Abstract
Objective:
Borderline personality disorder (BPD) is a devastating condition that causes intense disruption of patients' lives and relationships. Proper understanding of BPD neurobiology could help provide the basis for earlier and effective interventions. As neuroimaging studies of patients with BPD are still scarce, volumetric and geometric features of the cortical structure were assessed to ascertain whether structural cortical alterations are present in BPD patients.
Methods:
Twenty-five female outpatients with BPD underwent psychiatric evaluation (SCID-I and II) and a 1.5 T magnetic resonance imaging (MRI) brain scan. The control group comprised 25 healthy age-matched females. Images were processed with the FreeSurfer package, which allows analysis of cortical morphology with more detailed descriptions of volumetric and geometric features of cortical structure.
Results:
Compared with controls, BPD patients exhibited significant cortical abnormalities in the fronto-limbic and paralimbic regions of both hemispheres.
Conclusion:
Significant morphologic abnormalities were observed in patients with BPD on comparison with a healthy control group through a multimodal approach. This study highlights the involvement of regions associated with mood regulation, impulsivity, and social behavior in BPD patients and presents a new approach for further investigation through a method of structural analysis based on distinct and simultaneous volumetric and geometric parameters.
Magnetic resonance imaging; neuroimaging; borderline personality disorder; mental disorders
Introduction
Borderline personality disorder (BPD) is a devastating condition that affects 1 to 2% of the population and causes intense disruption of patients' lives and relationships.11. American Psychiatric Association. Diagnostic and statistical manual of mental disorders - DSM-IV-TR¯. 4th ed. Washington: American Psychiatric Publishing; 2004.,22. Minzenberg MJ, Fan J, New AS, Tang CY, Siever LJ. Frontolimbic structural changes in borderline personality disorder. J Psychiatr Res. 2008;42:727-33. Emotional and behavioral dyscontrol, as well as affective dysregulation, play a large role in this severe morbidity, and BPD is associated with high rates of suicidality.11. American Psychiatric Association. Diagnostic and statistical manual of mental disorders - DSM-IV-TR¯. 4th ed. Washington: American Psychiatric Publishing; 2004.,22. Minzenberg MJ, Fan J, New AS, Tang CY, Siever LJ. Frontolimbic structural changes in borderline personality disorder. J Psychiatr Res. 2008;42:727-33. Patients with BPD often exhibit impulsive behaviors (self-mutilation, substance abuse, sexual promiscuity, and binge eating), rapid mood changes, and a propensity toward intense negative emotional states, such as anger, anxiety, and dysphoria.33. Lis E, Greenfield B, Henry M, Guilé JM, Dougherty G. Neuroimaging and genetics of borderline personality disorder: a review. J Psychiatry Neurosci. 2007;32:162-73.,44. Lyoo IK, Han MH, Cho DY. A brain MRI study in subjects with borderline personality disorder. J Affect Disord. 1998;50:235-43.
Structural magnetic resonance imaging (MRI) studies have demonstrated volume
reduction of cerebral regions associated with affective regulation, such as the
hippocampus, amygdala, and anterior cingulate cortex (ACC), which probably
constitute part of the neural substrate of BPD symptomatology and would serve as
putative endophenotypes for this illness.44. Lyoo IK, Han MH, Cho DY. A brain MRI study in subjects with
borderline personality disorder. J Affect Disord.
1998;50:235-43.
5. Rüsch N, van Elst LT, Ludaescher P, Wilke M, Huppertz HJ,
Thiel T, et al. A voxel-based morphometric MRI study in female patients with
borderline personality disorder. Neuroimage. 2003;20:385-92.
6. Tebartz van Elst L, Hesslinger B, Thiel T, Geiger E, Haegele K,
Lemieux L, et al. Frontolimbic brain abnormalities in patients with borderline
personality disorder: a volumetric magnetic resonance imaging study. Biol
Psychiatry. 2003;54:163-71.
7. Chanen AM, Velakoulis D, Carison K, Gaunson K, Wood SJ, Yuen HP,
et al. Orbitofrontal amygdala and hippocampal volumes in teenagers with
first-presentation borderline personality disorder. Psychiatry Res.
2008;163:116-25.
8. Ruocco AC, Amirthavasagam S, Zakzanis KK. Amygdala and
hippocampal volume reductions as candidate endophenotypes for borderline
personality disorder: A meta-analysis of magnetic resonance imaging studies.
Psychiatry Res. 2012;201:245-52.-99. O'Neill A, Frodl T. Brain structure and function in
borderline personality disorder. Brain Struct Funct.
2012;217:767-82. Moreover, a fronto-limbic
model of affective dysregulation that also involves prefrontal and frontobasal brain
structures has been investigated in this population through functional neuroimaging
studies.22. Minzenberg MJ, Fan J, New AS, Tang CY, Siever LJ. Frontolimbic
structural changes in borderline personality disorder. J Psychiatr Res.
2008;42:727-33.
3. Lis E, Greenfield B, Henry M, Guilé JM, Dougherty G.
Neuroimaging and genetics of borderline personality disorder: a review. J
Psychiatry Neurosci. 2007;32:162-73.-44. Lyoo IK, Han MH, Cho DY. A brain MRI study in subjects with
borderline personality disorder. J Affect Disord.
1998;50:235-43.,1010. Koenigsberg HW, Fan J, Ochsner KN, Liu X, Guise KG, Pizzarello
S, et al. Neural correlates of the use of psychological distancing to regulate
responses to negative social cues: a study of patients with borderline
personality disorder. Biol Psychiatry. 2009;66:854-63.
