The elusive search for a biomarker of dissociative amnesia: an overstated response to understated findings?

Huntjens et al. (Huntjens, Otgaar, Pijnenborg, & Wessel, 2022) overstate that we claim to have found a biomarker for dissociative amnesia in DID (Dimitrova et al., 2021) as we made no such claim. Actually, we propose that reduced cornu ammonis 1 (CA1) volume might be a biomarker for dissociative amnesia in DID and emphasise the need for future studies to confirm our results. As in other publications of our pioneering research, we carefully chose words like ‘propose’, ‘indicate’ and ‘might’.

Huntjens et al. (2022) first concern is that we used a subjective rather than objective measure of dissociative amnesia, i.e. the subjective amnesia subscore of the DES a widely used and well-validated questionnaire. We consider subjectively reported debilitating symptoms to be at the core of any psychiatric disorder, therefore key to investigate. Absence of inter-identity amnesia in DID according to ‘objective measures’ in some experimental studies (see Table 1) does not mean that the subjective experience of amnesia is less debilitating and incapacitating; therefore, specialised treatment and research on how to relieve it remains needed (Corrigan & Hull, 2022; Reinders, Young, & Veltman, 2022). Furthermore, it is unclear what constitutes an ‘objective cognitive measure’. Objective measures should be free of internal and external influences. Regarding the latter, data should have been obtained in a controlled environment where no other factors can influence the data collected. It is unclear whether the data Huntjens et al., referred to meet these requirements, because it was not reported that researchers present during data acquisition were blind for the experimental tasks. Regarding internal influences, ‘the term objectivity typically refers to a mental state wherein one is uninfluenced by personal feelings or prejudices’ (Bornstein, 1999). This condition typically cannot be ascertained for cognitive/psychological data, and therefore ‘objective cognitive measures' arguably do not exist, unlike for example biochemical and structural brain measures.

Table 1. Studies examining inter-identity amnesia in individuals with dissociative identity disorder^a

BP, Biological Psychiatry; BRaT, Behaviour Research and Therapy; C&C, Consciousness and Cognition; CN, Cognitive neuropsychiatry; DID, dissociative identity disorder; IJoP, International Journal of Psychophysiology; JoAP, Journal of Abnormal Psychology; JoNaMD, Journal of nervous and mental disease; MPD, multiple personality disorder; M&C, Memory and Cognition; NI, NeuroImage; NY, New York; PET, positron emission tomography; PM, Psychological Medicine; PP, Plenum Press; PR, Psychiatry Research; PR:I, Psychiatry research: Neuroimaging; PTSD, post-traumatic stress disorder; rCBF, regional cerebral blood flow.

^a Case studies were excluded, these are reviewed in: Mangiulli, I., Otgaar, H., Jelicic, M., & Merckelbach, H. (2022). A critical review of case studies on dissociative amnesia. ClinicalPsychological Science, 10(2), 191–211. https://doi.org/10.1177/21677026211018194.

^b This is a book chapter.

^c Self-relevance is defined as a past autobiographical event, not experimentally related.

^d Van Heugten-van der Kloet, D., Huntjens, R., Giesbrecht, T., & Merckelbach, H. (2014). Self-reported sleep disturbances in patients with dissociative identity disorder and post-traumatic stressdisorder and how they relate to cognitive failures and fantasy proneness. Frontiers in Psychiatry, 5, 19. https://doi.org/10.3389/fpsyt.2014.00019.

^e Self-experimental is defined as an experimentally learned/induced autobiographical event, a self-relevance primed autobiographical event that is independent of the traumatic personal past.

^f Dorahy MJ, McKendry H, Scott A, Yogeeswaran K, Martens A, Hanna D. Reactive dissociative experiences in response to acute increases in shame feelings. Behaviour Research and Therapy. 2017; 89:75–85. https://doi.org/10.1016/j.brat.2016.11.007

As a second comment Huntjens et al., wonder if our results are specific to DID. We disagree, however, with their claim that controlling for specific co-morbid disorders leaves us without significant findings. Firstly, as for each comorbid disorder only few cases were present, we considered that disorder-specific effects could not be reliably assessed, hence we used the ‘all comorbidity’ option. Nevertheless, when accounting for individual comorbid disorders (see online Supplementary Table S4 of Dimitrova et al., 2021) some significant or trend level significant findings for left and right CA1 remained. Considering the trauma-related aetiology of DID (Chalavi et al., 2015b; Dalenberg et al., 2012) it is not surprising that co-morbid PTSD is frequently observed in individuals with DID. However, we do not agree that our ‘results equally favour the interpretation that PTSD and CA1 volume reduction are linked’. The sample we studied had a primary diagnosis of DID and in general not all individuals with PTSD report symptoms of dissociative amnesia; a study in PTSD with and without dissociative features is recommended to investigate if the association between CA1 volume and dissociative amnesia still holds.

