Disentangling Bradykinesia and Rigidity in Parkinson's Disease: Evidence from Short- and Long-Term Subthalamic Nucleus Deep Brain Stimulation.

OBJECTIVE: Bradykinesia and rigidity are considered closely related motor signs in Parkinson disease (PD), but recent neurophysiological findings suggest distinct pathophysiological mechanisms. This study aims to examine and compare longitudinal changes in bradykinesia and rigidity in PD patients treated with bilateral subthalamic nucleus deep brain stimulation (STN-DBS). METHODS: In this retrospective cohort study, the clinical progression of appendicular and axial bradykinesia and rigidity was assessed up to 15 years after STN-DBS in the best treatment conditions (ON medication and ON stimulation). The severity of bradykinesia and rigidity was examined using ad hoc composite scores from specific subitems of the Unified Parkinson's Disease Rating Scale motor part (UPDRS-III). Short- and long-term predictors of bradykinesia and rigidity were analyzed through linear regression analysis, considering various preoperative demographic and clinical data, including disease duration and severity, phenotype, motor and cognitive scores (eg, frontal score), and medication. RESULTS: A total of 301 patients were examined before and 1 year after surgery. Among them, 101 and 56 individuals were also evaluated at 10-year and 15-year follow-ups, respectively. Bradykinesia significantly worsened after surgery, especially in appendicular segments (p < 0.001). Conversely, rigidity showed sustained benefit, with unchanged clinical scores compared to preoperative assessment (p > 0.05). Preoperative motor disability (eg, composite scores from the UPDRS-III) predicted short- and long-term outcomes for both bradykinesia and rigidity (p < 0.01). Executive dysfunction was specifically linked to bradykinesia but not to rigidity (p < 0.05). INTERPRETATION: Bradykinesia and rigidity show long-term divergent progression in PD following STN-DBS and are associated with independent clinical factors, supporting the hypothesis of partially distinct pathophysiology. ANN NEUROL 2024;96:234-246.

Rigidity in Parkinson's disease: evidence from biomechanical and neurophysiological measures.

Although rigidity is a cardinal motor sign in patients with Parkinson's disease (PD), the instrumental measurement of this clinical phenomenon is largely lacking, and its pathophysiological underpinning remains still unclear. Further advances in the field would require innovative methodological approaches able to measure parkinsonian rigidity objectively, discriminate the different biomechanical sources of muscle tone (neural or visco-elastic components), and finally clarify the contribution to 'objective rigidity' exerted by neurophysiological responses, which have previously been associated with this clinical sign (i.e. the long-latency stretch-induced reflex). Twenty patients with PD (67.3 ± 6.9 years) and 25 age- and sex-matched controls (66.9 ± 7.4 years) were recruited. Rigidity was measured clinically and through a robotic device. Participants underwent robot-assisted wrist extensions at seven different angular velocities randomly applied, when ON therapy. For each value of angular velocity, several biomechanical (i.e. elastic, viscous and neural components) and neurophysiological measures (i.e. short and long-latency reflex and shortening reaction) were synchronously assessed and correlated with the clinical score of rigidity (i.e. Unified Parkinson's Disease Rating Scale-part III, subitems for the upper limb). The biomechanical investigation allowed us to measure 'objective rigidity' in PD and estimate the neuronal source of this phenomenon. In patients, 'objective rigidity' progressively increased along with the rise of angular velocities during robot-assisted wrist extensions. The neurophysiological examination disclosed increased long-latency reflexes, but not short-latency reflexes nor shortening reaction, in PD compared with control subjects. Long-latency reflexes progressively increased according to angular velocities only in patients with PD. Lastly, specific biomechanical and neurophysiological abnormalities correlated with the clinical score of rigidity. 'Objective rigidity' in PD correlates with velocity-dependent abnormal neuronal activity. The observations overall (i.e. the velocity-dependent feature of biomechanical and neurophysiological measures of objective rigidity) would point to a putative subcortical network responsible for 'objective rigidity' in PD, which requires further investigation.