To date, most structural neuroimaging studies performed in BPD have utilized
techniques based on voxel-based morphometry (VBM), which combines several geometric
parameters including thickness, surface area, and folding. As a consequence,
VBM-based findings cannot be attributed to a single biologically meaningful
process.1111. Panizzon MS, Fennema-Notestine C, Eyler LT, Jernigan TL,
Prom-Wormley E, Neale M, et al. Distinct genetic influences on cortical surface
area and cortical thickness. Cereb Cortex. 2009;19:2728-35.
12. Ecker C, Marquand A, Mourão-Miranda J, Johnston P, Daly EM,
Brammer MJ, et al. Describing the brain in autism in five dimensions: magnetic
resonance imaging-assisted diagnosis of autism spectrum disorder using a
multiparameter classification approach. J Neurosci.
2010;30:10612-23.-1313. Sowell ER, Thompson PM, Leonard CM, Welcome SE, Kan E, Toga AW.
Longitudinal mapping of cortical thickness and brain growth in normal children.
J Neurosci. 2004;24:8223-31. In addition, the literature has reported that approaches
based on cortical thickness seem to be more sensitive than VBM for identification of
regional gray matter changes.1414. Dale AM, Fischl B, Sereno MI. Cortical surface-based analysis.
I. Segmentation and surface reconstruction. Neuroimage.
1999;9:179-94. The routines
implemented in FreeSurfer, an automated cortical surface reconstruction method,
provide a technique that uses MRI intensity contrasts to obtain accurate volumetric
and geometric parameters that have been reliably used to investigate several
psychiatric and neurological disorders.1414. Dale AM, Fischl B, Sereno MI. Cortical surface-based analysis.
I. Segmentation and surface reconstruction. Neuroimage.
1999;9:179-94.
15. Fischl B, Sereno MI, Dale AM. 1999. Cortical surface-based
analysis. II: Inflation, flattening, and a surface-based coordinate system.
Neuroimage. 1999;9:195-207.
16. Fischl B, Dale AM. Measuring the thickness of the human cerebral
cortex from magnetic resonance images. Proc Nat Acad Sci USA.
2000;97:11050-5.-1717. Fischl B, van der Kouwe A, Destrieux C, Halgren E, Segonne F,
Salat DH, et al. Automatically parcellating the human cerebral cortex. Cereb
Cortex. 2004;14:11-22. In addition, accurate
methods for measuring cerebral cortical thickness offer a powerful tool for
understanding the neurobiological basis of a variety of brain disorders.1111. Panizzon MS, Fennema-Notestine C, Eyler LT, Jernigan TL,
Prom-Wormley E, Neale M, et al. Distinct genetic influences on cortical surface
area and cortical thickness. Cereb Cortex. 2009;19:2728-35.,1414. Dale AM, Fischl B, Sereno MI. Cortical surface-based analysis.
I. Segmentation and surface reconstruction. Neuroimage.
1999;9:179-94.
15. Fischl B, Sereno MI, Dale AM. 1999. Cortical surface-based
analysis. II: Inflation, flattening, and a surface-based coordinate system.
Neuroimage. 1999;9:195-207.
16. Fischl B, Dale AM. Measuring the thickness of the human cerebral
cortex from magnetic resonance images. Proc Nat Acad Sci USA.
2000;97:11050-5.-1717. Fischl B, van der Kouwe A, Destrieux C, Halgren E, Segonne F,
Salat DH, et al. Automatically parcellating the human cerebral cortex. Cereb
Cortex. 2004;14:11-22.
Based on the foregoing and on prior neuroimaging studies of BPD, the present study used a multimodal approach based on the FreeSurfer image analysis suite to conduct a more detailed investigation into structural cortical abnormalities in patients with BPD. We aimed to demonstrate that the neuroanatomical alterations in BPD patients comprise multiple cortical features when compared with controls. In addition, we hypothesized that differences in geometric and volumetric parameters would be present in regions associated with BPD, particularly the hippocampus, amygdala, ACC, and prefrontal and frontobasal areas.
Methods
Participants
Patients were recruited from the outpatient clinic of a tertiary referral center (Department of Psychiatry, Universidade Federal de São Paulo, São Paulo, Brazil), and all were receiving psychiatric and psychotherapeutic care at the time of the study. After Ethics Committee approval, the advantages and risks of participation were explained to the patients and informed consent was obtained. The inclusion criteria for the patient group were a current psychiatric diagnosis of BPD and having been treated at the study unit for at least 6 months. Although almost all patients enrolled had a past history of other psychiatric disorders, patients who met current criteria for any axis I or II psychiatric diagnoses besides BPD were excluded.
Psychiatric evaluation
Clinical and socio-demographic data including age, gender, educational attainment, family psychiatric history, and previous psychiatric treatment (including hospitalizations and pharmacotherapy) were collected by means of a questionnaire administered before imaging. The psychiatric evaluation was performed by the same psychiatrist (GMAF) through two structured instruments: the Structured Clinical Interview for DSM-IV Axis I Disorders and its Axis II counterpart (SCID-I and SCID-II respectively).1818. First MB, Spitzer PL, Gibbon M, Williams JB. Structured clinical interview for DSM-IV axis I disorders - patient edition (SCID-I/P, Version 2.0. 9/98 revision). New York: Biometrics Research Department, New York State Research Institute; 1998.,1919. Spitzer PL, Williams JB, Gibbon M, First MB. Structured clinical interview for DSM-III-R axis II disorders (SCID-II, Version 9/89). New York: Biometrics Research Department, New York State Research Institute; 1989.
Procedures
MRI scans of 25 female patients that fulfilled diagnostic criteria for BPD at the time of the study were compared to those of controls. The control group consisted of 25 age- and gender-matched healthy volunteers who were also evaluated by the same psychiatrist (GMAF) using the same instruments (SCID-I and SCID-II).1818. First MB, Spitzer PL, Gibbon M, Williams JB. Structured clinical interview for DSM-IV axis I disorders - patient edition (SCID-I/P, Version 2.0. 9/98 revision). New York: Biometrics Research Department, New York State Research Institute; 1998.,1919. Spitzer PL, Williams JB, Gibbon M, First MB. Structured clinical interview for DSM-III-R axis II disorders (SCID-II, Version 9/89). New York: Biometrics Research Department, New York State Research Institute; 1989. None of the controls had used antihistamines, alcohol, or other drugs in the 72 hours preceding psychiatric evaluation.
