Biomarkers of Pathological Dissociation: A Systematic Review

Highlights

• Neurofunctional biomarkers of pathological dissociation are the dorsomedial and dorsolateral prefrontal cortex, bilateral superior frontal regions, (anterior) cingulate, posterior association areas and basal ganglia.

• Neurostructural biomarkers of pathological dissociation are decreased hippocampal volume, basal ganglia volume and thalamus volume.

• As psychobiological markers for pathological dissociation increased oxytocin and prolactin and decreased tumor necrosis factor alpha (TNF-α) are proposed.

• No clear directional effects were found for psychophysiological and genetic biomarkers in relation to pathological dissociation.

Abstract

Pathological dissociation is a severe, debilitating and transdiagnostic psychiatric symptom. This review identifies biomarkers of pathological dissociation in a transdiagnostic manner to recommend the most promising research and treatment pathways in support of the precision medicine framework. A total of 205 unique studies that met inclusion criteria were included. Studies were divided into four biomarker categories, namely neuroimaging, psychobiological, psychophysiological and genetic biomarkers. The dorsomedial and dorsolateral prefrontal cortex, bilateral superior frontal regions, (anterior) cingulate, posterior association areas and basal ganglia are identified as neurofunctional biomarkers of pathological dissociation and decreased hippocampal, basal ganglia and thalamic volumes as neurostructural biomarkers. Increased oxytocin and prolactin and decreased tumor necrosis factor alpha (TNF-α) are identified as psychobiological markers. Psychophysiological biomarkers, including blood pressure, heart rate and skin conductance, were inconclusive. For the genetic biomarker category studies related to dissociation were limited and no clear directionality of effect was found to warrant identification of a genetic biomarker. Recommendations for future research pathways and possible clinical applicability are provided.

Introduction

Pathological dissociative symptoms are ubiquitous and of a transdiagnostic nature (Ellickson-Larew et al., 2020; Lyssenko et al., 2018; McKinnon et al., 2016). They range from mild detachment from the immediate surroundings to a failure to integrate one’s thoughts, feelings and memories, contributing to a lack of sense of self or identity. Psychoform dissociative symptoms can disrupt every area of psychological functioning and affect usually integrated functions such as consciousness, memory, personal identity, emotion or perception of the environment and the self (American Psychological Association, 2013), while somatoform dissociation affects body representation, motor control and behaviour.

Dissociation is mostly known from dissociative identity disorder (DID), the most severe, complex and controversial of the dissociative disorders (Brand et al., 2016; Bremner et al., 2010; Dalenberg et al., 2014, 2012, Giesbrecht et al., 2010a, 2008, Lynn et al., 2019, 2014; Merckelbach et al., 2016; Vissia et al., 2016), but is also a key feature of dissociative amnesia, dissociative fugue and depersonalisation-derealisation disorder (Sierra and David, 2011). Furthermore, dissociative symptoms present in a number of major disorders such as posttraumatic stress disorder (Lanius et al., 2012, 2010), psychosis (Holowka et al., 2003; Vogel et al., 2013; Yu et al., 2010), borderline personality disorder (Belli, 2014; Schmahl et al., 2004; Vermetten and Spiegel, 2014), major depressive disorder (Molina-Serrano et al., 2008; Parlar et al., 2016; Şar et al., 2013), bipolar disorder (Tuineag et al., 2020) and obsessive-compulsive disorder (Rufer et al., 2006).

Despite pathological dissociative symptoms being transdiagnostic and omnipresent, scientific research into the biology of pathological dissociation is scarce and scattered over decades of research, research methodologies and research paradigms and little is known about the neurobiology, psychobiological, psychophysiological and genetic similarities of pathological dissociative symptoms across psychiatric disorders. Studying the biology of pathological dissociation is of interest and importance because establishing biological characteristics of pathological dissociative symptoms can aid diagnosis (Reinders et al., 2019) or inform on pharmacological and non-pharmacological treatment response (Lanius et al., 2018). These biological characteristics are also referred to as “biomarkers”. More specifically, a biomarker is a measure of normal or pathological biological processes, or of a response to an exposure or intervention, including therapeutic interventions. Measures of biomarkers include medical imaging, such as (functional) magnetic resonance imaging (fMRI) and electroencephalogram (EEG), body fluids, such as saliva and blood, or physiologic characteristics, such as heart rate or blood pressure. To improve the understanding and use of biomarker terminology in biomedical research, clinical practice and medical product development, the Food and Drug Administration (FDA)-National Institutes of Health (NIH) Joint Leadership Council developed the BEST guidelines (Biomarkers, EndpointS, and other Tools). The BEST biomarker categories include: diagnostic biomarkers, pharmacodynamic/response biomarkers, susceptibility/risk biomarkers, prognostic biomarkers, predictive biomarkers, monitoring biomarkers and safety biomarkers (FDA-NIH Biomarker Working Group, 2016; Pitkänen et al., 2019; U.S. FDA, 2016). Diagnostic biomarkers of pathological dissociation can be used to confirm or detect the presence of a disorder involving pathological dissociation. Determining diagnostic biomarkers is also the first step towards proposing pharmacodynamic/response biomarkers and establishing susceptibility/risk biomarkers, prognostic biomarkers, predictive biomarkers, monitoring biomarkers and safety biomarkers (Mayeux, 2004).

