Reduced Anterior Cingulate and Orbitofrontal Volumes in Child Abuse–Related Complex PTSD
Objective: Classic posttraumatic stress disorder (PTSD) is associated with smaller hippocampus, amygdala, and anterior cingulate cortex (ACC) volumes. We investigated whether child abuse–related complex PTSD—a severe form of PTSD with affect dysregulation and high comorbidity—showed similar brain volume reductions.
Method: We used voxel-based morphometry to measure gray matter concentrations in referred outpatients with child abuse–related complex PTSD (n = 31) compared to matched healthy nontraumatized controls (n = 28). Complex PTSD was diagnosed using the Structured Clinical Interview for DSM-IV-TR and the Structured Clinical Interview for Disorders of Extreme Stress. All respondents were scanned on a 1.5-T magnetic resonance system at the VU Medical Center, Amsterdam, The Netherlands, between September 2005 and February 2006.
Results: As was hypothesized, patients with child abuse–related complex PTSD showed reductions in gray matter concentration in right hippocampus (PSVC corrected = .04) and right dorsal ACC (PSVC corrected = .02) compared to controls. In addition, a reduction in gray matter concentration in the right orbitofrontal cortex (OFC) was found. Severity of child abuse and PTSD-hyperarousal correlated negatively with ACC volume. Impulsivity correlated negatively with hippocampus volume, and anger, with hippocampus and OFC volume. Comorbidity of borderline personality disorder—compared to comorbid cluster C personality disorder—accounted for more extensive reductions in the ACC and OFC volume.
Conclusions: In complex PTSD, not only the hippocampus and the ACC but also the OFC seem to be affected, even in the absence of comorbid borderline personality disorder. These results suggest that neural correlates of complex PTSD are more severe than those of classic PTSD.
J Clin Psychiatry 2010;71(12):1636–1644
© Copyright 2010 Physicians Postgraduate Press, Inc.
Submitted: September 26, 2008; accepted July 7, 2009.
Online ahead of print: July 13, 2010 (doi:10.4088/JCP.08m04754blu).
Corresponding author: Kathleen Thomaes, MD, GGZ Ingeest, Department of Psychiatry, VU University Medical Center, A J Ernststraat 887, 1081 HL Amsterdam, The Netherlands (email@example.com).
Clinical presentation and prognosis of posttraumatic stress disorder (PTSD) are likely to vary with trauma characteristics. Type I traumas—single traumatic events such as a robbery or a natural disaster—are associated with classic forms of PTSD: ie, PTSD according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria, characterized by symptoms of re-experiencing, numbing, and hyperarousal.1 Type II traumas—repeated interpersonal traumas such as sexual and physical abuse—are associated with a more severe and chronic form of PTSD. After type II traumas, classic PTSD can be complicated by additional features such as impaired affect regulation (eg, enduring anger, impulsivity, and self-harm), dissociation, disturbances of self-image, somatization, and relational problems.2–4 This syndrome has been brought under the heading of PTSD with associated features in DSM-IV-TR1 or disorders of extreme stress not otherwise specified (DESNOS), and it is also known by clinicians as complex PTSD. Complex PTSD is associated with worse outcomes5–8 and high rates of comorbidity, especially with depressive and dissociative disorders, and with borderline personality disorder.9–11 It tends to run a chronic course in spite of considerable use of medical and psychiatric services.12 Sexual abuse affects 10% of Dutch and American women.9,13 The risk of PTSD following exposure to any type of trauma is 10%–20%, with the highest risk associated with assaultive violence.14 In a student population, prevalence of complex PTSD was found to be 1%.6
From a neurobiologic perspective, PTSD is associated with structural and functional changes in limbic structures, in particular the medial temporal lobe (MTL).15,16 A meta-analysis of 21 structural imaging studies on adults with chronic PTSD17 revealed a significantly smaller volume of the left amygdala, a region associated with (conditioned) fear responses. In addition, significantly smaller volumes of bilateral hippocampus, a key structure associated with declarative memory, were found. However, a number of magnetic resonance imaging (MRI) studies on PTSD have failed to reveal hippocampal atrophy,18–21 especially in children,22 acutely traumatized people,23 and elderly patients.24–26 Whether these negative findings are related to methodological issues or reflect pathogenetic differences is as yet unknown.
Whereas most structural MRI studies on PTSD have focused on MTL structures, it should be noted that these regions receive extensive inputs from other cortical areas involved in emotion processing,27 in particular the prefrontal cortex and the anterior cingulate cortex (ACC). Anterior cingulate cortex volume was also found to be reduced in PTSD, both with voxel-based morphometry (VBM)28–32 and region-of-interest (ROI)–based manual segmentation techniques.31,33,34 Anterior cingulate cortex volume was found to be inversely related to PTSD symptom severity.32 The ACC is involved in attention as well as in emotion regulation, and it is thought to be critically involved in the pathophysiology of PTSD.35 The ventral or emotional part of the ACC was found to be hypoactive in PTSD during symptom provocation and cognitive activation paradigms36 but hyperactive during dissociative states.37 Hyperactivity was also found in the dorsal part or cognitive division of the ACC during dissociative states and performance of a counting Stroop paradigm.38 Activity in the ACC and MTL regions was found to be negatively correlated to impulsivity and anger in borderline personality disorder,39–41 but to our knowledge the relationship between volume and these clinical variables has not yet been investigated.
