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Functional neurological disorder (FND), a condition at the intersection of neurology and psychiatry, is a common and disabling outpatient referral to neurology and neuropsychiatry clinics. In this perspective article, we focus on the motor spectrum of FND (mFND), including individuals with functional movement disorders (FND-movt), functional limb weakness/paresis (FND-par) and functional [psychogenic non-epileptic/dissociative] seizures (FND-seiz). Over the past several decades, there have been dedicated efforts within the neurologic and psychiatric communities to create \"rule-in\" diagnostic criteria, as well as thoughtful approaches to the clinical interview, delivery of the diagnosis and the development of a patient-centered treatment plan. These advances allow the promotion of good clinical practices in the outpatient assessment and management of mFND. Informed by the literature and our prior clinical experiences, we provide suggestions on how to evaluate individuals with suspected functional motor symptoms - including conducting sensitive psychiatric and psychosocial screenings. Additional sections discuss common \"rule-in\" neurological examination and semiologic signs of motor FND, as well as approaches to deliver the diagnosis and formulate a treatment plan based on individual patient needs. To aid the development of shared (partially overlapping) expertise that catalyzes an interdisciplinary approach to mFND, the use of physiotherapy for therapeutic motor retraining and cognitive behavioral therapy to examine relationships between symptoms, thoughts, behaviors and emotions are also discussed. Additional clinical research is needed to further refine and operationalize the assessment and management of mFND, across clinics, healthcare settings and countries.

BackgroundBrain imaging studies investigating grey matter in functional neurological disorder (FND) have used univariate approaches to report group-level differences compared with healthy controls (HCs). However, these findings have limited translatability because they do not differentiate patients from controls at the individual-level.Methods183 participants were prospectively recruited across three groups: 61 patients with mixed FND (FND-mixed), 61 age-matched and sex-matched HCs and 61 age, sex, depression and anxiety-matched psychiatric controls (PCs). Radial basis function support vector machine classifiers with cross-validation were used to distinguish individuals with FND from HCs and PCs using 134 FreeSurfer-derived grey matter MRI features.ResultsPatients with FND-mixed were differentiated from HCs with an accuracy of 0.66 (p=0.005; area under the receiving operating characteristic (AUROC)=0.74); this sample was also distinguished from PCs with an accuracy of 0.60 (p=0.038; AUROC=0.56). When focusing on the functional motor disorder subtype (FND-motor, n=46), a classifier robustly differentiated these patients from HCs (accuracy=0.72; p=0.002; AUROC=0.80). FND-motor could not be distinguished from PCs, and the functional seizures subtype (n=23) could not be classified against either control group. Important regions contributing to statistically significant multivariate classifications included the cingulate gyrus, hippocampal subfields and amygdalar nuclei. Correctly versus incorrectly classified participants did not differ across a range of tested psychometric variables.ConclusionsThese findings underscore the interconnection of brain structure and function in the pathophysiology of FND and demonstrate the feasibility of using structural MRI to classify the disorder. Out-of-sample replication and larger-scale classifier efforts incorporating psychiatric and neurological controls are needed.

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.

Background: In adults, epicardial adipose tissue (EAT) is associated with metabolic syndrome (MS) and coronary artery disease. EAT thickness is increased in obese youth, but total EAT volume and its correlation with cardiovascular risk factors have not been studied. Objectives: To determine EAT volume in adolescents and its association with obesity and cardiovascular risk factors. Methods: We performed a cross-sectional study including 48 pubertal adolescents (24 obese and 24 lean subjects, aged 13.6 ± 1.5 yr). EAT volume as well as visceral and subcutaneous abdominal adipose tissue volumes were obtained by magnetic resonance imaging. Anthropometrical parameters; blood pressure (BP); fasting serum triglycerides; total and low- and high-density lipoprotein (HDL-C) cholesterol; glucose; and insulin levels were measured. Results: Obese adolescents had higher EAT volume compared to lean controls (49.6 ± 18.0 vs. 17.6 ± 6.7 cm3, p < 0.0005). They also had significantly increased visceral abdominal fat volumes, systolic BP, serum triglycerides, and insulin levels, and decreased HDL-C concentration. EAT volume was significantly associated with anthropometrical indices and cardiovascular risk factors: waist circumference, systolic BP, triglycerides, HDL-C levels, and insulin resistance indices. Metabolic syndrome was present in 25% of obese adolescents. EAT volume was significantly higher in obese adolescents with MS compared to those without MS (63.5 ± 21.4 vs. 44.9 ± 14.6 cm3, p = 0.026). Conclusions: EAT volume, which is known to contribute to atherogenesis in adults, is increased in obese adolescents, and is associated with abdominal visceral fat, cardiovascular risk factors, and MS. Excessive EAT early in life may contribute to the development of premature cardiometabolic disease.

