The hippocampus and amygdala were the first neurostructural regions to be studied in dissociative disorders, including dissociative identity disorder (DID). A recent systematic reviewReference Roydeva and Reinders1 proposed decreased hippocampal volumes as a neurostructural biomarker for dissociative amnesia in DID. A later studyReference Dimitrova, Dean, Schlumpf, Vissia, Nijenhuis and Chatzi2 confirmed this proposal and specified that findings of smaller bilateral global hippocampus are likely to be driven by decreases in subregions of the hippocampus, namely the bilateral CA1, right CA4, right granule cell molecular layer of the dentate gyrus and left pre-subiculum. The study further proposed decreased bilateral CA1 subfield volumes as a biomarker for dissociative amnesia in DID.
Studies that investigated the structure of the amygdala in DID and other disorders that involve dissociation are more limited and less consistentReference Roydeva and Reinders1. Grey matter volumes of the amygdala in relation to dissociation have been found to be normal or preserved,Reference Chalavi, Vissia, Giesen, Nijenhuis, Draijer and Barker3,Reference Nicholson, Aybek, Kempton, Daly, Murphy and David4 increased or decreased.Reference Roydeva and Reinders1 Findings that global amygdala volume is normal in DID could be explained by low numbers of participants in the studies, preventing results from reaching statistical significance, or by adding a mixture of increased and decreased subfield volumes to a net finding of normal global amygdala volumes. The latter possibility is supported by a recent study in post-traumatic stress disorder (PTSD), a disorder that is closely related to DID,Reference Spiegel, Lewis-Fernández, Lanius, Vermetten, Simeon and Friedman5 that found a mixture of increased and decreased amygdala subregional volumes.Reference Morey, Clarke, Haswell, Phillips, Clausen and Mufford6 Studying the amygdala in dissociation is important because the amygdala has been assigned a pivotal role in neurofunctional biological models for dissociation in which it is hypothesised that dissociation involves emotional overmodulation of the amygdala by midline prefrontal regions.Reference Lanius, Vermetten, Loewenstein, Brand, Christian and Bremner7,Reference Reinders, Willemsen, den Boer, Vos, Veltman and Loewenstein8
In the current study we investigated amygdala volumes in individuals with DID and addressed two aims. Our first aim was to explore whether our previous finding of normal amygdala volume in this disorderReference Chalavi, Vissia, Giesen, Nijenhuis, Draijer and Barker3 might be due to low statistical power. To this end, we doubled the sample size. The second aim was to study both global and subfield amygdala volumes to investigate whether a mixture of increased and decreased subfield volumes caused a net result of normal global volumes.
Method
Participants
Data from a total of 75 women (only female participants with DID volunteered) were collected. There were 32 female volunteers with DID and 43 healthy controls matched for age, gender, years of education and ethnicity. Data were collected in The Netherlands at the University Medical Centre in Groningen (UMCG) and the Amsterdam Medical Centre (AMC) and in Switzerland at the University Hospital in Zurich (UHZ).Reference Dimitrova, Dean, Schlumpf, Vissia, Nijenhuis and Chatzi2,Reference Reinders, Chalavi, Schlumpf, Vissia, Nijenhuis and Jäncke9,Reference Reinders, Marquand, Schlumpf, Chalavi, Vissia and Nijenhuis10 All participants gave written informed consent in accordance with the Declaration of Helsinki and as dictated by ethical requirements of the Medical Ethical Committees of UMCG (reference number: METC2008.211) and AMC (reference number: MEC09/155) and by the cantonal ethical commission of Zurich (Kantonale Ethikkommission Zürich; reference number: E-13/2008). All participants were given the right to withdraw and were fully debriefed in line with the ethical requirements of the Declaration of Helsinki.
