Our study is the first to demonstrate smaller hippocampal and amygdalar volumes in female patients with dissociative identity disorder, compared to healthy female subjects. The patients with dissociative identity disorder in our study showed a 19.2% smaller hippocampal volume and a 31.6% smaller amygdalar volume, compared with the healthy subjects. Hippocampal/amygdalar volume ratios were larger in the dissociative identity disorder group than in the healthy comparison group.
All patients with dissociative identity disorder in this study also had a diagnosis of PTSD according to the DSM-IV-TR criteria and the Clinician-Administered PTSD Scale cutoff score. To our knowledge, this is the first study to confirm PTSD diagnoses in dissociative identity disorder patients by using the Clinician-Administered PTSD Scale, generally considered to be the gold-standard psychometric instrument for PTSD diagnosis. These results are consistent with the conceptualization of dissociative identity disorder as an extreme form of early-abuse-related PTSD.
There are virtually no previous empirical studies of the neurobiology of patients with dissociative identity disorder. Some early studies looked at psychophysiologial alterations in different states (31
). Other studies have shown alterations in memory in dissociative identity disorder (35
). In still other studies, researchers attempted to investigate divided attention tasks and memory function in subjects with dissociative identity disorder (36
Apart from single case reports, published brain imaging studies of dissociative disorders are few. In one study, patients with depersonalization disorder had higher activity in somatosensory association areas (40
). In another study, functional MRI was used to examine brain activation in PTSD patients in a dissociative state while reexperiencing traumatic memories; greater activation was found in the temporal, inferior, and medial frontal regions and in occipital, parietal, anterior cingulate, and medial prefrontal cortical regions (41
). A positron emission tomography study showed different patterns of activation with identity fluctuation in dissociative identity disorder (42
). Two studies found a negative correlation between dissociative symptom level (as measured with the Clinician-Administered Dissociative States Scale or the Dissociative Experiences Scale) and hippocampal volume as measured with MRI in women with PTSD related to early childhood sexual abuse (who had elevated levels of dissociative symptoms) (15
). Electrical stimulation of the hippocampus and adjacent regions in patients with epilepsy resulted in a number of dissociative-like symptoms, including feelings of déjà vu, depersonalization, derealization, and memory alterations (43
). Administration of ketamine, an antagonist of N
-methyl-D-aspartic acid (NMDA) receptors, which are highly concentrated in the hippocampus, resulted in dissociative symptoms in healthy subjects, including feelings of being out of body and of time standing still, perceptions of body distortions, and amnesia (45
). On the basis of these findings, we have hypothesized that stress, acting through NMDA receptors in the hippocampus, may mediate symptoms of dissociation (46
Clinical studies have found comorbid PTSD or a lifetime history of PTSD in 80%–100% of dissociative identity disorder patients (2
). Davidson and Foa (47
), in their summary of work by members of the APA DSM-IV Advisory Committee on PTSD, included multiple personality disorder/dissociative identity disorder among the disorders related to “abnormal stress reaction[s].” They stated that “a concerted research effort is needed to apply common methods to study…those disorders in which the original occurrence of trauma served as a necessary (i.e., etiological) factor” (pp. 234–235). Despite this suggestion, few researchers have attempted to use established psychometric instruments to assess PTSD in patients with dissociative identity disorder (2
). Further, no study of dissociative identity disorder patients has included the assessment of neurobiological measures that have been studied in PTSD populations. The study of the psychobiology of dissociative identity disorder patients, compared to that of PTSD patients and other clinical groups, may contribute to the ongoing debate about the validity of the dissociative identity disorder construct and contribute to alternative theories of its etiology. We acknowledge that this study does not imply that dissociative identity disorder is a distinct disorder.
There are several possible explanations for the current study findings. Previous studies have shown that dissociative identity disorder patients essentially universally report high rates of exposure to repeated stressful experiences in early life (5
). The hippocampus is a major target organ for glucocorticoids, which are released during stressful experiences. It has been hypothesized that prolonged exposure to glucocorticoids could lead to progressive atrophy of the hippocampus (48
). Smaller hippocampal volume in dissociative identity disorder could thus be related to stress exposure and could represent a neurobiological finding that dissociative identity disorder shares with other stress-related psychiatric disorders such as PTSD. The exact mechanism that could lead to smaller amygdalar volume in dissociative identity disorder is unclear. To our knowledge, the amygdala is not a target organ for glucocorticoids. In contrast to the volumetric assessment of the hippocampus, reliable measurement of amygdalar volume with MRI in human subjects has long been thought to be difficult to accomplish (29
). However, the use of MR cameras with good resolution, agreement on the structure boundaries, and the use of three-dimensional software packages enabled us to reliably measure both hippocampal and amygdalar volumes.
