Journal of Affective Disorders 139 (2012) 149–153

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Journal of Affective Disorders

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Research report

Microstructural white matter damage at orbitofrontal areas in borderlinepersonality disorder☆

José Luis Carrasco a,c,d,⁎, Kazuhiro Tajima-Pozo a, Marina Díaz-Marsá a,c,d, Ana Casado b,Juan J. López-Ibor a,c,d, Juan Arrazola b,c,d, Miguel Yus b,c

a Instituto de Psiquiatría y SaludMental, Hospital Clínico San Carlos, Facultad de Medicina, Universidad Complutense, Madrid, Spainb Departamento de Radiodiagnóstico. Hospital Clínico San Carlos, Spainc Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Spaind CIBERSAM (Spanish network for Biomedical Research in Mental Health), Spain

a r t i c l e i n f o

☆ None of the authors have any financial interests orthe content of this article.⁎ Corresponding author at: Department of Psychiatr

Carlos, Martin Lagos s/n, 28040 Madrid, Spain.E-mail address: kazutajima@hotmail.com (K. Tajim

0165-0327/$ – see front matter © 2011 Elsevier B.V. Adoi:10.1016/j.jad.2011.12.019

a b s t r a c t

Article history:Received 27 August 2011Received in revised form 14 November 2011Accepted 1 December 2011Available online 11 April 2012

Objectives: Prefrontal cortex plays a major role in the modulation of behaviors and emotionsthrough regulation of both information processing and impulse control. Low prefrontal func-tion in borderline personality disorder (BPD) has been consistently reported by a number ofstudies using neuropsychological assessments and functional neuroimaging techniques. Tofurther explore this findings, this study aimed to investigate microstructural damage of pre-frontal white matter tracts in subjects with BPD by using the novel, voxel-based approach,tract-based spatial statistics (TBSS).Methods: A Diffusion Tensor Image (DTI) study was performed in 28 patients with DSM-IV BPD(13 males and 15 females) and in 26 healthy control subjects. Voxel wise analysis was per-formed using TBSS (diffusion toolbox of FSL — functional MRI Software Library) to localize re-gions of white matter showing significant changes of fractional anisotropy (FA).Results: TBSS analysis revealed a statistically significant decrease of FA in the genu and rostralareas of the corpus callosum (pb0.005), as well as in left and right prefrontal white matter fas-ciculi (pb0.002) in BPD participants compared with controls. White matter abnormalitieswere not correlated with age, neurological symptoms or comorbid ADHD.Conclusions: Despite the reduced sample size, the results are in line with previous findings onreduced orbitofrontal functions in BPD with prominent affective-depressive feature and sug-gest that emotional and behavioral symptoms of BPD patients might be associated to damageat the connectivity tracts in these brain areas.

© 2011 Elsevier B.V. All rights reserved.

Keywords:Borderline personality disorderDiffusion Tensor ImagingDiffusion tractographyPrefrontal cortexCorpus callosumWhite matter

1. Introduction

Prefrontal cortex is considered to play a crucial role in thecontrol of behavior and impulses as well as in the regulationof emotions. Severely affected impulse control and affectiveregulation in borderline personality disorder (BPD) (Domes

conflicts related with

y, Hospital Clinico San

a-Pozo).

ll rights reserved.

et al., 2009; Frodl et al., 2010; Nielen et al., 2009; Rusch etal., 2010; Welborn et al., 2009) is clinically reflected by emo-tional instability, impulsive behaviors and self-aggression(Skodol et al., 2002). Recent neurobiological studies in BPDhave supported the hypothesis of brain dysfunctions at theprefrontal lobes and at the limbic areas (Minzenberg et al.,2008; Rusch et al., 2010; Rusch et al., 2007). Functional neu-roimaging studies using PET and fMRI have found decreasedorbitofrontal (De La Fuente et al., 1997; Shigemune et al.,2010; Soloff et al., 2000) and increased amygdala activationin association with the symptomatology of BPD (Brambillaet al., 2004; Chanen et al., 2008; De La Fuente et al., 1997;

150 J.L. Carrasco et al. / Journal of Affective Disorders 139 (2012) 149–153

Donegan et al., 2003; Donovan et al., 2000; Driessen et al.,2000; Goyer et al., 1994; Lyoo et al., 1998; Schmahl et al.,2003, 2009; Vermetten et al., 2006).