Participants and data included in the current study are identical to those in the investigations of the hippocampus as a neurostructural biomarker of dissociationReference Dimitrova, Dean, Schlumpf, Vissia, Nijenhuis and Chatzi2 and whole-brain morphological studies.Reference Reinders, Chalavi, Schlumpf, Vissia, Nijenhuis and Jäncke9,Reference Reinders, Marquand, Schlumpf, Chalavi, Vissia and Nijenhuis10 In sum: participants with DID were diagnosed by trained clinicians using the Structured Clinical Interview for DSM-IV Dissociative Disorders (SCID-D) and all had a comorbid diagnosis of PTSD or of PTSD in remission and other comorbidity as confirmed by participants and their personal therapists.Reference Reinders, Chalavi, Schlumpf, Vissia, Nijenhuis and Jäncke9,Reference Reinders, Marquand, Schlumpf, Chalavi, Vissia and Nijenhuis10 The control group was recruited through local newspaper advertisements. Exclusion criteria for all participants included age outside the range of 18–65 years, pregnancy, systemic or neurological illness, claustrophobia, metal implants in the body and substance misuse. Additional exclusion criteria for the control group included the presence of dissociative symptoms and a history of trauma, past or current psychiatric disorders and medication use. Participants in the control group were required to have no or limited (somatoform) dissociative symptoms and potentially traumatising experiences.Reference Reinders, Chalavi, Schlumpf, Vissia, Nijenhuis and Jäncke9,Reference Reinders, Marquand, Schlumpf, Chalavi, Vissia and Nijenhuis10
Data acquisition
Magnetic resonance imaging (MRI) data were collected using 3 T Philips whole-body scanners (Philips Medical Systems, Best, Netherlands) from centres in The Netherlands (AMC and UMCG) and Switzerland (UHZ). An optimised T 1-weighted anatomical MRI protocol for the three participating centres was used:Reference Chalavi, Simmons, Dijkstra, Barker and Reinders11 three-dimensional magnetisation-prepared rapid gradient-echo imaging (3-D MP-RAGE), repetition time TR = 9.95 ms, echo time TE = 5.6 ms, flip angle 8°, voxel size 1 × 1 × 1 mm3, number of slices 160, total scan time 10 min 14 s. Ratios of DID to control participants were approximately equal across the centres and the number of participants per group did not differ across centres (χ2 = 1.01, P = 0.603).
Volumetric analysis
MRI data were processed using FreeSurfer version 7.0 for MacOS (surfer.nmr.mgh.harvard.edu). This version allows the extraction of both global and subregions of the amygdala. Following full surface reconstruction and volumetric segmentation, volumetric measures for the whole amygdala, the lateral nucleus, basal nucleus, accessory basal nucleus, anterior amygdaloid area, central nucleus, medial nucleus, cortical nucleus, corticoamygdaloid transition and paralaminar nucleus for each hemisphere were extracted. Further, the total intercranial volume (TIV) was calculated. Full details on the methodology are published elsewhere.Reference Fischl12 For one participant from the control group, FreeSurfer was not able to complete the amygdala segmentation. Therefore, this participant was excluded from subsequent statistical analyses.
Statistical analysis
All analyses were performed using SPSS version 26 (www.ibm.com/uk-en/products/spss-statistics). Between-group differences in amygdala volumes for each hemisphere were tested with analyses of covariance (ANCOVA). Amygdala volumes acted as the dependent variable, group and centre as fixed categorical effects, and age and estimated TIV as continuous covariates. Group differences were investigated by comparing the estimated marginal means of the main effects with Bonferroni post hoc correction across all subregions and global volumes.
Results
Table 1 shows the descriptive statistics and the findings of the between-group analyses (ANCOVA) on amygdala global volumes and volumes of amygdala subregions. We did not find any significant differences between the DID and control groups for either the global amygdala volumes or for the volumes of amygdala subregions. There was only one trend showing decreased volume for the DID group, and that was in the left corticoamygdaloid transition area (F(1,66) = 3.839, P = 0.054, ηp2 = 0.55), with a mean decrease of 9.090 mm3.
Descriptive statistics and analyses of covariance (ANCOVA) between participants with dissociative identity disorder (DID) and healthy controls on amygdala volume
ηp2, partial eta squared.
a. 0.05 < P ≤ 0.1.
Discussion
The current study confirms our previous finding of normal amygdala volumes in DID.Reference Chalavi, Vissia, Giesen, Nijenhuis, Draijer and Barker3,Reference Nicholson, Aybek, Kempton, Daly, Murphy and David4
Although the hippocampus is sensitive to excessive stress hormones, which may explain its decreased volumes in DID,Reference Dimitrova, Dean, Schlumpf, Vissia, Nijenhuis and Chatzi2 the structure of the amygdala might be less sensitive to stress hormones than previously thought.Reference Barry, Murray, Fearon, Moutsiana, Johnstone and Halligan13 Several unknowns add to the difficulty in interpreting our findings. They include the potential influence of different kinds of stress (e.g. attachment loss, physical abuse and emotional neglect), the sensitivity of the structure of the amygdala to the frequency and intensity of its activation and to ontogenetic developmental phases, and lifetime prefrontal inhibition of amygdala activation.Reference Reinders, Willemsen, den Boer, Vos, Veltman and Loewenstein8,Reference Nijenhuis, Dorahy, Gold and O'Neil14 The last, which is a potentially neuroprotective effect, might be more pronounced in individuals with DID, who predominantly function as one or more dissociative identities that successfully avoid emotional cues, which might relate to frequent prefrontal inhibition of amygdala activity. These unknowns all open pathways for future research.