MRI data acquisition
All subjects underwent MRI examination of the brain using a 1.5 T MRI scanner (MAGNETOM Sonata[Maestro Class], Siemens AG, Medical Solutions, Erlangen, Germany) with an eight-channel head coil. Two conventional sequences were performed to rule out structural lesions: a) Axial T2-weighted FLAIR (fluid-attenuated inversion recovery) in a plane parallel to the anterior commissure-posterior commissure (AC-PC) line (TR [repetition time] 8500 ms, TE [echo time] 107 ms, IT [inversion time] 2500 ms, slice thickness 5.0 mm, slice interval 1.5 mm, FOV [field of view] 240 mm, matrix size 256 x 256, NEX [number of excitations]) 1); b) Sagittal T1-weighted gradient-echo volume acquisition for multiplanar reconstruction (TR 2000 ms, TE 3.42 ms, flip angle 15 degrees, FOV 245 mm, 1.0-mm slice thickness with no gaps for a total of 160 slices per slab, matrix size 256 x 256, NEX 1). All patients and controls included in the study had normal images on visual inspection. Scans displaying low image quality or clinical abnormalities were excluded.
Multimodal analysis
The T1-weighted structural MR images were preprocessed using the recon-all
pipeline of the FreeSurfer package with standard parameters. This pipeline is
documented in detail and freely available at the FreeSurfer website (http://surfer.nmr.mgh.harvard.edu). Further information can be
found in the cited literature.1414. Dale AM, Fischl B, Sereno MI. Cortical surface-based analysis.
I. Segmentation and surface reconstruction. Neuroimage.
1999;9:179-94.
15. Fischl B, Sereno MI, Dale AM. 1999. Cortical surface-based
analysis. II: Inflation, flattening, and a surface-based coordinate system.
Neuroimage. 1999;9:195-207.
16. Fischl B, Dale AM. Measuring the thickness of the human cerebral
cortex from magnetic resonance images. Proc Nat Acad Sci USA.
2000;97:11050-5.-1717. Fischl B, van der Kouwe A, Destrieux C, Halgren E, Segonne F,
Salat DH, et al. Automatically parcellating the human cerebral cortex. Cereb
Cortex. 2004;14:11-22. Five morphometric quantitative measures
of the cortex were compared between the study and control groups: average
convexity or concavity, mean radial curvature, metric distortion, cortical
thickness, and surface area. Further details about these measures can be found
in Ecker et al.1212. Ecker C, Marquand A, Mourão-Miranda J, Johnston P, Daly EM,
Brammer MJ, et al. Describing the brain in autism in five dimensions: magnetic
resonance imaging-assisted diagnosis of autism spectrum disorder using a
multiparameter classification approach. J Neurosci.
2010;30:10612-23.
Statistics
Clinical and demographic data were presented as mean ± standard deviation. Age and handedness matching between patients and controls was evaluated using the t-test for two independent samples and chi-square test respectively. The statistical significance level was set at 5%. The QDEC graphical interface of FreeSurfer was used to model and test the parameters of a general linear model (GLM) at each vertex across the cortical surface. In this model, we considered the cortical thickness and/or surface area as the response variable, group (BPD or control) as a fixed factor, and age as a nuisance variable. Results were corrected for multiple comparisons using the false discovery rate (pFDR < 0.05). Subcortical structure (i.e., amygdala and hippocampus) volumes were extracted from FreeSurfer output and analyzed using SPSS version 14.0.
Results
Demographic data and global brain measurements
Data from 25 female BPD patients and 25 female controls were included. Groups were matched by gender (p > 0.99), age (p = 0.82), handedness (p = 0.79), and years of schooling (p = 0.12). Among BPD patients, the mean duration of the disorder was 16.6±9.5 years. Regarding the number and type of psychotropic medications used, all BPD patients were taking at least one medication (antidepressant, mood stabilizer, or antipsychotic) at the time of the study. Twenty-four were taking a mood stabilizer, while 18 were taking antidepressants and 10 were using antipsychotics. At the time of psychiatric evaluation, six patients were on monotherapy, while 13 were taking two psychotropic medications and six patients were taking three psychotropic medications. Demographic data and global brain measurements of patients and controls are shown in Table 1.
FreeSurfer analysis
The segmented left and right hemispheres of both groups were compared through the geometric and morphometric parameters (thickness, volume, area/pial area, depth of sulcus, curvature, and metric distortion) available in the FreeSurfer package. As compared with controls, BPD patients exhibited significant alterations of those parameters in the limbic and paralimbic regions, among others, of both hemispheres. The main findings of multimodal analysis that are significant under a corrected threshold of pFDR = 0.05 are shown in Table 2 and in Figures 1 and 2. No structural differences were observed between groups taking a different number of medications.
Multimodal cortical features (area, deformation/Jacobian, curvature, depth of sulcus, and thickness) comparisons between BPD and controls represented in an inflated brain surface (medial vision). Red/yellow colors represent reduced regions in BPD and blue/purple colors represent increased regions in BPD. Values were corrected through FDR = 0.05 for display. BPD = borderline personality disorder; FDR = false discovery rate.
Multimodal cortical features (area, deformation/Jacobian, curvature, depth of sulcus, and thickness) comparisons between BPD and controls represented in an inflated brain surface (lateral vision). Red/yellow colors represent reduced regions in BPD and blue/purple colors represent increased regions in BPD. Values were corrected through FDR = 0.05 for display. BPD = borderline personality disorder; FDR = false discovery rate.
