1. Nepal Medical College and Teaching Hospital (NMC), Nepal: poojabanarjee1@gmail.com
2. Nepal Medical College and Teaching Hospital (NMC), Nepal: parshuram88@outlook.com
3. King Edward Medical University, Mayo Hospital, Lahore; wajiulhassan1022@gmail.com

*             Correspondence: poojabanarjee1@gmail.com

Keywords: dissociative disorders, dissociative identity disorder, functional neuroimaging

1. INTRODUCTION

Dissociation is the loss of integration in basic processes such identity, motor control, memory, consciousness, and perception [1]. These are well-established findings, but throughout the years, the categorization of dissociative disorders has changed significantly. Originally, it was included in the category of what are now known as somatoform disorders, which were formerly classified as neuroses. Two categories of hysterical neurosis—conversion type and dissociative type—as well as a hysterical (histrionic) mental disorder were included in the DSM-II [2]. However, the atheoretically-oriented DSM-III [3] separated hysterical neurosis into two categories: conversion type and dissociative type, which were classified as dissociative disorders and included psychological amnesia, multiple personality disorder, and conversion disorder in the context of somatoform disorders. Additionally, sleepwalking disorder was classified under the dissociative type of hysterical neurosis, and psychogenic pain disorder in the context of somatoform disorders. Up to DSM-IV-TR, this tendency was validated in later revisions [4]. The DSM-5 has retained the Dissociative Disorders, although it has added additional disorders (Dissociative Identity Disorder, Dissociative Amnesia, Depersonalization/Derealization Disorder, Other Specified Dissociative Disorder, and Unspecified Dissociative Disorder) and renamed some of the existing ones. To better reflect potential cultural differences, dissociative identity disorder is now defined in the DSM-5 as possession and/or identity fragmentation. Dissociative fugue is a subtype of dissociative amnesia as fugue is an uncommon disorder that not only causes amnesia but also sometimes involves confused wandering or loss of personality identity [5]. Since the two conditions frequently co-occur, depersonalization disorder also encompasses derealization. Meta-analyses have demonstrated that all types of childhood traumas are directly linked to dissociation in individuals with mental disorders [6]. In terms of individual symptoms, severe dissociation has been linked to exposure to childhood traumas [6, 7]. Actually, compared to patients with depressive disorders, those with dissociative identity disorder (DID) report having experienced more severe childhood traumas [8,9], whereas individuals with depersonalization disorder (DPD) report having experienced less childhood trauma [10,11]. Findings on brain abnormalities may assist unravel the mystery of whether identical illnesses with varying degrees of severity may have common neurological underpinnings and origin. Over the last forty years, dissociative disorders have been the subject of neuroimaging research that have suggested specific brain activity patterns in individuals who fall into this diagnostic group. These studies have demonstrated changes in regional cerebral blood flow (rCBF) or glucose metabolism (CMRglu) in the hippocampus (which is involved in memory and the removal of traumatic events), the basal ganglia, the temporal, parietal (implicated in dissociative and conversion phenomena), and orbitofrontal (likely involved in the integration of the self) cortices, among other areas. Their findings, however, have led them to draw disparate and occasionally contradictory conclusions, identifying hypoactivation in certain instances and hyperactivation in others [12,13, 14]. It’s also uncertain if the left or right hemisphere is more frequently affected by these changes, while current research points to the former as suffering more harm. Additionally, the majority of these studies are constrained by small sample sizes, comorbidity and diagnostic heterogeneity, and disease stage (onset, acute, or chronic). The amygdala’s activation is suppressed when dissociation occurs, according to established models that link it to greater recruitment in executive control regions such the ventromedial prefrontal cortex, anterior cingulate cortex, and inferior frontal gyri [16, 17] and because it is involved in the neurophysiology of multisensory integration [18], and because its processing can be affected in the event of out-of-body experiences during brain stimulation and lesion studies [19, 20], attention has also been drawn to the connectivity of temporal cortices, specifically the temporoparietal junctions. The hypothesis posited that patients diagnosed with dissociative disorders under the DSM could exhibit shared functional changes in many brain regions during task execution and/or resting state. These alterations would be consistent with reduced performance on neurocognitive tasks. We sought to identify the primary brain functional pattern linked to dissociative disorders in light of the low prevalence of these diagnoses, the paucity of functional neuroimaging studies, and the generally mixed findings of these investigations.

