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Selma Aybek

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9 papers

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YNICL Journal 2026 Journal Article

Altered microstate dynamics in Functional Neurological Disorder

Irene Lozzi
Cristina Concetti
Natascha Stoffel
Michael Mouthon
Miriam Braga
Michele Tinazzi
Mirta Fiorio
Selma Aybek

BACKGROUND: Functional Neurological Disorder (FND) presents with disabling and heterogeneous motor, sensory, and cognitive symptoms despite the absence of gross structural pathology. A key question is whether symptoms reflect disruptions in the intrinsic organization of brain networks. Electroencephalography (EEG) offers a high temporal resolution view of ongoing dynamics, making it a powerful means to probe such mechanisms. METHODS: We applied a seven-class microstate decomposition to resting-state EEG from 39 patients with FND and 47 matched healthy controls to characterize the temporal dynamics of brain activity. Microstate were labelled A-G according to established topographies. Symptom severity was assessed with the Simplified-Functional Movement Disorder Rating Scale, and correlations were tested. Logistic regression was used to assess group discrimination, with accuracy quantified by the area under the curve. RESULTS: Compared to controls, patients with FND exhibit significantly reduced duration of microstate G, associated with sensorimotor integration. This alteration correlated negatively with symptom severity scores and moderately discriminated groups. Transition probabilities analyses uncovered distinct patterns among microstates A, B and C, suggesting both an exaggerated shift from arousal-related to visual imagery networks and resistance to engage in self-referential processing. CONCLUSIONS: Our findings provide the first direct evidence of disrupted resting-state microstate organization across a heterogeneous FND cohort.

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YNICL Journal 2025 Journal Article

Modulating the sense of agency in functional neurological disorder using real-time fMRI neurofeedback: a proof-of-concept study

Eliane Müller
Serafeim Loukas
Salome Häuselmann
Cristina Concetti
Dimitri Van De Ville
Nicolas Gninenko
Selma Aybek

BACKGROUND: Disrupted sense of agency (SoA), the perceived loss of control over one's actions, is common in functional neurological disorder (FND) and linked to abnormal activation in agency-related networks, particularly the right temporoparietal junction (rTPJ). This proof-of-concept study tested whether fMRI neurofeedback (NF) could enhance SoA in FND by targeting the rTPJ. METHODS: In this single-arm feasibility study, 18 patients with mixed FND symptoms completed three NF trainings during an adaptive visuomotor task, receiving intermittent visual feedback of their rTPJ activity. Pre- and post-training assessments included subjective agency ratings, neuroimaging during a transfer task, and clinical evaluations. RESULTS: Group-level subjective agency significantly increased after training (p = 0.0083), driven by responders (n = 8) who exhibited rTPJ (p = 0.042) and supplementary motor area (SMA) upregulation (p = 0.015) in the first session, alongside consistent task engagement. Behavioral gains coincided with trend-level decreases in rTPJ-dorsolateral prefrontal cortex (dlPFC) connectivity (p = 0.098), while non-responders showed reduced rTPJ-SMA connectivity (p = 0.008). No group-level clinical improvements were observed, but higher initial rTPJ (p = 0.03, ρ = -0.78) and dlPFC (p = 0.03, ρ = -0.75) activation were negatively associated with changes in self-reported core symptoms. CONCLUSION: NF from rTPJ activity is feasible in FND and may enhance explicit SoA in a subset of patients through early neural modulation and sustained engagement. High inter-individual variability underscores the need for sham-controlled trials with optimized, engaging feedback designs and longitudinal monitoring to identify patients who could benefit from NF.