The above-reviewed volumetric reductions in PTSD have been attributed to both environmental (ie, stress) and genetic factors. Exposure to chronic stress has been shown to damage the hippocampus and the ACC in animal studies with a prospective design42 and in a human twin study.30 With regard to hippocampal atrophy in PTSD, the evidence is mixed. On the one hand, successful pharmacotherapy for PTSD was associated with enlargement of the hippocampus,43 compatible with the stress hypothesis and with neural plasticity. On the other hand, a twin study points at hippocampal atrophy as a genetically determined risk factor to develop PTSD rather than as a result of stress.44
Early life stress in particular, during a window of susceptibility, may have profound and enduring effects on the regulation of stress later in life. It has been shown that the risk for adult PTSD is higher (eg, in veterans or abused women) if there has been abuse during childhood as well.45,46 A history of childhood abuse is related to increased neuroendocrine stress reactivity, which is further enhanced when additional trauma is experienced in adulthood.47 There is also evidence that different brain regions have unique periods of heightened sensitivity to the effects of early stress.48 The above-mentioned meta-analysis by Karl et al17 concluded that childhood trauma may have greater impact on (right) hippocampus volume than trauma during adulthood. In a direct comparison of patients with PTSD following prolonged child abuse or after a single trauma during adulthood, however, hippocampus volume did not differ.49
In summary, reduced volumes of MTL regions (hippocampus and amygdala) and ACC have been found in classic PTSD. To date, it is unclear whether a similar pattern occurs in child abuse–related or complex PTSD. The main aim of the present study was to investigate if child abuse–related complex PTSD is associated with structural reductions in these brain areas compared to healthy controls and if additional brain areas are involved. In addition, we aimed to explore whether any abnormalities were correlated with PTSD and/or trauma severity, or rather with its complicating symptoms or comorbid psychopathology, such as dissociation, depression, and/ or borderline personality disorder symptoms (eg, impulsivity and anger). To this end, we compared regional gray matter (GM) concentration on a whole-brain voxel by voxel basis in patients with complex PTSD and matched healthy controls, and we performed regression analyses using these clinical variables as covariates. We hypothesized that, in child abuse–related complex PTSD, GM volumes of MTL regions (hippocampus and amygdala) and ACC would be reduced compared to healthy controls.
Thirty-three female patients with both classic and complex PTSD after childhood sexual and/or physical abuse and 30 healthy nonexposed female controls participated in the study. All patients were recruited by clinical referral to outpatient clinics of 4 Dutch mental health institutes (Amsterdam, Alkmaar, Castricum, and Utrecht). Subjects were interviewed between September 2005 and February 2006 by trained mental health workers with the Structured Trauma Interview (STI).50 In line with the STI, childhood sexual abuse was defined as repeated, forced sexual contact with a perpetrator in an intimate relationship before the age of 16. Severity of sexual abuse was classified as moderate (touching and groping) or severe (forms of penetration). Physical abuse was defined as repeated maltreatment that could have wounded the child; only moderate (ie, sometimes wounded) to severe forms (frequently wounded, confinement, battering) were included in this study. To assess the presence of classic (ie, according to DSM-IV-TR criteria) and complex PTSD, the Clinician Administered PTSD Scale (CAPS)51,52 and the Structured Clinical Interview for Disorders of Extreme Stress Not Otherwise Specified (SIDES; Van der Kolk BA, Pelcovitz D., Herman JL, et al; 1992, unpublished) were administered. To assess comorbid disorders, the Structured Clinical Interview for DSM-IV Axis I disorders (SCID-IV-I)53 and the Structured Interview for DSM-IV Axis II Personality disorders (SIDP-IV)54 were administered. Symptom severity was measured using the CAPS,51,52 Beck Depression Inventory (BDI),55 Dissociative Experiences Scale (DES),56 Borderline Personality Disorder Severity Index (BPDSI)57 and Symptom Checklist-90.58
Exclusion criteria were antisocial personality disorder; dissociative identity disorder (DID); recurrent psychoses and current alcohol or drug dependence or abuse (ie, not meeting DSM-IV-TR criteria for alcohol or drug abuse or dependence during the last month, but respondents were not requested to abstain from all alcohol and/or drug use prior to entry into the study); the use of psychotropic medication other than selective serotonin reuptake inhibitors (SSRIs) in stable dosage for at least a month or low dosage benzodiazepines (maximally 20 mg oxazepam or its equivalent); major neurologic and internal disorders affecting neuroendocrine function; serious head trauma (defined as loss of consciousness for more than 5 minutes); retained metal (eg, pacemaker or surgical clips), and pregnancy. Exclusion of DID was based on the amnesia part of the Structured Clinical Interview for Dissociative Disorders,59 and difficult cases were discussed with a diagnostic expert (N.D.).
Seventy-three patients were screened for participation; of these, 18 were excluded due to the use of tricyclic antidepressants or antipsychotics, 12 refused to participate because of fear of the scanning procedure, 5 had a history of serious head trauma, 2 were too obese to lie comfortably in the scanner, 2 had metal implants, and 1 had a major internal disease.
Female controls matched for age were recruited via advertisements in local newspapers. The Medical Ethical Committee of the VU University Medical Center, Amsterdam, The Netherlands, approved the present study. Written informed consent was obtained from each participant.
Structural magnetic resonance (MR) imaging was performed on a 1.5-T Sonata MR system (Siemens, Erlangen, Germany), equipped with a standard head coil, at the VU University Medical Center. To reduce motion artifacts, the subject’s head was immobilized using foam pads. A coronal 3D gradient-echo T1-weighted MR image (flip angle = 8°; TR = 2700 ms; TE = 4 ms; TI = 950 ms; BW = 190 Hz/pixel, matrix = 256 × 256, voxel size = 1 × 1 × 1.5 mm, 160 slices) was performed. All patients and controls were scanned on the same scanner using identical imaging parameters. A trained radiologist evaluated MRI scans, and there were no substantial abnormalities in any of the patients or controls. All respondents also participated in a functional MRI study, the results of which will be reported elsewhere.
MRI Data Processing
Image preprocessing was performed using statistical parametric mapping (SPM5) software (Wellcome Trust Centre for Neuroimaging, London, United Kingdom: www.fil.ion.ucl.ac.uk/spm), running in MATrix LABoratory 7.0 (MathWorks, Natick, Massachusetts). DICOM images were converted to Analyze format, followed by manual reorienting to the anterior commissure. Voxel-based morphometry involves a voxelwise comparison of the local concentration of GM between 2 groups of subjects. To this end, the images were segmented (in native space) into GM, white matter (WM), and cerebrospinal fluid probability maps using SPM5 default priors. The segmentation step also comprised a correction for image density nonuniformity to correct for density variations due to position differences of various brain structures within the MRI head coil. GM and WM images were then normalized to anatomic standard space as defined by the MNI-152 template available in SPM5 and resampled to 2 mm isotropic voxels. During normalization, a modulation step was included using the Jacobian determinants of the transformation to account for resulting volume changes. These modulated GM/WM maps were smoothed with an 8 mm full-width half-maximum Gaussian kernel to correct for remaining between-subject registration differences and to render the data more normally distributed, increasing the validity of parametric statistical tests. Because of the small size of the hippocampus, a 4 mm smoothing kernel was used for this structure, as has been recommended.30
Gray or white matter concentration is equivalent to the weighted average of the gray or white matter voxels located in the volume defined by the smoothing kernel, and according to previous studies, the regional gray or white matter concentration can be considered to represent the local amount of gray or white matter.60,61
Demographic data were analyzed using a Mann-Whitney test (since age and educational years were not normally distributed) and a χ2 test (for handedness).