The trend for decreased volume in the corticoamygdaloid transition area in our study might be due to scanner differences between the three centres as in the study by Morey and colleagues,Reference Morey, Clarke, Haswell, Phillips, Clausen and Mufford6 they found that the covariates age and scanner were significant for the corticoamygdaloid transition area. Although we were careful to use identical scanner sequences at all three centres and included centre as a covariate, residual variance related to scanner differences in the corticoamygdaloid transition area cannot be excluded and could contribute to our finding of a trend. Age was the second covariate found in the study by Morey and colleagues to be significantly associated with amygdala volume. The effect of age on amygdala volumes in a sample of individuals with DID has been independently discussedReference Spiegel15 for reported decreased amygdala volume.Reference Vermetten, Schmahl, Lindner, Loewenstein and Bremner16 However, in the current study age is not a contaminating factor in the finding of normal amygdala volumes because the DID and control group were carefully matched (t(72) = −0.55, P = 0.581).Reference Dimitrova, Dean, Schlumpf, Vissia, Nijenhuis and Chatzi2
This short report is part of a sequence of brain imaging papers that originated from a multicentre collaboration between two centres in The Netherlands and one in Switzerland. We found that structural imaging can aid a diagnosis of DID,Reference Reinders, Marquand, Schlumpf, Chalavi, Vissia and Nijenhuis10 that there is no evidence for DID to be a neurodevelopmental disorderReference Reinders, Chalavi, Schlumpf, Vissia, Nijenhuis and Jäncke9 and that hippocampal subregion CA1 can be proposed as a biomarker for dissociative amnesia.Reference Dimitrova, Dean, Schlumpf, Vissia, Nijenhuis and Chatzi2 The findings in these studies were all statistically significant, indicating that this data-set contains robust morphological aberration in relation to the diagnosis of DID and that normal amygdala volumes are a genuine finding. Therefore, we conclude that our previously reported normal amygdala volumes in DIDReference Chalavi, Vissia, Giesen, Nijenhuis, Draijer and Barker3 are upheld under increased statistical power and after investigating the independent contributions of subregions of the amygdala to its global volume.
Data availability
The data that support the findings of this study are available from the corresponding author on reasonable request.
Acknowledgements
We thank all the participants and their therapists. We thank Drs Nel Draijer, Mechteld Giesen, Ekaterina Weder and Eva Zimmermann for arranging participant inclusion and scanning as well as for the assessment of diagnostic interviews and their support as research clinicians.
Author contributions
All authors have approved the final version for publication and are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. A.A.T.S.R.: conceptualisation, data acquisition, funding acquisition, interpretation, methodology, project administration, resources, supervision, visualisation, writing – review and editing. L.I.D.: formal analysis, methodology, interpretation, software, visualisation, writing original draft and review and editing. Y.R.S. and S.C.: data acquisition, interpretation, methodology, project administration, software, writing – review and editing. E.M.V.: conceptualisation, data acquisition, formal analysis, interpretation, methodology, project administration, writing original draft and review and editing. E.R.S.N. and L.J.: conceptualisation, data acquisition, interpretation, methodology, writing – review and editing. D.J.V.: conceptualisation, funding acquisition, formal analysis, interpretation, supervision, writing – review and editing.
Funding
This article represents independent research part-funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. The views expressed are those of the authors and not necessarily those of the National Health Service, the NIHR or the Department of Health. A.A.T.S.R. was supported by The Netherlands Organization for Scientific Research (www.nwo.nl), NWO-VENI grant no. 451-07-009. S.C. was supported by a David Caul graduate research grant from the International Society for the Study of Trauma and Dissociation (ISSTD) (www.isst-d.org/about/awards.htm). Y.R.S. was supported by the Forschungskredit UZH (www.researchers.uzh.ch/de/funding/phd/fkcandoc.html).
Declaration of interest
D.J.V. and A.A.T.S.R. are members of the BJPsych Open editorial board and did not take part in the review or decision-making process of this paper.
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