TYPE Study Protocol

PUBLISHED 01 April 2025

DOI 10.3389/fpsyt.2025.1516920

DMN network and

OPEN ACCESS neurocognitive changes
EDITED BY
Cagdas Eker,
Ege University, Türkiye
associated with dissociative
REVIEWED BY
Kathrin Kollndorfer,
symptoms in major depressive
Medical University of Vienna, Austria
Kristen Willeumier,
Independent Researcher, Beverly Hills,
disorder: a research protocol
United States

*CORRESPONDENCE
Asli Ercan Dogan 1*, Herdem Aslan Genc 2,3, Sinem Balaç 3,4,
Asli Ercan Dogan Sevin Hun Senol 1, Görkem Ayas 3, Zafer Dogan 5, Emre Bora 6,7,
asdogan@ku.edu.tr
Deniz Ceylan 1,3,4,8 and Vedat Şar 1
RECEIVED 25 October 2024
ACCEPTED 26 February 2025
1
Department of Psychiatry, School of Medicine, Koç University, Istanbul, Türkiye, 2 Department of
PUBLISHED 01 April 2025 Child and Adolescent Psychiatry, School of Medicine, Koç University, Istanbul, Türkiye, 3 Graduate
School of Health Sciences, Koç University, Istanbul, Türkiye, 4 Koç University Research Center for
CITATION Translational Medicine (KUTTAM), Affective Laboratory, Istanbul, Türkiye, 5 Department of EEE, MLIP
Ercan Dogan A, Aslan Genc H, Balaç S, Research Group & KUIS AI Center, Koç, University, Istanbul, Türkiye, 6 Department of Neurosciences,
Hun Senol S, Ayas G, Dogan Z, Bora E, Institute of Health Sciences, Dokuz Eylül University, Izmir, Türkiye, 7 Department of Psychiatry, School
Ceylan D and Şar V (2025) DMN network of Medicine, Dokuz Eylül University, Izmir, Türkiye, 8 Department of Psychiatry and Psychology, Mayo
and neurocognitive changes associated Clinic, Rochester, MN, United States
with dissociative symptoms in major
depressive disorder: a research protocol.
Front. Psychiatry 16:1516920.
doi: 10.3389/fpsyt.2025.1516920 Introduction: Depression is a heterogeneous disorder with diverse clinical
COPYRIGHT presentations and etiological underpinnings, necessitating the identification of
© 2025 Ercan Dogan, Aslan Genc, Balaç, distinct subtypes to enhance targeted interventions. Dissociative symptoms,
Hun Senol, Ayas, Dogan, Bora, Ceylan and Şar.
This is an open-access article distributed under commonly observed in major depressive disorder (MDD) and linked to early life
the terms of the Creative Commons Attribution trauma, may represent a unique clinical dimension associated with specific
License (CC BY). The use, distribution or
reproduction in other forums is permitted,
neurocognitive deficits. Although emerging research has begun to explore the
provided the original author(s) and the role of dissociation in depression, most studies have provided only descriptive
copyright owner(s) are credited and that the analyses, leaving the mechanistic interplay between these phenomena
original publication in this journal is cited, in
accordance with accepted academic underexplored. The primary objective of this study is to determine whether
practice. No use, distribution or reproduction MDD patients with prominent dissociative symptoms differ from those without
is permitted which does not comply with
such symptoms in clinical presentation, neurocognitive performance, and
these terms.
markers of functional connectivity. This investigation will be the first to
integrate comprehensive clinical evaluations, advanced neurocognitive testing,
and high-resolution brain imaging to delineate the contribution of dissociative
symptoms in MDD.

Methods: We will recruit fifty participants for each of three groups: (1) depressive
patients with dissociative symptoms, (2) depressive patients without dissociative
symptoms, and (3) healthy controls. Diagnostic assessments will be performed
using the Structured Clinical Interview for DSM-5 (SCID) alongside standardized
scales for depression severity, dissociation, and childhood trauma.
Neurocognitive performance will be evaluated through a battery of tests
assessing memory, attention, executive function, and processing speed.
Structural and functional magnetic resonance imaging (MRI) will be conducted
on a 3 Tesla scanner, focusing on the connectivity of the Default Mode Network
with key regions such as the orbitofrontal cortex, insula, and posterior cingulate
cortex. Data analyses will employ SPM-12 and Matlab-based CONN and

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PRONTO tools, with multiclass Gaussian process classification applied to

differentiate the three groups based on clinical, cognitive, and imaging data.

Discussion: The results of this study will introduce a novel perspective on

understanding the connection between major depressive disorder and
dissociation. It could also aid in pinpointing a distinct form of depression
associated with dissociative symptoms and early childhood stressors.

Conclusion: Future research, aiming to forecast the response to biological and

psychological interventions for depression, anticipates this subtype and
provides insights.

