Essential Tremor accentuates the pattern of tremor-band coherence between upper-limb muscles.

Although Essential Tremor is one of the most common movement disorders, current treatment options are relatively limited. Peripheral tremor suppression methods have shown potential, but we do not currently know which muscles are most responsible for patients' tremor, making it difficult to optimize suppression methods. The purpose of this study was to quantify the relationships between the tremorogenic activity in muscles throughout the upper limb. Muscle activity was recorded from the 15 major superficial upper-limb muscles in 24 subjects with Essential Tremor while they held various postures or made upper-limb movements. We calculated the coherence in the tremor band (4-12 Hz) between the activity of all muscle pairs and the time-varying phase difference between sufficiently coherent muscle pairs. Overall, the observed pattern somewhat mirrored functional relationships: agonistic muscle pairs were most coherent and in phase, whereas antagonist and unrelated muscle pairs exhibited less coherence and were either consistently in phase, consistently antiphase, consistently out of phase (unrelated pairs only), or else inconsistent. Patients exhibited significantly more coherence than control subjects (p<0.001) in the vast majority of muscle pairs (95 out of 105). Furthermore, differences between patients and controls were most pronounced among agonists; thus, the coherence pattern existing in control subjects was accentuated in patients with ET. We conclude that tremor-band activity is broadly distributed among the muscles of the upper limb, challenging efforts to determine which muscles are most responsible for a patient's tremor.

Effects of TPH2 gene variation and childhood trauma on the clinical and circuit-level phenotype of functional movement disorders.

BACKGROUND: Functional movement disorders (FMDs), part of the wide spectrum of functional neurological disorders (conversion disorders), are common and often associated with a poor prognosis. Nevertheless, little is known about their neurobiological underpinnings, particularly with regard to the contribution of genetic factors. Because FMD and stress-related disorders share a common core of biobehavioural manifestations, we investigated whether variants in stress-related genes also contributed, directly and interactively with childhood trauma, to the clinical and circuit-level phenotypes of FMD. METHODS: Sixty-nine patients with a 'clinically defined' diagnosis of FMD were genotyped for 18 single-nucleotide polymorphisms (SNPs) from 14 candidate genes. FMD clinical characteristics, psychiatric comorbidity and symptomatology, and childhood trauma exposure were assessed. Resting-state functional connectivity data were obtained in a subgroup of 38 patients with FMD and 38 age-matched and sex-matched healthy controls. Amygdala-frontal connectivity was analysed using a whole-brain seed-based approach. RESULTS: Among the SNPs analysed, a tryptophan hydroxylase 2 (TPH2) gene polymorphism-G703T-significantly predicted clinical and neurocircuitry manifestations of FMD. Relative to GG homozygotes, T carriers were characterised by earlier FMD age of onset and decreased connectivity between the right amygdala and the middle frontal gyrus. Furthermore, the TPH2 genotype showed a significant interaction with childhood trauma in predicting worse symptom severity. CONCLUSIONS: This is, to our knowledge, the first study showing that the TPH2 genotype may modulate FMD both directly and interactively with childhood trauma. Because both this polymorphism and early-life stress alter serotonin levels, our findings support a potential molecular mechanism modulating FMD phenotype.

Outcome measurement in functional neurological disorder: a systematic review and recommendations.

OBJECTIVES: We aimed to identify existing outcome measures for functional neurological disorder (FND), to inform the development of recommendations and to guide future research on FND outcomes. METHODS: A systematic review was conducted to identify existing FND-specific outcome measures and the most common measurement domains and measures in previous treatment studies. Searches of Embase, MEDLINE and PsycINFO were conducted between January 1965 and June 2019. The findings were discussed during two international meetings of the FND-Core Outcome Measures group. RESULTS: Five FND-specific measures were identified-three clinician-rated and two patient-rated-but their measurement properties have not been rigorously evaluated. No single measure was identified for use across the range of FND symptoms in adults. Across randomised controlled trials (k=40) and observational treatment studies (k=40), outcome measures most often assessed core FND symptom change. Other domains measured commonly were additional physical and psychological symptoms, life impact (ie, quality of life, disability and general functioning) and health economics/cost-utility (eg, healthcare resource use and quality-adjusted life years). CONCLUSIONS: There are few well-validated FND-specific outcome measures. Thus, at present, we recommend that existing outcome measures, known to be reliable, valid and responsive in FND or closely related populations, are used to capture key outcome domains. Increased consistency in outcome measurement will facilitate comparison of treatment effects across FND symptom types and treatment modalities. Future work needs to more rigorously validate outcome measures used in this population.