As a third comment Huntjens et al., state that multiple testing is a problematic feature of our study. Here, we agree. We chose to provide comprehensive analyses and information based on experiences with reviewers who commonly ask for additional online supplementary materials; for example, for the current paper a reviewer requested the analyses correcting for co-morbidity. To allow for standard and strict literature driven a priori region of interest analyses we revisited the data analyses using the newest scientific information available for this rejoinder. Of the significant hippocampal subfields reported in Chalavi et al. (2015b) only the subiculum and CA regions 1 and 3 were considered relevant because they have been related to memory retrieval and to memory encoding/retrieval, respectively (Seok & Cheong, 2020); the presubiculum has only been linked to parasubiculum visuospatial processing (Dalton & Maguire, 2017). No evidence has been found for lateralisation of reduced hippocampal volume in relation to adverse childhood events (Hakamata, Suzuki, Kobashikawa, & Hori, 2022) guiding the analyses of total regional volumes. For the reanalysis we used independent sample t tests and report 1-tailed significance findings to test for decreased regional volumes only. Bonferroni multiple comparison correction for the three regions analysed was applied resulting in a significant finding of decreased volume of the CA1 (t(72) = 2.320, p = 0.035), but not for CA3 or the subiculum. A correlation analysis of CA1, the only significantly reduced hippocampal subfield volume, with dissociative amnesia was performed because this was the main clinical measure of interest. A significant correlation of r = −0.398, p = 0.015 was found. Regarding the comment of reusing the same dataset to test different hypotheses: this is not uncommon and is a practice followed by Huntjens et al., themselves (see Table 1). The volumetric data, brain regions, clinical variables and data analyses techniques were different in Dimitrova et al. (2021) than in previous publications (Chalavi et al. 2015a, 2015b; Reinders et al. 2018) and therefore a correction for multiple testing was not warranted. Taken together, when only testing the core hypothesis under consideration that ‘Smaller hippocampal subfield volumes will negatively correlate with higher severity of dissociative amnesia in individuals with DID’, our proposal that the CA1 is of interest for consideration as a biomarker for dissociative amnesia in DID holds. The remark by Huntjens et al., concerning causality is confusing because we have neither stated nor believe that dissociative amnesia is caused by reduced CA1 volume. Correlation does not imply causality.

A wealth of imaging data shows early childhood traumatisation associations with decreased hippocampal volume. For example, a systematic review of 27 previous meta-analyses found a 100% significant association between decreased hippocampal volume and adverse childhood experiences (Hakamata et al., 2022). Because the current study provides in-depth analyses of hippocampal volume using data analyses techniques not available previously while doubling participants numbers, we assume that the absence of significant associations in Chalavi et al. (2015a, 2015b) is due to lower statistical power and/or less refined data analysis techniques (see also Reinders et al., 2022). In Chalavi et al. (2015b) the merged volumes of CA2/CA3 and CA4/DG significantly differed between groups. In our paper (Dimitrova et al., 2021) these regions were split and did not reach statistical significance. However, the hippocampal CA1 subregion in Chalavi et al. (2015b) and Dimitrova et al. (2021) can be compared directly. We propose that the reason for CA1 becoming significant is due to improved data processing techniques and increased statistical power. Consequently, we disagree that our current results are inconsistent with our previously published results.

A smaller hippocampus does not necessarily mean reduced functionality, as functionality might be compensated by increased or specialised dendrite sprouting. Therefore, our findings need not be incompatible with the ability of individuals with DID to rapidly change access to neutral or trauma-related experiences. A recent study using 7 Tesla fMRI indicated that CA1-3 are involved in both memory encoding and retrieval (Seok & Cheong, 2020). How individuals with DID are able to achieve this highly specialised functioning of the CA1-3 while its volume is reduced remains unknown and could be a topic for future research. We realise that the sentence ‘propose that traumatisation, specifically emotional neglect, is interlinked with dissociative amnesia in having a detrimental effect on hippocampal volume’ was possibly interpreted differently by Huntjens et al.. We did not intend to imply that dissociative amnesia causes a smaller hippocampus. On the contrary, dissociation is more likely to be neuroprotective instead of neurotoxic due to less stress hormones being released. A clarified rephrasing of this sentence is: ‘propose that dissociative amnesia is interlinked with traumatisation, specifically emotional neglect, which may have a detrimental effect on hippocampal CA1 subvolume.’

In sum, we consider that our proposal that CA1 may be a biomarker for dissociative amnesia is justified and merits further investigation. Regarding the paper by Marek et al. (2022), other experts in the field have expressed fears that ‘this paper may be overestimating unreliability’ (Stephen Smith in Callaway (2022)) and have stated that with careful selection of participants and sophisticated data analyses methods it might be possible to find stronger associations between brain scans and behaviour than reported by Marek et al. (2022); our study fits these requirements. Additionally, we are particularly confused that Huntjens et al., ‘… question the need for assuming the existence of a special mechanism like dissociation that is supposed to banish traumatic memories from conscious awareness’. They offer ‘dysfunctional beliefs’ as an alternative explanation, hence another ‘special mechanism’. The idea is far from new, as Janet (1904) proposed that dissociative identities committed to daily life functioning may develop a phobia of traumatic memories. Patients may recollect a trauma as an event but believe it does not pertain to them and inhibit emotional reactivity. Phobia of traumatic memory is furthermore incorporated in the theory of structural dissociation (Steele, Van der Hart, & Nijenhuis, 2005; Van der Hart, Nijenhuis, & Steele, 2006). We thus do not claim that traumatic memories are ‘banished’ from conscious awareness but hold and have demonstrated that different prototypical dissociative identities may recollect traumatic experiences to different degrees and in different ways (Reinders et al., 2006, 2012). As such, ‘conceptualizing reports of dissociative amnesia as the result of dysfunctional beliefs about the self and one's memory functioning’ is indeed ‘a way forward out of the controversy surrounding this disorder’ because it seems that Huntjens et al., join our way of thinking about dissociative amnesia in DID, which we wholeheartedly welcome.