Statistical parametric mapping software was employed to assess regional differences in GM/WM density between patients and controls, using analysis of covariance with total GM/WM volume as a covariate. In addition, regression analyses were performed to investigate the correlation between WM/GM changes and trauma/symptom severity, using the STI, CAPS, BDI, DES, and BPDSI. For our a priori ROIs, we adopted a threshold of P < .05 corrected for multiple comparisons with an extent threshold of 5 voxels, employing the small volume correction option implemented in SPM5 of 3.5 mL for the hippocampus (each side) and 10 mL for bilateral dorsal ACC, similar to previous research.30 For exploratory purposes, other regional group differences and results of regression analyses are reported at a threshold of P < .001 uncorrected with an additional extent threshold of 10 voxels.
One patient panicked during the scanning session; in addition, the structural MRI scans of 1 patient and 2 controls had to be discarded due to technical problems, leaving 31 patients and 28 controls for MRI data analysis. Matching variables of both groups are listed in Table 1. All subjects were female by inclusion. Controls matched well with regard to age and handedness. Education years in patients were lower compared to control subjects, but this difference, although statistically significant, was presumably not meaningful (10.8 vs 11.4 years).
Click figure to enlarge
Click figure to enlarge
Click figure to enlarge
In Table 2, clinical status variables are shown. All patients had suffered repeated trauma of moderate to severe intensity before the age of 16: 58% of patients had experienced both physical and sexual abuse, 33% only sexual abuse, and 9% only physical abuse during childhood. Furthermore, it was found that 73% of patients had also been abused as adults. Controls had experienced no sexual or physical abuse or other major psychotraumatic experiences.
All patients met criteria for PTSD (CAPS) and for complex PTSD (SIDES) by inclusion. Patients had a mean of 2.7 (SD = 1.8) Axis I diagnoses (DSM-IV-TR), mostly depressive and anxiety disorders. One respondent was found to have alcohol-dependence later during the course of the study. We decided not to exclude her. Patients had a mean of 0.9 (SD = 0.8) Axis II diagnoses (DSM-IV-TR), mainly borderline and cluster C personality disorders.
Symptom ratings from our patients were indicative of severe PTSD (mean CAPS score: 88.5, SD = 15.0; cutoff score = 40, indicating PTSD) and severe depression (BDI: 29.3, SD = 10.0; cutoff for severe depression = 30), as well as moderate-to-severe dissociation (DES: 23.9, SD = 14.5), and borderline pathology (BPDSI: 22.9, SD = 7.9; > 15 indicative of borderline personality disorder). Nine patients (27%) had a score higher than 35 on the DES, which is indicative of dissociative disorder NOS.62,63
Medication use in our patient group was restricted to SSRIs in a stable dosage for at least 1 month before entering the study (21 subjects, ie, 64%; mean fluoxetine-equivalent dose = 35.7 mg, SD = 18.6) and/or benzodiazepines in low dosage (16 subjects, ie, 48%; mean oxazepam equivalent = 11.9 mg, SD = 4.0).
Results for group comparisons with regard to regional GM volume differences are listed in Table 3. In patients, GM concentration was reduced in the right dorsal anterior cingulate cortex (ACC) and right hippocampus relative to healthy controls (Figure 1). In addition, patients showed smaller GM concentrations in the right orbitofrontal cortex (OFC), in the right dorsolateral prefrontal cortex (DLPFC) and right supplementary motor area (SMA). We did not find regions in which GM concentration was increased in patients relative to controls, nor did we observe WM differences between groups.
Click figure to enlarge
Additional multiple regression analyses (Table 4) revealed a negative correlation between dorsal ACC volume and (1) severity of child abuse and (2) the hyperarousal cluster of the CAPS within the group of patients with complex PTSD. Other clusters of the CAPS (re-experiencing and avoidance), BDI (severity of depression), DES (severity of dissociation) or BPDSI were not correlated with ACC volume. Child abuse and impulsivity—as measured by the BPDSI—were inversely correlated with hippocampus volume. Furthermore, anger (BPDSI)—as is illustrated in Figure 2—was negatively correlated with the volume of the OFC extending into the medial temporal lobe. No other clinical variables were correlated with hippocampus or OFC volume.
Click figure to enlarge
Click figure to enlarge
Post hoc analyses revealed that patients with both complex PTSD and borderline personality disorder (n = 10) showed smaller GM concentrations in the dorsal ACC (peak at 8, 52, 4; k = 30, z = 3.58, P < .001) and in the OFC (peak at 0, 14, −24; k = 26, z = 3.53, P < .001) than patients with complex PTSD and a cluster C personality disorder (n = 10). Comparing complex PTSD patients with comorbid major depressive disorder (MDD; n = 20) to non-MDD complex PTSD patients (n = 11) did not reveal significant GM differences.
In the present VBM study, complex PTSD patients (n = 31) were found to have reduced GM concentrations in the right hippocampus, right ACC, and OFC, compared to nontraumatized controls (n = 28). Moreover, severity of impulsivity was negatively correlated with hippocampus volume, and severity of anger with the volume of the OFC extending into the medial temporal lobe.