Insights into Chronic Functional Movement Disorders: The Value of Qualitative Psychiatric Interviews.

BACKGROUND: Patients with functional movement disorders (FMDs) are commonly seen by neurologists and psychosomatic medicine psychiatrists. Research literature provides scant information about the subjective experiences of individuals with this often chronic problem. OBJECTIVE: To enhance our understanding of psychologic aspects of FMDs by conducting qualitative interviews of research subjects. METHODS: In total, 36 patients with FMDs were recruited from the Human Motor Control clinic at the National Institutes of Health. Each subject participated in a qualitative psychiatric interview and a structured diagnostic psychiatric interview. RESULTS: Of our 36 subjects, 28 had current or lifetime psychiatric disorders in addition to conversion disorder and 22 had current disorders. Qualitative interviews provided rich information on patients' understanding of their illnesses and impaired cognitive processing of emotions. CONCLUSION: Our study supports the addition of open-ended qualitative interviews to delineate emotional dynamics and conceptual frameworks among such patients. Exploratory interviews generate enhanced understanding of such complex patients, above and beyond that gained by assessing DSM diagnostic comorbidities.

Related F-box proteins control cell death in Caenorhabditis elegans and human lymphoma.

Cell death is a common metazoan cell fate, and its inactivation is central to human malignancy. In Caenorhabditis elegans, apoptotic cell death occurs via the activation of the caspase CED-3 following binding of the EGL-1/BH3-only protein to the antiapoptotic CED-9/BCL2 protein. Here we report a major alternative mechanism for caspase activation in vivo involving the F-box protein DRE-1. DRE-1 functions in parallel to EGL-1, requires CED-9 for activity, and binds to CED-9, suggesting that DRE-1 promotes apoptosis by inactivating CED-9. FBXO10, a human protein related to DRE-1, binds BCL2 and promotes its degradation, thereby initiating cell death. Moreover, some human diffuse large B-cell lymphomas have inactivating mutations in FBXO10 or express FBXO10 at low levels. Our results suggest that DRE-1/FBXO10 is a conserved regulator of apoptosis.

Tic Disorders, Anti-Tic Medications, and Risk of Atopy.

Objective: To clarify patterns of comorbid atopic disorders in children with tic disorders compared to controls, and to evaluate whether medications commonly used for treatment of tics and attention deficit hyperactivity disorder (ADHD) are associated with differing risks of atopy. Background: Inflammatory mechanisms are increasingly recognized as playing a role in a range of neuropsychiatric disorders. The association between tic disorders, ADHD, obsessive-compulsive disorder (OCD) and atopic disorders is uncertain. Methods: We performed a retrospective cohort study using the global electronic health records database TriNetX. Using odds ratios, we compared the risk of atopy in children with tic disorder (n = 4508), ADHD (n = 83,569), and/or OCD (n = 1555) to controls (n = 758 290). To analyze the risk of developing atopy with use of different medications commonly prescribed to treat tics and ADHD, we performed a separate analysis including children with tic disorder, ADHD, and/or OCD who had initiated treatment with one of these medications. Binary logistic regression controlling for age and sex was used to calculate odds ratios. Results: Children with tic disorder, ADHD, or OCD were more likely than controls to have comorbid atopy. Children who had taken clonidine, guanfacine, methylphenidate, or dexmethylphenidate were more likely to develop an atopic disorder than controls. Conclusions: Our study suggests a link between atopic disorders and tic disorders, ADHD, and OCD. Although the underlying mechanism for this association remains unclear, medication use may play a role.

Distribution of tremorogenic activity among the major superficial muscles of the upper limb in persons with Essential tremor.