KEYWORDS

depression, dissociation, childhood trauma, functional connectivity, neurocognitive function

Introduction Dissociation: a critical concern in

young age
Major Depressive Disorder (MDD) has a significant impact on
both disability and mortality among young people (1–3). The onset Dissociative symptoms such as depersonalization, derealization,
of psychiatric disorders often occurs in adolescence and early confusion, flashbacks, and amnesia are significantly more common
adulthood, with three-quarters of adults experiencing their first in individuals with MDD compared to the general population,
symptoms before age 24. The average age of onset is 14.5 years for particularly in young populations (9–14). Approximately 45% of
any psychiatric disorder and 19.5 years for MDD (1, 2). MDD adolescents in clinical settings meet the diagnostic criteria for a
affects about 16% of individuals aged 16–24. In this group, specific dissociative disorder as outlined in the DSM-5 (13, 14) and
depression not only reduces quality of life and functional capacity over 60% of patients with depressive disorders exhibit clinically
but also significantly contributes to early mortality, with suicide significant dissociation (15). Involving a disruption in memory,
being the third leading cause of death among individuals aged 15– identity, consciousness, or perception of the environment,
29 (4). These alarming statistics emphasize the urgent need for a dissociation often serves as a coping mechanism for trauma and
better understanding of MDD’s causes and effects in young people. emotional distress (16, 17). Notably, more than half of individuals
Despite extensive research into the causes of Major Depressive with MDD report traumatic experiences in childhood (18). Recent
Disorder (MDD), understanding its underlying mechanisms research yield that those with both depression and dissociation
remains a significant challenge. This limited comprehension report even higher childhood trauma scores compared to those with
contributes to clinical difficulties, such as low treatment response only one of them (19). These findings suggest that those with both
rates and obstacles in developing new therapeutic targets, thereby MDD and dissociative symptoms may constitute a distinct
adding to the global disease burden (5). The clinical and biological subgroup with unique clinical needs. In fact, underdiagnosed
diversity of MDD, coupled with the limitations of traditional dissociative symptoms can act as a confounding factor in entire
subtypes (e.g., endogenous/reactive, typical/atypical), fails to spectrum psychiatry (10), complicating the interpretation of
capture the disorder’s full complexity (6). Depression, though findings, including MDD.
categorized under a single diagnosis, manifests with varied As a treating point to address this problem, a dissociative
symptoms, severity levels, and comorbidities, making subtype has been formalized for Post-Traumatic Stress Disorder
standardized treatment difficult (7). To address this heterogeneity, (PTSD) in DSM-5 already (20). Proposals for a dissociative subtype
researchers emphasize the need to identify hidden subtypes using have been made for schizophrenia as well (21, 22). Following this
new variables and transdiagnostic approaches which could enhance line of thought, Sar (23) formulated the concept of “dissociative
understanding and lead to more targeted treatments (8). depression”, defined as the presence of a chronic dissociative
disorder in individuals who meet the criteria for a MDD
Abbreviations: MDD, major depressive disorder; DID, Dissociative Identity diagnosis. The prevalence of dissociative depression fitting this
Disorder; PTSD, post-traumatic stress disorder; mPFC, medial prefrontal definition was found to be 4.1% in a sample of women
cortex; PCC, posterior cingulate cortex; PCu, precuneus cortex; fMRI, representing the entire city of Sivas, Turkey (12). This potential
functional magnetic resonance imaging; BOLD, the blood oxygen level subtype of MDD is associated with early onset, treatment resistance,
dependent; DLPFC, dorsolateral prefrontal cortex; DMN, Default Mode and more severe symptoms, including impulsivity, rapid mood
Network; TMS, transcranial magnetic resonance; OFC, orbitofrontal cortex. changes, psychotic symptoms, self-harm, suicidality, higher rates

