BOLD signal variability as potential new biomarker of functional neurological disorders.

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.

Perspectives on the diagnosis and management of functional cognitive disorder: An international Delphi study.

BACKGROUND: Current proposed criteria for functional cognitive disorder (FCD) have not been externally validated. We sought to analyse the current perspectives of cognitive specialists in the diagnosis and management of FCD in comparison with neurodegenerative conditions. METHODS: International experts in cognitive disorders were invited to assess seven illustrative clinical vignettes containing history and bedside characteristics alone. Participants assigned a probable diagnosis and selected the appropriate investigation and treatment. Qualitative, quantitative and inter-rater agreement analyses were undertaken. RESULTS: Eighteen diagnostic terminologies were assigned by 45 cognitive experts from 12 countries with a median of 13 years of experience, across the seven scenarios. Accurate discrimination between FCD and neurodegeneration was observed, independently of background and years of experience: 100% of the neurodegenerative vignettes were correctly classified and 75%-88% of the FCD diagnoses were attributed to non-neurodegenerative causes. There was <50% agreement in the terminology used for FCD, in comparison with 87%-92% agreement for neurodegenerative syndromes. Blood tests and neuropsychological evaluation were the leading diagnostic modalities for FCD. Diagnostic communication, psychotherapy and psychiatry referral were the main suggested management strategies in FCD. CONCLUSIONS: Our study demonstrates the feasibility of distinguishing between FCD and neurodegeneration based on relevant patient characteristics and history details. These characteristics need further validation and operationalisation. Heterogeneous labelling and framing pose clinical and research challenges reflecting a lack of agreement in the field. Careful consideration of FCD diagnosis is advised, particularly in the presence of comorbidities. This study informs future research on diagnostic tools and evidence-based interventions.

Does Diglossia Impact Brain Structure? Data from Swiss German Early Diglossic Speakers.

(1) Background: Bilingualism has been reported to shape the brain by inducing cortical changes in cortical and subcortical language and executive networks. Similar yet different to bilingualism, diglossia is common in Switzerland, where the German-speaking population switches between an everyday spoken Swiss German (CH-GER) dialect and the standard German (stGER) used for reading and writing. However, no data are available for diglossia, defined as the use of different varieties or dialects of the same language, regarding brain structure. The aim of our study is to investigate if the presence of this type of diglossia has an impact on the brain structure, similar to the effects seen in bilingualism. (2) Methods: T1-weighted anatomical MRI scans of participants were used to compare the grey matter density and grey matter volume of 22 early diglossic CH-GER-speaking and 20 non-diglossic French-speaking right-handed university students, matched for age, linguistics and academic background. The images were processed with Statistical Parametric Mapping SPM12 and analyzed via voxel- and surface-based morphometry. (3) Results: A Bayesian ANCOVA on the whole brain revealed no differences between the groups. Also, for the five regions of interest (i.e., planum temporale, caudate nucleus, ACC, DLPFC and left interior parietal lobule), no differences in the cortical volume or thickness were found using the same statistical approach. (4) Conclusion: The results of this study may suggest that early diglossia does not shape the brain structure in the same manner as bilingualism.

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

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.

Functional neurological signs in hypermobile Ehlers-Danlos syndrome and hypermobile spectrum disorders with suspected neuropathic pain.

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.

Cortisol in functional neurological disorders: State, trait and prognostic biomarkers.

OBJECTIVE: Biological stress dysregulation, such as a flattened cortisol awakening response (CAR), has been identified in functional neurological disorder (FND). This longitudinal study aimed to explore whether CAR alterations in FND serve as state or trait biomarkers, assessing temporal changes in cortisol and clinical outcomes to test its prognostic value. METHODS: Salivary cortisol was measured in 53 patients with mixed FND at two visits separated by eight months (M0 and M8). CAR was calculated based on five consecutive samples, each taken with 15-min time intervals, collected upon awakening, whereas cortisol amplitude (CAmp) was calculated as the difference between the morning peak and the afternoon trough. Clinical outcome was assessed with the Functional Movement Disorder Rating Scale (S-FMDRS), Clinical global impression (CGI) scores for severity (CGI-S) and improvement (CGI-I) and the short-form health survey (SF-36). RESULTS: No differences in CAR levels were found between M0 and M8 regardless of clinical outcome (remained flattened). However, a good clinical outcome was associated with an earlier peak in the CAR (p = .013, odds ratio: 1.78; 95%-confidence interval: 0.095-1.13). A higher CAmp at M0 predicted a better outcome at M8 (ß = 1.14, 95%-confidence interval:0.15-2.13, p = .03). CONCLUSION: A flattened CAR might represent a trait marker for FND, when an earlier peak in the CAR may serve as a state biomarker. The CAmp demonstrates predictive power for clinical outcome, potentially representing a prognostic biomarker for FND. Further replication and follow-up studies are essential to confirm this suggested role of cortisol as a multifaceted biomarker of FND.