OBJECTIVE: Peripheral tremor suppression has the potential to reduce tremor, but we do not currently know where best to intervene. The purpose of this study was to characterize the distribution of tremorogenic activity among upper-limb muscles. METHODS: Surface electromyography was recorded from the 15 major superficial muscles of the upper limb while 25 patients with Essential Tremor performed postural and kinetic tasks. We defined tremorogenic activity as power in the tremor band (4-8 Hz) and determined the distribution of this power among muscles. RESULTS: The distribution varied considerably between patients (mean r = 0.58), but on average, the greatest power was found in the anterior deltoid and extensor carpi ulnaris muscles. Other muscles with high power included the extensor carpi radialis, pectoralis major, lateral deltoid, and brachialis muscles. This distribution was similar (mean r ≥ 0.88) for postural and kinetic tremor, various limb configurations, repetitions, and patient characteristics (sex, tremor severity, age of onset, and duration). CONCLUSIONS: We identified a rough pattern in which muscles opposing gravity appeared to have the highest tremor-band power; we hypothesize that the distribution of tremorogenic muscle activity depends in part on the distribution of voluntary activity required by the task. SIGNIFICANCE: Understanding which muscles exhibit the most tremorogenic activity is one of the steps in the pursuit of optimizing peripheral tremor suppression.

Gender disparity and abuse in functional movement disorders: a multi-center case-control study.

BACKGROUND: To determine gender differences in rates of sexual and physical abuse in functional movement disorders compared to controls and evaluate if the gender disparity of functional movement disorders is associated with abuse history. METHODS: We performed a retrospective case-control study of self-reported trauma data from 696 patients (512 women) with functional movement disorders from six clinical sites compared to 141 controls (98 women) and population data. Chi-square was used to assess gender and disorder associations; logistic regression was used to model additive effects of abuse and calculate the attributable fraction of abuse to disorder prevalence. RESULTS: Higher rates of sexual abuse were reported by women (35.3%) and men (11.5%) with functional movement disorders compared to controls (10.6% of women; 5.6% of men). History of sexual abuse increased the likelihood of functional movement disorders among women by an odds ratio of 4.57 (95% confidence interval 2.31-9.07; p < 0.0001) and physical abuse by an odds ratio of 2.80 (95% confidence interval 1.53-5.12; p = 0.0007). Population attributable fraction of childhood sexual abuse to functional movement disorders in women was 0.12 (0.05-0.19). No statistically significant associations were found in men, but our cohort of men was underpowered despite including multiple sites. CONCLUSIONS: Our study suggests that violence against women may account for some of the gender disparity in rates of functional movement disorders. Most people with functional movement disorders do not report a history of abuse, so it remains just one among many relevant risk factors to consider.

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

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.

Distribution of tremor among the major degrees of freedom of the upper limb in subjects with Essential Tremor.

OBJECTIVE: Although Essential Tremor is one of the most common movement disorders, we do not currently know which muscles are most responsible for tremor. Determining this requires multiple steps, one of which is characterizing the distribution of tremor among the degrees of freedom (DOF) of the upper limb. METHODS: Upper-limb motion was recorded while 22 subjects with ET performed postural and kinetic tasks involving a variety of limb configurations. We calculated the mean distribution of tremor among the seven DOF from the shoulder to the wrist, as well as the effect of limb configuration, repetition, and subject characteristics (sex, tremor onset, duration, and severity) on the distribution. RESULTS: On average, kinetic tremor was greatest in forearm pronation-supination and wrist flexion-extension, intermediate in shoulder internal-external rotation and wrist radial-ulnar deviation and then shoulder flexion-extension and elbow flexion-extension, and least in shoulder abduction-adduction. The average distribution of postural tremor was similar except for forearm pronation-supination, which played a smaller role than in kinetic tremor. Limb configuration and subject characteristics did significantly affect tremor, but practically only in forearm pronation-supination and wrist flexion-extension. There were no significant differences between repetitions, indicating that the distribution was consistent over the duration of the experiment. CONCLUSIONS: This paper presents a thorough characterization of tremor distribution from the shoulder to the wrist. SIGNIFICANCE: Understanding which DOF exhibit the most tremor may lead to more targeted peripheral tremor suppression.

Pseudobulbar Affect in Parkinsonian Disorders: A Review.

