Mitigating Initial Orthostatic Hypotension: Mechanistic Roles of Muscle Contraction Versus Sympathetic Activation

Background: Initial orthostatic hypotension (IOH) is defined by a large drop in blood pressure (BP) within 15 s of standing. IOH often presents during an active stand, but not with a passive tilt, suggesting that a muscle activation reflex involving lower body muscles plays an important role. To our knowledge, there is no literature exploring how sympathetic activation affects IOH. We hypothesized involuntary muscle contractions before standing would significantly reduce the drop in BP seen in IOH while increasing sympathetic activity would not. Methods: Study participants performed 4 sit-to-stand maneuvers including a mental stress test (serial 7 mental arithmetic stress test), cold pressor test, electrical stimulation, and no intervention. Continuous heart rate and beat-to-beat BP were measured. Cardiac output and systemic vascular resistance were estimated from these waveforms. Data are presented as mean±SD. Results: A total of 23 female IOH participants (31±8 years) completed the study. The drops in systolic BP following the serial 7 mental arithmetic stress test (−26±12 mm Hg; P =0.004), cold pressor test (−20±15 mm Hg; P <0.001), and electrical stimulation (−28±12 mm Hg; P =0.01) were significantly reduced compared with no intervention (−34±11 mm Hg). The drops in systemic vascular resistance following the serial 7 mental arithmetic stress test (−391±206 dyne×s/cm 5 ; P =0.006) and cold pressor test (−386±179 dyne×s/cm 5 ; P =0.011) were significantly reduced compared with no intervention (−488±173 dyne×s/cm 5 ). Cardiac output was significantly increased upon standing (7±2 L/min) compared with during the sit (6±1 L/min; P <0.001) for electrical stimulation. Conclusion: Sympathetic activation mitigates the BP response in IOH, while involuntary muscle contraction mitigates the BP response and reduces symptoms. Active muscle contractions may induce both of these mechanisms of action in their pretreatment of IOH. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03970551.

Pharmacological treatment for Tourette syndrome in children and adults: What is the quality of the evidence? A systematic review

Background: Tourette syndrome (TS) is a neurodevelopmental disorder characterised by involuntary muscle movements manifesting as motor and vocal tics. In the majority, tics are manageable without medication. Where tics cause discomfort or impair function, behavioural or pharmaceutical treatments may be considered. Aims: To provide a meticulous examination of the quality of evidence for the current pharmacological treatments for TS. Methods: PubMed and Google Scholar were searched to identify randomised, placebo-controlled trials (RCTs) of aripiprazole, risperidone, clonidine, guanfacine, haloperidol, pimozide, tiapride and sulpiride for the treatment of tics in children and adults with TS. Quality of reporting and risk of bias were assessed against the CONSORT checklist and Cochrane risk of bias criteria, respectively. Results: Seventeen RCTs were identified. Response rates reached 88.6% for aripiprazole, 68.9% for clonidine, 62.5% for risperidone and 19% for guanfacine. Statistically significant improvements were reported for all medications compared to placebo in at least one study and for at least one measure of tic severity. Most studies predated the CONSORT and Cochrane criteria and did not score highly when assessed on these measures. Conclusions: There are relatively few placebo-controlled trials of commonly prescribed medications. Studies are often of poor quality and short duration. There is evidence for the efficacy of each medication, but no drug is clearly superior. Clonidine and guanfacine are better tolerated than antipsychotics, but less effective. There is too little evidence to determine whether adults respond differently from children.

The patient-reported experience of living with Wilson disease

Aim: This research was conducted to collect patient-reported data on the experience of living with Wilson disease and to broaden the existing knowledge of a rare neurometabolic disease with varied clinical manifestations. Materials & methods: Adult patients with Wilson disease or caregivers were recruited through a Wilson disease association or advocacy group, and asked to complete an online survey that assessed various aspects of living with Wilson disease. Survey data were analyzed descriptively. Results: 21 adults with Wilson disease completed the survey. Respondents reported experiencing signs, symptoms and diagnoses related to movement (e.g., involuntary muscle contractions [n = 9, 42.9%]), cognition (e.g., anxiety [n = 15, 71.4%]) and liver problems. Respondents most frequently reported medication regimen and financial burden as the most bothersome impacts of Wilson disease. Conclusion: The data expand the existing knowledge of this rare neurometabolic disease with heterogeneous clinical manifestations.