Smaller hippocampal and amygdalar volumes have been reported in three earlier studies in which patients with borderline personality disorder were compared to healthy subjects (18
). Driessen et al. (18
) found that hippocampal volume was approximately 16% smaller and amygdalar volume 8% smaller in patients with borderline personality disorder, compared to healthy subjects. Schmahl et al. (19
) found a 13.1% smaller hippocampal volume and a 21.9% smaller amygdalar volume in borderline personality disorder patients (all of whom had a history of childhood abuse) than in healthy comparison subjects. Tebartz van Elst et al. (20
) reported a 20%–21% smaller hippocampal volume and a 23%–25% smaller amygdalar volume at both sides in patients with borderline personality disorder, compared to healthy subjects. Early studies in PTSD patients did not show significantly smaller amygdalar volumes. However, a study of patients with PTSD related to early abuse showed a 15% smaller left amygdalar volume in the patients, compared with matched healthy subjects (14
), and a recent study showed smaller amygdalar volumes in police officers with PTSD (51
). These findings suggest that early abuse associated with a stress-related psychiatric disorder may be related to smaller amygdalar volume. In addition, these findings are in contrast to findings from studies of depression that have shown no differences or larger amygdalar volume in depressed patients, compared with healthy subjects (52
Besides glucocorticoids, other neurotransmitters/neuromodulators such as glutamate, serotonin, and endogenous opioids could have an effect on hippocampal and amygdalar volumes (53
). Genetic factors that could contribute to the smaller hippocampal and amygdalar volumes that are found in patients with dissociative identity disorder could increase the risk for the development of the disorder (54
). In an application of this argument to PTSD, stress may not cause hippocampal damage; rather, individuals who were born with smaller hippocampal volume would be at greater risk for development of PTSD (55
). Consistent with this hypothesis, abused subjects without dissociative identity disorder in the current study had larger hippocampal and amygdalar volumes than non-abused subjects without dissociative identity disorder. Larger hippocampal and/or amygdalar volume may be protective in the face of early trauma.
Our finding that the ratio of hippocampal volume to amygdalar volume discriminated the patients from the healthy comparison subjects has not been reported in previous volumetric studies. This finding suggests that dissociative identity disorder is associated with relatively greater volume reductions in the amygdala than in the hippocampus.
Our study had several limitations. As a group, the comparison subjects were significantly younger than the dissociative identity disorder patients. Age-related structural alterations in the hippocampus have been identified (56
); however, there are no previous findings of a relationship between age and hippocampal or amygdalar volume in women in the 20–50-year age group (57
), the age group represented by the subjects in our study. In a study of the effects on hippocampal volume of age and sex in early adulthood, Pruessner et al. (57
) reported a significant negative correlation of age with both left and right hippocampal volumes (a reduction in hippocampal volume of about 1%–1.5% per year) in men only. In women no such relationship was found. No significant effect of age was found for amygdalar volume in either men or women. It is hypothesized that the estrogen level in young adult women protects against loss of volume of the hippocampus. Changes in estrogen level associated with entering menopause could therefore have contributed to hippocampal volumetric alterations, and it is possible that a few of the dissociative identity disorder patients in our study could have entered menopause. Sullivan et al. (58
), however, found no difference in hippocampal volume in pre- versus postmenopausal women. These studies add support to an analysis in which dissociative identity disorder patients and healthy subjects are compared without adjustment for effects of age. Accordingly, we believe the significance levels for the between-group comparisons of both hippocampal and amygdalar volumes are valid without correction for this factor. Yet the design would have been stronger if the groups were age-matched.
In addition, we did not perform volumetry of subcortical regions (e.g., the caudate nucleus) to obtain comparison measures. This step would have enabled us to correlate the volume measurements of structures of interest with those of brain regions that are presumed to be unaffected. However, we did use whole brain volume as a covariate. Another limitation was that the dissociative identity disorder subjects were so ill that they could not be safely included in the study as medication-free outpatients, whereas the comparison subjects were medication free during the study. Medication has been shown to influence the volume of the hippocampus. In rodents, antidepressant treatment has been shown to increase neurogenesis in the hippocampus (59
). A single study in humans has also demonstrated an increase in hippocampal volume associated with treatment with paroxetine (60
). Therefore, it is possible that the differences in hippocampal volume and possibly in amygdalar volume for the dissociative identity disorder group could have been even larger if the patients had not been taking medication. Finally, a potential limitation of this study is that all of the patients with dissociative identity disorder also met the criteria for PTSD, which makes it impossible to establish that the findings are not related to the comorbid PTSD diagnosis. However, patients with true dissociative identity disorder without PTSD essentially do not exist. We hope that the current study will promote a conceptualization of PTSD and dissociative identity disorder as related trauma-spectrum disorders (61
These findings may have clinical implications for the treatment of dissociative identity disorder patients. For example, an understanding of dissociative identity disorder as a trauma-related disorder that involves neural circuitry alterations in brain areas associated with memory that are also affected in PTSD may help clinicians better understand the symptoms presented by patients in treatment sessions. Neurobiological studies that support the validity of the diagnosis of dissociative identity disorder will help to advance research in this area. Findings that link dissociative identity disorder to other trauma-related disorders may help improve nosological approaches to this disabling disorder.