Progressive encephalomyelitis with rigidity and myoclonus: a pediatric case report and literature review.

BACKGROUND: Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a rare and life-threatening autoimmune disease of the central nervous system. So far, only ten cases of PERM have been reported in children worldwide, including the one in this study. CASE PRESENTATION: We report a case of an 11-year-old boy with PERM with an initial presentation of abdominal pain, skin itching, dysuria, urinary retention, truncal and limb rigidity, spasms of the trunk and limbs during sleep, deep and peripheral sensory disturbances, and dysphagia. A tissue-based assay using peripheral blood was positive, demonstrated by fluorescent staining of mouse cerebellar sections. He showed gradual and persistent clinical improvement after immunotherapy with intravenous immunoglobulin, steroids, plasmapheresis and rituximab. CONCLUSIONS: We summarized the diagnosis and treatment of a patient with PERM and performed a literature review of pediatric PERM to raise awareness among pediatric neurologists. A better comprehension of this disease is required to improve its early diagnosis, treatment, and prognosis.

Spinal cord stimulation for the symptomatic treatment of rigidity and painful spasm in a case of stiff person syndrome.

BACKGROUND: Stiff person syndrome (SPS) is a rare neuroimmunological disorder characterized by rigidity and painful spasm primarily affecting the truncal and paraspinal musculature due to autoimmune-mediated neuronal hyperexcitability. Spinal cord stimulation (SCS) is an approved therapy for managing painful neuropathic conditions, including diabetic peripheral neuropathy and refractory angina pectoris. We describe the novel use of SCS for the treatment of spasm and rigidity in a 49-year-old man with seropositive stiff person syndrome (SPS). The patient was treated with intravenous immunoglobulin (IVIG) and oral medications over a 13-month period with minimal improvement, prompting consideration of SCS. To our knowledge, this is the first report of the successful use of SCS in SPS with the demonstration of multifaceted clinical improvement. METHODS: Following a successful temporary SCS trial, permanent implantation was performed. Spasm/stiffness (Distribution of Stiffness Index; Heightened Sensitivity Scale; Penn Spasm Frequency Scale, PSFS), disability (Oswestry Disability Index, ODI; Pain Disability Index, PDI), depression (Patient Health Questionnaire-9, PHQ-9), sleep (Pittsburgh Sleep Quality Index, PSQI), fatigue (Fatigue Severity Scale, FSS), pain (Numerical Pain Rating Scale, NPRS), quality of life (EuroQoL 5 Dimension 5 Level, EQ-5D-5L), and medication usage were assessed at baseline, 6-month, and 10-month postimplantation. RESULTS: ODI, PHQ-9, FSS, NPRS, PSQI, and EQ-5D-5L scores showed a notable change from baseline and surpassed the defined minimal clinically important difference (MCID) at 6-month and 10-month follow-up. Oral medication dosages were reduced. CONCLUSIONS: The novel use of SCS therapy in seropositive SPS resulted in functional improvement and attenuation of symptoms. We present possible mechanisms by which SCS may produce clinical response in patients with SPS and aim to demonstrate proof-of-concept for a future comprehensive pilot study evaluating SCS-mediated response in SPS.

Clinical, genetic, and functional characterization of the glycine receptor ß-subunit A455P variant in a family affected by hyperekplexia syndrome.

