Using VBM, we demonstrated decreased gray matter concentrations in BPD compared to control subjects in ventral cingulate gyrus and several regions of the medial temporal cortex, including hippocampus, amygdala, parahippocampal gyrus and uncus. Decreased gray matter concentrations in medial temporal cortex were attributable primarily to female BPD subjects, especially those with histories of childhood abuse, while male, but not female, BPD subjects showed diminished gray matter concentrations in anterior cingulate compared to controls. Covarying for depressed mood rendered group differences in the ventral cingulate cortex non-significant, but had less effect on differences in medial temporal cortex. Covarying for history of aggression (LHA) had relatively little effect on group differences, while covarying for impulsivity (BIS), rendered all previously noted voxel-level group differences non-significant. Co-variation does not prove statistical mediation; however, these results suggest a more robust effect for impulsivity on gray matter concentrations in BPD compared to aggression. These exploratory VBM studies suggest that structural differences between BPD and HC subjects may be related, in part, to gender, depressed mood, and trait impulsivity, which should be assessed in confirmatory studies.
We are aware of only one prior VBM study in subjects with BPD. Rusch et al. (2003)
compared 20 female BPD subjects to 21 controls and found loss of gray matter concentration in the left basolateral amygdala among BPD subjects, but not in hippocampus, or PFC. Subjects were excluded for current major depression, substance use or eating disorders. This study followed and extended a small ROI morphometry study by Tebartz van Elst et al. (2003)
, which found large volume reductions in 8 female BPD subjects compared to 8 healthy controls in hippocampus (20 – 21% decrease) and amygdala bilaterally (23–25%), but also in left orbitofrontal cortex (24%), and anterior cingulate (26%). Although we also found diminished gray matter concentration in Lt. amygdala in female BPD subjects relative to controls, our VBM results more closely resemble Tebarz van Elst’s (2003)
ROI morphometry study. i.e. We found diminished gray matter concentrations in BPD subjects in cingulate cortex, hippocampus and amygdala bilaterally in our combined gender sample, and in hippocampus and amygdala bilaterally in our female-only sample. Rusch et al. (2003)
also reported bilateral loss of gray matter concentration in the fusiform gyrus (occipitotemporal cortex), which proved non-significant after correction for multiple comparisons. Gray matter was diminished bilaterally in the fusiform gyrus in our combined gender sample, and in left fusiform gyrus among our female BPD subjects. The fusiform gyrus is involved in recognition of facial expression, and is modulated by projections from the amygdala. Studies using fMRI suggest that this function is abnormal in BPD, and may be related to the borderline patients’ affective instability (Herpertz et al., 2001
). Differences in sample selection between our study and that of Rusch et al. (2003)
, especially in regard to co-morbidity, may contribute to the differing results.
In our combined gender sample, we noted decreased gray matter concentrations in BPD subjects in ventral cingulate, and, among male BPD subjects, in anterior cingulate, bilaterally. Diminished volumes in anterior cingulate among BPD subjects have been previously reported in ROI morphometry studies (Tebartz van Elst et al., 2003
; Hazlett et al., 2005
) and related to increased impulsivity (Hazlett et al., 2005
). Gender differences in impulsivity may explain our finding decreased gray matter concentration in anterior cingulate among male, but not female BPD subjects in our study.
Contrary to expectation, we did not find structural abnormalities in the orbital frontal or ventromedial PFC among BPD subjects. Some, but not all, ROI morphometry studies in BPD have noted decreased volumes in anterior prefrontal and orbital frontal cortex (Tebartz van Elst et al., 2003
; Hazlett et al., 2005
). Hazlett et al. (2005)
found a relationship between decreased gray matter volume in anterior prefrontal cortex (BA 10) and increased impulsiveness (BIS) in BPD subjects compared to controls. This large sample study (n=50) is noteworthy for a predominance of male subjects (60%) and co-morbidity with schizotypal personality disorder (26%). In contrast, our BPD subjects are predominately female, with only one subject meeting Axis II criteria for schizotypal personality disorder. Although we found no structural abnormalities in these areas, PET studies in BPD subjects and other impulsive PDs have demonstrated functional abnormalities in orbital frontal and ventromedial PFC which may contribute to impulsive-aggression, behavioral disinhibition, and affective instability in BPD.
PET studies in BPD subjects have demonstrated hypometabolism in anterior cingulate cortex, orbital and ventromedial PFC (De La Fuenta et al., 1997
; Soloff et al., 2003
). Orbital frontal and ventromedial PFC are known to be important in response inhibition, regulation of impulsivity and reactive aggression (Blair, 2004
; Weinberger et al., 1993
). Impulsive BPD subjects, and other impulsive PDs, have diminished metabolic responses to serotonergic activation (by fenfluramine (FEN), or meta-chlorophenylpiperazine (m-CPP)) in these same prefrontal cortical areas (Siever et al., 1999
; New et al., 2002
; Soloff et al., 2000
; Soloff et al., 2005
). Impulsivity and impulsive-aggression may be mediated, in part, by diminished serotonergic regulation or loss of connectivity in these prefrontal areas and related brain circuits.