2. MATERIALS AND METHODS

To find functional neuroimaging studies on individuals with a diagnosis of dissociative disorder (i.e., dissociative identity disorder, depersonalization disorder, dissociative amnesia, and other or not specified dissociative disorders), an international scientific database PubMed (http://www.pubmed.gov; accessed on 2 August 2022) was searched. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA Statement) [21] were adhered to by us in terms of methodology. Using the title/abstract filter, we first searched the PubMed database for the terms “dissociative disord*,” “dissociative amnesia,” “identity disorder,” “PET,” “MRI,” “positron emission,” “functional magnetic resonance imaging,” and “spectroscopy.” Second, we gathered further research by looking through the reviews of the subject and the bibliographies of pertinent publications from the previous stage or via the PubMed database’s “related article” feature. Notwithstanding the inclusion of healthy controls in the research, we included articles on functional neuroimaging studies in samples of patients with dissociative disorders (Dissociative Identity Disorder, Dissociative Amnesia, Depersonalization/Derealization Disorder, Other Specified Dissociative Disorder, and Unspecified Dissociative Disorder) as defined by the DSM criteria. Studies on children, reviews, case reports, case studies, pharmaceutical trials, research using methods other than functional neuroimaging, and studies involving individuals with other mental illnesses were all eliminated. Working separately from one another, three reviewers went over each record and report, gathered data, and then jointly confirmed that the process was appropriate and reread the results and data that were included. By evaluating the sample size, participant inclusion/exclusion criteria, sample consistency, methodology, and other factors, two reviewers independently determined the likelihood of bias in each included study [22]. They also used the Scottish Intercollegiate Guidelines Network (SIGN) quality assessment tool. This study was not registered and prepared according to a predetermined methodology. We followed our methodical procedures without the usage of automated tools. We examined 61 studies using these criteria, and then we eliminated 48 of them. Of these, 26 had no bearing on the topic, 6 were case reports/case studies [15,23,24,25,26,27], 1 was centered on schizophrenia [28], 1 studied adolescents with PTSD [29], 1 studied healthy subjects [30], 7 employed structural neuroimaging methods [31,32,33,34,35,36,37], and 3 did not address dissociative disorders [38,39, 40]. Finally, 13 studies that were published between 2006 and 2022 were considered [14, 33, 34, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50]. Based on the brain regions of affected patients that have been consistently found to be malfunctioning, we categorized the research in our discussion. Changes in neural cortical and subcortical activation patterns and changes in neural metabolism connected with the diagnosis of a dissociative disorder and/or with the severity of symptoms in individuals with a dissociative disorder were the primary study outcomes for which data were sought. Using the SIGN quality evaluation tool, the study’s possible methodological quality and bias risk were evaluated [22]. Every study tackled a pertinent and well-defined subject. However, the two groups under analysis in each of the 13 research are drawn from source populations that are similar to one another except for the component in question. Age disparities, for example, were uncommon but not statistically significant. Although there were no dropouts in the studies that were evaluated, none of the research indicated the proportion of participants in each group that were asked to participate. Every study has well-defined objectives, the DSM’s approach to diagnosing a patient is very dependable, and these standards are used globally to determine all psychiatric diagnoses. Confidence intervals are always given when examining alterations in a subject’s brain function. In summary, the largest potential for bias stems from the small sample size of the research, which may inflate the relevance of the findings [51]. Nevertheless, the results are deemed credible due to the low prevalence of dissociative disorders in the general population. There is proof that the disease and specific alterations in brain function are related, when one takes into account clinical factors, the assessment of the employed methodology, and the study’s statistical power. Furthermore, all included studies demonstrate consistent findings with no publication bias, no imprecisions, no serious limitations, and no serious indirectness, in accordance with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system of grading the quality of evidence and grading strength of recommendations in systematic reviews [52]. This system also takes into consideration the two aforementioned studies (view Table 1), which included two different diagnoses in the subject group and therefore have a higher risk of selection bias. We can ultimately conclude that the quality of the evidence is excellent after taking into account all of the studies, their suitability for diagnosis, appropriate confounding control, and other elements of design, conduct, and analysis that affect the likelihood of bias. Future systematic studies on this subject should ideally provide a thorough summary of the data on all significant functional brain alterations associated with dissociative disorders. Figure 1 is a summary of the search process.