Discussion
The aim of this study was to conduct an exploratory investigation of structural fronto-limbic abnormalities, particularly in the hippocampus, amygdala, ACC, and prefrontal and frontobasal structures, in a group of 25 female patients with BPD. Toward this end, we used the FreeSurfer image analysis suite, an innovative method that can contribute to this area of research by offering different and simultaneous volumetric and geometric parameters.
Cortical morphology is of great interest in both normal development and in a wide
variety of neurodegenerative and neuropsychiatric disorders. However, manual methods
for estimating cortical thickness from neuroimaging data are labor-intensive,
requiring several days' effort by a trained anatomist. Furthermore, the highly
folded nature of the cortex is problematic for manual techniques, frequently
resulting in measurement errors in regions in which the cortical surface is not
perpendicular to any of the cardinal axes.1111. Panizzon MS, Fennema-Notestine C, Eyler LT, Jernigan TL,
Prom-Wormley E, Neale M, et al. Distinct genetic influences on cortical surface
area and cortical thickness. Cereb Cortex. 2009;19:2728-35.,1414. Dale AM, Fischl B, Sereno MI. Cortical surface-based analysis.
I. Segmentation and surface reconstruction. Neuroimage.
1999;9:179-94.
15. Fischl B, Sereno MI, Dale AM. 1999. Cortical surface-based
analysis. II: Inflation, flattening, and a surface-based coordinate system.
Neuroimage. 1999;9:195-207.
16. Fischl B, Dale AM. Measuring the thickness of the human cerebral
cortex from magnetic resonance images. Proc Nat Acad Sci USA.
2000;97:11050-5.-1717. Fischl B, van der Kouwe A, Destrieux C, Halgren E, Segonne F,
Salat DH, et al. Automatically parcellating the human cerebral cortex. Cereb
Cortex. 2004;14:11-22. On the other hand, the automated alternative methods
available based on voxel morphometry (such as VBM) perform only indirect analyses of
gray matter concentration and volume, producing an unspecific mixture of geometric
parameters including thickness, surface area, and folding.1414. Dale AM, Fischl B, Sereno MI. Cortical surface-based analysis.
I. Segmentation and surface reconstruction. Neuroimage.
1999;9:179-94.
15. Fischl B, Sereno MI, Dale AM. 1999. Cortical surface-based
analysis. II: Inflation, flattening, and a surface-based coordinate system.
Neuroimage. 1999;9:195-207.
16. Fischl B, Dale AM. Measuring the thickness of the human cerebral
cortex from magnetic resonance images. Proc Nat Acad Sci USA.
2000;97:11050-5.-1717. Fischl B, van der Kouwe A, Destrieux C, Halgren E, Segonne F,
Salat DH, et al. Automatically parcellating the human cerebral cortex. Cereb
Cortex. 2004;14:11-22. As a consequence,
VBM-based findings cannot be attributed to a single biologically meaningful process,
thus precluding insights regarding important pathophysiological aspects associated
with various neuropsychiatric disorders.1111. Panizzon MS, Fennema-Notestine C, Eyler LT, Jernigan TL,
Prom-Wormley E, Neale M, et al. Distinct genetic influences on cortical surface
area and cortical thickness. Cereb Cortex. 2009;19:2728-35.
12. Ecker C, Marquand A, Mourão-Miranda J, Johnston P, Daly EM,
Brammer MJ, et al. Describing the brain in autism in five dimensions: magnetic
resonance imaging-assisted diagnosis of autism spectrum disorder using a
multiparameter classification approach. J Neurosci.
2010;30:10612-23.-1313. Sowell ER, Thompson PM, Leonard CM, Welcome SE, Kan E, Toga AW.
Longitudinal mapping of cortical thickness and brain growth in normal children.
J Neurosci. 2004;24:8223-31. Since evidence suggests
that alterations in cortical thickness and surface (pial) area reflect different
neurobiological processes and are associated with different genetic mechanisms,
approaches based on cortical morphology could contribute to our understanding of the
underpinnings of a number of neurodegenerative and psychiatric disorders.1111. Panizzon MS, Fennema-Notestine C, Eyler LT, Jernigan TL,
Prom-Wormley E, Neale M, et al. Distinct genetic influences on cortical surface
area and cortical thickness. Cereb Cortex. 2009;19:2728-35.,1414. Dale AM, Fischl B, Sereno MI. Cortical surface-based analysis.
I. Segmentation and surface reconstruction. Neuroimage.
1999;9:179-94.
15. Fischl B, Sereno MI, Dale AM. 1999. Cortical surface-based
analysis. II: Inflation, flattening, and a surface-based coordinate system.
Neuroimage. 1999;9:195-207.
16. Fischl B, Dale AM. Measuring the thickness of the human cerebral
cortex from magnetic resonance images. Proc Nat Acad Sci USA.
2000;97:11050-5.-1717. Fischl B, van der Kouwe A, Destrieux C, Halgren E, Segonne F,
Salat DH, et al. Automatically parcellating the human cerebral cortex. Cereb
Cortex. 2004;14:11-22. Moreover, studies have
noted that such approaches seem to be more sensitive than VBM for identification of
regional gray matter changes.1717. Fischl B, van der Kouwe A, Destrieux C, Halgren E, Segonne F,
Salat DH, et al. Automatically parcellating the human cerebral cortex. Cereb
Cortex. 2004;14:11-22.
Studies have highlighted that cortical thickness is likely to reflect dendritic
arborization or changing myelination at the gray-white matter interface.2020. Rakic P. Defects of neuronal migration and the pathogenesis of
cortical malformations. Prog Brain Res. 1988;73:15-37.