Hyperekplexia is a rare neurological disorder characterized by exaggerated startle responses affecting newborns with the hallmark characteristics of hypertonia, apnea, and noise or touch-induced nonepileptic seizures. The genetic causes of the disease can vary, and several associated genes and mutations have been reported to affect glycine receptors (GlyRs); however, the mechanistic links between GlyRs and hyperekplexia are not yet understood. Here, we describe a patient with hyperekplexia from a consanguineous family. Extensive genetic screening using exome sequencing coupled with autozygome analysis and iterative filtering supplemented by in silico prediction identified that the patient carries the homozygous missense mutation A455P in GLRB, which encodes the GlyR ß-subunit. To unravel the physiological and molecular effects of A455P on GlyRs, we used electrophysiology in a heterologous system as well as immunocytochemistry, confocal microscopy, and cellular biochemistry. We found a reduction in glycine-evoked currents in N2A cells expressing the mutation compared to WT cells. Western blot analysis also revealed a reduced amount of GlyR ß protein both in cell lysates and isolated membrane fractions. In line with the above observations, coimmunoprecipitation assays suggested that the GlyR α1-subunit retained coassembly with ßA455P to form membrane-bound heteromeric receptors. Finally, structural modeling showed that the A455P mutation affected the interaction between the GlyR ß-subunit transmembrane domain 4 and the other helices of the subunit. Taken together, our study identifies and validates a novel loss-of-function mutation in GlyRs whose pathogenicity is likely to cause hyperekplexia in the affected individual.

High risk and low prevalence diseases: Adult bacterial meningitis.

INTRODUCTION: Acute bacterial meningitis in adults is a rare but serious condition that carries a high rate of morbidity. OBJECTIVE: This review highlights pearls and pitfalls of acute bacterial meningitis in adults, including presentation, diagnosis, and management in the emergency department (ED) based on current evidence. DISCUSSION: Meningitis encompasses a broad spectrum of disease involving inflammation of the meninges and subarachnoid space. It classically presents with fever, nuchal rigidity, and altered mental status, but this triad is not present in all cases. Up to 95% of patients will have at least two of the following four cardinal symptoms: fever, nuchal rigidity, altered mental status, and headache. The most common bacterial etiologies are S. pneumoniae and N. meningitidis. Cerebrospinal fluid testing obtained by lumbar puncture remains the gold standard in diagnosis. Head computed tomography prior to lumbar puncture may not be necessary in most patients. Empiric treatment consists of vancomycin, ceftriaxone, and dexamethasone. Elevated intracranial pressure should be managed using established neurocritical care strategies. CONCLUSION: A better understanding of the pearls and pitfalls of acute bacterial meningitis can assist emergency clinicians in pursuing its timely diagnosis and management.

An Unusual Cause of Fever, Neck Pain, and Neck Stiffness: Acute Calcific Tendinitis of the Longus Colli Muscle.

BACKGROUND: Acute calcific tendinitis (ACT) of the longus colli muscle (LCM) is an inflammatory response due to deposition of calcium hydroxyapatite crystals. It is typically correlated with whiplash and overuse injuries. A common presentation of this inflammatory response is acute but progressive neck pain. It is a rare but important cause of neck pain that should be considered on a differential diagnosis when distinguishing between life-threatening conditions and non-life-threatening causes of neck pain. CASE REPORT: A 51-year-old woman presented to the emergency department (ED) reporting a mild sore throat that progressed to acute neck pain and stiffness. She also reported fatigue, fever, myalgias, and nausea. In the ED, the patient was tachycardic, hypertensive, and mildly febrile with normal oxygen saturation. Examination revealed meningismus and was negative for lymphadenopathy, oropharyngeal findings, and neurologic deficits. Laboratory studies were significant for leukocytosis. Computed tomography (CT) neck was obtained and was notable for calcification of the superior left longus colli muscle with prevertebral and retropharyngeal space edema along the muscle body. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: ACT of the LCM is a benign, self-limited condition that can present with features overlapping emergent causes of acute neck pain. Correct diagnosis relies on characteristic radiographic findings on CT. Fortunately, patients may be discharged home with a short course of anti-inflammatories and corticosteroids with near-complete resolution of symptoms. Emergency physicians, therefore, can rule out life-threatening causes of neck pain, while also making a definitive diagnosis and initiating effective management for this pathology.

Inspiratory laryngeal stridor as the main feature of progressive encephalomyelitis with rigidity and myoclonus: a case report and literature review.