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YNICL Journal 2025 Journal Article

Reduced microstructural white matter integrity is associated with the severity of physical symptoms in functional neurological disorder

Nicolas Gninenko
Eliane Müller
Selma Aybek

BACKGROUND: Functional neurological disorder (FND) is linked to functional changes in brain networks without an underlying brain lesion. However, the dichotomy between functional and structural changes has been challenged by research suggesting that not only functional but also anatomical alterations in the gray and white matter may underlie a subset of symptoms. This study aimed to characterize white matter microstructural integrity and its association with patient-reported and clinician-rated physical symptoms' severity in a large sample of FND patients. METHODS: Diffusion-weighted imaging data were collected from 85 FND patients with mixed symptoms and 75 healthy controls (HCs), together with illness duration, clinician-rated (S-FMDRS & CGI), and patient-reported (SF-36) symptom severity. Microstructural integrity was computed based on probabilistic tractography using the Desikan-Killiany parcellation. RESULTS: Compared to HCs, patients with FND presented widespread reduced microstructural integrity stemming from regions such as the right lateral orbitofrontal cortex, insula, putamen, and superior temporal regions. After adjusting for depression and anxiety, these differences were no longer significant. Within-group analysis revealed that reduced microstructural integrity, particularly in the left precuneus and left superior parietal cortex, was strongly correlated with both patient-reported and clinician-evaluated severity of physical symptoms in FND patients. CONCLUSION: Patients with FND present widespread reduced microstructural integrity in the brain, predominantly originating from temporoparietal, paralimbic and associated regions involved in emotion regulation and body awareness. These changes seem to be partly explained by comorbid mood disorders and the severity of physical symptoms, suggesting a plasticity phenomenon rather than trait biomarkers, which warrants further investigation in longitudinal study designs.

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YNICL Journal 2024 Journal Article

BOLD signal variability as potential new biomarker of functional neurological disorders

Ayla Schneider
Samantha Weber
Anna Wyss
Serafeim Loukas
Selma Aybek

BACKGROUND: Functional neurological disorder (FND) is a common neuropsychiatric condition with established diagnostic criteria and effective treatments but for which the underlying neuropathophysiological mechanisms remain incompletely understood. Recent neuroimaging studies have revealed FND as a multi-network brain disorder, unveiling alterations across limbic, self-agency, attentional/salience, and sensorimotor networks. However, the relationship between identified brain alterations and disease progression or improvement is less explored. METHODS: This study included resting-state functional magnetic resonance imaging (fMRI) data from 79 patients with FND and 74 age and sex-matched healthy controls (HC). First, voxel-wise BOLD signal variability was computed for each participant and the group-wise difference was calculated. Second, we investigated the potential of BOLD signal variability to serve as a prognostic biomarker for clinical outcome in 47 patients who attended a follow-up measurement after eight months. RESULTS: The results demonstrated higher BOLD signal variability in key networks, including the somatomotor, salience, limbic, and dorsal attention networks, in patients compared to controls. Longitudinal analysis revealed an increase in BOLD signal variability in the supplementary motor area (SMA) in FND patients who had an improved clinical outcome, suggesting SMA variability as a potential state biomarker. Additionally, higher BOLD signal variability in the left insula at baseline predicted a worse clinical outcome. CONCLUSION: This study contributes to the understanding of FND pathophysiology, emphasizing the dynamic nature of neural activity and highlighting the potential of BOLD signal variability as a valuable research tool. The insula and SMA emerge as promising regions for further investigation as prognostic and state markers.

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YNICL Journal 2024 Journal Article

Response to the Letter Concerning the Publication: Neuroimaging in Functional Neurological Disorder: State of the Field and Research Agenda. Perez DL et al. Neuroimage Clin. 2021;30:102623

David L. Perez
Timothy R. Nicholson
Ali A. Asadi-Pooya
Matthew Butler
Alan J. Carson
Anthony S. David
Quinton Deeley
Ibai Diez

In their letter, Tuller and colleagues raise concerns regarding the following introductory phrase and the linked Stone et al (2010) reference: "this renewed interest parallels recognition that FND [functional neurological disorder] is the 2nd most common outpatient neurologic diagnosis."While we appreciate there is complexity to epidemiological considerations in FND, we do not agree with the concerns raised.We share our perspective on this matter with the following four points:

