Functional neurological disorders (FND) are common sources of disability in medicine. Patients have often been misdiagnosed, correctly diagnosed after lengthy delays, and/or subjected to poorly ...delivered diagnoses that prevent diagnostic understanding and lead to inappropriate treatments, iatrogenic harm, unnecessary and costly evaluations, and poor outcomes.
Functional Neurological Symptom Disorder/Conversion Disorder was adopted by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, replacing the term psychogenic with functional and removing the criterion of psychological stress as a prerequisite for FND. A diagnosis can now be made in an inclusionary manner by identifying neurological signs that are specific to FNDs without reliance on presence or absence of psychological stressors or suggestive historical clues. The new model highlights a wider range of past sensitizing events, such as physical trauma, medical illness, or physiological/psychophysiological events. In this model, strong ideas and expectations about these events correlate with abnormal predictions of sensory data and body-focused attention. Neurobiological abnormalities include hypoactivation of the supplementary motor area and relative disconnection with areas that select or inhibit movements and are associated with a sense of agency. Promising evidence has accumulated for the benefit of specific physical rehabilitation and psychological interventions alone or in combination, but clinical trial evidence remains limited.
Functional neurological disorders are a neglected but potentially reversible source of disability. Further research is needed to determine the dose and duration of various interventions, the value of combination treatments and multidisciplinary therapy, and the therapeutic modality best suited for each patient.
The sense of agency (SoA) refers to the perception that an action is the consequence of one's own intention. Studies exploring the SoA with neuroimaging techniques summarized the available data and ...confirmed a role of fronto-parietal areas and subcortical structures. However, these studies focused on specific regions of interest. We thus conducted a whole-brain meta-analysis to verify which regions emerge as significant for the SoA, specifically during motor execution. We performed a systematic search on PubMed, PsycINFO and Cochrane databases with the following inclusion criteria: studies investigating SoA with a visuo-motor task by means of neuroimaging in healthy subjects. We performed a quantitative, whole-brain, meta-analysis of neural correlates of the SoA based on the activation likelihood estimation. Of the 785 articles identified by our search, 22 studies met our inclusion criteria (169 foci, 295 subjects for decreased agency, and 58 foci, 165 subjects for normal agency). Neural correlates of decreased agency were the bilateral temporo-parietal junction (MNI: 50,-54,14; -44,-52,42; -48,-56,8). Normal agency showed no significant clusters of activation. This meta-analysis confirmed the key role of areas responsible for decreased SoA during motor control, whereas normal agency did not show a specific neural signature. This study sets the ground for future regions-of-interest analyses of neural correlates of SoA, as well as potential neuromodulation studies, which might be relevant in medical conditions presenting with abnormal SoA.
Stressful life events and maltreatment have traditionally been considered crucial in the development of conversion (functional neurological) disorder, but the evidence underpinning this association ...is not clear. We aimed to assess the association between stressors and functional neurological disorder.
We systematically reviewed controlled studies reporting stressors occurring in childhood or adulthood, such as stressful life events and maltreatment (including sexual, physical abuse, and emotional neglect) and functional neurological disorder. We did a meta-analysis, with assessments of methodology, sources of bias, and sensitivity analyses.
34 case-control studies, with 1405 patients, were eligible. Studies were of moderate-to-low quality. The frequency of childhood and adulthood stressors was increased in cases compared with controls. Odds ratios (OR) were higher for emotional neglect in childhood (49% for cases vs 20% for controls; OR 5·6, 95% CI 2·4-13·1) compared with sexual abuse (24% vs 10%; 3·3, 2·2-4·8) or physical abuse (30% vs 12%; 3·9, 2·2-7·2). An association with stressful life events preceding onset (OR 2·8, 95% CI 1·4-6·0) was stronger in studies with better methods (interviews; 4·3, 1·4-13·2). Heterogeneity was significant between studies (I
21·1-90·7%). 13 studies that specifically ascertained that the participants had not had either severe life events or any subtype of maltreatment all found a proportion of patients with functional neurological disorder reporting no stressor.
Stressful life events and maltreatment are substantially more common in people with functional neurological disorder than in healthy controls and patient controls. Emotional neglect had a higher risk than traditionally emphasised sexual and physical abuse, but many cases report no stressors. This outcome supports changes to diagnostic criteria in DSM-5; stressors, although relevant to the cause in many patients, are not a core diagnostic feature. This result has implications for ICD-11.
None.
To evaluate the neural correlates of implicit processing of negative emotions in motor conversion disorder (CD) patients.
An event related fMRI task was completed by 12 motor CD patients and 14 ...matched healthy controls using standardised stimuli of faces with fearful and sad emotional expressions in comparison to faces with neutral expressions. Temporal changes in the sensitivity to stimuli were also modelled and tested in the two groups.
We found increased amygdala activation to negative emotions in CD compared to healthy controls in region of interest analyses, which persisted over time consistent with previous findings using emotional paradigms. Furthermore during whole brain analyses we found significantly increased activation in CD patients in areas involved in the 'freeze response' to fear (periaqueductal grey matter), and areas involved in self-awareness and motor control (cingulate gyrus and supplementary motor area).
In contrast to healthy controls, CD patients exhibited increased response amplitude to fearful stimuli over time, suggesting abnormal emotional regulation (failure of habituation / sensitization). Patients with CD also activated midbrain and frontal structures that could reflect an abnormal behavioral-motor response to negative including threatening stimuli. This suggests a mechanism linking emotions to motor dysfunction in CD.
•Higher BOLD variability in somatomotor, salience and limbic networks in FND.•Better clinical outcome at follow-up associated with higher variability in SMA.•Higher insular variability at baseline ...predicted a worse clinical outcome.•BOLD signal variability might present a prognostic and state biomarker for FND.
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.
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.
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.
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.
•Patients entered more frequently into insular-somatomotor co-activation.•Patients entered less often into insular co-activation with subcortical regions.•Dynamic alterations correlated with ...alpha-amylase and duration of illness.•Functional alterations reflect prioritizing allostatic mechanisms due to alert.
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.
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.
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.
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.
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.
To test whether resting-state (RS) functional magnetic resonance imaging could discriminate patients suffering from mFND from healthy controls.
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.
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.
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.
•We classified FND patients from controls with 68% accuracy using resting-state fMRI.•Right caudate-amygdala connectivity best discriminated patients with FND from controls.•Future additional steps are needed before translation to clinical use.•This could be used in complement of clinical signs for the diagnosis of FND.
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