Non-invasive neuromodulation of the right temporoparietal junction using theta-burst stimulation in functional neurological disorder.

Background: Disrupted 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. Methods: In 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. Results: At 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. Conclusion: Aberrant 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.

How Treatment Motivation Predicts Favorable Outcomes in Interdisciplinary Multimodal Pain Treatment Among Patients with Chronic Primary Pain.

As motivation for psychological treatment at intake has been shown to predict favorable outcomes after an inpatient stay, this study aimed to further characterize the different components of psychological treatment motivation that predict favorable treatment outcomes. 294 inpatients with chronic primary pain participating in an interdisciplinary multimodal pain treatment in a tertiary psychosomatic university clinic completed a battery of psychological questionnaires at intake and discharge. Treatment motivation was assessed at intake using the scales of the FPTM-23 questionnaire, while pain intensity, pain interference, anxiety, and depression were assessed both at intake and discharge. After treatment, pain intensity, pain interference, anxiety, and depression were significantly reduced. While higher levels on the FPTM-23 scale of suffering predicted smaller decreases in anxiety after treatment, higher scores on the scale of hope, i.e., lower levels of hopelessness, predicted lower levels of pain interference, anxiety, and depression after treatment. None of the scales of treatment motivation predicted pain intensity levels after treatment. Above and beyond providing symptom relief, reducing hopelessness and fostering hope regarding the treatment process and outcome might help clinicians treat patients with chronic primary pain more effectively.

Healthcare employment as a risk factor for functional neurological disorder: A case-control study.

BACKGROUND AND PURPOSE: Female gender, younger age and stressful life events are known predisposing factors for functional neurological disorders (FNDs). Employment in a healthcare profession has also been suggested to be a predisposing factor. We set out to conduct a large-scale case-control study to estimate the rate employment in a healthcare profession among people with FND. METHODS: We included 200 consecutive patients with a confirmed diagnosis of FND, referred to our clinic at University Hospital Bern Switzerland between October 1, 2016, and August 1, 2019. In addition, we included a control group of 200 patients with a confirmed neurological disorder, matched for age and gender, seen during the same period. The primary endpoint was to compare the prevalence of healthcare professionals between the groups. We also describe the clinical manifestations and concomitant psychiatric diagnoses in the FND cohort. RESULTS: Female gender was predominant (70%), and the participants' mean age was 37 years. The proportion of healthcare professionals in the FND patients was 18% (33/186), which was significantly higher than in the control group, in which it was 10.6% (17/189; p = 0.019, 95% confidence interval odds ratio 1.168-4.074). Most healthcare professionals in both cohorts were nurses (21/33 among FND patients, 10/17 among controls). Among FND patients, 140 (70%) had motor symptoms and 65 (32.5%) had a concomitant psychiatric diagnosis. CONCLUSION: This case-control study confirmed a higher rate of employment in healthcare professions in patients with FND, suggesting two potential mechanisms of FND: exposure to models/specific knowledge about neurological symptoms or stress-related professional factors. This warrants further studies on underlying mechanisms and prevention.

Setting up Functional Neurological Disorder Treatment Services: Questions and Answers.

Functional neurologic disorder (FND) is commonly encountered across outpatient and inpatient medical settings. Given the potential for a high burden of disability in some patients and mounting evidence for the efficacy of FND-specific multidisciplinary treatment services, expanding clinical services for this population is a necessity. In this perspective article, we discuss considerations for creating FND services, including the types of services that exist, how to start, how to identify appropriate referrals, and how to develop and monitor individualized treatment plans. In addition, we discuss how this effort can be done sustainably - balancing patient needs with limited healthcare resources.

[Overview of care management principles in functional neurological disorders]. / Synthèse des principes et schémas de prise en charge dans les troubles neurologiques fonctionnels.