Our VBM results are consistent with ROI morphometry studies which report associations between childhood abuse, hippocampal and amygdala volume loss in BPD compared to control subjects (Driessen et al., 2000
; Schmahl et al., 2003
; Brambilla et al., 2004
; Irle et al., 2005
). In the context of BPD, duration and severity of childhood traumatization have been related to degree of hippocampal volume loss (Driessen et al., 2000
; Irle et al., 2005
). These studies contrasted BPD and healthy control subjects, but not abused and non-abused BPD
subjects. Since half of research subjects ascertained for a BPD diagnosis have no reported history of childhood physical or sexual abuse (Soloff et al., 2002
), contrasting abused and non-abused BPD
subjects controls for the effect of diagnosis alone. Although our sample sizes for this contrast were small, we found significantly decreased concentrations of gray matter in Rt. amygdala and Rt. parahippocampal gyrus in abused compared to non-abused BPD females.
Hippocampal volume loss among female BPD inpatients has also been directly correlated with histories of multiple hospitalizations (Zetsche et al., 2007
). Zetsche et al. (2006
) reported an ROI morphometry study of 25 female inpatients with extensive co-morbid psychiatric diagnoses (e.g. 68% current MDD, 32% PTSD), and current psychotropic drug use (80%). In this sample, hippocampal volume was not related to sexual abuse, or impulsivity (BIS), but was inversely related to aggression (LHA). In contrast, we reported a robust statistical effect on VBM results for impulsivity (BIS) but not for aggression (LHA). The two studies differ greatly in sample characteristics, especially in regard to degree of illness severity and comorbidity. (e.g. Our subjects were all living in the community and were free of psychotropic medications a minimum of 2 – 6 weeks prior to the scan.) Within our total sample, we found a relationship between depressed mood (HamD) and both impulsivity (BIS) (rho=0.65, P<0.001, n=54) and aggression (LHA) (rho = 0.44, P=0.001, n=55), suggesting the need to control for interaction effects of depressed mood when examining the relationship of aggression and impulsivity on brain volumes.
In this same sample, Zetsche et al. (2006)
also reported an increase
in amygdala volumes bilaterally among BPD subjects with comorbid MDE compared to non-depressed BPD subjects, and a significant positive correlation between depression scores (HamD-21) and Lt. amygdala volumes. Although contrary to prior reports in subjects with BPD, increased amygdala volumes have been reported in some studies of patients with MDE (Frodl et al., 2003
; Lange and Irle, 2004
), though not all (Sheline et al., 1999
, Mervaala et al., 2000
). Zetsche et al. (2006)
caution that comorbidity with MDE can lead to discrepant findings between studies with regard to amygdala measurements in BPD.
We found increased gray matter concentration in the Rt. putamen in male, but not female, BPD subjects compared to controls. In an earlier ROI morphometry study conducted in our laboratory, Brambilla et al. (2004)
reported increased bilateral putamen volumes associated with co-morbid substance use disorder in a mixed gender sample of 10 BPD subjects compared to healthy controls. Because our sample overlaps with that of Brambilla et al. (2004)
(i.e., 4 BPD males were in both studies), finding increased gray matter concentration in the putamen in BPD subjects in our study suggests concurrence between methods. Our sample had too few subjects with Axis I substance use disorder to allow a meaningful test of the association with putamen volumes.