Reduced hippocampal volume is consistent with the extensive literature on hippocampal atrophy in “classic” PTSD,17 as is the reduced ACC volume, although this latter finding has been less often replicated.28–34 To our knowledge, this is the first study that replicates this finding in child abuse–related complex PTSD. In previous studies on child abuse–related PTSD,49,64–66 that also reported hippocampal volume loss, complex PTSD and Axis II comorbidity were not assessed, so that the results are difficult to compare. In our patients, dorsal ACC volume correlated inversely with severity of the PTSD hyperarousal cluster and trauma severity, while in other studies on PTSD, a negative correlation has been found between ACC volume and the re-experiencing cluster30 and total score of CAPS.32
In contrast, our finding of reduced right OFC volume in complex PTSD patients has been observed only once in classic PTSD (in cancer survivors)67 and in MDD,68 but appears to be in line with imaging studies in borderline personality disorder patients69,70 that have shown both structural,69,70 and functional41,71 OFC abnormalities. The OFC is thought to be involved in the extinction of conditioned fear, emotion regulation, and the retrieval of emotional memory,67,72 and it is associated with impulsivity.41
Finally, patients showed a smaller GM volume of the right DLPFC and bilateral SMA, areas that are involved in executive functions, for example (verbal) working memory.73 To our knowledge, smaller volumes of these areas have not been found in PTSD before, although abnormal functioning of the DLPFC has been found in PTSD (both hypoactivity74 and hyperactivity75) and in dissociative disorder (hyperactivity).76
In the present study, impulsivity ratings were negatively correlated with hippocampus volume, and anger ratings were negatively correlated with OFC volume extending into the MTL. Both impulsivity and anger are clinically relevant symptoms of complex PTSD, and they are characteristic for borderline personality disorder as well. Treatment outcome in PTSD patients has been found to be negatively affected by anger severity.77–80 In the long term, symptoms of impulsivity (eg, self-mutilation and suicide efforts) tend to resolve more quickly than affective symptoms (eg, anger), which may represent more enduring aspects of the disorder.81 The presence of comorbid borderline personality disorder is likely to require more structured treatments,82,83 but not all complex PTSD patients meet criteria for borderline personality disorder. It has been suggested that complex PTSD contains an externalizing subgroup (with predominantly anger and impulsivity, eg, aggression toward others or self-injurious behavior as in borderline personality disorder) and an internalizing subgroup (with predominantly subassertiveness and avoidance).84 A post hoc analysis on our data revealed that patients with both complex PTSD and borderline personality disorder showed smaller GM concentrations in the dorsal ACC and OFC than patients with complex PTSD and a cluster C personality disorder, implying that the externalizing subgroup had more severe abnormalities than the internalizing subgroup. These results should be interpreted with care, however, because of the small sample size of this post hoc analysis.
Regional brain volume reductions, as observed in the present study, are presumably not specific for PTSD. Major depressive disorder has been reported to be associated with a smaller hippocampal volume as well, especially after multiple episodes.85 Interestingly, however, a comparison of MDD patients with early childhood abuse versus nontraumatized MDD patients revealed hippocampal volume loss in the trauma-exposed group only.86 Furthermore, hippocampal volume was found to be reduced in patients with DID,87,88 but not in DID without comorbid PTSD,89 and in borderline personality disorder.90–93 Moreover, severity of the experienced trauma was negatively correlated with hippocampal volume. Reduced ACC volume has similarly been found in MDD but only after 3 or more episodes94 and in borderline personality disorder.70,95 Thus, volume loss in the hippocampus and ACC may not be specific for PTSD but may be a feature of psychiatric disorders related to (complex) trauma.
In the present study, depression and dissociation severity were not correlated with ACC, OFC, and hippocampus volumes. Furthermore, a post hoc analysis revealed that the presence of comorbid MDD could not account for volume differences observed in our complex PTSD group. In addition, we failed to observe amygdala atrophy in our complex PTSD patients, as has been found in classic PTSD and also in MDD,96 borderline personality disorder,97,98 and DID.87,88 The role of comorbid depression with regard to amygdala volume is not yet clear, in view of the fact that another study reported larger amygdala volumes in borderline personality disorder patients with comorbid MDD compared to borderline personality disorder without MDD.99
Our study has both strengths and limitations. The sample size in the present study (31 complex PTSD subjects and 28 controls) is fairly high for VBM studies, while the clinical heterogeneity of our population—inherent to complex PTSD—can be considered a strength as well as a limitation of the present study. Consequently, although we excluded current alcohol or drug dependence or abuse, we did not request subjects to refrain from alcohol or drug use prior to entry into the study. Another potential limitation is the use of SSRIs, which we decided to allow based on considerations regarding feasibility and generalizability. Although long-term SSRI treatment has been associated with increased hippocampal volume,43 those results should be considered preliminary since they were part of an open, uncontrolled study, and to our knowledge replications have not yet been published. Moreover, if SSRI use may result in increased hippocampal volume, this possibility cannot explain our findings of decreased MTL volume in the complex PTSD group. Furthermore, although VBM is an objective and comprehensive assessment of regional anatomic differences throughout the brain,60,61 it has its limitations as well. False-positive or false-negative VBM findings cannot be completely ruled out, especially with regard to the detection of structural changes in very small brain regions.100 Additionally, VBM may be biased against finding group differences in areas that are spatially complex.101 And finally, we cannot rule out the possibility that the abnormalities detected by VBM in our study reflected group differences in the shape of brain structures rather than their volume.29
In conclusion, we investigated structural brain abnormalities in child abuse–related complex PTSD, characterized by severe PTSD symptoms, severe affect dysregulation, and severe comorbidity on DSM-IV Axis I and II. On the one hand, decreased ACC and hippocampal volume in child abuse–related complex PTSD was found to be similar to findings in the literature regarding other forms of PTSD. On the other hand, our finding of reduced OFC volume associated with impulsivity and anger ratings are more in agreement with studies in patients with borderline personality disorder, although only about a third of our complex PTSD patients fulfilled criteria for borderline personality disorder, and complex PTSD patients without comorbid borderline personality disorder showed smaller OFC volumes as well. Furthermore, these correlates have been found in other trauma-related disorders, suggesting that these correlates are not disorder specific but trauma specific. Although we did not compare classic and complex PTSD directly, these results suggest that complex PTSD is likely to be considered a worse and indeed more complex neural condition than classic PTSD.
Drug name: fluoxetine (Prozac and others).
Author affiliation: GGZ Ingeest and Department of Psychiatry, VU University Medical Center (all authors), and AMC Academic Psychiatric Center (Dr Veltman), Amsterdam, The Netherlands.
Potential conflicts of interest: None reported.
Funding/support: This study was made possible by financing of ZonMw, the Netherlands organization for health research and innovation (grant number 100-002-020), GGZ Ingeest, the Institute for Clinical and Experimental Neurosciences and the VU University Medical Center, Amsterdam. This study was wholly federally funded and did not involve treatment, medications, or devices.
Previous presentation: A part of this article was presented at the First Biannual International Conference of the European Society for Trauma and Dissociation (www.estd.org), April 17–19, 2008; Amsterdam, The Netherlands.