After more than twenty years of academic research on functional neurological disorders (FND) throughout the world, a standardized care management strategy has emerged to allow a more adapted care offer to patients with FND, as close as possible to their experience and their needs. With regard to this special issue on FND in collaboration with L'Encéphale and at the initiative of the Neuropsychiatry section of the AFPBN (French Association of Biological Psychiatry and Neuropsychopharmacology), we would like to suggest a summary of all topics discussed in more detail in each article of this special issue, in order to facilitate its reading. We therefore cover the following themes: the initial contact with a patient with FND, the diagnostic process in favor of a positive diagnosis, the physiological, neural and psychological basis of FND, the diagnostic announcement (and its intangibles), the therapeutic patient education in FND, the general principles of therapeutic management through a personalized and multidisciplinary care program, and the validated therapeutic tools available according to the symptoms identified. This article is designed to be of broad interest on FND, supported by tables and figures showing the key points of all these steps, to keep an educational purpose at most. We hope that through this special issue, each health professional will be able to grasp this knowledge and this framework of care as easily and quickly as possible, in order to participate in the standardization of the care offer.

Connecting Women in Neurosciences: A networking project to sustain mutual empowerment in young, female clinical neuroscientists.

Simultaneously acquiring broad clinical knowledge and scientific expertise is a major challenge for young clinical scientists. Female researchers may face additional hurdles in their career, for example, due to unconscious bias. We aimed to address clinical, research, and gender-related challenges among young female clinical neuroscientists. We implemented a peer-led networking group dedicated to increasing clinical and scientific knowledge, improve soft skills, and encourage exchange between fellow residents. In monthly meetings, two participants hold short presentations on a clinical topic or scientific method, followed by a discussion and feedback to the presenter. Afterwards, participants network and discuss challenges they face in their daily experience. Nine neurology residents at a Swiss University Hospital with ≤3 years of training participated in the Connecting Women in Neurosciences project from August 2020 to June 2021. In a qualitative evaluation, participants reported they felt empowered by these meetings and profited from their new network. We identified several challenges in combining clinical and research activities, some of which participants perceived to be gender-related. In addition to women-only meetings, we will promote events addressing all interested researchers. Peer-to-peer networking is an easy and low-budget intervention to encourage female residents to engage in research activities, profit from each other's expertise, and promote interdisciplinary teamwork. It can provide a protected environment to discuss and overcome in particular gender-related challenges. We encourage young colleagues to regularly engage in structured networking activities with their local peers.

Identification and Characterization of Pain Processing Patterns Among Patients With Chronic Primary Pain: A Replication.

OBJECTIVES: To develop individual and effective treatment plans for patients with chronic pain, we aimed to replicate Grolimund and colleagues' empirical categorization of chronic pain patients on a new and larger sample. Moreover, this work aimed to extend previous knowledge by considering various treatment outcomes and exploratorily analyzing which coping skills might be particularly relevant for treatment success in each subtype. MATERIALS AND METHODS: Latent class analysis was used to identify homogenous subtypes with different pain processing patterns using the pain processing questionnaire (FESV). RESULTS: By analyzing 602 inpatients with chronic primary pain, we identified 3 subtypes: (1) severely burdened individuals with low coping skills , (2) mildly burdened individuals with high coping skills , and (3) moderately burdened individuals with moderate coping skills. Pain interference, psychological distress, and cognitive and behavioral coping skills improved after treatment in all subtypes. Pain-related mental interference significantly improved only in subtypes (1) and (3). Only individuals of subtype (3) reported significant reductions in pain intensity after treatment. Exploratory regression analysis suggested that of subtype (1), the most promising targets in reducing pain interference and psychological distress posttreatment might be to foster relaxation techniques, counteractive activities, and cognitive restructuring . None of the FESV dimensions significantly predicted treatment outcomes among individuals of subtype (2). Individuals of subtype (3) might benefit the most from experiencing more competence during treatment. DISCUSSION: Our findings highlight the importance of identifying and characterizing subtypes of chronic primary pain patients and that these subtypes should be considered for individualized and effective treatment.

Functional neurological disorder is a feminist issue.

Functional neurological disorder (FND) is a common and disabling disorder, often misunderstood by clinicians. Although viewed sceptically by some, FND is a diagnosis that can be made accurately, based on positive clinical signs, with clinical features that have remained stable for over 100 years. Despite some progress in the last decade, people with FND continue to suffer subtle and overt forms of discrimination by clinicians, researchers and the public. There is abundant evidence that disorders perceived as primarily affecting women are neglected in healthcare and medical research, and the course of FND mirrors this neglect. We outline the reasons why FND is a feminist issue, incorporating historical and contemporary clinical, research and social perspectives. We call for parity for FND in medical education, research and clinical service development so that people affected by FND can receive the care they need.

War experiences and relationship problems predict pain sensitivity cross-sectionally among patients with chronic primary pain.