Pseudobulbar affect (PBA) is a neurological symptom of inappropriate and uncontrollable laughter or crying that occurs secondary to a variety of neurological conditions, including parkinsonian disorders. PBA is a socially and emotionally debilitating symptom that has been estimated to affect 3.6% to 42.5% of the population with Parkinson's disease. While indexing measures and treatment options for PBA have been extensively studied in neurological conditions such as amyotrophic lateral sclerosis and multiple sclerosis, there has been considerably less attention given in the literature to PBA in parkinsonian disorders. The purpose of this review is to discuss the pathophysiology of PBA, its prevalence and impact on quality of life in parkinsonian disorders, and the treatment options currently available. Areas requiring further study, including the development of standardized, cross-culturally validated methods of symptom assessment, and evidence-based studies exploring the efficacy of current treatment options in parkinsonian disorders, are also highlighted.

Functional Speech and Voice Disorders: Case Series and Literature Review.

BACKGROUND: Functional disorders of speech and voice, subtypes of functional movement disorders, represent abnormalities in speech and voice that are thought to have an underlying psychological cause. These disorders exhibit several positive and negative features that distinguish them from organic disorders. METHODS AND RESULTS: We describe the clinical manifestations of functional disorders of speech and voice, and illustrate these features using six clinical cases. CONCLUSIONS: Functional disorders of speech and voice may manifest in a variety of ways, including dysphonia, stuttering, or prosodic abnormalities. Given that these disorders have been understudied and may resemble organic disorders, diagnosis may be challenging. Appropriate treatment may be quite effective, highlighting the importance of prompt and accurate diagnosis.

Gray matter differences in patients with functional movement disorders.

OBJECTIVE: To explore alterations in gray matter volume in patients with functional movement disorders. METHODS: We obtained T1-weighted MRI on 48 patients with clinically definite functional movement disorders, a subset of functional neurologic symptom disorder characterized by abnormal involuntary movements, and on 55 age- and sex-matched healthy controls. We compared between-group differences in gray matter volume using voxel-based morphometry across the whole brain. All participants in addition underwent a thorough neuropsychological battery, including the Hamilton Anxiety and Depression Scales and the Childhood Trauma Questionnaire. To determine whether confounding factors such as comorbid depression, anxiety, or childhood trauma exposure contributed to the observed structural changes, nonparametric correlation analysis was performed. RESULTS: Patients with functional movement disorders exhibited increased volume of the left amygdala, left striatum, left cerebellum, left fusiform gyrus, and bilateral thalamus, and decreased volume of the left sensorimotor cortex (whole-brain corrected p ≤ 0.05). Volumetric differences did not correlate with measures of disease duration or patient-rated disease severity. CONCLUSION: This study demonstrates that patients with functional movement disorders exhibit structural gray matter abnormalities in critical components of the limbic and sensorimotor circuitry. These abnormalities may represent a premorbid trait rendering patients more susceptible to disease, the disease itself, or a compensatory response to disease.

Impaired self-agency in functional movement disorders: A resting-state fMRI study.

OBJECTIVE: To investigate the neural mechanisms underlying impaired self-agency in patients with functional movement disorders using resting-state functional MRI (fMRI). METHODS: We obtained resting-state fMRI on 35 patients with clinically definite functional movement disorders and 35 age- and sex-matched healthy controls. Between-group differences in functional connectivity from the right temporo-parietal junction (TPJ), a region previously demonstrated to play a critical role in self-agency by comparing internal predictions of movement with actual external events, were assessed using t tests. All participants were screened for psychiatric diagnoses using a structured clinical interview and completed the Beck Depression Inventory and Childhood Trauma Questionnaire. RESULTS: Compared to the healthy controls, patients with functional movement disorders showed decreased functional connectivity between the right TPJ and the right sensorimotor cortex, cerebellar vermis, bilateral supplementary motor area, and right insula. These findings were independent of depression, anxiety, and childhood trauma scores included in our assessment as covariates. CONCLUSIONS: The decreased functional connectivity between the right TPJ and bilateral sensorimotor regions observed in patients with functional movement disorders supports a model whereby impaired motor feed-forward together with altered sensory feedback from sensorimotor regions and areas of sensorimotor integration to the right TPJ contributes to patients' impaired sense of self-agency.

Impaired resting vagal tone in patients with functional movement disorders.