Diffusion Tensor Imaging (DTI) techniques have been usedto assess impairment of connectivity in brain areas, throughthe evaluation of white matter integrity (Brambilla et al.,2004; Butts et al., 1996; Chanen et al., 2008; de Crespignyet al., 1999; Driessen et al., 2000; Kucharczyk et al., 1991;Moseley et al., 1990; Nunes et al., 2009; Schmahl et al., 2003,2009; Tsuruda et al., 1991; Vermetten et al., 2006). The mostaccepted DTI measure is fractional anisotropy (FA), which re-flects the magnitude of a tensor attributable to anisotropicdiffusion (Stejskal EO, 1965). Tract-based spatial statistics(TBSS) is a novel technique that obtains relative measures ofFA, thereby allowing comparison of individual scores withoutthe confounding variable of overall brain differences. TBSSaims to improve the sensitivity, objectivity and interpretabil-ity of analysis of multi-subject diffusion imaging studies.

Data from previous DTI studies have shown abnormalfunctioning of prefrontal areas in BPD patients, althoughmost included specifically selected samples with particularconditions such as attention-deficit hyperactivity disorder(Rusch et al., 2007) or female patients with severe self injuri-ous behavior or dissociative symptoms (Grant et al., 2007).The aim of this study was to investigate white matter integri-ty in a representative sample of patients with BPD. The dem-onstration of neural abnormalities at the prefrontal cortexmight support preliminary evidence of prefrontal functionaldeficit in BPD and will increase our knowledge on the neuralsubstrate for behavioral dyscontrol in BPD.

2. Methods

Approval from the local ethics committee was obtained.Patients participated voluntarily in the study after written in-formed consent was signed. Participants were recruited froma personality disorder unit of a general hospital during a peri-od of 6 months. Each patient fulfilling the BPD diagnostic cri-teria who did not meet any exclusion criteria (see below) wasoffered to participate in the study. 30 BPD patients (17 fe-males, 13 males) (mean age 25.5 years [19–44]) entered thestudy. The control group consisted of 25 healthy subjects(14 females, 11 males) with no family history of schizophre-nia or bipolar disorder. Their mean age was 25.17 years(range 21 to 32 years). There was no differences betweenthe BPD group and the control group for age (t=0.46,p=0.65) or for educational level (16.4 vs 17.1 years of educa-tion respectively; −t=0.42, p=0.74).

Participants were assessed for axis I disorders with theStructured Clinical Interview for DSM-IV (First MB et al.,2002) and the SCID-II for diagnosis of personality disorders(First MB et al., 1994). Current episodes of major depression(all patients scores below 12 in the Hamilton DepressionRating Scale) or substance dependence were consideredexclusion criteria as were also a life-time diagnosis of schizo-phrenic disorder, bipolar disorder or organic mental disor-ders. Patients were free of unstable medical conditions orneurological disorders. All patients had received treatmentin a specialized day-hospital for BPD for at least 3 monthsprior to the study. At the time of the study patients were sta-bilized for emotional and behavioral symptoms (all patients

scored below 14 in the Zanarini BPD Rating Scale) to the ex-tent that medication could be completely withdrawn for thestudy. All patients were free of medication at least 2 weeksprior to the study.

T1-weighted MR images were acquired using a 1.5 T Signa5× scanner (GE Medical Systems) with a 3D-SPGR sequence(TR=24 ms, TE=5ms, flip angle=40°, matrix size 256×256,field of view 23 cm, slice thickness 1.2 mm, total slices 128,NEX=1). The diffusion tensor sequence acquired fourteen7.5-mm-thick slices (TR=10 s, TE=99 ms, TI=2.2 s,b=750 s/mm, δ=31ms, Δ=73ms).