BACKGROUND: Most patients suffering from chronic pain are more susceptible to pain and pressure due to higher pain sensitivity. Since psychosocial factors play a central role in developing and maintaining chronic pain, investigating associations between pain sensitivity and psychosocial stressors promises to advance the biopsychosocial understanding of chronic pain. OBJECTIVES: We aimed to replicate Studer et al.'s (2016) findings about associations of psychosocial stressors with pain sensitivity in a new sample of patients with chronic primary pain (ICD-11, MG30.0). METHODS: A pain provocation test was used on both middle fingers and earlobes to assess pain sensitivity among 460 inpatients with chronic primary pain. Potentially life-threatening accidents, war experiences, relationship problems, certified inability to work, and adverse childhood experiences were assessed as potential psychosocial stressors. Structural equation modeling was used to investigate associations between psychosocial stressors and pain sensitivity. RESULTS: We partially replicated Studer et al.'s findings. Similar to the original study, patients with chronic primary pain showed enhanced pain sensitivity values. Within the investigated group, war experiences (ß = 0.160, p < .001) and relationship problems (ß = 0.096, p = .014) were associated with higher pain sensitivity. In addition, the control variables of age, sex, and pain intensity also showed a predictive value for higher pain sensitivity. Unlike Studer et al., we could not identify a certified inability to work as a predictor of higher pain sensitivity. CONCLUSIONS: This study showed that beyond age, sex, and pain intensity, the psychosocial stressors of war experiences and relationship problems were associated with higher pain sensitivity.

Improvements in pain coping predict treatment success among patients with chronic primary pain.

OBJECTIVE: Given the increasing incidence and prevalence of chronic pain, effective treatments for chronic pain are needed. This study aimed to investigate the role of cognitive and behavioral pain coping regarding the prediction of treatment outcomes among inpatients with chronic primary pain participating in an interdisciplinary multimodal treatment program. METHODS: At intake and discharge, 500 patients with chronic primary pain completed questionnaires on pain intensity, pain interference, psychological distress, and pain processing. RESULTS: Patients' symptoms, cognitive and behavioral pain coping improved significantly after treatment. Similarly, separate cognitive and behaviroal coping skills improved significantly after treatment. Hierarchical linear models revealed no significant associations of pain coping with reductions in pain intensity. Whereas the overall level and improvements in cognitive pain coping predicted reductions in pain interference and psychological distress, the overall level and improvements in behavioral pain coping were associated with reductions in pain interference alone. DISCUSSION: Since pain coping seems to influence both pain interference and psychological distress, improving cognitive and behavioral pain coping during an interdisciplinary multimodal pain treatment seems to be a key component in the successful treatment of inpatients with chronic primary pain, enabling them to function better physically and mentally despite their chronic pain. Clinically, it might be worth fostering and exercising cognitive restructuring as well as action planning in treatment to reduce both pain interference and psychological distress levels post-treatment. In addition, practicing relaxation techniques might help reduce pain interference post-treatment, whereas making experiences of personal competence might help reduce psychological distress post-treatment.

Motive Satisfaction Among Patients with Chronic Primary Pain: A Replication.

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.

Multivariate classification provides a neural signature of Tourette disorder.

BACKGROUND: Tourette disorder (TD), hallmarks of which are motor and vocal tics, has been related to functional abnormalities in large-scale brain networks. Using a fully data driven approach in a prospective, case-control study, we tested the hypothesis that functional connectivity of these networks carries a neural signature of TD. Our aim was to investigate (i) the brain networks that distinguish adult patients with TD from controls, and (ii) the effects of antipsychotic medication on these networks. METHODS: Using a multivariate analysis based on support vector machine (SVM), we developed a predictive model of resting state functional connectivity in 48 patients and 51 controls, and identified brain networks that were most affected by disease and pharmacological treatments. We also performed standard univariate analyses to identify differences in specific connections across groups. RESULTS: SVM was able to identify TD with 67% accuracy (p = 0.004), based on the connectivity in widespread networks involving the striatum, fronto-parietal cortical areas and the cerebellum. Medicated and unmedicated patients were discriminated with 69% accuracy (p = 0.019), based on the connectivity among striatum, insular and cerebellar networks. Univariate approaches revealed differences in functional connectivity within the striatum in patients v. controls, and between the caudate and insular cortex in medicated v. unmedicated TD. CONCLUSIONS: SVM was able to identify a neuronal network that distinguishes patients with TD from control, as well as medicated and unmedicated patients with TD, holding a promise to identify imaging-based biomarkers of TD for clinical use and evaluation of the effects of treatment.