Acknowledgment: The authors thank Natalie Ran, MSc, Rinkse de Vries, MSc, and Monique Burger, MSc (psychologists), and Sietske A. N. Renkema, MD, and Froukje E. de Vries, MD (assistant psychiatrists), for performing the clinical assessments; Zsuzsika Sjoerds, MSc (psychologist), for extensive MRI analyses in this project; and all patients and controls for participating in this study. At the time of the study, the acknowledged individuals were affiliated with GGZ Ingeest, Department of Psychiatry, A. J. Ernststraat, Amsterdam, The Netherlands, and have no potential conflicts of interest to report.
1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington DC: American Psychiatric Association; 2000.
2. Herman JL. Complex PTSD: a syndrome in survivors of prolonged and repeated trauma. J Trauma Stress. 2006;5(3):377–391. doi:10.1002/jts.2490050305.
3. van der Kolk BA, Pelcovitz D, Roth S, et al. Dissociation, somatization, and affect dysregulation: the complexity of adaptation of trauma. Am J Psychiatry. 1996;153(suppl):83–93. PubMed
4. Zlotnick C, Zakriski AL, Shea MT, et al. The long-term sequelae of sexual abuse: support for a complex posttraumatic stress disorder. J Trauma Stress. 1996;9(2):195–205. PubMed doi:10.1002/jts.2490090204
5. Breslau N. Outcomes of posttraumatic stress disorder. J Clin Psychiatry. 2001;62(suppl 17):55–59. PubMed
6. Ford JD, Stockton P, Kaltman S, et al. Disorders of extreme stress (DESNOS) symptoms are associated with type and severity of interpersonal trauma exposure in a sample of healthy young women. J Interpers Violence. 2006;21(11):1399–1416. PubMed doi:10.1177/0886260506292992
7. Green BL, Goodman LA, Krupnick JL, et al. Outcomes of single versus multiple trauma exposure in a screening sample. J Trauma Stress. 2000;13(2):271–286. PubMed doi:10.1023/A:1007758711939
8. Terr LC. Childhood traumas: an outline and overview. Am J Psychiatry. 1991;148(1):10–20. PubMed
9. Kessler RC, Sonnega A, Bromet E, et al. Posttraumatic stress disorder in the National Comorbidity Survey. Arch Gen Psychiatry. 1995;52(12):1048–1060. PubMed
10. McGlashan TH, Grilo CM, Skodol AE, et al. The Collaborative Longitudinal Personality Disorders Study: baseline Axis I/II and II/II diagnostic co-occurrence. Acta Psychiatr Scand. 2000;102(4):256–264. PubMed doi:10.1034/j.1600-0447.2000.102004256.x
11. Sar V, Akyüz G, Doğan O. Prevalence of dissociative disorders among women in the general population. Psychiatry Res. 2007;149(1-3):169–176. PubMed doi:10.1016/j.psychres.2006.01.005
12. Höing M, van Engen A, Ensink B, et al. Hulp aan slachtoffers van seksueel geweld: een inventarisatie en kwaliteitsevaluatie van de behandeling van slachtoffers van seksueel geweld in de GGZ en de vrouwenopvang in Nederland. Delft, The Netherlands: Eburon; 2003.
13. Draijer N. Sexual Traumatization in Childhood. Long-Term Impact of Sexual Abuse of Girls. Amsterdam, the Netherlands: SUA; 1990.
14. Breslau N, Kessler RC, Chilcoat HD, et al. Trauma and posttraumatic stress disorder in the community: the 1996 Detroit Area Survey of Trauma. Arch Gen Psychiatry. 1998;55(7):626–632. PubMed doi:10.1001/archpsyc.55.7.626
15. Elzinga BM, Bremner JD. Are the neural substrates of memory the final common pathway in posttraumatic stress disorder (PTSD)? J Affect Disord. 2002;70(1):1–17. PubMed doi:10.1016/S0165-0327(01)00351-2
16. Sapolsky RM. Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders. Arch Gen Psychiatry. 2000;57(10):925–935. PubMed doi:10.1001/archpsyc.57.10.925
17. Karl A, Schaefer M, Malta LS, et al. A meta-analysis of structural brain abnormalities in PTSD. Neurosci Biobehav Rev. 2006;30(7):1004–1031. PubMed doi:10.1016/j.neubiorev.2006.03.004
18. Fennema-Notestine C, Stein MB, Kennedy CM, et al. Brain morphometry in female victims of intimate partner violence with and without posttraumatic stress disorder. Biol Psychiatry. 2002;52(11):1089–1101. PubMed doi:10.1016/S0006-3223(02)01413-0
19. Jatzko A, Rothenhöfer S, Schmitt A, et al. Hippocampal volume in chronic posttraumatic stress disorder (PTSD): MRI study using two different evaluation methods. J Affect Disord. 2006;94(1–3):121–126. PubMed doi:10.1016/j.jad.2006.03.010
20. Pederson CL, Maurer SH, Kaminski PL, et al. Hippocampal volume and memory performance in a community-based sample of women with posttraumatic stress disorder secondary to child abuse. J Trauma Stress. 2004;17(1):37–40. PubMed doi:10.1023/B:JOTS.0000014674.84517.46
21. Winter H, Irle E. Hippocampal volume in adult burn patients with and without posttraumatic stress disorder. Am J Psychiatry. 2004;161(12):2194–2200. PubMed doi:10.1176/appi.ajp.161.12.2194
22. De Bellis MD, Keshavan MS, Shifflett H, et al. Brain structures in pediatric maltreatment-related posttraumatic stress disorder: a sociodemographically matched study. Biol Psychiatry. 2002;52(11):1066–1078. PubMed doi:10.1016/S0006-3223(02)01459-2
23. Bonne O, Brandes D, Gilboa A, et al. Longitudinal MRI study of hippocampal volume in trauma survivors with PTSD. Am J Psychiatry. 2001;158(8):1248–1251. PubMed doi:10.1176/appi.ajp.158.8.1248
24. Freeman T, Kimbrell T, Booe L, et al. Evidence of resilience: neuroimaging in former prisoners of war. Psychiatry Res. 2006;146(1):59–64. PubMed doi:10.1016/j.pscychresns.2005.07.007
25. Golier JA, Yehuda R, De Santi S, et al. Absence of hippocampal volume differences in survivors of the Nazi Holocaust with and without posttraumatic stress disorder. Psychiatry Res. 2005;139(1):53–64. PubMed doi:10.1016/j.pscychresns.2005.02.007
26. Yehuda R, Golier JA, Tischler L, et al. Hippocampal volume in aging combat veterans with and without post-traumatic stress disorder: relation to risk and resilience factors. J Psychiatr Res. 2007;41(5):435–445. PubMed doi:10.1016/j.jpsychires.2005.12.002