INTRODUCTION: The autonomic nervous system plays an integral role in the maintenance of homeostasis during times of stress. The functioning of the autonomic nervous system in patients with functional movement disorders (FMD) is of particular interest given the hypothesis that converted psychological stress plays a critical role in FMD disease pathogenesis. We sought to investigate autonomic nervous system activity in FMD patients by examining heart rate variability (HRV), a quantitative marker of autonomic function. METHODS: 35 clinically definite FMD patients and 38 age- and sex-matched healthy controls were hospitalized overnight for continuous electrocardiogram recording. Standard time and frequency domain measures of HRV were calculated in the awake and asleep stages. All participants underwent a thorough neuropsychological battery, including the Hamilton Anxiety and Depression scales and the Beck Depression Inventory. RESULTS: Compared to controls, patients with FMD exhibited decreased root mean square of successive differences between adjacent NN intervals (RMSSD) (p = 0.02), a marker of parasympathetic activity, as well as increased mean heart rate (p = 0.03). These measures did not correlate with the depression and anxiety scores included in our assessment as potential covariates. CONCLUSION: In this exploratory study, patients with FMD showed evidence of impaired resting state vagal tone, as demonstrated by reduced RMSSD. This decreased vagal tone may reflect increased stress vulnerability in patients with FMD.

The "Whack-a-Mole" Sign in Functional Movement Disorders.

Making the diagnosis of functional movement disorders can be challenging. Identifying positive physical signs and diagnostic maneuvers is critical to this process. Distractibility, entrainability, and variability are examples of classic physical findings in these patients. In this case series, we identify and characterize another phenomenon observed in some of these patients. In this phenomenon, movement suppression of one body part is followed by immediate reemergence of movement in another. We propose that this phenomenon be referred to as the "whack-a-mole" sign. This name is derived from the arcade game whack-a-mole, in which a mole, when hit into its original hole, re-emerges elsewhere. We present a case series of 4 patients with functional movement disorders who exhibit this sign.

A biological measure of stress levels in patients with functional movement disorders.

INTRODUCTION: While the presence of co-existing psychological stressors has historically been used as a supportive factor in the diagnosis of functional neurological disorders, many patients with functional neurological disorders deny the presence of these stressors. The stress response circuitry in these patients remains largely unexplored. METHODS: We performed an observational study examining biological stress levels in patients with functional movement disorders as compared with matched healthy controls. Specifically, we compared levels of circulating cortisol, the end-product of the hypothalamic-pituitary-adrenal axis. Salivary cortisol samples were collected from patients with "clinically definite" functional movement disorders (n = 33) and their age- and sex-matched controls (n = 33). Collections were performed at five standardized time points, reflecting participants' diurnal cortisol cycles. To rule out confounders, participants also underwent extensive psychological assessment including Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Hamilton Anxiety Rating Scale, and Hamilton Rating Scale for Depression. RESULTS: Patients with functional movement disorders did not differ from matched controls with respect to levels of circulating cortisol. CONCLUSION: We demonstrate that current stress levels are not altered in patients with functional movement disorders. Our results warrant careful review of current management of patients with functional neurological symptoms, and suggest that the insistence on heightened stress levels in these patients is unjustified.

Enhanced derivation of mouse ESC-derived cortical interneurons by expression of Nkx2.1.

Forebrain GABAergic interneurons are divided into subgroups based on their neurochemical markers, connectivity and physiological properties. Abnormal interneuron function is implicated in the pathobiology of neurological disorders such as schizophrenia, autism, and epilepsy. Studies on interneuron development and their role in disease would benefit from an efficient mechanism for the production and selection of specific interneuron subgroups. In this study, we engineered a mouse embryonic stem cell (mESC) line for doxycycline-inducible expression of Nkx2.1, a required transcription factor for cortical interneurons derived from the medial ganglionic eminence (MGE). This mESC line was modified to express GFP in Lhx6(+) cells, a marker of newly postmitotic and mature MGE-derived cortical interneurons. The addition of doxycycline to differentiating ESCs efficiently induced Nkx2.1 protein and increased the production of GFP(+) cells. Transplantation of GFP(+) putative interneuron precursors resulted in migratory, morphological, and neurochemical features consistent with cortical interneuron fates. To test the hypothesis that Sonic hedgehog (Shh) primarily influences cortical interneuron fate determination through the induction of Nkx2.1, ESCs were grown with doxycycline and the Shh antagonist cyclopamine. We found induced Nkx2.1 renders Shh signaling dispensable for the generation of MGE-derived interneurons. These results demonstrate that inducible expression of fate determining genes in embryonic stem cells can be used to study fate determination of the developing forebrain.