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of antipsychotic prescriptions, and higher comorbidity with PTSD, cognitive task results remain inconsistent (48). Despite the
borderline and antisocial personality disorders (24–28). As a evidence linking dissociation to cognitive impairments, further
potential indicator of suicidality, self-harm behavior, and need for research is necessary to clarify the mechanisms driving these
psychosocial intervention in young adults, this concept warrants dysfunctions and to explore how they manifest across different
further investigation (9, 15, 29). However, more research is needed populations and contexts. A single cross-sectional study
to establish clinical parameters for distinguishing between MDD investigating the relationship between dissociative symptoms and
with and without dissociative symptoms. Given that the adolescence cognitive functions in individuals with MDD found that
is the age group with highest prevalences of dissociative disorders in derealization was associated with impairments in verbal and
clinical settings, and that these disorders often have an early onset, visual memory, whereas depersonalization was linked to reduced
including childhood, dissociative depression becomes also a critical processing speed (49). Interestingly, depersonalization symptoms
concept for age groups before adulthood (13, 30). correlated with enhanced attentional performance in low-stimulus
environments. However, the study’s small sample size—23 patients
with MDD and 20 healthy controls—limits the generalizability of
Neuropsychological findings: memory these findings. Notably, the role of dissociative symptoms in
disturbances as the target symptom cognitive dysfunction within MDD remains underexplored,
presenting an unresolved clinical question.
Cognitive dysfunction is prevalent in various mental disorders,
including MDD and dissociative disorders, affecting verbal memory,
attention, and executive function (31). In MDD, approximately 27% of Resting state DMN functional connectivity:
patients exhibit global neurocognitive deficits (32), including MDD and dissociation
impairments in span attention, learning and memory, processing
speed, psychomotor speed, and executive functions, often persisting The Default Mode Network (DMN) is a large-scale brain
even after symptomatic remission (33–36). In dissociative disorders, network primarily composed of the medial prefrontal cortex
memory impairments are a prominent feature, with higher dissociation (mPFC), posterior cingulate cortex (PCC), and precuneus. This
levels linked to deficits in verbal memory, delayed recall, general network is most active during rest and is associated with self-
memory, and long-term memory (37, 38). Pathological dissociative referential thinking, daydreaming, memory recall, and spontaneous
experiences, such as amnesia and depersonalization/derealization, are processing of stimuli. Conversely, its activity diminishes during
inversely related to overall memory performance; individuals with high tasks requiring external attention. The DMN supports advanced
dissociation levels perform worse on immediate visual memory tasks cognitive functions such as introspection, autobiographical
compared to those with low dissociation levels (39). memory, decision-making, and perception of the external world.
A systematic review and meta-regression analysis revealed that Functional magnetic resonance imaging (fMRI) has significantly
depression scores, rather than dissociative experiences, are advanced our understanding of the DMN and other networks, like
significantly associated with decreased memory specificity (40). the salience and dorsal attention networks, by measuring changes in
However, dissociation is also linked to impairments in attention the blood-oxygen-level-dependent (BOLD) signal (50).
and executive functioning, with highly dissociative individuals MDD is associated with significant alterations in the functional
exhibiting heightened distractibility and reduced cognitive connectivity of the DMN. These alterations have been detected both
inhibition (41). Studies have shown that dissociative symptoms are within the subregions of the DMN and between the DMN and other
associated with poor performance on attentional tasks, especially key emotion-regulating networks such as the salience and affective
when trauma-relevant distractors are present (42, 43). Deficits in networks. Aberrant connectivity within the DMN, particularly
executive functioning, such as impaired cognitive flexibility and hyperconnectivity in the mPFC and PCC, is frequently reported in
problem-solving abilities, have also been observed in this MDD. This hyperconnectivity has been implicated in the maladaptive
population (44). Adolescents with a dissociative disorder have self-referential processing and rumination commonly observed in
shown impairments in working memory, sustained attention, visual depression. The connection between the anterior and posterior nodes
learning and memory, and verbal memory (45). Another study found of the DMN has consistently shown alterations in MDD. Studies
that adolescents with dissociative disorder performed worse on using the anterior DMN as the seed region report dissociation
executive function tasks (Wisconsin card sorting test), arithmetic, between the anterior and posterior DMN, while those using the
coding, and maze tests compared to healthy adolescents (31). posterior DMN as the seed report increased connectivity between the
The relationship between dissociation and cognitive two nodes. In healthy volunteers, a distinct anterior-posterior
dysfunction is complex and not always straightforward. Some subnetwork within the DMN contributes to different aspects of
studies have found that higher dissociation levels correlate with self-generated thought (51, 52). Leech and Sharp (53) hypothesized
reduced attention and verbal memory performance (46). However, that increased PCC connectivity with anterior DMN regions relates
other research has not observed a significant association between to internally directed attention and rumination in depression,
dissociation severity and neurocognitive test outcomes (47). A although the effects of functional connectivity changes between
recent systematic review highlighted that self-reported cognitive anterior and posterior subnetworks remain poorly understood (54).
difficulties align with dissociative experiences, while objective Reduced connectivity between anterior and posterior DMN nodes in

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FIGURE 1
DMN and associated regions in depression. Red lines represent increase in connectivity; green line represent a decrease in connectivity. Red and
green dotted line represents altered connectivity.

MDD is supported by structural connectivity reductions in an stimulation (TMS) in MDD. These findings suggest that alterations in
sgACC-posterior DMN-based network (55). DMN connectivity not only contribute to the pathophysiology of
Figure 1 summarizes findings related to functional connectivity depression but also have implications for predicting and personalizing
of the DMN in MDD. A meta-analysis identified increased treatment strategies. Understanding these connectivity patterns can
connectivity between the DMN and regions such as the medial aid in developing targeted interventions for individuals with MDD.
prefrontal cortex (mPFC), dorsolateral prefrontal cortex (DLPFC),
and hippocampus (56). This finding is further supported by a
systematic review demonstrating heightened connectivity within Resting state DMN functional connectivity:
the anterior DMN (57). Despite the typical reduction in gray matter within and between networks
volume in these regions, functional activity within the DMN
paradoxically increases during resting states in individuals with Dissociation is a psychological condition characterized by the
MDD (58–61). Similar connectivity patterns have been observed in presence of unresolved internal processes related to trauma, such as
adolescents with MDD, suggesting that these alterations may repetitive and unproductive thinking patterns known as “rumination”.
emerge early in the disorder’s course (62). As mentioned above, DMN is active during self-referential thinking
However, connectivity differences may depend on illness and becomes deactivated during external processes that need attention
chronicity. A study involving 1.300 participants found increased (65); therefore, heightened activity in the DMN challenges of shifting
DMN connectivity in individuals with recurrent MDD but not in from internal ideas, often experienced during dissociation, to outward
those experiencing a first-episode, drug-naïve depression (63). thoughts becomes more apparent. Hyperactivity in the bilateral
Furthermore, research has identified two distinct neurobiological superior frontal regions and the medial segments of the inferior
subtypes of depression based on DMN connectivity patterns, which frontal and middle frontal regions were identified as
may help explain the heterogeneity of clinical presentations. The neurofunctional biomarkers of pathological dissociation (66). A
predominant subtype, observed in 70–80% of MDD patients, is transdiagnostic study investigated the brain connectivity markers of
characterized by hyperconnectivity within the DMN, particularly dissociation during resting state and reported that functional
among its core hubs, and is considered the more “typical” form of connectivity between the orbitofrontal locus and retrosplenial cortex
depression. In contrast, a smaller subgroup (20–30% of patients) was negatively related to the DES score, whereas connectivity between
exhibits DMN hypoconnectivity, which has been linked to higher the orbitofrontal region and other default mode regions was positively
rates of comorbid anxiety disorders, recurrent or chronic depressive related to the DES score (67). Another study conducted on women
episodes, and a greater prevalence among female patients (63). with borderline personality disorder revealed a link between DES
Similarly, a review by Dichter et al. (64) examined predictors of scores and the resting-state functional connectivity of the amygdala
treatment response in MDD using resting-state fMRI. The review with the dorsolateral prefrontal cortex and fusiform gyrus (68). Paul
concluded that increased functional connectivity between frontal and et al. (69) discovered a correlation between higher symptoms of
limbic brain regions was associated with a positive response to depersonalization and reduced connectivity between the extrastriate
antidepressant treatment. Conversely, hyperconnectivity within the body area (a brain region linked with body parts and motions) and the
DMN was linked to treatment resistance to transcranial magnetic DMN in individuals with MDD.