In glioma, microglia and infiltrating macrophages are exposed to factors that force them to produce cytokines and chemokines, which contribute to tumor growth and to maintaining a pro-tumorigenic, immunosuppressed microenvironment. We demonstrate that housing glioma-bearing mice in enriched environment (EE) reverts the immunosuppressive phenotype of infiltrating myeloid cells, by modulating inflammatory gene expression. Under these conditions, the branching and patrolling activity of myeloid cells is increased, and their phagocytic activity is promoted. Modulation of gene expression depends on interferon-(IFN)-γ produced by natural killer (NK) cells. This modulation disappears in mice depleted of NK cells or lacking IFN-γ, and was mimicked by exogenous interleukin-15 (IL-15). Further, we describe a key role for brain-derived neurotrophic factor (BDNF) that is produced in the brain of mice housed in EE, in mediating the expression of IL-15 in CD11b cells. These data define novel mechanisms linking environmental cues to the acquisition of a pro-inflammatory, anti-tumor microenvironment in mouse brain.

The obesity paradox refers to a category of subjects who may be less prone to develop co-morbidities, such as type 2 diabetes. Cardiorespiratory fitness (CRF) has been identified as one of the key factors. We aimed at exploring the difference in insulin metabolism between fit and unfit obese adolescents. We recruited 22 obese adolescents and assessed CRF during an incremental treadmill test. According to a cut-off at 80% of predicted maximal oxygen consumption (VO max), subjects were separated into low or normal CRF. Body composition was determined by densitometry. Serum levels of insulin were measured sequentially during an oral glucose tolerance test and insulin secretion responses were calculated. Compared to adolescents with normal CRF, the ones with low CRF had higher insulin resistance indices (p=0.023) and insulin secretion response (p=0.010), independently of the body mass index z-score. Interventions in obese adolescents should focus on the maintenance or improvement of CRF to at least 80% of predicted VO max. Indeed, this cut-off was significantly related to insulin secretion responses, independently of the adiposity level. A CRF above the proposed cut-off may prevent the development of insulin resistance.

BackgroundFacioscapulohumeral dystrophy (FSHD) is associated with partial chromatin relaxation of the DUX4 retrogene containing D4Z4 macrosatellite repeats on chromosome 4, and transcriptional de-repression of DUX4 in skeletal muscle. The common form of FSHD, FSHD1, is caused by a D4Z4 repeat array contraction. The less common form, FSHD2, is generally caused by heterozygous variants in SMCHD1.MethodsWe employed whole exome sequencing combined with Sanger sequencing to screen uncharacterised FSHD2 patients for extra-exonic SMCHD1 mutations. We also used CRISPR-Cas9 genome editing to repair a pathogenic intronic SMCHD1 variant from patient myoblasts.ResultsWe identified intronic SMCHD1 variants in two FSHD families. In the first family, an intronic variant resulted in partial intron retention and inclusion of the distal 14 nucleotides of intron 13 into the transcript. In the second family, a deep intronic variant in intron 34 resulted in exonisation of 53 nucleotides of intron 34. In both families, the aberrant transcripts are predicted to be non-functional. Deleting the pseudo-exon by CRISPR-Cas9 mediated genome editing in primary and immortalised myoblasts from the index case of the second family restored wild-type SMCHD1 expression to a level that resulted in efficient suppression of DUX4.ConclusionsThe estimated intronic mutation frequency of almost 2% in FSHD2, as exemplified by the two novel intronic SMCHD1 variants identified here, emphasises the importance of screening for intronic variants in SMCHD1. Furthermore, the efficient suppression of DUX4 after restoring SMCHD1 levels by genome editing of the mutant allele provides further guidance for therapeutic strategies.

In glioma, microglia and infiltrating macrophages are exposed to factors that force them to produce cytokines and chemokines, which contribute to tumor growth and to maintaining a pro-tumorigenic, immunosuppressed microenvironment. We demonstrate that housing glioma-bearing mice in enriched environment (EE) reverts the immunosuppressive phenotype of infiltrating myeloid cells, by modulating inflammatory gene expression. Under these conditions, the branching and patrolling activity of myeloid cells is increased, and their phagocytic activity is promoted. Modulation of gene expression depends on interferon-(IFN)-γ produced by natural killer (NK) cells. This modulation disappears in mice depleted of NK cells or lacking IFN-γ, and was mimicked by exogenous interleukin-15 (IL-15). Further, we describe a key role for brain-derived neurotrophic factor (BDNF) that is produced in the brain of mice housed in EE, in mediating the expression of IL-15 in CD11b+ cells. These data define novel mechanisms linking environmental cues to the acquisition of a pro-inflammatory, anti-tumor microenvironment in mouse brain.