27. Rolls ET, Kesner RP. A computational theory of hippocampal function, and empirical tests of the theory. Prog Neurobiol. 2006;79(1):1–48. PubMed doi:10.1016/j.pneurobio.2006.04.005
28. Chen S, Xia W, Li L, et al. Gray matter density reduction in the insula in fire survivors with posttraumatic stress disorder: a voxel-based morphometric study. Psychiatry Res. 2006;146(1):65–72. PubMed doi:10.1016/j.pscychresns.2005.09.006
29. Corbo V, Clément MH, Armony JL, et al. Size versus shape differences: contrasting voxel-based and volumetric analyses of the anterior cingulate cortex in individuals with acute posttraumatic stress disorder. Biol Psychiatry. 2005;58(2):119–124. PubMed doi:10.1016/j.biopsych.2005.02.032
30. Kasai K, Yamasue H, Gilbertson MW, et al. Evidence for acquired pregenual anterior cingulate gray matter loss from a twin study of combat-related posttraumatic stress disorder. Biol Psychiatry. 2008;63(6):550–556. PubMed doi:10.1016/j.biopsych.2007.06.022
31. Kitayama N, Quinn S, Bremner JD. Smaller volume of anterior cingulate cortex in abuse-related posttraumatic stress disorder. J Affect Disord. 2006;90(2–3):171–174. PubMed doi:10.1016/j.jad.2005.11.006
32. Yamasue H, Kasai K, Iwanami A, et al. Voxel-based analysis of MRI reveals anterior cingulate gray-matter volume reduction in posttraumatic stress disorder due to terrorism. Proc Natl Acad Sci U S A. 2003;100(15):9039–9043. PubMed doi:10.1073/pnas.1530467100
33. Rauch SL, Shin LM, Segal E, et al. Selectively reduced regional cortical volumes in post-traumatic stress disorder. Neuroreport. 2003;14(7):913–916. PubMed doi:10.1097/00001756-200305230-00002
34. Woodward SH, Kaloupek DG, Streeter CC, et al. Decreased anterior cingulate volume in combat-related PTSD. Biol Psychiatry. 2006;59(7):582–587. PubMed doi:10.1016/j.biopsych.2005.07.033
35. Rauch SL, Shin LM, Phelps EA. Neurocircuitry models of posttraumatic stress disorder and extinction: human neuroimaging research—past, present, and future. Biol Psychiatry. 2006;60(4):376–382. PubMed doi:10.1016/j.biopsych.2006.06.004
36. Francati V, Vermetten E, Bremner JD. Functional neuroimaging studies in posttraumatic stress disorder: review of current methods and findings. Depress Anxiety. 2007;24(3):202–218. PubMed doi:10.1002/da.20208
37. Lanius RA, Williamson PC, Boksman K, et al. Brain activation during script-driven imagery induced dissociative responses in PTSD: a functional magnetic resonance imaging investigation. Biol Psychiatry. 2002;52(4):305–311. PubMed doi:10.1016/S0006-3223(02)01367-7
38. Shin LM, Bush G, Whalen PJ, et al. Dorsal anterior cingulate function in posttraumatic stress disorder. J Trauma Stress. 2007;20(5):701–712. PubMed doi:10.1002/jts.20231
39. Leyton M, Okazawa H, Diksic M, et al. Brain Regional alpha-[11C]methyl-L-tryptophan trapping in impulsive subjects with borderline personality disorder. Am J Psychiatry. 2001;158(5):775–782. PubMed doi:10.1176/appi.ajp.158.5.775
40. Oquendo MA, Krunic A, Parsey RV, et al. Positron emission tomography of regional brain metabolic responses to a serotonergic challenge in major depressive disorder with and without borderline personality disorder. Neuropsychopharmacology. 2005;30(6):1163–1172. PubMed doi:10.1038/sj.npp.1300689
41. Silbersweig D, Clarkin JF, Goldstein M, et al. Failure of frontolimbic inhibitory function in the context of negative emotion in borderline personality disorder. Am J Psychiatry. 2007;164(12):1832–1841. PubMed doi:10.1176/appi.ajp.2007.06010126
42. Sapolsky RM. Stress, Glucocorticoids, and Damage to the nervous system: the current state of confusion. Stress. 1996;1(1):1–19. PubMed doi:10.3109/10253899609001092
43. Vermetten E, Vythilingam M, Southwick SM, et al. Long-term treatment with paroxetine increases verbal declarative memory and hippocampal volume in posttraumatic stress disorder. Biol Psychiatry. 2003;54(7):693–702. PubMed doi:10.1016/S0006-3223(03)00634-6
44. Gilbertson MW, Shenton ME, Ciszewski A, et al. Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma. Nat Neurosci. 2002;5(11):1242–1247. PubMed doi:10.1038/nn958
45. Clancy CP, Graybeal A, Tompson WP, et al. Lifetime trauma exposure in veterans with military-related posttraumatic stress disorder: association with current symptomatology. J Clin Psychiatry. 2006;67(9):1346–1353. PubMed doi:10.4088/JCP.v67n0904
46. Weisbart CE, Thompson R, Pelaez-Merrick M, et al. Child and adult victimization: sequelae for female caregivers of high-risk children. Child Maltreat. 2008;13(3):235–244. PubMed doi:10.1177/1077559508318392
47. Heim C, Newport DJ, Wagner D, et al. The role of early adverse experience and adulthood stress in the prediction of neuroendocrine stress reactivity in women: a multiple regression analysis. Depress Anxiety. 2002;15(3):117–125. PubMed doi:10.1002/da.10015
48. Teicher MH, Tomoda A, Andersen SL. Neurobiological consequences of early stress and childhood maltreatment: are results from human and animal studies comparable? Ann N Y Acad Sci. 2006;1071:313–323. PubMed
49. Bonne O, Vythilingam M, Inagaki M, et al. Reduced posterior hippocampal volume in posttraumatic stress disorder. J Clin Psychiatry. 2008;69(7):1087–1091. PubMed doi:10.4088/JCP.v69n0707
50. Draijer N. Structured Trauma Interview. Amsterdam, the Netherlands: Free University, Department of Psychiatry; 1989.
51. Blake DD, Weathers FW, Nagy LM, et al. The development of a clinician-administered PTSD Scale. J Trauma Stress. 1995;8(1):75–90. PubMed doi:10.1002/jts.2490080106
52. Hovens JE, van der Ploeg HM, Klaarenbeek MT, et al. The assessment of posttraumatic stress disorder: with the Clinician Administered PTSD Scale: Dutch results. J Clin Psychol. 1994;50(3):325–340. PubMed doi:10.1002/1097-4679(199405)50:3<325::AID-JCLP2270500304>3.0.CO;2-M
53. First MB, Spitzer RL, Williams JBW, et al. Structured Clinical Interview for DSM-IV Diagnoses (SCID-I). Washington, DC: American Psychiatric Association; 1995.