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Previous studies have revealed the significance of the learning has shown promising results: a multiclass Gaussian
orbitofrontal cortex (OFC) in dissociative disorders, as indicated process classification model distinguished dissociative subtype of
by our team’s findings. Two studies by Sar et al. (11, 70 looked at PTSD with up to 91.63% accuracy based on spontaneous neural
brain blood flow and found that people with chronic dissociative activity, and 85% accuracy based on amygdala connectivity (83).
disorder had less activity on both sides of the orbitofrontal cortex Another study using the same method has distinguished individuals
compared to a healthy control group. The “orbitofrontal with and without dissociative subtype of PTSD from healthy
hypothesis” posits a potential link between dissociative depression individuals with 80.4% accuracy based on insula connectivity (84).
and the OFC, a region known for its crucial role in affect regulation
and its high susceptibility to early-life stressors (71, 72). This
hypothesis emphasizes the need to study the networks associated Objectives and hypothesis
with the OFC in dissociative disorders. The dysfunctional
connectivity of cortical-subcortical circuitries in OFC due to Depression is a leading cause of morbidity and mortality in
chronic stress during developmental periods forms an enduring young adults, yet its heterogeneous nature complicates
vulnerability for psychiatric disorders (72). understanding its pathophysiology and treatment resistance.
The insula is thought to have a key role in processing emotional Notably, dissociative symptoms are prevalent in youth depression,
states, acting as a bridge between subcortical brain regions that shaping distinct clinical and prognostic trajectories. Subtyping
receive visceral sensations and frontal lobe regions that determine youth depression based on the presence of dissociative symptoms
the emotional and motivational significance of these sensations. It is is crucial for enhancing the consistency of future research and the
believed that the insula plays a role in regulating two resting state development of personalized treatments. In light of these
networks: the anterior insula, which affects brain regions in both the considerations, this study addresses three critical questions. First,
default mode network (involved in internal observation) and the is MDD with dissociative symptoms in young adults a distinct
central executive network (involved in emotional evaluation), and clinical subtype characterized by an earlier onset of depression,
the posterior insula, which maintains connections with more severe symptomatology, and higher rates of self-harm and
sensorimotor areas involved in environmental monitoring. Forner suicidal ideation? Second, are dissociative symptoms linked to
(73) conducted a thorough review that explores the inverse greater cognitive deficits—particularly in memory, attention, and
connection between mindfulness and dissociation, highlighting executive functions? Finally, can differences in resting-state DMN
the significance of reduced connectivity between the medial connectivity, especially in the mPFC and PCC, serve as
frontal cortex and insula in dissociation. To our knowledge, there neurobiological markers to distinguish between these subgroups?
are no studies yet which specifically investigate the resting state To answer these questions, the study will compare young adults
functional connectivity in individuals with MDD and with MDD who exhibit prominent dissociative symptoms (Dis+)
accompanying dissociative symptoms. However, examining against those without dissociative features (Dis–), as well as a group
research on DMN connectivity in relation to dissociation can of healthy controls. We will employ a multimodal approach that
provide insights (74, 75). Similar studies on MDD suggest that integrates comprehensive clinical evaluations, neuropsychological
altered connectivity, especially in treatment-resistant cases, might testing, and advanced neuroimaging techniques. In particular,
be linked to concurrent dissociative symptoms. resting-state functional magnetic resonance imaging (fMRI) will
be used to assess DMN connectivity, while machine learning
algorithms will facilitate the classification of participants based on
Machine learning classification in clinical, cognitive, and imaging data.
detecting subtypes By delineating the clinical and neurobiological distinctions
between MDD subtypes, this work promises to refine the
Machine learning algorithms are being utilized to classify understanding of depression’s heterogeneity and pave the way for
psychiatric subgroups and predict treatment responses using more targeted, personalized treatment interventions. In doing so, it
behavioral, genetic, electrophysiological, and imaging-based data. may not only improve diagnostic precision but also enhance
In depression research, most studies focus on differentiating therapeutic outcomes for young patients grappling with the dual
depressed individuals from healthy controls, while some aim to challenges of depression and dissociation.
predict treatment response. However, fewer studies specifically The study will address the following four hypotheses: (1)
target the distinction between depression subtypes, highlighting a patients in the Dis+ group will exhibit an earlier onset of
gap in research (76). A data-driven study analyzing DMN patterns depression, more frequent depressive episodes, increased
in depression identified two biological subtypes with increased and psychiatric comorbidity, higher rates of self-harm behavior and
decreased DMN activation (77). Machine learning has been widely suicidal ideation, more frequent childhood trauma, insecure
applied in psychiatry for predicting suicidality (78), bipolar disorder interpersonal attachment patterns, and greater difficulty in
(79, 80), psychotic symptoms (81), and prediction of postpartum emotion regulation compared to the Dis- group; (2) both
depression (82), with its their use steadily increasing. However, the depression groups (Dis+ and Dis-) are expected to show impaired
differentiation of dissociative symptoms in depression using performance on neuropsychological tests compared to healthy
machine learning remains unexplored. In PTSD, machine controls and within the depression subgroups, the Dis+ group