Monitoring Involuntary Muscle Activity in Acute Patients with Upper Motor Neuron Lesion by Wearable Sensors: A Feasibility Study

Sustained involuntary muscle activity (IMA) is a highly disabling and not completely understood phenomenon that occurs after a central nervous system lesion. We tested the feasibility of in-field IMA measuring at an acute rehabilitation ward. We used wearable probes for single differential surface EMG (sEMG), inclusive of a 3D accelerometer, onboard memory and remote control. We collected 429 h of data from the biceps brachii of 10 patients with arm plegia. Data quality was first verified in the time and frequency domains. Next, IMA was automatically identified based on the steady presence of motor unit action potential (MUAP) trains at rest. Feasibility was excellent in terms of prep time and burden to the clinical staff. A total of 350.5 h of data (81.7%) were reliable. IMA was found in 85.9 h (25%). This was often present in the form of exceedingly long-lasting trains of one or a few MUAPs, with differences among patients and variability, both within and between days in terms of IMA duration, root mean square (RMS) and peak-to-peak amplitude. Our results proved the feasibility of using wearable probes for single differential sEMG to identify and quantify IMA in plegic muscles of bedridden acute neurological patients. Our results also suggest the need for long-lasting acquisitions to properly characterize IMA. The possibility of easily assessing IMA in acute inpatients can have a huge impact on the management of their postures, physiotherapy and treatments.

Differential expression of striatal proteins in a mouse model of DOPA-responsive dystonia reveals shared mechanisms among dystonic disorders

Dystonia is characterized by involuntary muscle contractions that cause debilitating twisting movements and postures. Although basal ganglia dysfunction is implicated in many forms of dystonia, the underlying mechanisms are unclear. Therefore, to reveal abnormal striatal cellular processes and pathways implicated in dystonia, we used an unbiased proteomic approach in a knockin mouse model of DOPA-responsive dystonia, a model in which the striatum is known to play a central role in the expression of dystonia. Fifty-seven of the 1805 proteins identified were differentially regulated in DOPA-responsive dystonia mice compared to control mice. Most differentially regulated proteins were associated with gene ontology terms that implicated either mitochondrial or synaptic dysfunction whereby proteins associated with mitochondrial function were generally over-represented whereas proteins associated with synaptic function were largely under-represented. Remarkably, nearly 20% of the differentially regulated proteins identified in our screen are associated with pathogenic variants that cause inherited dystonic disorders in humans suggesting shared mechanisms across many different forms of dystonia.

Acupuncture treatment for spasticity after brain injury

Spasticity after brain injury is a neurological sequela caused by damage to upper motor neurons. The primary symptoms are involuntary muscle activity, decreased muscle strength, and joint contracture. Acupuncture as a therapeutic method to regulate central nervous system function has been studied widely in recent years. Many clinical experiments have proved that acupuncture has positive effects on spasticity after brain injury. In this review, we discuss recent research of acupuncture treatment and the need for large randomized controlled trials.

Modeling the Effect of Excitation on Depth of Anesthesia Monitoring in γ-Aminobutyric Acid Type A Receptor Agonist ABP-700

Background γ-Aminobutyric acid type A (GABAA) receptor agonists are known to cause involuntary muscle movements. The mechanism of these movements is not known, and its relationship to depth of anesthesia monitoring is unclear. We have explored the effect of involuntary muscle movement on the pharmacokinetic-pharmacodynamic model for the GABAA receptor agonist ABP-700 and its effects on the Bispectral Index (BIS) as well as the Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) scores. Methods Observations from 350 individuals (220 men, 130 women) were analyzed, comprising 6,312 ABP-700 concentrations, 5,658 ABP-700 metabolite (CPM-acid) concentrations, 25,745 filtered BIS values, and 6,249 MOAA/S scores, and a recirculatory model developed. Various subject covariates and pretreatment with an opioid or a benzodiazepine were explored as covariates. Relationships between BIS and MOAA/S models and involuntary muscle movements were examined. Results The final model shows that the pharmacokinetics of ABP-700 are characterized by small compartmental volumes and rapid clearance. The BIS model incorporates an effect-site for BIS suppression and a secondary excitatory/disinhibitory effect-site associated with a risk of involuntary muscle movements. The secondary effect-site has a threshold that decreases with age. The MOAA/S model did not show excitatory effects. Conclusions The GABAA receptor agonist ABP-700 shows the expected suppressive effects for BIS and MOAA/S, but also disinhibitory effects for BIS associated with involuntary muscle movements and reduced by pretreatment. Our model provides information about involuntary muscle movements that may be useful to improve depth of anesthesia monitoring for GABAA receptor agonists. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Advances in the pathophysiology of adult-onset focal dystonias: recent neurophysiological and neuroimaging evidence

Focal dystonia is a movement disorder characterized by involuntary muscle contractions that determine abnormal postures. The traditional hypothesis that the pathophysiology of focal dystonia entails a single structural dysfunction (i.e. basal ganglia) has recently come under scrutiny. The proposed network disorder model implies that focal dystonias arise from aberrant communication between various brain areas. Based on findings from animal studies, the role of the cerebellum has attracted increased interest in the last few years. Moreover, it has been increasingly reported that focal dystonias also include nonmotor disturbances, including sensory processing abnormalities, which have begun to attract attention. Current evidence from neurophysiological and neuroimaging investigations suggests that cerebellar involvement in the network and mechanisms underlying sensory abnormalities may have a role in determining the clinical heterogeneity of focal dystonias.