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AbstractFunctional neurological disorder (FND), previously regarded as a diagnosis of exclusion, is now a rule-in diagnosis with available treatments. This represents a major step toward destigmatizing the disorder, which was often doubted and deemed untreatable. FND is prevalent, generally affecting young and middle aged adults, and can cause severe disability in some individuals. An early diagnosis, with subsequent access to evidence based rehabilitative and/or psychological treatments, can promote recovery—albeit not all patients respond to currently available treatments. This review presents the latest advances in the use of validated rule-in examination signs to guide diagnosis, and the range of therapeutic approaches available to care for patients with FND. The article focuses on the two most frequently identified subtypes of FND: motor (weakness and/or movement disorders) and seizure type symptoms. Twenty two studies on motor and 27 studies on seizure type symptoms report high specificities of clinical signs (64-100%), and individual signs are reviewed. Rehabilitative interventions (physical and occupational therapy) are treatments of choice for functional motor symptoms, while psychotherapy is an emerging evidence based treatment across FND subtypes. The literature to date highlights heterogeneity in responses to treatment, underscoring that more research is needed to individualize treatments and develop novel interventions.

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.

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.

Functional neurological disorders’ (FND) neuropathophysiology has been described as multi-network disturbances including aberrancies in the agency network highlighting the role of the right temporo-parietal junction (rTPJ). Refining the relevance of the rTPJ, we applied a co-activation pattern (CAP) based approach using the rTPJ as a seed in 58 patients with motor FND compared to 58 age- and sex-matched healthy controls (HC). Firstly, CAPs were derived from HC to identify functional alterations in the rTPJ network in FND patients. Secondly, motor subgroup characteristics in patients were examined using CAPs derived from the patient group. Compared to HC, patients were found to enter less frequently a state characterized by salience network and default mode network (DMN) co-activation along with executive control and somatomotor networks co-deactivation. Additionally, patients entered more often a state depicted by somatomotor-salience co-activation and DMN co-deactivation. Comparing motor subgroups, patients with functional weakness (FW) remained longer in a state characterised by salience and dorsal/ventral attention network co-activation and DMN co-deactivation compared to patients with no functional weakness (no-FW). FND patients overall exhibited a reduced coupling of the DMN and an increased coupling of the somatomotor network with the rTPJ compared to controls. Patient subgroups differed regarding coupling between the rTPJ and the attention network and DMN. rTPJ dynamic network alterations might reflect hampered flexibility in brain state switching and altered self-referential processes linked to impaired motor planning and execution, which seem to also differ between symptom types, indicating a potential phenotypic biomarker.

Objective Dissociative seizures are paroxysmal disruptions of awareness and behavioral control in the context of affective arousal. Alterations in stress‐related endocrine function have been demonstrated, but the timescale of dissociation suggests that the central locus coeruleus (LC) noradrenergic system is likely pivotal. Here, we investigate whether LC activation at rest is associated with altered brain network dynamics. Methods A preliminary co‐activation pattern (CAP) analysis of resting‐state functional magnetic resonance imaging (fMRI) in 14 patients with dissociative seizures and 14 healthy controls was performed by using the LC as a seeding region. The red nucleus served as a control condition. Entry rates, durations, and state transition probabilities of identified CAPs were calculated. Analyses were corrected for demographic, technical, and clinical confounders including depression and anxiety. Results Three LC‐related CAPs were identified, with the dominant two showing inverse activations and deactivations of the default mode network and the attention networks, respectively. Analysis of transition probabilities between and within the three CAPs revealed higher state persistence in patients compared to healthy controls for both CAP2LC (Cohen's d = −0.55; p = 0.01) and CAP3LC (Cohen's d = −0.57; p = 0.01). The control analysis using the red nucleus as a seed yielded similar CAPs, but no significant between‐group differences in transition probabilities. Significance Higher state persistence of LC‐CAPs in patients with dissociative seizures generates the novel hypothesis that arousal‐related impairments of network switching might be a candidate neural mechanism of dissociation. Plain Language Summary Dissociative seizures often arise during high affective arousal. The locus coeruleus is a brain structure involved in managing such acute arousal states. We investigated whether the activity of the locus coeruleus correlates with activity in other regions of the brain (which we refer to as “brain states”), and whether those brain states were different between patients with dissociative seizures and healthy controls. We found that patients tended to stay in certain locus coeruleus‐dependent brain states instead of switching between them. This might be related to the loss of awareness and disruptions of brain functions (“dissociation”) that patients experience during seizures.