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will exhibit more pronounced impairments, particularly in verbal participants and/or their legal guardians. This study is also funded
and visual memory, when compared to the Dis- group; (3) both by the Scientific and Technological Research Council of Turkey
depressed groups will show reductions in cortical thickness, surface ̇
(TÜBITAK) with 1001 - The Scientific and Technological Research
area, and gray matter volume in specific brain regions compared to Projects Funding Program and Koç University.
healthy controls and additionally, both groups will show increased Sample size calculation was performed by using OpenEpi, based
resting-state connectivity within the default mode network (DMN), on the average and standard deviations of PHQ-9 scores from the
with differing levels of functional connectivity between the study by Fung et al. (15). The calculation determined that a
orbitofrontal cortex (OFC), insula, posterior cingulate cortex minimum of 31 participants per group is required to detect
(PCC), and DMN; (4) a machine learning model based on significant differences in psychopathology between the Dis+ and
neurocognitive test results and imaging data will differentiate Dis- groups, with a 95% confidence interval and 80% power. For
between the Dis+, Dis-, and healthy control groups with at least machine learning analyses, an area under the ROC curve (AUC)
80% accuracy. calculation indicated that each group requires at least 24
This study will be the first to investigate functional connectivity participants to achieve 95% confidence and 80% power, assuming
changes associated with dissociative symptoms in MDD. Thus, this an AUC of 0.75 or higher. To enhance statistical power and account
investigation is timely and significant. Through this comprehensive for data losses or the need for adjustments in multiple comparisons,
approach, the study aims to contribute to a paradigm shift in the each group will consist of 50 participants.
diagnosis and treatment of depression, particularly in the context of
its complex interplay with dissociative phenomena. This refined
perspective is expected to inform both clinical practice and future Study design
research, ultimately enhancing the quality of care for young
individuals with MDD. This research is a cross-sectional study comparing three groups:
(1) patients with MDD and dissociative symptoms (Dis+), (2)
patients with MDD without dissociative symptoms (Dis-), and (3)
Material and methods healthy control participants. The study will include clinical
assessments, neurocognitive testing, and resting-state functional
This is a single-centered study that will be carried out at the connectivity analysis using MRI. Figure 2 summarizes the
Psychiatry Department or KUPTEM outpatient clinics of Koç recruitment and study procedures.
University School of Medicine. Inclusion and exclusion criteria Patients aged 15 to 25, of both biological sexes, diagnosed with
will be established to identify eligible individuals for participation in Major Depressive Disorder (MDD) based on DSM-5 criteria and
the study. The project has received approval and is under the seeking treatment at the Psychiatry Department or KUPTEM
supervision of the Human Ethics Committee of Koç University and outpatient clinics of Koç University School of Medicine, will be
Koç University Hospital Medical Advisory Committee. Prior to recruited for this study. Healthy controls of the same age range and
participation, written informed consent will be obtained from the similar gender distribution will also be included.

FIGURE 2
Recruiting participants and conducting clinical and diagnostic interviews. DES, Dissociative Experiences Scale; HDS, Hamilton Depression Scale;
SCID, Structured Clinical Interview for DSM Disorders. From: BioRender.com.