54. Pfohl B, Blum N, Zimmerman M. Structured Interview for DSM-IV Personality (SIDP-IV). Washington, DC: American Psychiatric Press, Inc; 1997.
55. Beck AT, Steer RA, Garbin MG. Psychometric properties of the Beck Depression Inventory: twenty-five years of evaluation. Clin Psychol Rev. 1988;8(1):77–100.
56. Bernstein EM, Putnam FW. Development, reliability, and validity of a dissociation scale. J Nerv Ment Dis. 1986;174(12):727–735. PubMed doi:10.1097/00005053-198612000-00004
57. Arntz A, van den Hoorn M, Cornelis J, et al. Reliability and validity of the borderline personality disorder severity index. J Pers Disord. 2003;17(1):45–59. PubMed doi:10.1521/pedi.18.104.22.16853
58. Derogatis LR, Lipman RS, Covi L. SCL-90: an outpatient psychiatric rating scale—preliminary report. Psychopharmacol Bull. 1973;9(1):13–28. PubMed
59. Steinberg M, Rounsaville B, Cicchetti DV. The Structured Clinical Interview for DSM-III-R Dissociative Disorders: preliminary report on a new diagnostic instrument. Am J Psychiatry. 1990;147(1):76–82. PubMed
60. Ashburner J, Friston KJ. Voxel-based morphometry: the methods. Neuroimage. 2000;11(6 pt 1):805–821. PubMed doi:10.1006/nimg.2000.0582
61. Ashburner J, Friston KJ. Why voxel-based morphometry should be used. Neuroimage. 2001;14(6):1238–1243. PubMed doi:10.1006/nimg.2001.0961
62. Putnam FW, Carlson EB, Ross CA, et al. Patterns of dissociation in clinical and nonclinical samples. J Nerv Ment Dis. 1996;184(11):673–679. PubMed doi:10.1097/00005053-199611000-00004
63. Van Ijzendoorn MH, Schuengel C. The measurement of dissociation in normal and clinical populations: meta analytic validation of the dissociative experiences scale (DES). Clin Psychol Rev. 1996;16(5):365–382. doi:10.1016/0272-7358(96)00006-2
64. Bremner JD, Randall P, Vermetten E, et al. Magnetic resonance imaging-based measurement of hippocampal volume in posttraumatic stress disorder related to childhood physical and sexual abuse: a preliminary report. Biol Psychiatry. 1997;41(1):23–32. PubMed doi:10.1016/S0006-3223(96)00162-X
65. Bremner JD, Vythilingam M, Vermetten E, et al. MRI and PET study of deficits in hippocampal structure and function in women with childhood sexual abuse and posttraumatic stress disorder. Am J Psychiatry. 2003;160(5):924–932. PubMed doi:10.1176/appi.ajp.160.5.924
66. Stein MB, Koverola C, Hanna C, et al. Hippocampal volume in women victimized by childhood sexual abuse. Psychol Med. 1997;27(4):951–959. PubMed doi:10.1017/S0033291797005242
67. Hakamata Y, Matsuoka Y, Inagaki M, et al. Structure of orbitofrontal cortex and its longitudinal course in cancer-related post-traumatic stress disorder. Neurosci Res. 2007;59(4):383–389. PubMed doi:10.1016/j.neures.2007.08.012
68. Lacerda AL, Keshavan MS, Hardan AY, et al. Anatomic evaluation of the orbitofrontal cortex in major depressive disorder. Biol Psychiatry. 2004;55(4):353–358. PubMed doi:10.1016/j.biopsych.2003.08.021
69. Chanen AM, Velakoulis D, Carison K, et al. Orbitofrontal, amygdala and hippocampal volumes in teenagers with first-presentation borderline personality disorder. Psychiatry Res. 2008;163(2):116–125. PubMed doi:10.1016/j.pscychresns.2007.08.007
70. Tebartz van Elst L, Hesslinger B, Thiel T, et al. Frontolimbic brain abnormalities in patients with borderline personality disorder: a volumetric magnetic resonance imaging study. Biol Psychiatry. 2003;54(2):163–171. PubMed doi:10.1016/S0006-3223(02)01743-2
71. Soloff PH, Meltzer CC, Becker C, et al. Impulsivity and prefrontal hypometabolism in borderline personality disorder. Psychiatry Res. 2003;123(3):153–163. PubMed doi:10.1016/S0925-4927(03)00064-7
72. Milad MR, Rauch SL. The role of the orbitofrontal cortex in anxiety disorders. Ann N Y Acad Sci 2007;1121(Dec):546-561.
