=10.19, d.f.=1/25, P<0.01; F=15.90, d.f.=1/25, P<0.01, respectively) (Table 1, Fig. 1). When BPD patients with a history of childhood abuse (n=6) were compared with healthy controls, there were still significant differences between groups for right (BPD: 3.20F0.17; control: 3.95F0.54, F=13.70, d.f.=1/19, P=0.00) and left hippocampus (BPD: 3.00F0.38; control: 4.03F0.43 ml, F=16.30, d.f.=1/19, P=0.00). When BPD subjects with no

history of childhood abuse (n=4) were compared with healthy controls, we found no significant differences between groups in right and left hippocampal volumes (ANCOVA with age, gender and ICV as covariates, P>0.05). Compared with healthy controls, BPD subjects had significantly larger right and left putamen volumes, with age, gender and ICV as covariates ( F=8.56, d.f.=1/25, P<0.01; F=5.95, d.f.=1/25, P=0.02, respectively) (Table 2, Fig. 1). This finding was associated with the presence of a current comorbid diagnosis of a substance use disorder. In the comparison of BPD subjects with substance use disorders (n=4) to healthy controls, right and left putamen volumes were significantly enlarged in the BPD group (BPD right: 3.80F0.64; control right: 2.35F0.88, F=9.31, d.f.=1/19, P=0.00; BPD left: 4.68F0.79; control left: 3.18F0.91 ml, F=9.20, d.f.=1/19, P=0.00). However, in the comparison of BPD subjects with no comorbid substance use disorder (n=6) to healthy controls, there were no significant between-group differences (ANCOVA with age, gender and ICV as covariates, P>0.05). No significant differences were found between the two groups for caudate, DLPFC, temporal lobes, amygdala, total brain volumes (ANCOVA with age, gender and ICV as covariates, P>0.05) (Table 2), or for ICV (ANCOVA with age and gender as covariates, P>0.05). The BPD patients’ 24-item HDRS scores (meanFS.D.=12.8F5.9) did not significantly correlate with any anatomical measures (partial correlation coefficient controlled for ICV, P>0.05).

4. Discussion Two main findings are shown by this preliminary study. First, consistent with Driessen et al. (2000) and Schmahl et al. (2003), we found abnormally decreased hippocampus volumes in BPD patients, especially in those with a childhood history of abuse. Second, we found enlarged putamen volumes in BPD individuals compared with healthy controls, especially in BPD subjects with comorbid substance use disorders. It has been suggested that early traumatic experiences may play a role in reducing hippocampus size in

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Fig. 1. Hippocampus and putamen volumes in healthy controls and borderline personality disorder patients. Borderline personality disorder (BPD) patients compared with healthy controls had significantly smaller right (a) ( P<0.01) and left (b) hippocampus volumes ( P<0.01) and significantly larger right (c) ( P<0.01) and left (d) putamen volumes ( P=0.02) (ANCOVA, age, gender and ICV as covariates).

BPD patients (Driessen et al., 2000; Schmahl et al., 2003). Driessen et al. (2000) also found a negative correlation between volumes of the hippocampus and the extent and duration of traumatic experiences. However, the functional implications of hippocampal volume reduction in BPD are unclear. The hippocampus plays a key role in memory consolidation, a crucial process that converts short-term memory into long-lasting memory in the neocortex, and in memory

retrieval (Cipolotti et al., 2001; Wittenberg and Tsien, 2002). Disrupting the structural integrity of the hippocampus could result in neurocognitive deficits, perhaps including the memory processing of childhood traumatic experiences. This could be a contributing factor to the frequently noted dissociative symptoms of the borderline patient, which are associated with childhood abuse, perceptual distortions and identity instability (Murray, 1979; Zanarini et

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Table 2 Anatomical measures in healthy controls and borderline personality disorder patients Volumes (ml)

Healthy controls n = 20

BPD patients n = 10

F

P

Right hippocampus Left hippocampus Right amygdala Left amygdala Right temporal lobe gray matter Left temporal lobe gray matter Right DLPFC gray matter Left DLPFC gray matter Right putamen Left putamen Right caudate Left caudate Total brain gray matter Total brain white matter

3.95F0.54 4.03F0.43 2.22F0.57 2.11F0.54 61.70F8.71 63.70F10.63 8.51F1.02 9.09F1.03 2.35F0.88 3.18F0.91 2.30F0.68 2.70F0.61 684.86F62.00 482.15F67.16

3.25F0.34 3.22F0.48 1.92F0.35 1.74F0.38 63.19F5.25 64.65F6.64 9.18F1.76 8.97F1.86 3.41F0.66 4.04F0.87 2.53F0.52 2.66F0.30 694.38F76.43 412.21F64.75

10.19 15.90 0.78 2.16 1.49 1.45 0.66 0.07 8.56 5.95 0.60 0.05 0.88 3.75

<0.01 <0.01 0.38 0.15 0.23 0.24 0.42 0.80 <0.01 0.02 0.45 0.82 0.36 0.06

Volumes are reported as meanFS.D. BPD = borderline personality disorder; DLPFC = dorsolateral prefrontal cortex. ANCOVA analyses with age, gender, and ICV as covariates (d.f.=1/25).