Figure 1: PRISMA Flow Chart

3. RESULTS AND DISCUSSION

The most notable functional alterations have been discovered throughout the patients’ limbic systems, mainly when they completed specific tasks whose performance may have been impacted by the illness. The Theory of Structural Dissociation of the Personality in DID, which holds that patients retain traumatic memories fixed in the emotional part (EP) while some personality parts are apparently normal (ANP) in order to mentally avoid traumatic memories, served as the foundation for various functional neuroimaging studies [41]. When human faces depicting neutrality and anger were shown on the EP sections of DID patients, the right parahippocampal gyrus was hyperactivated compared to the ANP part and the EP part of controls (female actresses). The clinical traits of EP, such as fixation on traumatic memories and propensity to evoke traumatic memories with particular stimuli, can be linked to this outcome. Consequently, it may be related to the physiological role of the parahippocampal gyrus in the preservation of autobiographical memory, particularly the right one [53, 54]. When both neutral and furious faces were displayed, the ANP portion of DID patients showed a drop in whole-brain activity. In a PET research conducted during traumatic re-evocation in a traumatic state of identity (TIS) in individuals with DID, the insula displayed metabolic alterations [44], corroborating the compromised emotional processing, interoception, and physiological alarm response [55]. In fact, during egocentric learning in these patients, the insula appears to hyperactivate [46].  Nonetheless, it appears that dissociative disorders preserve some odd functions, if not enhance them. In contrast to controls, women with dissociative amnesia or DID demonstrated intact attentional visuospatial mnemonic performance during an egocentric virtual maze learning test [46]. Despite this, a more severe clinical picture was associated with improved performance and was linked to hyperactivation of the precuneus and cingulate gyrus [47]. The hypothesis that egocentric learning and egocentric tasks may be better in dissociative disorders than in healthy controls because dissociative defenses have improved and worked in preventing the development of PTSD [46] or more severe psychiatric disorders is supported by the results of another study in which DPD patients showed greater activation of the anterior cingulate during self-related processing [45]. In fact, in traumatic vs neutral identity states, as well as during assessments of within-identity states in DID patients, the cingulate gyrus, right anterior, and middle cingulate cortex appear to be hypoactivated [34]. Additionally, certain paralimbic system neuronal functions have exhibited abnormalities in DPD patients. During face processing (self vs. stranger), the right anterior cingulate cortex (ACC) becomes hyperactive. This has been suggested to be a correlate of conflict between the conscious and unconscious parts of self-processing in DPD [48]. According to certain theories, the difficulty faced by DPD patients is not with recognizing their own faces consciously, but rather with doing so unconsciously [45, 56]. This phenomenon is linked to the ACC’s hyperactivation during conflict detection and resolution, which helps to explain why patients experience agony when experiencing acute depersonalization states. Additionally, DPD patients demonstrated decreased activation of the amygdala in response to faces expressing emotions [48]. This data could be interpreted, as has been previously predicted in other studies on the subject, particularly on PTSD [57,58,59], as a response to traumatic events. A distinct pattern of activity in the left amygdala and right hippocampus has been linked to DID [50], because the latter is involved in autobiographical memory and plays a function in the Papez memory circuit. According to a neurobiological model of DID, severe stress may cause a shift in participation from the hippocampus to the caudate [50], which will be discussed later in relation to its hyperactivation during traumatic identity state condition. Compared to healthy controls (actors), DID patients displayed hyperactivation of the prefrontal cortex during resting state, especially in the dorsomedial area and other portions of the default mode network (DMN) [33]. This implies that when DID patients need to focus on themselves, they become more engaged. The same thing occurred when they were in the neutral personality state and responded to words associated to trauma as opposed to neutral terms [50], for example, if prefrontal activation may reduce the hyperarousal state caused by trauma re-evocation. Conversely, while at rest, the middle frontal gyrus was hypoactivated in healthy controls [33]. In comparison to healthy controls, a PET research has revealed decreased resting state metabolism of the right inferolateral prefrontal cortex in patients with dissociative amnesia-related autobiographical memory loss [42]. This area performs a variety of functions; in particular, it is engaged in higher order control mechanisms [63], emotion regulation [62], self-regulatory processes [61], and active memory retrieval [60, 62]. Reduced activation of the ventromedial prefrontal cortex and left frontal pole has been seen at fMRI during an n-back working memory test in patients with DID who are experiencing identity trauma [43]. Furthermore, a lower number of errors made throughout the task has been linked to this lower activation, as well as poorer memory performance. These findings may be connected to DID symptoms like anxiety, flashbacks, and reliving traumatic experiences. Indeed, a different study has shown that, in contrast to a neutral identity state, patients with DID have a hypoactivation of the frontal cortex while they are in an identity traumatic condition and during within-identity state assessment [34]. However, given the critical role this region plays in related tasks, trauma resurrection may also be related to impaired mentalization capacity (prefrontal deactivation), as it is mostly associated with sensorimotor and anxiety-related symptoms [64]. The existence of a retracted field of awareness in DID patients may possibly be related to these dysfunctions in the frontal brain during traumatic states of identity [43]. When