73. Veltman DJ, de Ruiter MB, Rombouts SA, et al. Neurophysiological correlates of increased verbal working memory in high-dissociative participants: a functional MRI study. Psychol Med. 2005;35(2):175–185. PubMed doi:10.1017/S0033291704002971
74. Clark CR, McFarlane AC, Morris P, et al. Cerebral function in posttraumatic stress disorder during verbal working memory updating: a positron emission tomography study. Biol Psychiatry. 2003;53(6):474–481. PubMed doi:10.1016/S0006-3223(02)01505-6
75. Moores KA, Clark CR, McFarlane AC, et al. Abnormal recruitment of working memory updating networks during maintenance of trauma-neutral information in post-traumatic stress disorder. Psychiatry Res. 2008;163(2):156–170. PubMed doi:10.1016/j.pscychresns.2007.08.011
76. Elzinga BM, Ardon AM, Heijnis MK, et al. Neural correlates of enhanced working-memory performance in dissociative disorder: a functional MRI study. Psychol Med. 2007;37(2):235–245. PubMed doi:10.1017/S0033291706008932
77. Cloitre M, Stovall-McClough KC, Miranda R, et al. Therapeutic alliance, negative mood regulation, and treatment outcome in child abuse-related posttraumatic stress disorder. J Consult Clin Psychol. 2004;72(3):411–416. PubMed doi:10.1037/0022-006X.72.3.411
78. Feeny NC, Zoellner LA, Foa EB. Treatment outcome for chronic PTSD among female assault victims with borderline personality characteristics: a preliminary examination. J Pers Disord. 2002;16(1):30–40. PubMed doi:10.1521/pedi.22.214.171.12455
79. Foa EB. Psychosocial treatment of posttraumatic stress disorder. J Clin Psychiatry. 2000;61(suppl 5):43–48, discussion 49–51. PubMed
80. Orth U, Cahill SP, Foa EB, et al. Anger and posttraumatic stress disorder symptoms in crime victims: a longitudinal analysis. J Consult Clin Psychol. 2008;76(2):208–218. PubMed doi:10.1037/0022-006X.76.2.208
81. Zanarini MC, Frankenburg FR, Reich DB, et al. The subsyndromal phenomenology of borderline personality disorder: a 10-year follow-up study. Am J Psychiatry. 2007;164(6):929–935. PubMed doi:10.1176/appi.ajp.164.6.929
82. Cloitre M, Koenen KC. The impact of borderline personality disorder on process group outcome among women with posttraumatic stress disorder related to childhood abuse. Int J Group Psychother. 2001;51(3):379–398. PubMed doi:10.1521/ijgp.51.3.379.49886
83. Lau M, Kristensen E. Outcome of systemic and analytic group psychotherapy for adult women with history of intrafamilial childhood sexual abuse: a randomized controlled study. Acta Psychiatr Scand. 2007;116(2):96–104. PubMed doi:10.1111/j.1600-0447.2006.00977.x
84. Miller MW, Fogler JM, Wolf EJ, et al. The internalizing and externalizing structure of psychiatric comorbidity in combat veterans. J Trauma Stress. 2008;21(1):58–65. PubMed doi:10.1002/jts.20303
85. Videbech P, Ravnkilde B. Hippocampal volume and depression: a meta-analysis of MRI studies. Am J Psychiatry. 2004;161(11):1957–1966. PubMed doi:10.1176/appi.ajp.161.11.1957
86. Vythilingam M, Heim C, Newport J, et al. Childhood trauma associated with smaller hippocampal volume in women with major depression. Am J Psychiatry. 2002;159(12):2072–2080. PubMed doi:10.1176/appi.ajp.159.12.2072
87. Ehling T, Nijenhuis ER, Krikke AP. Volume of discrete brain structures in complex dissociative disorders: preliminary findings. Prog Brain Res. 2008;167:307–310. PubMed doi:10.1016/S0079-6123(07)67029-0
88. Vermetten E, Schmahl C, Lindner S, et al. Hippocampal and amygdalar volumes in dissociative identity disorder. Am J Psychiatry. 2006;163(4):630–636. PubMed doi:10.1176/appi.ajp.163.4.630
89. Weniger G, Lange C, Sachsse U, et al. Amygdala and hippocampal volumes and cognition in adult survivors of childhood abuse with dissociative disorders. Acta Psychiatr Scand. 2008;118(4):281–290. PubMed doi:10.1111/j.1600-0447.2008.01246.x
90. Brambilla P, Soloff PH, Sala M, et al. Anatomical MRI study of borderline personality disorder patients. Psychiatry Res. 2004;131(2):125–133. PubMed doi:10.1016/j.pscychresns.2004.04.003
91. Driessen M, Herrmann J, Stahl K, 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(12):1115–1122. PubMed doi:10.1001/archpsyc.57.12.1115
92. Irle E, Lange C, Sachsse U. Reduced size and abnormal asymmetry of parietal cortex in women with borderline personality disorder. Biol Psychiatry. 2005;57(2):173–182. PubMed doi:10.1016/j.biopsych.2004.10.004
93. Zetzsche T, Preuss UW, Frodl T, et al. Hippocampal volume reduction and history of aggressive behaviour in patients with borderline personality disorder. Psychiatry Res. 2007;154(2):157–170. PubMed doi:10.1016/j.pscychresns.2006.05.010
94. Yucel K, McKinnon MC, Chahal R, et al. Anterior cingulate volumes in never-treated patients with major depressive disorder. Neuropsychopharmacology. 2008;33(13):3157–3163. PubMed doi:10.1038/npp.2008.40
95. Hazlett EA, New AS, Newmark R, et al. Reduced anterior and posterior cingulate gray matter in borderline personality disorder. Biol Psychiatry. 2005;58(8):614–623. PubMed doi:10.1016/j.biopsych.2005.04.029
96. Hamilton JP, Siemer M, Gotlib IH. Amygdala volume in major depressive disorder: a meta-analysis of magnetic resonance imaging studies. Mol Psychiatry. 2008;13(11):993–1000. PubMed doi:10.1038/mp.2008.57
97. Rüsch N, van Elst LT, Ludaescher P, et al. A voxel-based morphometric MRI study in female patients with borderline personality disorder. Neuroimage. 2003;20(1):385–392. PubMed doi:10.1016/S1053-8119(03)00297-0
98. Tebartz van Elst L, Ludaescher P, Thiel T, et al. Evidence of disturbed amygdalar energy metabolism in patients with borderline personality disorder. Neurosci Lett. 2007;417(1):36–41. PubMed doi:10.1016/j.neulet.2007.02.071
99. Zetzsche T, Frodl T, Preuss UW, et al. Amygdala volume and depressive symptoms in patients with borderline personality disorder. Biol Psychiatry. 2006;60(3):302–310. PubMed doi:10.1016/j.biopsych.2005.11.020
100. Wright IC, Ellison ZR, Sharma T, et al. Mapping of grey matter changes in schizophrenia. Schizophr Res. 1999;35(1):1–14. PubMed doi:10.1016/S0920-9964(98)00094-2
101. Davatzikos C. Why voxel-based morphometric analysis should be used with great caution when characterizing group differences. Neuroimage. 2004;23(1):17–20. PubMed doi:10.1016/j.neuroimage.2004.05.010