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The study will consist of three groups: use the Hamilton Depression Scale to assess the severity of
depression. This project will develop a sociodemographic and
1. Dis+ Depression Group: 50 participants diagnosed with psychiatric history form that will compile sociodemographic and
MDD who also exhibit dissociative symptoms. general medical details, including the age of onset of psychiatric
2. Dis- Depression Group: 50 participants diagnosed with symptoms, treatments received, number of depressive episodes, and
MDD but without dissociative symptoms. childhood experiences such as parental loss or placement in
3. Healthy Control Group: 50 participants without any alternative care. Given our study’s focus on dissociative
psychiatric or mental health conditions. phenomena, we will use the Dissociative Experiences Scale (DES)
to assess chronic dissociation; scores of 30 or higher will be
indicative of pathological dissociation. Complementarily, the
Somatoform Dissociation Questionnaire (SDQ) will be
Inclusion and exclusion criteria administered to evaluate somatic symptoms arising from
for participation dissociation (e.g., conversion symptoms and medically
unexplained pain). To better understand the influence of
The inclusion criteria of Dis+ (patients with MDD with interpersonal dynamics on clinical presentation, we will assess
dissociation) as follows: (1) aged 15–25, (2) right-handed, (3) attachment styles using the Relationship Scales Questionnaire
diagnosed with MDD via SCID-5, (4) Hamilton Depression Scale (RSQ-30). Emotional regulation will be evaluated using both the
score ≥ 14, (5) Dissociative Experiences Scale (DES) score ≥ 30, (6) Difficulty in Emotion Regulation Scale Short Form (DERS-16) and
SCID-D score of at least 2 (mild) on at least one dissociative the Hypomania Symptom Checklist (HCL), the latter helping to
dimension (amnesia, depersonalization, derealization, identity identify mood elevation or subthreshold manic features that may
confusion, or identity alteration). complicate the clinical picture. Finally, the Childhood Trauma
For the Dis- Depression Group (MDD without dissociative Questionnaire Revised Form (CTQ-33) will be employed to
symptoms) are as follows: (1) aged 15–25, (2) right-handed, (3) quantify early adverse experiences, which are known to contribute
diagnosed with MDD via SCID-5, (4) Hamilton Depression Scale to both depressive and dissociative symptomatology.
score ≥ 14, (5) DES score < 10, (5) SCID-D dissociative dimension
scores all below 2 (mild). Application of neuropsychological tests
The inclusion criteria for healthy control group are as follows: to participants
(1) aged 15–25, (2) right-handed, (3) no psychiatric diagnosis, (4) Following the diagnostic and clinical interviews, participants
no scores ≥ 2 on any SCID-D dissociative dimension, (5) Hamilton will undergo a comprehensive battery of neuropsychological tests
Depression Scale score ≤ 7, (6) DES score < 10, and (7) no administered within the same week. This battery, which lasts
psychiatric history or significant family history of MDD, bipolar approximately two hours, is designed to assess multiple cognitive
disorder, psychotic disorders, or neurodevelopmental disorders. domains implicated in MDD and dissociative disorders. The testing
The exclusion criteria of patients for all the groups are (1) visual will be conducted by trained research assistants under the
or hearing impairments, (2) left-handedness, (3) use of supervision of an experienced researcher, within a controlled
benzodiazepines or psychostimulants within 72 hours prior to environment between 9:00 a.m. and 12:00 p.m., with a 30-minute
imaging or neuropsychological assessments, (4) diagnosis of bipolar break provided to ensure participants are rested and not affected by
disorder, schizophrenia, or other psychotic spectrum disorders, (5) fatigue or hunger. The selected tests include:
neurological disorders or decompensated systemic medical
conditions, (6) history of neurosurgical intervention or head Rey Auditory Verbal Learning Test (RAVLT): Assesses verbal
trauma with loss of consciousness, (7) active alcohol or substance learning and memory, providing measures of both
use disorder within six weeks prior to imaging, (8) contraindications immediate and delayed recall.
to MRI, (9) pregnancy, postpartum, or breastfeeding. Wisconsin Card Sorting Test (WCST): Evaluates executive
functions, particularly cognitive flexibility and problem-
solving abilities.
Assessment tools Digit Span Test: Measures attention and working
memory capacity.
Semi-structured interview schedules and
symptom lists administered by clinicians Stroop Test: Assesses cognitive inhibition and attentional
To ensure a robust and standardized diagnostic evaluation, we c o n t r o l by r e q u i r i n g p a r t i c i p a n t s t o s u p p r e s s
will employ the Structured Clinical Interview for DSM (SCID) to automatic responses.
diagnose Major Depressive Disorder (MDD) and identify Trail Making Tests A and B: Evaluate processing speed, visual
psychiatric comorbidities. For our adolescent population, a child attention, and task-switching capabilities.
and adolescent psychiatrist will administer the KSADS-5—the Category Fluency Test: Assesses semantic memory and
Turkish adaptation of the SCID—ensuring that developmental executive function through the rapid generation of words
and cultural considerations are appropriately addressed. We will within specific categories.