BACKGROUND: Progressive encephalomyelitis with rigidity and myoclonus (PERM) is an acute, potentially life-threatening, yet curable neuro-immunological disease characterized by spasms, muscular rigidity, and brainstem and autonomic dysfunction. The clinical features of glycine receptor (GlyR) antibody-positive PERM may be overlooked, particularly with some unusual symptoms. CASE PRESENTATION: A 52-year-old man was admitted to the hospital for evaluation of tension headache for 20 days and mild dysarthria. These symptoms were followed by panic, profuse sweating, severe dysarthria, dizziness, unsteady gait, and paroxysmal muscle spasms. Brain magnetic resonance imaging and cerebrospinal fluid analysis were normal. The patient's condition steadily deteriorated. He repeatedly presented with rigidity, panic attacks, severe anxiety, paroxysmal inspiratory laryngeal stridor, cyanosis of the lips, and intractable epilepsy. Electromyography showed multiple myoclonic seizures, a single generalized tonic-clonic seizure, and a single generalized tonic seizure. Screening for autoimmune encephalitis antibodies revealed anti-GlyR antibodies in his cerebrospinal fluid. Immunomodulatory pulse therapy with steroids and immunoglobulin resulted in expeditious improvement of the symptoms within 2 weeks, and a follow-up at 5 weeks showed consistent clinical improvement. CONCLUSION: Our case highlights that inspiratory laryngeal stridor is an important symptom of PERM. Our observation widens the spectrum of the clinical presentation of anti-GlyR antibody-positive PERM, where early identification is a key to improving prognosis.

Age-Specific Clinical Features of Pediatric Malignant Hyperthermia: A Review of 187 Cases Over 60 Years in Japan.

BACKGROUND: Malignant hyperthermia (MH) is an inherited muscle disorder induced by volatile anesthetics and depolarizing muscle relaxants. While the incidence of MH is high in young, there are few reports on the clinical features of pediatric MH. In this study, we selected pediatric cases from an MH database and analyzed the clinical findings by age group. We hypothesized that there would be age-related differences in the clinical characteristics. METHODS: A retrospective analysis of MH data collected in our database during 1960 to 2020 was performed to identify pediatric subjects (≤18 years) with a Clinical Grading Scale of ≥35, indicating "very likely" or "almost certain" MH. We compared clinical characteristics among the 0 to 24 month, 2 to 12 year, and 13 to 18 year (youngest, middle, and oldest, respectively) age groups. RESULTS: Data were available for 187 patients: 15 in the youngest age group, 123 in the middle-aged group, and 49 in the oldest age group. Of these, 55 patients (29.4%) had undergone muscle biopsy and muscle contracture test. The mortality rates during the study period were 13.3%, 13.8%, 20.4%, and 15.5% in the youngest, middle, and oldest cohorts and overall, respectively. In contrast, the overall mortality rate from 2000 to 2020 was 8.8%. The most frequent initial symptoms of MH were elevated temperature (46.7%) and generalized muscular rigidity (26.7%) in the youngest cohort, masseter spasm (35.0%) and generalized muscular rigidity (19.5%) in the middle cohort, and elevated end-tidal carbon dioxide (26.5%) and tachycardia (22.4%) in the oldest cohort. Physical examination revealed that elevated temperature, sinus tachycardia, and respiratory acidosis occurred frequently in all groups. The middle cohort had high frequencies of masseter spasm (58.4%; P = .02) and dark urine (75.5%; P = .01) compared to those in the oldest groups, and had a higher peak creatine kinase level compared to those in the 3 groups. Skeletal muscle symptoms tended to be more common in patients administered succinylcholine (generalized muscular rigidity, P = .053; masseter spasm, P < .0001; dark urine, P < .0001). In particular, masseter spasm and dark urine were more common in the middle cohort when succinylcholine was administered (masseter spasm: versus youngest cohort, P = .06, versus oldest cohort, P = .027; dark urine: versus youngest cohort, P = .0072, versus oldest cohort, P = .0015). CONCLUSIONS: The clinical characteristics of pediatric patients with MH vary according to age group. The difference in initial symptoms of MH depending on age group is noteworthy information for the early diagnosis of MH.