In our combined gender sample, increased
gray matter concentrations were also found in BPD subjects in a very large area of the Rt. cerebrum extending from the Rt. superior frontal gyrus posteriorly and across the parietal lobe to the precuneus. Similar results were obtained in the female-only analysis, but not among male subjects. In contrast, an ROI morphometry study by Irle et al. (2005)
volumes of Rt. parietal cortex in BPD compared to control subjects, and a significant direct relationship between Rt. parietal cortex volumes, psychotic symptoms and schizoid personality traits among BPD patients. Patients studied by Irle et al. (2005)
were co-morbid for current depression (60%), lifetime or current PTSD (37%), depersonalization disorder (77%) and other Axis I comorbid disorders, and had significantly lower IQ and marked neuropsychological test performance deficits compared to normal controls. Our sample does not reflect this degree of clinical severity or comorbidity, which may confound results
4.1. PFC, the hippocampal-amygdala complex, and BPD
The medial temporal cortex (including the hippocampal-amygdala complex) has extensive connections to the orbital and ventral medial PFC, and contributes to emotion regulation and impulse control. The amygdala assesses facial expressions and emotions in social situations (especially negative emotions), and generates fear and anxiety in response to perceived threat. At times of stress, the hippocampal-amygdala complex modulates and regulates expression of fear responses (Davidsonet al., 1999
; Davis, 2001
; Philips and LeDoux, 1992
). Loss of inhibitory regulation in these limbic circuits results in disinhibited fear responding, anger and impulsive-aggressive behavior, core characteristics of BPD (Philips and LeDoux, 1992
). The hippocampus is also involved in attentional monitoring of emotional states, addressing discrepancies between current perception of reality and past representations in associative working memory. The integrity of the hippocampal-orbitomedial PFC circuit is important in maintaining cognitive-emotional control of behavior (Wall and Messier, 2001
Structural studies of subjects with BPD may be confounded by Axis I co-morbidity, especially MDD, PTSD, and alcohol use disorders (AUD), each of which may be associated with structural abnormalities. In addition, childhood ADHD may persist into adulthood and confound studies of BPD with overlap in symptoms relative to impulsivity and affect regulation. ADHD has also been associated with structural brain abnormalities (Faraone et al.,2000
ROI morphometry studies in MDD have described diminished volumes in the subgenual prefrontal cortex (Drevets, 1997
), medial orbitofrontal cortex (gyrus rectus) (Bremner et al., 2002
), hippocampus and amygdala (Sheline et al., 1996
; Bremner et al., 2000
; Mervaala et al.,2000
; Frodl et al., 2002). Volume loss is found in post-depressed patients in remission (Bremner et al.,2002
), and correlates with total lifetime duration of depression (Sheline et al.,1999
), introducing a potential confounding effect on interpretation of structural studies (Sheline et al., 2000
). In our sample, 16 subjects (47.1%) had past histories of MDD.
Diminished hippocampal volumes are also reported in subjects with PTSD (Stein et al.,1997
; Bremner et al., 1997
). In our study, only two BPD subjects (5.9%) met SCID criteria for current PTSD, and 1 for a lifetime diagnosis (3%). Our results appear at variance with the findings of Bremner et al. (2003)
, who asserted that “abuse per se in the absence of PTSD does not lead to deficits in hippocampal structure or function.” (op.cit. p. 929). In some subjects, though not all, BPD may represent a characterologic resolution of childhood PTSD (Gunderson and Sabo, 1993
, for review, Zanarini M., 2000
). As adults, these patients no longer have acute PTSD symptoms or meet SCID criteria for PTSD. Hippocampal atrophy may be related to childhood PTSD in these BPD adults. This view is consistent with preclinical evidence of the effects of early adverse experiences on brain development (Kaufman et al., 2000
A current diagnosis of AUD was found in 3 BPD subjects (8.8%), and 4 with a lifetime diagnosis (11.8%). In adults, AUD has been associated with volume loss in the frontal lobes, including the PFC (Pfefferbaum et al., 1997
). In adolescents, early onset AUD has been associated with volume loss in both PFC and hippocampus (De Bellis et al., 2000
, De Bellis et al., 2005
There is great overlap in clinical features of adult ADHD and BPD, especially in regard to impulsivity and affective instability (Davids and Gastpar, 2005
; Dowson et al., 2004
). In one study of adult subjects with BPD, 60% scored above a diagnostic threshold for ADHD symptoms on a retrospective, self rated scale (the Wender Utah Rating Scale) (Fossati et al., 2002
). Among adults with ADHD (diagnosed retrospectively), 20.3% also meet criteria for co-morbid BPD (Miller et al., 2007
). Despite areas of symptom overlap, adult ADHD can be discriminated from BPD using scales specifically designed for adult ADHD (e.g. the Attention-Deficit Scales for Adults (Dowson et al., 2004
). It remains unclear whether the co-occurrence of ADHD and BPD represent two independent disorders or whether childhood ADHD is a risk factor for the development of BPD in adulthood (Thatcher et al., 2005
). ADHD has been associated with structural abnormalities on neuroimaging, especially in prefrontal and anterior cingulate volumes (Seidman et al., 2006
). Subjects in our protocol were diagnosed using the SCID I and IPDE, which do not screen for ADHD. However, using all available clinical data, including medical records, only one subject was found to have a co-morbid diagnosis of ADHD.
Gender differences found in structural studies of BPD may be related to clinical characteristics or co-morbid conditions which are differentially distributed by gender, and have their own effects on structure (e.g. sexual abuse in females, antisocial personality disorder (ASPD) in males). In the current sample, we found no significant differences by gender in suicide attempter status, number of hospital admissions, incidence of sexual or physical abuse, or pooled Axis I depressive diagnoses; however, co-morbid ASPD was more frequently diagnosed among male BPD subjects (58.3%) compared to BPD females (9.1%, p.004, Fisher’s exact, 2 sided). Male, but not female, BPD subjects have decreased gray matter concentrations in anterior cingulate bilaterally, which may be related to the neurobiology of impulsivity and aggression. Large sample studies are needed to control for gender, clinical characteristics, Axis I and Axis II co-morbidities, suggesting an important indication for VBM as an exploratory method.