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YNICL Journal 2024 Journal Article

Transient resting-state salience-limbic co-activation patterns in functional neurological disorders

Samantha Weber
Janine Bühler
Serafeim Loukas
Thomas A.W. Bolton
Giorgio Vanini
Rupert Bruckmaier
Selma Aybek

BACKGROUND: Functional neurological disorders were historically regarded as the manifestation of a dynamic brain lesion which might be linked to trauma or stress, although this association has not yet been directly tested yet. Analysing large-scale brain network dynamics at rest in relation to stress biomarkers assessed by salivary cortisol and amylase could provide new insights into the pathophysiology of functional neurological symptoms. METHODS: Case-control resting-state functional magnetic resonance imaging study of 79 patients with mixed functional neurological disorders (i.e., functional movement disorders, functional seizures, persistent perceptual-postural dizziness) and 74 age- and sex-matched healthy controls. Using a two-step hierarchical data-driven neuroimaging approach, static functional connectivity was first computed between 17 resting-state networks. Second, dynamic alterations in these networks were examined using co-activation pattern analysis. Using a partial least squares correlation analysis, the multivariate pattern of correlation between altered temporal characteristics and stress biomarkers as well as clinical scores were evaluated. RESULTS: Compared to healthy controls, patients presented with functional aberrancies of the salience-limbic network connectivity. Thus, the insula and amygdala were selected as seed-regions for the subsequent analyses. Insular co-(de)activation patterns related to the salience network, the somatomotor network and the default mode network were detected, which patients entered more frequently than controls. Moreover, an insular co-(de)activation pattern with subcortical regions together with a wide-spread co-(de)activation with diverse cortical networks was detected, which patients entered less frequently than controls. In patients, dynamic alterations conjointly correlated with amylase measures and duration of symptoms. CONCLUSION: The relationship between alterations in insular co-activation patterns, stress biomarkers and clinical data proposes inter-related mechanisms involved in stress regulation and functional (network) integration. In summary, altered functional brain network dynamics were identified in patients with functional neurological disorder supporting previously raised concepts of impaired attentional and interoceptive processing.

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YNICL Journal 2022 Journal Article

Multi-centre classification of functional neurological disorders based on resting-state functional connectivity

Samantha Weber
Salome Heim
Jonas Richiardi
Dimitri Van De Ville
Tereza Serranová
Robert Jech
Ramesh S. Marapin
Marina A.J. Tijssen

BACKGROUND: Patients suffering from functional neurological disorder (FND) experience disabling neurological symptoms not caused by an underlying classical neurological disease (such as stroke or multiple sclerosis). The diagnosis is made based on reliable positive clinical signs, but clinicians often require additional time- and cost consuming medical tests and examinations. Resting-state functional connectivity (RS FC) showed its potential as an imaging-based adjunctive biomarker to help distinguish patients from healthy controls and could represent a "rule-in" procedure to assist in the diagnostic process. However, the use of RS FC depends on its applicability in a multi-centre setting, which is particularly susceptible to inter-scanner variability. The aim of this study was to test the robustness of a classification approach based on RS FC in a multi-centre setting. METHODS: This study aimed to distinguish 86 FND patients from 86 healthy controls acquired in four different centres using a multivariate machine learning approach based on whole-brain resting-state functional connectivity. First, previously published results were replicated in each centre individually (intra-centre cross-validation) and its robustness across inter-scanner variability was assessed by pooling all the data (pooled cross-validation). Second, we evaluated the generalizability of the method by using data from each centre once as a test set, and the data from the remaining centres as a training set (inter-centre cross-validation). RESULTS: FND patients were successfully distinguished from healthy controls in the replication step (accuracy of 74%) as well as in each individual additional centre (accuracies of 73%, 71% and 70%). The pooled cross validation confirmed that the classifier was robust with an accuracy of 72%. The results survived post-hoc adjustment for anxiety, depression, psychotropic medication intake, and symptom severity. The most discriminant features involved the angular- and supramarginal gyri, sensorimotor cortex, cingular- and insular cortex, and hippocampal regions. The inter-centre validation step did not exceed chance level (accuracy below 50%). CONCLUSIONS: The results demonstrate the applicability of RS FC to correctly distinguish FND patients from healthy controls in different centres and its robustness against inter-scanner variability. In order to generalize its use across different centres and aim for clinical application, future studies should work towards optimization of acquisition parameters and include neurological and psychiatric control groups presenting with similar symptoms.