Progressive encephalomyelitis with rigidity and myoclonus (PERM).

Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a subtype of stiff-person syndrome (formerly stiff-man syndrome). It is rare and disabling, and characterised by brainstem symptoms, muscle stiffness, breathing issues and autonomic dysfunction. We describe a 65-year-old man who presented with odynophagia together with tongue and neck swelling, followed by multiple cranial nerve palsies culminating in bilateral vocal cord paralysis with acute stridor. He subsequently developed progressive generalised hypertonia and painful limb spasms. Serum antiglycine receptor antibody was strongly positive, but antiglutamic acid decarboxylase and other antibodies relating to stiff-person syndrome were negative. We diagnosed PERM and gave intravenous corticosteroids and immunoglobulins without benefit; however, following plasma exchange he has made a sustained improvement.

Antiparkinsonian activity of Tabebuia impetiginosa bark and biochemical analysis of dopamine in rat brain homogenates.

OBJECTIVES: Improving economy and well-being in developing nations like India has expanded life expectancy and changed the attention from transmittable to non transmittable diseases such as Parkinson's disease. Tabebuia impetiginosa has been utilized by cultivators as a general tonic, immunostimulant, adaptogen and also in motor disorders. The present investigation was to explore the antiparkinsonian activity of Tabebuia impetiginosa bark by experimental methods. MATERIALS AND METHODS: Control group-I was served with distilled water. Group-II was considered as pathological control [1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) 2mg/nostrils i.n, Reserpine 40mg/kg s.c, Haloperidol 0.5mg/kg, i.p]. Group-III served with standard drug (Apomorphine 40mg/kg, s.c). Group IV and V received aqueous extract of Tabebuia impetiginosa bark in doses of 300 and 500mg/kg/day respectively. Tremor, hypokinesia, muscular rigidity, catatonia, postural immobility, postural instability and catalepsy were assessed for antiparkinsonian activity. RESULTS: The bark extract served group exhibited the increased levels of dopamine (5700±1.84ng/g) when compared to control groups (4300±3.17ng/g). The extract at both the doses displayed a significant reduction in postural flexion, moderate decrease in tremor, muscular rigidity and postural immobility scores but do not exhibit significant lowering of hypokinesia score in reserpine induced Parkinsonian model. The reduction in catatonia and catalepsy scores is more remarkable in case of high dose of extract (500mg/kg) compared to standard drug in Neuroleptic induced Parkinsonism. CONCLUSION: The findings demonstrate that Tabebuia impetiginosa bark extract has significant anti-cataleptic potentials and the antioxidant effect of the bark may also be a significant contributor to its antiparkinsonian activity.

Systemic delivery of human GlyR IgG antibody induces GlyR internalization into motor neurons of brainstem and spinal cord with motor dysfunction in mice.

AIMS: Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a life-threatening condition often associated with highly raised serum antibodies to glycine receptors (GlyRs); these bind to the surface of large neurons and interneurons in rodent brain and spinal cord sections and, in vitro, inhibit function and reduce surface expression of the GlyRs. The effects in vivo have not been reported. METHODS: Purified plasma IgG from a GlyR antibody-positive patient with PERM, and a healthy control (HC), was injected daily into the peritoneal cavity of mice for 12 days; lipopolysaccharide (LPS) to open the blood-brain barrier, was injected on days 3 and 8. Based on preliminary data, behavioural tests were only performed 48 h post-LPS on days 5-7 and 10-12. RESULTS: The GlyR IgG injected mice showed impaired ability on the rotarod from days 5 to 10 but this normalized by day 12. There were no other behavioural differences but, at termination (d13), the GlyR IgG-injected mice had IgG deposits on the neurons that express GlyRs in the brainstem and spinal cord. The IgG was not only on the surface but also inside these large GlyR expressing neurons, which continued to express surface GlyR. CONCLUSIONS: Despite the partial clinical phenotype, not uncommon in passive transfer studies, the results suggest that the antibodies had accessed the GlyRs in relevant brain regions, led to antibody-mediated internalization and increased GlyR synthesis, compatible with the temporary loss of function.