21. Armstrong E, Schleicher A, Omran H, Curtis M, Zilles K. The
ontogeny of human gyrification. Cereb Cortex. 1995;5:56-63.-2222. Van Essen DC. A tension-based theory of morphogenesis and
compact wiring in the central nervous system. Nature.
1997;385:313-8. On
the other hand, surface area is influenced by the division of progenitor cells in
the embryological periventricular area, and is associated with the number of
minicolumns.1111. Panizzon MS, Fennema-Notestine C, Eyler LT, Jernigan TL,
Prom-Wormley E, Neale M, et al. Distinct genetic influences on cortical surface
area and cortical thickness. Cereb Cortex. 2009;19:2728-35.
12. Ecker C, Marquand A, Mourão-Miranda J, Johnston P, Daly EM,
Brammer MJ, et al. Describing the brain in autism in five dimensions: magnetic
resonance imaging-assisted diagnosis of autism spectrum disorder using a
multiparameter classification approach. J Neurosci.
2010;30:10612-23.-1313. Sowell ER, Thompson PM, Leonard CM, Welcome SE, Kan E, Toga AW.
Longitudinal mapping of cortical thickness and brain growth in normal children.
J Neurosci. 2004;24:8223-31.,2020. Rakic P. Defects of neuronal migration and the pathogenesis of
cortical malformations. Prog Brain Res. 1988;73:15-37. Finally, geometric
differences (depth of sulcus, curvature, and metric distortion) are predominantly
linked with the development of neuronal connections and cortical pattern of
connectivity, and are thus a marker for cerebral development.2121. Armstrong E, Schleicher A, Omran H, Curtis M, Zilles K. The
ontogeny of human gyrification. Cereb Cortex. 1995;5:56-63.,2222. Van Essen DC. A tension-based theory of morphogenesis and
compact wiring in the central nervous system. Nature.
1997;385:313-8. Therefore, it is
likely that the maps produced by approaches based on cortical morphology reflect
multiple genetic and/or neurobiological etiologies, which need further
investigation.2020. Rakic P. Defects of neuronal migration and the pathogenesis of
cortical malformations. Prog Brain Res. 1988;73:15-37.
21. Armstrong E, Schleicher A, Omran H, Curtis M, Zilles K. The
ontogeny of human gyrification. Cereb Cortex. 1995;5:56-63.-2222. Van Essen DC. A tension-based theory of morphogenesis and
compact wiring in the central nervous system. Nature.
1997;385:313-8.
Evidence suggests that the components of the fronto-limbic network, such as the ACC,
orbitofrontal cortex (OFC), dorsolateral prefrontal cortex, and amygdala-hippocampus
complex, are potentially involved in BPD pathophysiology; these structures have been
investigated in previous region-of-interest- and VBM-based studies.44. Lyoo IK, Han MH, Cho DY. A brain MRI study in subjects with
borderline personality disorder. J Affect Disord.
1998;50:235-43.
5. Rüsch N, van Elst LT, Ludaescher P, Wilke M, Huppertz HJ,
Thiel T, et al. A voxel-based morphometric MRI study in female patients with
borderline personality disorder. Neuroimage. 2003;20:385-92.-66. Tebartz van Elst L, Hesslinger B, Thiel T, Geiger E, Haegele K,
Lemieux L, et al. Frontolimbic brain abnormalities in patients with borderline
personality disorder: a volumetric magnetic resonance imaging study. Biol
Psychiatry. 2003;54:163-71.,2323. Brunner R, Henze R, Parzer P, Kramer J, Feigl N, Lutz K, et al.
Reduced prefrontal and orbitofrontal gray matter in female adolescents with
borderline personality disorder: is it disorder specific? Neuroimage.
2010;49:114-20. In addition, there is
mounting evidence that patients with BPD exhibit deficits in structure and function
of the ACC, OFC, and amygdala-hippocampus complex.44. Lyoo IK, Han MH, Cho DY. A brain MRI study in subjects with
borderline personality disorder. J Affect Disord.
1998;50:235-43.
5. Rüsch N, van Elst LT, Ludaescher P, Wilke M, Huppertz HJ,
Thiel T, et al. A voxel-based morphometric MRI study in female patients with
borderline personality disorder. Neuroimage. 2003;20:385-92.-66. Tebartz van Elst L, Hesslinger B, Thiel T, Geiger E, Haegele K,
Lemieux L, et al. Frontolimbic brain abnormalities in patients with borderline
personality disorder: a volumetric magnetic resonance imaging study. Biol
Psychiatry. 2003;54:163-71.,2323. Brunner R, Henze R, Parzer P, Kramer J, Feigl N, Lutz K, et al.
Reduced prefrontal and orbitofrontal gray matter in female adolescents with
borderline personality disorder: is it disorder specific? Neuroimage.
2010;49:114-20. Structural neuroimaging studies have already suggested the
presence of neuroanatomical abnormalities of limbic structures in both the right and
left hemispheres in BPD patients.77. Chanen AM, Velakoulis D, Carison K, Gaunson K, Wood SJ, Yuen HP,
et al. Orbitofrontal amygdala and hippocampal volumes in teenagers with
first-presentation borderline personality disorder. Psychiatry Res.
2008;163:116-25.,88. Ruocco AC, Amirthavasagam S, Zakzanis KK. Amygdala and
hippocampal volume reductions as candidate endophenotypes for borderline
personality disorder: A meta-analysis of magnetic resonance imaging studies.
Psychiatry Res. 2012;201:245-52.,2424. Jackowski AP, Araújo Filho GM, Almeida AG, Araújo CM,
Reis M, Nery F, et al. The involvement of the orbitofrontal cortex in
psychiatric disorders: an update of neuroimaging findings. Rev Bras Psiquiatr.
2012;34:207-12.