The processing of the diffusion tensor images was per-formed using software tools from the FMRIB software library(SIENA).Voxelwise statistical analysis of the FA data was car-ried out using TBSS. First, FA images were created by fitting atensor model to the raw diffusion data using FDT (FMRIB'sDiffusion Toolbox), and brain-extracted using BET (BrainExtraction Tool). All subjects' FA data were then alignedinto a common space using the nonlinear registration toolFNIRT (FMRIB's Non-Linear Image Registration Tool), whichuses a b-spline representation of the registration warp field.Next, the mean FA image was created and thinned to createa mean FA skeleton which represents the centers of all tractscommon to the group. The mean skeleton image is createdusing threshold value of 0.2 for the FA level. Each subject'saligned FA data was then projected onto this skeleton andthe resulting data fed into voxelwise cross-subject statisticsfor group comparisons.

The high resolution three dimensional datasets acquiredwere also processed using FSL software tools. Brain tissuevolume, normalized for subject head size, was estimatedwith SIENAX (Structural Image Evaluation, using Normalisa-tion of Atrophy). SIENAX starts by extracting brain and skullimages from the single whole-head input data. The brainimage is then affine-registered to MNI152 space (using theskull image to determine the registration scaling); this is pri-marily in order to obtain the volumetric scaling factor, to beused as normalization for head size. Next, tissue-type seg-mentation with partial volume estimation is carried out inorder to calculate total volume of brain tissue (including sep-arate estimates of volumes of gray matter, white matter, pe-ripheral gray matter and ventricular CSF).

3. Results

TBSS analysis of fractional anisotropy values showed asignificant decrease in the knee and anterior part of corpuscallosum's body, and in the orbito-frontal white matter ofBPD participants (pb0.005) (Detailed results, MNI152 coor-dinates, cluster size and confidence levels are presented inTable 1). Patients with BPD showed no higher FA regions incomparison with controls (Fig. 1).

No other significant differences were detected betweenpatients and controls at other regions of brain white matter.No significant correlations were found between the FA ab-normalities and the time of duration of the disease.

4. Discussion

Significant damage of white matter orbitofrontal regionsis suggested by FA reduction in patients with BPD compared

Table 1TBSS analysis of reduced FA in BPD participants compared with control group.

Cluster index Anatomic location p Coordinates MNI mm(x,y,z)

1 Left hemisphere, corticospinal tract 0.002 −20 −18 491 Left hemisphere, corticospinal tract 0.002 −21 −32 481 Left hemisphere, corticospinal tract 0.002 −22 −38 471 Left hemisphere, prefrontal white matter 0.002 −19 −6 451 Left hemisphere, prefrontal white matter 0.002 −20 −56 451 Left hemisphere, prefrontal white matter 0.002 −25 −45 422 Left hemisphere, prefrontal white matter 0.005 −19 −57 312 Left hemisphere. Corpus callosum 0.005 −22 −56 232 Left hemisphere. Corpus callosum 0.005 −27 −62 192 Left hemisphere. Corpus callosum 0.005 −26 −57 172 Left hemisphere. Corpus callosum 0.005 −26 -61 152 Left hemisphere. Corpus callosum 0.005 −25 −57 123 Left hemisphere. Left frontal white matter. Lower frontooccipital fascicle, anterior thalamic radiation 0.005 −34 34 83 Left hemisphere. Left frontal white matter. Lower frontooccipital fascicle, anterior thalamic radiation 0.005 −39 31 73 Left hemisphere. Left frontal white matter. Lower frontooccipital fascicle, anterior thalamic radiation 0.005 −36 34 6

151J.L. Carrasco et al. / Journal of Affective Disorders 139 (2012) 149–153

with healthy controls. DTI study of patients and controlsshowed reduced FA at the genu and the anterior area of thebody of corpus callosum and in orbitofrontal bilateral whitematter in BPD patients. The importance of prefrontal cortexin the modulation and inhibition of the inputs from the amyg-dala has been consistently demonstrated (Rolls, 2004a, 2004b).Therefore, impairment of the fronto-limbic connectivityresulting from white matter damage at prefrontal areas mightexplain some of the impulsive behavioral features of BPD.