Glycine Receptor Autoantibodies Impair Receptor Function and Induce Motor Dysfunction.

OBJECTIVE: Impairment of glycinergic neurotransmission leads to complex movement and behavioral disorders. Patients harboring glycine receptor autoantibodies suffer from stiff-person syndrome or its severe variant progressive encephalomyelitis with rigidity and myoclonus. Enhanced receptor internalization was proposed as the common molecular mechanism upon autoantibody binding. Although functional impairment of glycine receptors following autoantibody binding has recently been investigated, it is still incompletely understood. METHODS: A cell-based assay was used for positive sample evaluation. Glycine receptor function was assessed by electrophysiological recordings and radioligand binding assays. The in vivo passive transfer of patient autoantibodies was done using the zebrafish animal model. RESULTS: Glycine receptor function as assessed by glycine dose-response curves showed significantly decreased glycine potency in the presence of patient sera. Upon binding of autoantibodies from 2 patients, a decreased fraction of desensitized receptors was observed, whereas closing of the ion channel remained fast. The glycine receptor N-terminal residues 29 A to 62 G were mapped as a common epitope of glycine receptor autoantibodies. An in vivo transfer into the zebrafish animal model generated a phenotype with disturbed escape behavior accompanied by a reduced number of glycine receptor clusters in the spinal cord of affected animals. INTERPRETATION: Autoantibodies against the extracellular domain mediate alterations of glycine receptor physiology. Moreover, our in vivo data demonstrate that the autoantibodies are a direct cause of the disease, because the transfer of human glycine receptor autoantibodies to zebrafish larvae generated impaired escape behavior in the animal model compatible with abnormal startle response in stiff-person syndrome or progressive encephalitis with rigidity and myoclonus patients. ANN NEUROL 2020;88:544-561.

Advances in hyperekplexia and other startle syndromes.

Startle, a basic alerting reaction common to all mammals, is described as a sudden involuntary movement of the body evoked by all kinds of sudden and unexpected stimulus. Startle syndromes are heterogeneous groups of disorders with abnormal and exaggerated responses to startling events, including hyperekplexia, stimulus-induced disorders, and neuropsychiatric startle syndromes. Hyperekplexia can be attributed to a genetic, idiopathic, or symptomatic cause. Excluding secondary factors, hereditary hyperekplexia, a rare neurogenetic disorder with highly genetic heterogeneity, is characterized by neonatal hypertonia, exaggerated startle response provoked by the sudden external stimuli, and followed by a short period of general stiffness. It mainly arises from defects of inhibitory glycinergic neurotransmission. GLRA1 is the major pathogenic gene of hereditary hyperekplexia, along with many other genes involved in the function of glycinergic inhibitory synapses. While about 40% of patients remain negative genetic findings. Clonazepam, which can specifically upgrade the GABARA1 chloride channels, is the main and most effective administration for hereditary hyperekplexia patients. In this review, with the aim at enhancing the recognition and prompting potential treatment for hyperekplexia, we focused on discussing the advances in hereditary hyperekplexia genetics and the expound progress in pathogenic mechanisms of the glycinergic-synapse-related pathway and then followed by a brief overview of other common startle syndromes.

Wooden Chest syndrome: The atypical pharmacology of fentanyl overdose.