The current paper aims to determine diagnostic biomarkers of pathological dissociation through a systematic review and to propose possible pharmacodynamic/response biomarkers for future research. To date no such efforts have been made and our systematic review will provide novel information on biomarkers involved in pathological dissociation. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Moher et al., 2009) we selected studies measuring biomarkers across neuroimaging, psychobiology, physiology and genetics research in relation to pathological dissociation independent of psychiatric disorders. We then distilled results according to biomarker findings and specified the directionality and frequency of the pathological biological processes under investigation for graphical display and ultimate diagnostic biomarker identification. These biomarkers can be further investigated as an indicator of symptom mechanisms (diagnostic biomarkers) and of response to treatment (pharmacodynamic/response biomarkers, prognostic biomarkers and predictive biomarkers) in a precision medicine framework (Insel, 2014).

Precision medicine relates to the individualization of diagnosis, treatment and prognosis of mental disorders. The rationale behind the precision medicine framework is that uncovering the mechanisms behind symptoms, which span transdiagnostically, will ideally be used as a base for subsequent therapeutic, diagnostic and prognostic advancements (Insel, 2014; Insel and Cuthbert, 2015). In order to fulfil this, researchers are encouraged to focus on identifying specific measurable biomarkers underlying psychiatric symptoms (Cuthbert and Insel, 2013). This research based approach to psychiatry was developed by the National Institute of Mental Health (NIMH), which began the Research Domain Criteria (RDoC) project with the goal of developing a different, research based classification system for mental disorders (National Research Council (US) Committee on A Framework for Developing a New Taxonomy of Disease, 2011). RDoC is the newest and a third diagnostic system for psychiatry. The Statistical Manual of Mental Disorders (DSM) is the most prominent Western diagnostic system, but classification of disorders is subject to controversy (Cuthbert and Insel, 2013). The second diagnostic system is the International Classification of Diseases (ICD), developed by the World Health Organization for more varied health setting across the world. RDoC aims to classify mental disorders based on behaviour and neurobiological measures across heterogeneous disorder categories and differs from the DSM-5 and ICD-11 in that it is a research classification system rather than intended for routine clinical use. Although differences exist across the three diagnostic systems the aim to alleviate suffering from poor mental health is central in all three classification systems.

Obtaining diagnostic biomarkers of pathological dissociation is of high clinical importance because many patients with a dissociative pathology share a history of years of misdiagnoses, inefficient pharmacological treatment and repeated hospitalizations (Chu et al., 2011; Reinders et al., 2019). Evidence indicates that pathological dissociation is a negative predictor of psychotherapy response in various pathological samples (Kleindienst et al., 2011; Lanius, 2015; Spitzer et al., 2007). Only a segment of individuals suffering from dissociative pathology will respond to long-term psychological treatment (Brand et al., 2012). Evidence-based pharmacotherapy for pathological dissociative symptoms is lacking, especially because pathological dissociation is still under-researched and its underlying neurobiological mechanisms remain poorly understood (Lanius, 2015). There is no golden standard for pharmacological treatment for dissociation resulting in high attrition rates of conventional drug therapies (Dalenberg et al., 2012; Tamar-Gurol et al., 2008). In those who are compliant with pharmacological treatment, dissociation is still associated with poor response (Brand et al., 2012; Loewenstein, 1994). Currently there are hardly any new specific pharmacotherapy developments or randomized control trials for people with dissociative disorders. Overall this leads to years of incorrect treatment, protracted personal suffering and high direct and indirect societal costs (Lloyd, 2016; Myrick et al., 2017) and shows an urgent need for novel approaches in dissociation treatment. Understanding the biomedical underpinnings of pathological dissociation and conjoint diagnostic and pharmacodynamic/response biomarker data could help in facilitating more tailored treatment avenues for individuals who suffer from pathological dissociative symptoms.

Regarding pathological biological processes in relation to pathological dissociation, two neurobiological models have been described (Lanius et al., 2010; Reinders et al., 2014) and they both propose that severe pathological dissociation coincides with hyperactivity of the prefrontal cortex and the cingulate, as well as of the posterior association areas and parahippocampal gyri during overmodulation of emotion regulation. However, these two models were formulated on the basis of two separate psychiatric diagnoses and need further review to investigate whether they are representative of the psychobiology of pathological dissociation in a transdiagnostic manner (Krause-Utz et al., 2017; Lanius et al., 2018). The current paper aims to provide further insight into the biological underpinnings of pathological dissociative phenomena through a systematic review and the unique compilation of a list of biomarker findings. In addition to synthesizing evidence regarding the neurobiology of pathological dissociation to test the two models for pathological dissociation in transdiagnostic manner, this review also evaluates the scientific research into the psychobiology, psychophysiology and genetics of pathological dissociation. Furthermore, recommendations for possible research pathways are provided to aid novel treatment development for pathological dissociation. Ultimately these recommendations could contribute to novel pharmacological developments and the stratification of individualized treatment.