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YNICL Journal 2021 Journal Article

Neuroimaging in Functional Neurological Disorder: State of the Field and Research Agenda

David L. Perez
Timothy R. Nicholson
Ali A. Asadi-Pooya
Indrit Bègue
Matthew Butler
Alan J. Carson
Anthony S. David
Quinton Deeley

Functional neurological disorder (FND) was of great interest to early clinical neuroscience leaders. During the 20th century, neurology and psychiatry grew apart - leaving FND a borderland condition. Fortunately, a renaissance has occurred in the last two decades, fostered by increased recognition that FND is prevalent and diagnosed using "rule-in" examination signs. The parallel use of scientific tools to bridge brain structure - function relationships has helped refine an integrated biopsychosocial framework through which to conceptualize FND. In particular, a growing number of quality neuroimaging studies using a variety of methodologies have shed light on the emerging pathophysiology of FND. This renewed scientific interest has occurred in parallel with enhanced interdisciplinary collaborations, as illustrated by new care models combining psychological and physical therapies and the creation of a new multidisciplinary FND society supporting knowledge dissemination in the field. Within this context, this article summarizes the output of the first International FND Neuroimaging Workgroup meeting, held virtually, on June 17th, 2020 to appraise the state of neuroimaging research in the field and to catalyze large-scale collaborations. We first briefly summarize neural circuit models of FND, and then detail the research approaches used to date in FND within core content areas: cohort characterization; control group considerations; task-based functional neuroimaging; resting-state networks; structural neuroimaging; biomarkers of symptom severity and risk of illness; and predictors of treatment response and prognosis. Lastly, we outline a neuroimaging-focused research agenda to elucidate the pathophysiology of FND and aid the development of novel biologically and psychologically-informed treatments.

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YNICL Journal 2018 Journal Article

Identifying motor functional neurological disorder using resting-state functional connectivity

Jennifer Wegrzyk
Valeria Kebets
Jonas Richiardi
Silvio Galli
Dimitri Van De Ville
Selma Aybek

BACKGROUND: Motor functional neurological disorder (mFND) is a clinical diagnosis with reliable features; however, patients are reluctant to accept the diagnosis and physicians themselves bear doubts on potential misdiagnoses. The identification of a positive biomarker could help limiting unnecessary costs of multiple referrals and investigations, thus promoting early diagnosis and allowing early engagement in appropriate therapy. OBJECTIVES: To test whether resting-state (RS) functional magnetic resonance imaging could discriminate patients suffering from mFND from healthy controls. METHODS: We classified 23 mFND patients and 25 age- and gender-matched healthy controls based on whole-brain RS functional connectivity (FC) data, using a support vector machine classifier and the standard Automated Anatomic Labeling (AAL) atlas, as well as two additional atlases for validation. RESULTS: Accuracy, specificity and sensitivity were over 68% (p = 0.004) to discriminate between mFND patients and controls, with consistent findings between the three tested atlases. The most discriminative connections comprised the right caudate, amygdala, prefrontal and sensorimotor regions. Post-hoc seed connectivity analyses showed that these regions were hyperconnected in patients compared to controls. CONCLUSIONS: The good accuracy to discriminate patients from controls suggests that RS FC could be used as a biomarker with high diagnostic value in future clinical practice to identify mFND patients at the individual level.

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