WHAT IS KNOWN AND OBJECTIVE: A large percentage of opioid overdose fatalities involve fentanyl or one of its legal or illegal analogs (F/FAs). Is there something about the pharmacology of these drugs that make them unusually dangerous in an overdose? COMMENT: Some of the reasons for the dangers of overdose of F/FAs is their high potency and low cost (that leads to wide distribution). But it is rarely asked if the basic pharmacology of F/FAs differ in some fundamental way from conventional opioids such as morphine and heroin. In addition to centrally mediated respiratory depression via opioid receptors, F/FAs cause rigidity in the key respiratory muscles of the chest, upper airway and diaphragm ("wooden chest syndrome," WCS) by a non-opioid mechanism. WHAT IS NEW AND CONCLUSION: WCS is an atypical pharmacology of F/FAs. Because of its rapid onset and non-opioid mechanism, WCS makes F/FA overdose particularly dangerous.

Overdoses due to fentanyl and its analogues (F/FAs) push naloxone to the limit.

WHAT IS KNOWN AND OBJECTIVE: Food and Drug Administration (FDA) risk evaluation and mitigation strategies (REMs) encourage emergency responders, paramedics, law enforcement agents, and even laypeople to be trained in the administration of naloxone with the intent of rescuing individuals from a known or suspected opioid overdose. COMMENT: Although naloxone is generally safe and effective at reversing respiratory depression caused by a conventional opioid such as morphine or heroin by competing with the opioid and displacing it from the µ-opioid receptor, questions increasingly are arising as to whether naloxone can adequately reverse opioid overdoses that may involve the potent opioids fentanyl and its analogues (F/FAs). In other words, as more and more opioid overdoses involve F/FAs, can naloxone keep up? WHAT IS NEW AND CONCLUSION: As a competitive antagonist at µ-opioid receptors, naloxone is often a life-saving agent in cases of overdose caused by conventional opioids, but it may not be versatile or powerful enough to combat the rising tide of overdoses due to fentanyl and its illicit analogues, or in cases of overdose involving combinations of opioids and non-opioids.

Charged residues at the pore extracellular half of the glycine receptor facilitate channel gating: a potential role played by electrostatic repulsion.

KEY POINTS: The Arg271Gln mutation of the glycine receptor (GlyR) causes hereditary hyperekplexia. This mutation dramatically compromises GlyR function; however, the underlying mechanism is not yet known. This study, by employing function and computation methods, proposes that charged residues (including the Arg residue) at the pore extracellular half from each of the five subunits of the homomeric α1 GlyR, create an electrostatic repulsive potential to widen the pore, thereby facilitating channel opening. This mechanism explains how the Arg271Gln mutation, in which the positively charged Arg residue is substituted by the neutral Gln residue, compromises GlyR function. This study furthers our understanding of the biophysical mechanism underlying the Arg271Gln mutation compromising GlyR function. ABSTRACT: The R271(19')Q mutation in the α1 subunit of the glycine receptor (GlyR) chloride channel causes hereditary hyperekplexia. This mutation dramatically compromises channel function; however, the underlying mechanism is not yet known. The R271 residue is located at the extracellular half of the channel pore. In this study, an Arg-scanning mutagenesis was performed at the pore extracellular half from the 262(10') to the 272(20') position on the background of the α1 GlyR carrying the hyperekplexia-causing mutation R271(19')Q. It was found that the placement of the Arg residue rescued channel function to an extent inversely correlated with the distance between the residue and the pore central axis (perpendicular to the plane of the lipid bilayer). Accordingly, it was hypothesized that the placed Arg residues from each of the five subunits of the homomeric α1 GlyR create an electrostatic repulsive potential to widen the pore, thereby facilitating channel opening. This hypothesis was quantitatively verified by theoretical computation via exploiting basic laws of electrostatics and thermodynamics, and further supported by more experimental findings that the placement of another positively charged Lys residue or even a negatively charged Asp residue also rescued channel function in the same manner. This study provides a novel mechanism via which charged residues in the pore region facilitate channel gating, not only for the disease-causing 19'R residue in the GlyR, but also potentially for charged residues in the same region of other ion channels.