Our results are in accordance with previous studies show-ing a reduction of FA in BPD patients with comorbid ADHD(Rusch et al., 2007). The abnormalities found at prefrontaland cingulate white matter might provide some explanationsfor previous results in studies using PET (Goyer et al., 1994;Soloff et al., 2000, 2005) and fMRI (Brunner et al., 2010;Minzenberg et al., 2007; Rusch et al., 2007). Decreased FA

Fig. 1. Fig. 1 shows reduced fractional anisotropy areas in BPD participants in compa(yellow-orange color). FMD (corrected pb0.005). The FA skeleton model obtainedcorresponds to the standard FMRIB58.

in our study reveals microstructural damage at corpus callo-sum and prefrontal areas which are probably related to thefunctional fronto-limbic deficits in BPD described in the men-tioned studies. In this line, a recent study with magnetoen-cephalography in BPD demonstrated a significant reductionof orbitofrontal activity in response to emotional stimuliwhich was specifically associated to the presence of chronicdepressive features in these patients (Diaz-Marsa et al.,2011).

Other DTI studies in affective disorders found decreasedFA in dorsolateral prefrontal white matter in major depres-sive disorder subjects (Blood et al., 2001; Bora et al., 2004;Wu et al., 2011), and lower FA in the genu of bipolar disordersubjects (Adler et al., 2004; Versace et al., 2009; Yurgelun-Todd et al., 2007). All these findings further support the hy-pothesis that frontal brain minor damage may be associated

rison with healthy controls (HC). Significant reduction voxels were detectedfrom 24 patients and controls appears in green, and the background image

152 J.L. Carrasco et al. / Journal of Affective Disorders 139 (2012) 149–153

to affective disorders. Prefrontal cortex is considered to play acrucial role in the control of behavior and in emotional regu-lation, which are usually severely impaired in affective disor-ders (Domes et al., 2009; Nielen et al., 2009). Therefore, ourresults support the idea that borderline personality disordershares fundamental psychobiological features with affectivedisorders.

The hypothesis that neural tissue damage might partici-pate in the pathophysiology of impulse and behavioraldysregulation in BPD is also supported by a number of neuro-psychological research studies (Arza et al., 2009; Seres et al.,2009; Volker et al., 2009). Most of these studies have shownextensive deficits in tests assessing prefrontal performance,including executive functioning, verbal memory, conceptualdiscrimination and impulse control.

To the best of our knowledge, this is the third DTI studydemonstrating abnormalities in white matter prefrontal fibersin BPD patients comparedwith healthy controls. However, sev-eral limitations should be mentioned that affect the conclu-sions, including medication of patients and heterogeneity ofthe BPD concept. Although our patients were unmedicated atthe time of the study, many of them had received long-termmedications previously that could have produced minor braindamage. On the other side, white matter changes are not uni-form across all BPD patients and fiber damage might be associ-ated to specific clinical features of the disorder, such aschronicity, comorbidity with other axis II disorders, cognitivedysfunctions or global severity. These questions should be in-vestigated in large sample of patients or in longitudinal studies.Another limitation is that diffusion tensor scans aremore proneto artifact, including bulk motion, chemical shift artifacts, spa-tial distortion, and partial volume effects compared with stan-dard MRI, the imaging mechanism used in most volumetricstudies. Additionally the resolution of our DTI is lower com-pared with the most recent DTI studies.

The small sample size limits the ability to generalize thefindings to the global population of BPD patients, but at leastshows the need to investigate neural damage in thesedisorder.

In summary, significantly impaired white matter integrityat orbitofrontal and callosum brain regions was found in BPDin our study compared with healthy subjects. Whether thisfinding could be associated with the clinical features andthe neurocognitive impairment in BPD patients has to beaddressed in future studies with larger samples.

Role of the funding sourceThere was no any sponsor in this study.

Conflict of interestAll authors declare that they have no conflicts of interest.

Acknowledgments

This study was financed through grants from the Spanish Government(to Dr. Díaz-Marsá FIS 07-0176 and Dr. Carrasco FIS 07-0172).

None of the authors acknowledges any conflict of interest in relation tothis research.

Dr. Carrasco has full access to all the data in the study and takes respon-sibility for the integrity of the data and the accuracy of the data analysis.

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