BackgroundDisrupted sense of agency (SoA)—the sense of being the agent of one’s own actions—has been demonstrated in patients with functional neurological disorder (FND), and a key area of the corresponding neuronal network is the right temporoparietal junction (rTPJ). Several functional MRI (fMRI) studies have found hypoactivation as well as hyperactivation of the rTPJ in FND. In a proof-of-concept study, we tested whether repetitive transcranial magnetic stimulation (rTMS) over the rTPJ could restore this aberrant activity.MethodsIn a randomised, crossover, single-blinded, sham-controlled study design, theta-burst stimulation (tb-rTMS) was applied over the rTPJ in 23 patients with FND and 19 healthy controls (HC), with each participant undergoing three stimulatory visits (inhibitory continuous TBS (cTBS), excitatory intermittent TBS (iTBS) and sham). During fMRI, participants played a visuomotor task artificially reducing their SoA (manipulated agency, MA), repeated after each neurostimulation. We compared brain activity and behavioural SoA as primary outcomes before and after tb-rTMS and investigated the feasibility of tb-rTMS over the rTPJ in FND as secondary outcome.ResultsAt baseline, patients showed decreased accuracy in detecting reduced agency compared with controls (p<0.001), paralleled by lower brain activation in the rTPJ during MA (p=0.037, volume of interest). A region of interest analysis on the rTPJ showed no effect of the sham condition in FND or HC (p=0.917; p=0.375) but revealed a significant effect of stimulation protocol (cTBS/iTBS, p=0.037) in patients with FND, with the excitatory protocol increasing the blood-oxygen-level-dependent (BOLD) signal, whereas this effect was not found in HC. In neither group, a behavioural effect of tb-rTMS was observed.ConclusionAberrant processing of agency in FND was confirmed at baseline, reflected in behavioural outcome and reduced activity in the rTPJ. Tb-rTMS over this key region elicited neuronal changes in patients, paving ways for future studies exploring TMS as neurobiologically informed intervention to restore SoA in FND. We critically discuss methodological intricacies and outline further steps in this research line.

We set out to replicate findings of significant (a) reductions in pain, psychological distress, and motivational incongruence (i.e., insufficient motive satisfaction) after interdisciplinary multimodal pain treatment and (b) associations between reductions in motivational incongruence (i.e., improved motive satisfaction) and decreases in psychological distress (Vincent et al., Journal of Clinical Psychology in Medical Settings 28:331–343, 2021). 475 Patients with chronic primary pain completed standardized self-reported questionnaires assessing motivational incongruence, psychological distress, pain intensity, and pain interference at intake and discharge from a tertiary psychosomatic university clinic. We used hierarchical linear models to analyze motivational incongruence’s effects on psychological distress. We partially replicated Vincent et al.’s findings. Significant reductions in pain, psychological distress, and motivational incongruence after treatment were found. Reductions in motivational incongruence were associated with reductions in psychological distress. Similarly, a better motive satisfaction mediated the relationship between pain interference and psychological distress. Our findings show that reducing motivational incongruence may be a key component of treating chronic primary pain; we recommend to assess and target motivational incongruence to improve interdisciplinary multimodal pain treatment.

The sense of agency is an important aspect of motor control. Impaired sense of agency has been linked to several medical conditions, including schizophrenia and functional neurological disorders. A complex brain network subserves the sense of agency, and the right temporoparietal junction is one of its main nodes. In this paper, we tested whether transcranial magnetic stimulation over the right temporoparietal junction elicited behavioural changes in the sense of agency. In experiment 1, 15 healthy participants performed a behavioural task during functional MRI, with the goal of localizing the area relevant for the sense of agency in the right temporoparietal junction. In the task, the movement of a cursor (controlled by the participants) was artificially manipulated, and the sense of agency was either diminished (turbulence) or enhanced (magic). In experiment 2, we applied transcranial magnetic stimulation in 20 healthy participants in a sham-controlled, crossover trial with excitatory, inhibitory or sham (vertex) stimulation. We measured the summary agency score, an indicator of the sense of agency (lower values correspond to diminished sense of agency). Experiment 1 revealed a peak of activation during agency manipulation in the right temporoparietal junction (Montreal Neurological Institute coordinates x, y, z: 68, −26, 34). Experiment 2 showed that inhibition of the right temporoparietal junction significantly reduced the summary agency score in both turbulence (from −14.4 ± 11.4% to −22.5 ± 8.9%), and magic (from −0.7 ± 5.8% to −4.4 ± 4.4%). We found no excitatory effects, possibly because of a ceiling effect (because healthy participants have a normal sense of agency) or noneffectiveness of the excitatory protocol. Our experiments showed that the network subserving the sense of agency was amenable to neuromodulation in healthy participants. This sets the ground for further research in patients with impaired sense of agency. DRKS00012992 (German clinical trials registry).

Background The hypermobile Ehlers–Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) are connective tissue disorders characterized by generalized joint hypermobility, associated with chronic pain and several symptoms, such as fatigue, dysautonomia, as well as psychiatric co‐morbidities. Clinical observations of unusual manifestations during systematic sensory testing raised the question of a possible co‐existence with a functional neurological disorder (FND). Hence, this study aimed to assess the presence of positive functional neurological signs (FNS) in a cohort of patients with hEDS/HSD. Methods The clinical data of hEDS/HSD patients (N = 24) were retrospectively analyzed and compared to a prospectively recruited age‐/sex‐matched healthy control group (N = 22). Four motor‐ and three sensory‐positive FNS were assessed. Results Twenty‐two patients (92%) presented at least one motor or sensory FNS. Five patients (21%) presented only a single FNS, 14 presented between 2 and 4 FNS (58%), and 3 patients presented 5 or more FNS (12%). None of the healthy controls presented motor FNS, and only two presented a sensory FNS. Conclusions The presence of FNS in hEDS/HSD deserves better clinical detection and formal diagnosis of FND to offer more adequate care in co‐morbid situations. In fact, FND can severely interfere with rehabilitation efforts in hEDS/HSD, and FND‐targeted physical therapy should perhaps be combined with EDS/HSD‐specific approaches. This paper aimed to assess the presence of positive functional neurological signs (FNS) in a cohort of patients with hEDS/HSD. This figure shows the number of FNS and the coexistence between sensory (blue) and motor (red) FNS.