25. Schmahl CG, Elzinga BM, Vermetten E, Sanislow C, McGlashan TH,
Bremner JD. Neural correlates of memories of abandonment in women with and
without borderline personality disorder. Biol Psychiatry.
2003;54:142-51.
26. Driessen M, Herrmann J, Stahl K, Zwaan M, Meier S, Hill A, et
al. Magnetic resonance imaging volumes of the hippocampus and the amygdala in
women with borderline personality disorder and early traumatization. Arch Gen
Psychiatry. 2000;57:1115-22.-2727. Brambilla P, Soloff PH, Sala M, Nicoletti MA, Keshavan MS,
Soares JC. Anatomical MRI study of borderline personality disorder patients.
Psychiatry Res. 2004;131:125-33. As these areas are
associated with affective regulation, such reductions might be biological substrates
of BPD symptomatology.55. Rüsch N, van Elst LT, Ludaescher P, Wilke M, Huppertz HJ,
Thiel T, et al. A voxel-based morphometric MRI study in female patients with
borderline personality disorder. Neuroimage. 2003;20:385-92.,66. Tebartz van Elst L, Hesslinger B, Thiel T, Geiger E, Haegele K,
Lemieux L, et al. Frontolimbic brain abnormalities in patients with borderline
personality disorder: a volumetric magnetic resonance imaging study. Biol
Psychiatry. 2003;54:163-71.,2525. Schmahl CG, Elzinga BM, Vermetten E, Sanislow C, McGlashan TH,
Bremner JD. Neural correlates of memories of abandonment in women with and
without borderline personality disorder. Biol Psychiatry.
2003;54:142-51.
26. Driessen M, Herrmann J, Stahl K, Zwaan M, Meier S, Hill A, et
al. Magnetic resonance imaging volumes of the hippocampus and the amygdala in
women with borderline personality disorder and early traumatization. Arch Gen
Psychiatry. 2000;57:1115-22.-2727. Brambilla P, Soloff PH, Sala M, Nicoletti MA, Keshavan MS,
Soares JC. Anatomical MRI study of borderline personality disorder patients.
Psychiatry Res. 2004;131:125-33. The present study revealed significant
morphological abnormalities of cortical thickness, volume, mean curvature, metric
distortion, surface area, and depth of sulcus in such areas among BPD patients.
These findings are in agreement with previous structural neuroimaging studies
involving BPD patients, and highlight the involvement of these areas in the
regulation of mood reactivity, impulsivity, and social behavior, which are
considered dysfunctional in these patients.22. Minzenberg MJ, Fan J, New AS, Tang CY, Siever LJ. Frontolimbic
structural changes in borderline personality disorder. J Psychiatr Res.
2008;42:727-33.
3. Lis E, Greenfield B, Henry M, Guilé JM, Dougherty G.
Neuroimaging and genetics of borderline personality disorder: a review. J
Psychiatry Neurosci. 2007;32:162-73.
4. Lyoo IK, Han MH, Cho DY. A brain MRI study in subjects with
borderline personality disorder. J Affect Disord.
1998;50:235-43.
5. Rüsch N, van Elst LT, Ludaescher P, Wilke M, Huppertz HJ,
Thiel T, et al. A voxel-based morphometric MRI study in female patients with
borderline personality disorder. Neuroimage. 2003;20:385-92.-66. Tebartz van Elst L, Hesslinger B, Thiel T, Geiger E, Haegele K,
Lemieux L, et al. Frontolimbic brain abnormalities in patients with borderline
personality disorder: a volumetric magnetic resonance imaging study. Biol
Psychiatry. 2003;54:163-71.
Furthermore, studies have also observed structural alterations of the superior
(precuneus and postcentral gyrus) and inferior parietal cortices in BPD patients,
suggesting a possible role of parietal structures in dissociative symptoms and
identity disturbance in women with BPD.2828. Irle E, Lange C, Sachsse U. Reduced size and abnormal asymmetry
of parietal cortex in women with borderline personality disorder. Biol
Psychiatry. 2005;57:173-82.
29. Irle E, Lange C, Weniger G, Sachsse U. Size abnormalities of the
superior parietal cortices are related to dissociation in borderline personality
disorder. Psychiatry Res. 2007;156:139-49.-3030. Rüsch N, Luders E, Lieb K, Zahn R, Ebert D, Thompson PM, et
al. Corpus callosum abnormalities in women with borderline personality disorder
and comorbid attention-deficit hyperactivity disorder. J Psychiatry Neurosci.
2007;32:417-22. In addition, other studies
have found dysfunctions of structural connectivity involving parietal and temporal
areas in female BPD patients.55. Rüsch N, van Elst LT, Ludaescher P, Wilke M, Huppertz HJ,
Thiel T, et al. A voxel-based morphometric MRI study in female patients with
borderline personality disorder. Neuroimage. 2003;20:385-92.,3030. Rüsch N, Luders E, Lieb K, Zahn R, Ebert D, Thompson PM, et
al. Corpus callosum abnormalities in women with borderline personality disorder
and comorbid attention-deficit hyperactivity disorder. J Psychiatry Neurosci.
2007;32:417-22. Given the role of the parietal cortex in the
integration of many emotional and cognitive functions, such as sensory information
and visuospatial processing, this raises the possibility that dysfunction of such
processes in BPD may be at least partly caused by parietal impairment.2828. Irle E, Lange C, Sachsse U. Reduced size and abnormal asymmetry
of parietal cortex in women with borderline personality disorder. Biol
Psychiatry. 2005;57:173-82.
29. Irle E, Lange C, Weniger G, Sachsse U. Size abnormalities of the
superior parietal cortices are related to dissociation in borderline personality
disorder. Psychiatry Res. 2007;156:139-49.-3030. Rüsch N, Luders E, Lieb K, Zahn R, Ebert D, Thompson PM, et
al. Corpus callosum abnormalities in women with borderline personality disorder
and comorbid attention-deficit hyperactivity disorder. J Psychiatry Neurosci.