GABAergic changes in the thalamocortical circuit in Parkinson's disease.

Parkinson's disease is characterized by bradykinesia, rigidity, and tremor. These symptoms have been related to an increased gamma-aminobutyric acid (GABA)ergic inhibitory drive from globus pallidus onto the thalamus. However, in vivo empirical evidence for the role of GABA in Parkinson's disease is limited. Some discrepancies in the literature may be explained by the presence or absence of tremor. Specifically, recent functional magnetic resonance imaging (fMRI) findings suggest that Parkinson's tremor is associated with reduced, dopamine-dependent thalamic inhibition. Here, we tested the hypothesis that GABA in the thalamocortical motor circuit is increased in Parkinson's disease, and we explored differences between clinical phenotypes. We included 60 Parkinson patients with dopamine-resistant tremor (n = 17), dopamine-responsive tremor (n = 23), or no tremor (n = 20), and healthy controls (n = 22). Using magnetic resonance spectroscopy, we measured GABA-to-total-creatine ratio in motor cortex, thalamus, and a control region (visual cortex) on two separate days (ON and OFF dopaminergic medication). GABA levels were unaltered by Parkinson's disease, clinical phenotype, or medication. However, motor cortex GABA levels were inversely correlated with disease severity, particularly rigidity and tremor, both ON and OFF medication. We conclude that cortical GABA plays a beneficial rather than a detrimental role in Parkinson's disease, and that GABA depletion may contribute to increased motor symptom expression.

New Sensor and Wearable Technologies to Aid in the Diagnosis and Treatment Monitoring of Parkinson's Disease.

Parkinson's disease (PD) is a degenerative disorder of the brain characterized by the impairment of the nigrostriatal system. This impairment leads to specific motor manifestations (i.e., bradykinesia, tremor, and rigidity) that are assessed through clinical examination, scales, and patient-reported outcomes. New sensor-based and wearable technologies are progressively revolutionizing PD care by objectively measuring these manifestations and improving PD diagnosis and treatment monitoring. However, their use is still limited in clinical practice, perhaps because of the absence of external validation and standards for their continuous use at home. In the near future, these systems will progressively complement traditional tools and revolutionize the way we diagnose and monitor patients with PD.

Probabilistic sweet spots predict motor outcome for deep brain stimulation in Parkinson disease.

OBJECTIVE: To investigate whether functional sweet spots of deep brain stimulation (DBS) in the subthalamic nucleus (STN) can predict motor improvement in Parkinson disease (PD) patients. METHODS: Stimulation effects of 449 DBS settings in 21 PD patients were clinically and quantitatively assessed through standardized monopolar reviews and mapped into standard space. A sweet spot for best motor outcome was determined using voxelwise and nonparametric permutation statistics. Two independent cohorts were used to investigate whether stimulation overlap with the sweet spot could predict acute motor outcome (10 patients, 163 settings) and long-term overall Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) improvement (63 patients). RESULTS: Significant clusters for suppression of rigidity and akinesia, as well as for overall motor improvement, resided around the dorsolateral border of the STN. Overlap of the volume of tissue activated with the sweet spot for overall motor improvement explained R2 = 37% of the variance in acute motor improvement, more than triple what was explained by overlap with the STN (R2 = 9%) and its sensorimotor subpart (R2 = 10%). In the second independent cohort, sweet spot overlap explained R2 = 20% of the variance in long-term UPDRS-III improvement, which was equivalent to the variance explained by overlap with the STN (R2 = 21%) and sensorimotor STN (R2 = 19%). INTERPRETATION: This study is the first to predict clinical improvement of parkinsonian motor symptoms across cohorts based on local DBS effects only. The new approach revealed a distinct sweet spot for STN DBS in PD. Stimulation overlap with the sweet spot can predict short- and long-term motor outcome and may be used to guide DBS programming. ANN NEUROL 2019;86:527-538.