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Symbol Digit Modalities Test (SDMT): Measures processing separation, tissue segmentation, registration, modulation, and
speed and attention via rapid symbol-digit pairing. smoothing. Images will be inspected for misalignments and
Verbal Fluency Test: Evaluates language production and corrected manually if needed. Processed brain structures will be
executive control during word retrieval tasks. partitioned into gyri using a cortical parcellation tool based on the
Auditory Consonant Trigram Test: Assesses auditory working Destrieux atlas. Cortical thickness will be examined with FreeSurfer,
memory and sustained attention. including motion correction, non-brain tissue removal, tissue
segmentation, and topographic surface calculation. Quality
These tests were selected because they have demonstrated control will follow the ENIGMA protocol and visual inspection.
sensitivity to the cognitive deficits commonly observed in MDD Preprocessing steps involve removing non-brain structures, volume
and dissociative disorders, and their validity has been well- labeling, intensity normalization, white matter segmentation,
established in prior clinical research (85). By using this surface atlas registration, and gyri labeling. Group comparisons
comprehensive battery, we aim to capture a broad profile of will use a general linear model with a p-value < 0.05, adjusted for
neurocognitive functioning, which will enable us to examine the multiple comparisons.
associations between cognitive performance, dissociative
symptoms, and the neurobiological markers of MDD. Examination and statistical analysis of fMRI
functional connectivity
This study will use seed-based correlation analysis (SCA) to
Statistical analysis examine resting-state connectivity. Seed regions will be selected
based on anatomical areas associated with pathology, such as the
SPSS and GraphPad will be used to describe clinical data with OFC, insula, and posterior cingulate cortex (PCC). Regions of
counts/percentages for categorical data and means/medians for interest (ROIs) will be identified using the Automated Anatomical
continuous data. Neuropsychological test scores will be recorded Labeling (AAL) atlas. Functional connectivity will be analyzed using
with means, standard deviations, and interquartile ranges, with Z the MATLAB-based CONN toolbox, generating seed-voxel and
scores for visualizations. Group comparisons will use ANOVA or ROI-ROI maps. Correlation matrices will be created by converting
ANCOVA for normally distributed data, with covariates used to R-values to standard z-values. Seed-based connectivity maps will be
control for confounding factors. Non-normally distributed data will generated for each participant, followed by group-level analyses. A
be transformed prior to analysis. Multivariate methods and voxel threshold of p ≤ 0.001 and a cluster size threshold of p ≤ 0.05
principal component analysis will be used, with adjustments for will be applied. Group comparisons (controls, dis-depression, and
multiple comparisons. In order to control for the increased risk of dis+ depression) will be conducted using ANOVA, with corrections
Type I errors due to multiple comparisons, a Bonferroni correction for multiple comparisons.
was applied to all correlation analyses, with the significance
threshold adjusted accordingly (a_corrected = 0.05/n). Multiclass Gaussian Process Classification
Machine Learning (MGPC)
Acquisition of functional and anatomical images Functional and structural brain images, along with
and preprocessing neuropsychological tests, will be used to differentiate between
A 3 Tesla Siemens Skyra device with 64-channel and 20-channel healthy controls, dis-depression, and dis+ depression groups
head coils will be used for functional and anatomical imaging. through multivariate machine learning classification using the
Participants are instructed to remain still and awake during the PRONTO toolbox within SPM12. PRONTO includes four
scan. Spatial image preprocessing, including BOLD and MPRAGE classification algorithms: SVM, BGPC, MGPC, and L1-multiple
images, will be done using SPM12. This includes realignment, co- kernel learning. For our three-group classification, MGPC will be
registration, normalization, and spatial smoothing. Functional the primary model. If MGPC proves insufficient, we will use BGPC
images will be registered to the T1-weighted template, segmented, for binary classifications, coding the ‘healthier’ condition as y = -1.
normalized to an MNI template, and smoothed with a 6 mm Our analysis will follow five steps: determining the dataset, selecting
Gaussian kernel. Motion regressors will be created using ART the feature set, evaluating the model with LOOCV, estimating the
software. The data will be filtered to minimize low-frequency drift model, and preparing weight calculations and AUC scores.
and high-frequency noise. Functional images will be realigned and
resliced, excluding the first four volumes, to prevent saturation Dataset determination and features selection
effects. Data will be excluded for excessive head motion, and mean Resting-state connectivity maps and neuropsychological test
displacement will be included as a covariate in further analyses, scores will be used as inputs, applying the DARTEL gray matter
tested for group differences using ANOVA. method. Features will include voxel-level data, age, education, and
test scores. Top features will be selected based on Kendall tau
Examination of fMRG brain volumes, surface area, correlations and Gaussian process covariance functions. The data
and cortical thickness will be normalized using linear and principal component methods.
We will use voxel-based analysis with the FSL program for MGPC, Simple-MKL, SVM, and BGPC algorithms will be used with
regional gray matter analysis. Pre-analysis steps include brain tissue LOOCV for model evaluation. Performance will be measured by