2007;32:417-22.
Although significant reductions in limbic and paralimbic areas have been reported even in adolescents with first-presentation BPD, such findings have not been observed as specific for BPD.3131. Takahashi T, Chanen AM, Wood SJ, Yücel M, Tanino R, Suzuki M, et al. Insular cortex volume and impulsivity in teenagers with first-presentation borderline personality disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33:1395-400.,3232. Takahashi T, Chanen AM, Wood SJ, Walterfang M, Harding IH, Yücel M, et al. Midline brain structures in teenagers with first-presentation borderline personality disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33:842-6. Moreover, the development of volume alterations during the course of BPD has also been suggested in the literature, but this hypothesis has yet to be clarified through longitudinal studies.3131. Takahashi T, Chanen AM, Wood SJ, Yücel M, Tanino R, Suzuki M, et al. Insular cortex volume and impulsivity in teenagers with first-presentation borderline personality disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33:1395-400.,3232. Takahashi T, Chanen AM, Wood SJ, Walterfang M, Harding IH, Yücel M, et al. Midline brain structures in teenagers with first-presentation borderline personality disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33:842-6. However, despite the wide variability of neurobiological processes associated with each morphometric and geometric parameters, almost all of the morphological alterations observed in BPD patients in the present study occurred in limbic and paralimbic regions, which reinforces the involvement of these areas in the pathophysiology of BPD.
Since the present study included a large number of patients taking psychiatric
medication, the potential effect of psychotropic drugs on brain structures and their
possible effect on neuroimaging should be considered. Recent biological theories on
the pathophysiology of psychiatric disorders have stated that symptoms could be a
consequence of aberrant intrasynaptic neurotransmitter concentrations, probably
associated with impairment of structural plasticity and resulting in gray matter
volume reductions. In accordance with this hypothesis, psychotropic drugs may act by
correcting the neurotransmitter dysfunctions and, consequently, the volume
reductions.3333. Phillips ML, Travis MJ, Fagiolini A, Kupfer DJ. Medication
effects in neuroimaging studies of bipolar disorder. Am J Psychiatry.
2008;165:313-20.
34. Fuchs E, Czéh B, Kole MH, Michaelis T, Lucassen PJ.
Alterations of neuroplasticity in depression: the hippocampus and beyond. Eur
Neuropsychopharmacol. 2004;14:S481-90.-3535. Navari S, Dazzan P. Do antipsychotic drugs affect brain
structure? A systematic and critical review of MRI findings. Psychol Med.
2009;39:1763-77. Longitudinal studies utilizing structural neuroimaging
techniques comparing drug-naïve patients before and after psychotropic
treatment have observed positive effects3333. Phillips ML, Travis MJ, Fagiolini A, Kupfer DJ. Medication
effects in neuroimaging studies of bipolar disorder. Am J Psychiatry.
2008;165:313-20.,3434. Fuchs E, Czéh B, Kole MH, Michaelis T, Lucassen PJ.
Alterations of neuroplasticity in depression: the hippocampus and beyond. Eur
Neuropsychopharmacol. 2004;14:S481-90.,3636. Li CT, Lin CP, Chou KH, Chen IY, Hsieh JC, Wu CL, et al.
Structural and cognitive deficits in remitting and non-remitting recurrent
depression: a voxel-based morphometric study. Neuroimage.
2010;50:347-56. or no brain structure modification3535. Navari S, Dazzan P. Do antipsychotic drugs affect brain
structure? A systematic and critical review of MRI findings. Psychol Med.
2009;39:1763-77. after psychotropic treatment, while functional neuroimaging
studies have observed enhancements in neuroplasticity and in brain
connectivity.3737. Light SN, Heller AS, Johnstone T, Kolden GG, Peterson MJ, Kalin
NH, et al. Reduced right ventrolateral prefrontal cortex activity while
inhibiting positive affect is associated with improvement in hedonic capacity
after 8 weeks of antidepressant treatment in major depressive disorder. Biol
Psychiatry. 2011;70:962-8.
38. Sekar S, Van Audekerke J, Vanhoutte G, Lowe AS, Blamire AM, Van
der Linden A, et al. Neuroanatomical targets of reboxetine and bupropion as
revealed by pharmacological magnetic resonance imaging. Psychopharmacology
(Berl). 2011;217:549-57.
39. Pardo BM, Garolera M, Ariza M, Pareto D, Salamero M, Valles V,
et al. Improvement of cognitive flexibility and cingulate blood flow correlates
after atypical antipsychotic treatment in drug-naive patients with first-episode
schizophrenia. Psychiatry Res. 2011;194:205-11.-4040. Ettinger U, Williams SC, Fannon D, Premkumar P, Kuipers E,
Möller HJ, et al. Functional magnetic resonance imaging of a parametric
working memory task in schizophrenia: relationship with performance and effects
of antipsychotic treatment. Psychopharmacology (Berl).
2011;216:17-27.
The findings reported herein should be interpreted in the context of a number of
limitations. The relatively small number of patients enrolled may preclude wider
conclusions. In addition, these findings cannot be applied to all BPD patients,
especially to male subjects. Since we aimed to examine a homogeneous group of BPD
patients and because both gender and handedness are known to be potential
confounders for structural brain analyses, the study was restricted to women. Some
relevant clinical aspects of BPD, such as impulsivity, suicidality, and suicide
attempts, were not assessed through specific instruments in the present study, and
also constitute an important limitation. Moreover, since we chose to enroll only BPD
patients with no current psychiatric comorbidity so as to refine our analysis, the
generalizability of the present findings to the typical BPD patient, who presents
with various psychiatric comorbidities, should be interpreted with caution. Finally,
although FreeSurfer analysis of cortical morphology could present a series of
limitations regarding segmentation errors, intensity normalization, pial surface
misplacements, skull strip errors, and topological defects,1111. Panizzon MS, Fennema-Notestine C, Eyler LT, Jernigan TL,
Prom-Wormley E, Neale M, et al. Distinct genetic influences on cortical surface
area and cortical thickness. Cereb Cortex. 2009;19:2728-35.,1414. Dale AM, Fischl B, Sereno MI. Cortical surface-based analysis.