compared to healthy controls, it has been observed that individuals with DID or not defined dissociative illness exhibit hyperactivation in other prefrontal areas (left anterior and dorsolateral cortices) during verbal working memory tests [14]. This phenomenon also appears to occur in the left parietal lobe. Patients with DPD can also draw the same conclusions [47, 49]. When exposed to neutral memories, the same group of patients showed improvements in working memory ability, which is consistent with the functional alterations observed at fMRI. This result may be associated with a distinct cognitive processing style that these patients eventually acquire. It is crucial to emphasize that neutral memories trigger hyperactivation in these regions because, as we have already observed, frontoparietal activity is decreased in traumatic states of identity [43]. When similar patients are instead given egocentric tasks to complete, the opposite occurs, i.e., hypoactivation in the inferior parietal lobe [46]. If this finding is task-dependent or a diagnostic correlate, further information is needed to understand it. Numerous investigations have additionally verified the existence of neurofunctional alterations in the prefrontal cortex of individuals with DPD. In fact, during face processing (self-vs. stranger faces), these patients displayed hyperactivation of the bilateral medial prefrontal cortices (PFCs) and left middle frontal gyrus (MFG), as well as the right anterior cingulate cortex [45,49]. Increased activity of medial PFCs was directly linked with the severity of depersonalization. A deficiency in implicit self-processing is consistent with this [45]. Dissociative disorders appear to cause abnormalities in other dispersed cortical areas in addition to what has previously been mentioned above. In the EP regions of DID patients, the left occipito-temporal junction was hyperactivated in comparison to the EP regions of controls, which is consistent with the role of this area of the cortex in face-sensitivity [41]. Furthermore, during the resting state, the primary somatosensory cortex and motor-related regions were hyperactivated in the EP of DID patients [33]. This result could be explained by the fact that DID patients’ EP is more resting-state focused on the self and tactile perceptions, leading to self-awareness, as well as a greater propensity to participate in motor reactions, such as when they are alert from prior traumas. The research that we incorporated has indicated functional alterations in many different cortical areas, suggesting that dissociative phenomena are intricate and that their neurophysiopathological correlates need to be clarified further. In cases of dissociative disorder, alterations in subcortical activity patterns have been seen, primarily in the thalamic regions. When DID patients’ EP parts were shown neutral human faces, they exhibited a hyperactivation in the brainstem region in comparison to the EP parts of controls (female actors), which is correlated with clinical characteristics of DID, such as hyperarousal [41]. When healthy controls simulate ANP as opposed to EP, the same phenomenon was observed [33]. Weniger et al.’s [46] discovery that the thalamus hyperactivates in healthy controls in relation to females with dissociative disorders and a history of childhood trauma supports this conclusion as well. The first biological models of dissociation in trauma survivors, in which the thalamus plays a central role, are correlated with thalamic hyperactivation. Study [65] has described that dysfunctional fear extinction processes following traumas provide a further explanation for this thalamic hyperactivation [66]. According to a different PET study, metabolic alterations in the bilateral caudate nucleus were observed during a trauma re-evocation in TIS in patients with DID. These findings are likely related to the caudate nucleus’s involvement in the neurophysiology of anxiety disorders, obsessive-compulsive disorders (OCD), and generally in fear processing dysfunction [67-70].  Results have indicated that the caudate hypoactivates during egocentric tasks in dissociative disorders [46], while the caudate nucleus of DID patients hyperactivates during traumatic identity state condition [34], in response to personal trauma scripts. The latter can be explained by the fact that the caudate nucleus, or dorsal striatum, is involved in both maintaining the altered identity state and transitioning between identity states [71]. This comprehensive review’s primary weakness is the paucity of functional neuroimaging research on dissociative disorders. We have therefore concentrated on the full range of dissociative disorders, and as a result, the eligibility requirements were varied. Another constraint is the use of only one database (PubMed), although we ran a supplementary search by checking the bibliographies of pertinent papers. The majority of the included studies had samples with less than 45 patients, which may involve a large risk of bias [51]. In addition, two studies had samples with mixed diagnoses, which may have resulted in a high risk of bias. These factors should be taken into consideration when interpreting the results of our systematic review.

4. CONCLUSION

In conclusion, dissociative disorders are the focus of very few functional neuroimaging investigations at this time. However, it is possible to highlight some consistent data regarding the correlations between these disorders and cerebral functioning. Prefrontal brain dysfunction appears to be widespread and has been linked to DPD’s depersonalization phenomenon as well as DID’s neutral and traumatic identity states. Additionally, adjustments in identity state and maintenance of an altered mental status in DID patients were linked to modifications in the caudate’s functional neuronal network. Anterior Cingulate Gyrus malfunction appears to play a role in DID as well. It has been claimed that dissociative disorders cause disruption in the parietal, temporal, and insular cortices, as well as other areas related to proprioception, interoception, self-awareness, and theory of mind. To find more individualized treatments, further research is required to elucidate the neurofunctional underpinnings of individual dissociative disorders in afflicted patients.

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