Frontiers in Psychiatry 08 frontiersin.org

Ercan Dogan et al. 10.3389/fpsyt.2025.1516920

accuracy, specificity, sensitivity, predicted probabilities, and AUC neuroimaging data offers several advantages to address this question.
scores. Permutation testing (1,000 times) will identify significant The comprehensive clinical and cognitive assessment battery will allow
features, creating a discriminative map based on p-values. us to characterize the phenomenology and neurocognitive profile
associated with dissociative symptoms in MDD. Using measures of
hypomania, emotion dysregulation, and anger in addition to depression
Discussion and dissociation symptoms can provide important information for
assessing and prioritizing clinical risks between the two groups.
This proposed study aims to investigate whether MDD with The inclusion of adolescents is another strength of the study
dissociative symptoms represents a qualitatively distinct subtype because it has been shown that early-onset depression has negative
from MDD without dissociative features in young adults. This impacts on overall well-being, academics, and professional life.
distinction could significantly enhance our understanding of the Suicide, on the other hand, ranks fourth among causes of death
role that psychosocial stress during developmental years plays in in the 15-29 age group (4). These findings demonstrate the need for
the onset of depressive disorders. By combining detailed clinical and a new field in psychiatry focusing on young adults. Considering the
cognitive assessments with advanced neuroimaging analysis of DMN developmental causes and continuity of depression, limiting young
connectivity using deep learning, we hope to elucidate key differences adulthood to the age of 18 is an artificial distinction, and including
between these potential MDD subtypes. If our hypothesis is adolescence in this process would better meet the requirements of
supported by the results, it could lead to a paradigm shift in our this study.
approach to the diagnosis and treatment of MDD. First of all, it could The identification of subtypes that categorically match the
suggest the need for specialized interventions targeting dissociative etiology could lead to a better understanding of the pathogenesis
symptoms in this subgroup. Furthermore, DMN connectivity of depression and allow for the diversification of treatment research.
patterns identified through deep learning could potentially serve as If we identify significant effects of dissociative symptoms in
a biomarker to aid in distinguishing these subtypes. depression, this approach could harmonize with the results of
Additionally, this research could pave the way for future studies similar studies on other disorders, such as post-traumatic stress
exploring the underlying mechanisms linking dissociation and disorder and schizophrenic spectrum disorder, stimulate the
depression, potentially uncovering novel biomarkers that could development of new studies on autism spectrum disorder and
inform more effective therapeutic strategies. Dissociative attention deficit hyperactivity disorder, and contribute to the
symptoms also can influence the results of clinical and biological exploration of transdiagnostic dimensions in psychiatry and a
research on these disorders as a “confounding” factor, raising more precise understanding of the epigenetic effects of stress.
questions about possible dissociative subtypes in populations such However, several limitations should be considered. The cross-
as PTSD (20), schizophrenia (21, 22), and MDD (24, 25, 27) to sectional nature of this study limits causal inferences about the
achieve more precise study outcomes related to their clinical course relationship between dissociation and depression. Longitudinal
and underlying biology. Moreover, by integrating neuroimaging research will be needed to determine whether dissociative
techniques with clinical assessments, we may gain deeper insights symptoms precede depression onset or emerge as a consequence.
into the brain’s functional architecture in individuals experiencing Additionally, while our focus on young adults reduces age-related
these co-occurring conditions. If our hypothesis regarding confounds, it may limit generalizability to other age groups.
differences in neurocognitive performance between Dis+ and Dis- In conclusion, this study represents an important step toward
groups is confirmed, it could suggest that dissociative symptoms in understanding the role of dissociative symptoms in MDD and
MDD are associated with distinct cognitive profiles, potentially potentially identifying neurobiologically distinct subtypes. The
indicating different underlying neural mechanisms. This could findings could inform more personalized approaches to the
ultimately lead to tailored interventions that address the specific diagnosis and treatment of depression, particularly in young
needs of patients based on their cognitive and dissociative adults experiencing dissociative phenomena. Future research
characteristics, enhancing the precision of mental health care. building on these results may lead to improved outcomes for this
Additionally, exploring the interplay between these cognitive challenging subgroup of MDD patients.
profiles and treatment responses may reveal critical pathways for
optimizing therapeutic outcomes, paving the way for personalized
approaches in managing both depression and dissociation. Ethics statement
Dissociative experiences in MDD have been associated with
increased illness severity, suicidality, and worse treatment outcomes, The study was approved by The Koç University Human Ethics
but it remains unclear whether MDD with dissociative features Committee (protocol no. 2023.014.IRB1.002) and the Koç
represents a more severe form of depression or a qualitatively distinct University Hospital Medical Advisory Committee. Written
subtype with unique underlying neurobiology. Our proposed informed consent to participate in this study will be provided by
multimodal approach combining clinical, cognitive, and the participants’ or their legal guardian for minors.

Frontiers in Psychiatry 09 frontiersin.org

Ercan Dogan et al. 10.3389/fpsyt.2025.1516920

Author contributions Conflict of interest

AE: Conceptualization, Methodology, Writing – original draft, The authors declare that the research was conducted in the
Writing – review & editing. HA: Conceptualization, Visualization, absence of any commercial or financial relationships that could be
Writing – original draft, Writing – review & editing. SB: Writing – construed as a potential conflict of interest.
original draft, Writing – review & editing. SH: Writing – original draft,
Writing – review & editing. GA: Writing – original draft, Writing –
review & editing. ZD: Writing – original draft, Writing – review &
editing. EB: Writing – original draft, Writing – review & editing. DC:
Generative AI statement
Conceptualization, Methodology, Writing – original draft, Writing –
The author(s) declare that no Generative AI was used in the
review & editing. VŞ: Conceptualization, Writing – original draft,
creation of this manuscript.
Writing – review & editing.

Funding Publisher’s note

The author(s) declare that financial support was received for the All claims expressed in this article are solely those of the authors
research and/or publication of this article. This work is supported and do not necessarily represent those of their affiliated
by the Scientific and Technological Research Council of Turkey organizations, or those of the publisher, the editors and the
̇
(TÜBITAK) with 1001 - The Scientific and Technological Research reviewers. Any product that may be evaluated in this article, or
Projects Funding Program and Koç University under project no. claim that may be made by its manufacturer, is not guaranteed or
222S516 and protocol no. 2023.014.IRB1.002, respectively. endorsed by the publisher.

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