al., 2000b). Deficits in perception, memory and ‘executive’ frontal functions have been demonstrated in BPD subjects using a variety of standard neuropsychological tests (O’Leary et al., 1991; Swirsky-Sacchetti et al., 1993). These neurocognitive deficits may explain, in part, the difficulties of BPD patients in accurate recall of past experiences (especially emotional experiences) and their difficulty in maintaining a continuous sense of self. We did not find any differences between BPD and healthy subjects for the amygdala, as previously reported by two prior controlled MRI studies (Schmahl et al., 2003; Tebartz van Elst et al., 2003). In an extension study, the group of Ebert et al., using a voxel-based morphometry technique, was only able to partially replicate their prior findings of reduced bilateral amygdala (Tebartz van Elst et al., 2003), showing significant reduction of the left hippocampus/amygdala complex in a larger sample of BPD individuals (Rusch et al., 2003). Also, in another MRI study, Driessen et al. (2000) reported an abnormal reduction in volume only for the left amygdala in BPD subjects, but the significance of this finding ( P=0.04) disappeared after Bonferroni correction. Thus, MRI studies investigating the structural anatomy of the amygdala in BPD have reported conflicting findings, and MRI studies involving larger patient samples will be needed to elucidate this issue. Also,

no differences between BPD patients and healthy controls were found for the temporal lobe, DLPFC, caudate and total brain volumes, replicating the findings of previous MRI studies (Lyoo et al., 1998; Driessen et al., 2000; Rusch et al., 2003; Tebartz van Elst et al., 2003). Our study did not include examination of subgenual prefrontal and orbitofrontal cortices, which have demonstrated hypometabolism and diminished responsiveness to serotonergic activation on PET studies in subjects with BPD compared with healthy controls (Goyer et al., 1994; De La Fuente et al., 1997; Siever et al., 1999; Soloff et al., 2000b). Preliminary results from a recent MRI study showed smaller left orbitofrontal cortex and right anterior cingulate cortex in eight BPD patients compared with healthy controls (Tebartz van Elst et al., 2003). Future MRI studies should further explore the anatomy of these prefrontal subregions in BPD patients. We found abnormally enlarged putamen volumes in BPD subjects, particularly in those with comorbid substance use disorders. Adverse effects of alcohol on basal ganglia metabolism have been previously reported in alcoholics (Volkow et al., 1994; Oishi et al., 1999; Braus et al., 2001). Abnormally enlarged putamen volumes have also been recently found in cocaine-dependent subjects (Jacobsen et al., 2001). This suggests that the effects of substance/alcohol

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abuse are potentially deleterious for the anatomy of the putamen. Increased volumes of basal ganglia have also been related to the use of antipsychotics in schizophrenic patients (Keshavan et al., 1994; Lang et al., 2001). In our present study, only one patient received neuroleptic drugs (i.e. haloperidol), which occurred 7 years before the MRI. Therefore, it is very unlikely that prior antipsychotic medications could have affected the anatomy of the putamen in our BPD sample. The putamen is considered to be part of the reward/learning system, which is a neuronal network mediating goal-directed behaviors (Hikosaka et al., 1999; Delgado et al., 2000; Schultz et al., 2000). An altered reward/learning circuit could contribute to difficulties in delaying/inhibiting behavioral responses in BPD, and may be related to impulsivity and aggressiveness. Recent PET studies showed diminished serotonergic function (Soloff et al., 2000b; Leyton et al., 2001) and hypometabolism (De La Fuente et al., 1997) in the basal ganglia of BPD subjects compared with healthy controls, suggesting a role for the putamen in borderline psychopathology. Specific limitations of our study should be considered. The sample size was modest (BPD=10, controls=20), especially for the comparisons of patient subsamples, but comparable to the samples of Schmahl et al. (2003) and Tebartz van Elst et al. (2003). The majority of BPD patients had at least one comorbid diagnosis, typically major depression, dysthymia, or comorbid substance use disorders, which are conditions that very often occur concurrently with BPD (Soloff et al., 2000a; Skodol et al., 2002a). Our sample was representative of BPD subjects seen in usual clinical practice. Excluding all subjects with Axis I comorbidity would create a non-representative BPD sample that could ultimately limit the generalizability of the findings. Comorbid major depressive episodes may have confounding effects on brain morphology and function (Soares and Mann, 1997; Brambilla et al., 2002). The absence of correlation between brain volumes and HRDS scores in this study suggests acutely depressed mood may have no relationship to structural brain change. Abnormally decreased hippocampal volumes have been found in studies of unipolar major depression (Sheline et al., 1996; Bremner et al., 2000; Steffens et al., 2000; Vythilingam et al., 2002). A

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history of major depressive disorder could synergistically contribute to hippocampal volume loss along with the effects of early childhood trauma (Vythilingam et al., 2002). Depressive disorders are highly comorbid with BPD, and both depression and childhood maltreatment are associated with stress-related hypercortisolism. As a technical limitation, re-slicing the MRIs along the anterior –posterior commissure line was not performed before the tracing procedures. This was not performed because the software used for these measurements does not allow reorientation of the images. However, MRIs were acquired very carefully utilizing a procedure to standardize head positioning and minimize the variance due to head position, as previously reported (Brambilla et al., 2003). In conclusion, our preliminary findings of smaller hippocampi in BPD are consistent with results of prior MRI studies. As the hippocampus is highly sensitive to the effects of stress, early traumatic experiences may play a role in causing hippocampal atrophy in BPD. This study is the first to report putamen enlargement in BPD, which could be related to substance abuse. Further MRI studies will be needed to replicate these findings and to explore the relationship between measures of affective dysregulation, impulsive-aggression, neurocognitive deficits and volumetric abnormalities in BPD.

Acknowledgements This work was supported by grants MH 01736, MH 30915, MH 48463 and MO1RR0056. Parts of this work were presented at the Society of Biological Psychiatry Annual Meeting, May 16 – 18, 2002, Philadelphia, Pennsylvania.

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