I. Segmentation and surface reconstruction. Neuroimage.
1999;9:179-94.
15. Fischl B, Sereno MI, Dale AM. 1999. Cortical surface-based
analysis. II: Inflation, flattening, and a surface-based coordinate system.
Neuroimage. 1999;9:195-207.
16. Fischl B, Dale AM. Measuring the thickness of the human cerebral
cortex from magnetic resonance images. Proc Nat Acad Sci USA.
2000;97:11050-5.-1717. Fischl B, van der Kouwe A, Destrieux C, Halgren E, Segonne F,
Salat DH, et al. Automatically parcellating the human cerebral cortex. Cereb
Cortex. 2004;14:11-22. no BPD patients or controls had to be
excluded from this study for such reasons.
In conclusion, the present study observed significant cortical morphologic
alterations in BPD patients as compared with healthy age- and gender-matched
controls and provides new possibilities for neuroimaging studies in BPD through a
novel method of structural analysis that can contribute to this line of research by
offering more detailed descriptions of volumetric and geometric cortical surface
features.1111. Panizzon MS, Fennema-Notestine C, Eyler LT, Jernigan TL,
Prom-Wormley E, Neale M, et al. Distinct genetic influences on cortical surface
area and cortical thickness. Cereb Cortex. 2009;19:2728-35.
12. Ecker C, Marquand A, Mourão-Miranda J, Johnston P, Daly EM,
Brammer MJ, et al. Describing the brain in autism in five dimensions: magnetic
resonance imaging-assisted diagnosis of autism spectrum disorder using a
multiparameter classification approach. J Neurosci.
2010;30:10612-23.-1313. Sowell ER, Thompson PM, Leonard CM, Welcome SE, Kan E, Toga AW.
Longitudinal mapping of cortical thickness and brain growth in normal children.
J Neurosci. 2004;24:8223-31. The present results can also contribute to further
investigations of more specific neurobiological processes involved in the
pathophysiology of BPD. Although these data support the hypothesis of limbic,
paralimbic, and parietal involvement in the pathophysiology of BPD symptoms,
additional neuroimaging studies of BPD patients are highly encouraged to improve our
understanding of the biological underpinnings of this disorder.
This work received financial support from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).
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29Irle E, Lange C, Weniger G, Sachsse U. Size abnormalities of the superior parietal cortices are related to dissociation in borderline personality disorder. Psychiatry Res. 2007;156:139-49.
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30Rüsch N, Luders E, Lieb K, Zahn R, Ebert D, Thompson PM, et al. Corpus callosum abnormalities in women with borderline personality disorder and comorbid attention-deficit hyperactivity disorder. J Psychiatry Neurosci. 2007;32:417-22.
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31Takahashi T, Chanen AM, Wood SJ, Yücel M, Tanino R, Suzuki M, et al. Insular cortex volume and impulsivity in teenagers with first-presentation borderline personality disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33:1395-400.
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32Takahashi T, Chanen AM, Wood SJ, Walterfang M, Harding IH, Yücel M, et al. Midline brain structures in teenagers with first-presentation borderline personality disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33:842-6.
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33Phillips ML, Travis MJ, Fagiolini A, Kupfer DJ. Medication effects in neuroimaging studies of bipolar disorder. Am J Psychiatry. 2008;165:313-20.
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34Fuchs E, Czéh B, Kole MH, Michaelis T, Lucassen PJ. Alterations of neuroplasticity in depression: the hippocampus and beyond. Eur Neuropsychopharmacol. 2004;14:S481-90.
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35Navari S, Dazzan P. Do antipsychotic drugs affect brain structure? A systematic and critical review of MRI findings. Psychol Med. 2009;39:1763-77.
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36Li CT, Lin CP, Chou KH, Chen IY, Hsieh JC, Wu CL, et al. Structural and cognitive deficits in remitting and non-remitting recurrent depression: a voxel-based morphometric study. Neuroimage. 2010;50:347-56.
-
37Light SN, Heller AS, Johnstone T, Kolden GG, Peterson MJ, Kalin NH, et al. Reduced right ventrolateral prefrontal cortex activity while inhibiting positive affect is associated with improvement in hedonic capacity after 8 weeks of antidepressant treatment in major depressive disorder. Biol Psychiatry. 2011;70:962-8.
-
38Sekar S, Van Audekerke J, Vanhoutte G, Lowe AS, Blamire AM, Van der Linden A, et al. Neuroanatomical targets of reboxetine and bupropion as revealed by pharmacological magnetic resonance imaging. Psychopharmacology (Berl). 2011;217:549-57.
-
39Pardo BM, Garolera M, Ariza M, Pareto D, Salamero M, Valles V, et al. Improvement of cognitive flexibility and cingulate blood flow correlates after atypical antipsychotic treatment in drug-naive patients with first-episode schizophrenia. Psychiatry Res. 2011;194:205-11.
-
40Ettinger U, Williams SC, Fannon D, Premkumar P, Kuipers E, Möller HJ, et al. Functional magnetic resonance imaging of a parametric working memory task in schizophrenia: relationship with performance and effects of antipsychotic treatment. Psychopharmacology (Berl). 2011;216:17-27.
Publication Dates
-
Publication in this collection
Mar 2014
History
-
Received
25 Feb 2013 -
Accepted
1 Sept 2013