Diaphragm Compound Muscle Action Potential Research Articles

Enhanced endoplasmic reticulum RyR1 receptor phosphorylation leads to diaphragmatic dysfunction in septic rats

To explore the role of endoplasmic reticulum ryanodine receptor 1 (RyR1) expression and phosphorylation in sepsis- induced diaphragm dysfunction. Thirty SPF male SD rats were randomized equally into 5 groups, including a sham-operated group, 3 sepsis model groups observed at 6, 12, or 24 h following cecal ligation and perforation (CLP; CLP-6h, CLP-12h, and CLP-24h groups, respectively), and a CLP-24h group with a single intraperitoneal injection of KN- 93 immediately after the operation (CLP-24h+KN-93 group). At the indicated time points, diaphragm samples were collected for measurement of compound muscle action potential (CMAP), fatigue index of the isolated diaphragm and fitted frequencycontraction curves. The protein expression levels of CaMK Ⅱ, RyR1 and P-RyR1 in the diaphragm were detected using Western blotting. In the rat models of sepsis, the amplitude of diaphragm CMAP decreased and its duration increased with time following CLP, and the changes were the most obvious at 24 h and significantly attenuated by KN-93 treatment (P < 0.05). The diaphragm fatigue index increased progressively following CLP (P < 0.05) irrespective of KN- 93 treatment (P>0.05). The frequency-contraction curve of the diaphragm muscle decreased progressively following CLP, and was significantly lower in CLP-24 h group than in CLP-24 h+KN-93 group (P < 0.05). Compared with that in the sham-operated group, RyR1 expression level in the diaphragm was significantly lowered at 24 h (P < 0.05) but not at 6 or 12 following CLP, irrespective of KN-93 treatment; The expression level of P-RyR1 increased gradually with time after CLP, and was significantly lowered by KN-93 treatment at 24 h following CLP (P < 0.05). The expression level of CaMKⅡ increased significantly at 24 h following CLP, and was obviously lowered by KN-93 treatment (P < 0.05). Sepsis causes diaphragmatic dysfunction by enhancing CaMK Ⅱ expression and RyR1 receptor phosphorylation in the endoplasmic reticulum of the diaphragm.

MEASUREMENT OF DIAPHRAGMATIC DYSFUNCTION AND PHRENIC NERVE PALSY IN PATIENTS UNDERGOING THORACIC SURGERY FOR LUNG- OR ESOPHAGEAL CANCER

<h3>Introduction and Objective</h3> Thoracic surgery carries a substantial risk of postoperative pulmonary complications. Recent studies have shown that the risk of postoperative pulmonary complications is significantly higher in patients suffering from postoperative diaphragmatic dysfunction. Diaphragmatic dysfunction may be accompanied by phrenic nerve palsy. However, the extent of phrenic nerve palsy and its association with diaphragmatic dysfunction following thoracic surgery is unknown. Therefore, we aimed to quantify changes in diaphragmatic function and phrenic nerve conductance in patients undergoing thoracic surgery for lung- or esophageal cancer using ultrasonographic measures and phrenic nerve conduction studies. <h3>Design and Methods</h3> This was a prospective observational study including patients scheduled for pulmonary lobectomy or esophageal resection. Examinations were carried out the day prior to surgery and respectively 3 days and 10-14 days after surgery. Endpoints for diaphragmatic function included ultrasonographic measurements of diaphragmatic excursion of the posterior part of the right hemidiaphragm, excursion of the hemidiaphragmatic top point, change in intrathoracic area and diaphragmatic thickening fraction. Ultrasonographic measurements were recorded during a standardized respiration cycle. Endpoints for phrenic nerve conductance included baseline-to-peak amplitude, peak-to-peak amplitude and transmission delay of the diaphragmatic compound muscle action potential (CMAP). Measurements for both diaphragmatic- and phrenic nerve recordings were assessed for both the surgical side and the non-surgical side of the thorax and thus measured over time. <h3>Results</h3> We included 40 patients of which 13 had pulmonary lobectomies and 27 had esophageal resections performed. Significant reductions in diaphragmatic excursion were seen on the surgical side of the thorax for all excursion measures (posterior part of the right hemidiaphragm, p < 0.001; hemidiaphragmatic top point, p < 0.001; change in intrathoracic area, p < 0.001) (Figure 1). Conversely, all ultrasound excursion measures did not change significantly on the non-surgical side. Diaphragmatic thickening fraction did not change significantly on either side. For phrenic nerve measures, significant reductions were seen for both CMAP amplitude measures on the surgical side (baseline-to-peak, p < 0.001; peak-to-peak, p < 0.001) and non-surgical side (baseline-to-peak, p < 0.001; peak-to-peak, p < 0.001). Transmission delay also changed significantly between assessments on both the surgical (p =0.041) and the non-surgical side (p =0.021) (Figure 2). <h3>Conclusion</h3> Thoracic surgery caused a significant unilateral reduction in diaphragmatic excursion on the surgical side of the thorax, whereas the contralateral hemidiaphragm's excursion did not decrease significantly. Diaphragmatic compound muscle action potential amplitude was reduced significantly bilaterally. Therefore, our findings show that a postoperative reduction in diaphragmatic excursion is accompanied by partial phrenic nerve palsy, which may be a contributing factor in the pathogenesis of postoperative pulmonary complications.

Differences between diaphragmatic compound muscle action potentials recorded from over the sternum and lateral chest wall in healthy subjects

To report normative data for diaphragmatic compound muscle action potentials (DCMAPs) recorded from over the sternum and lateral chest wall (LCW) and highlight factors that may contribute to variations in DCMAP parameters at the two sites. The phrenic nerve of seventy-three healthy subjects was bilaterally stimulated at the posterior border of the sternocleidomastoid muscle. DCMAPs from over the sternum and LCW were recorded (inspiration/expiration). Normative values of sternal and LCW DCMAPs were presented. The mean values of latency of LCW DCMAPs, duration of sternal DCMAPs and area from both recording sites are close to values reported by other studies. The mean values of latency of sternal DCMAPs are higher than that reported by other studies. Significant differences were found between sternal and LCW potentials in the mean latency, amplitude, and area (p < 0.001). The duration did not differ between the two sites. Differences were found between inspiration and expiration, right and left sides, and men and women. Regression analysis showed a relation between latency of sternal and LCW potentials and age. Latency (LCW potentials) and amplitude and area (sternal/LCW potentials) were related to gender. Amplitude (LCW potentials/inspiration) and area (sternal potentials/inspiration) were related to chest circumference (p = 0.023 and 0.013 respectively). Area (sternal potentials/expiration) was related to the BMI (p = 0.019). Our normative values for sternal and LCW DCMAPs are provided. Notable differences in the DCMAPs parameters were detected between the two recording sites, inspiration and expiration, right and left, and men and women. The technique of phrenic nerve should be standardized.

Thoracic Excursion Is a Biomarker for Evaluating Respiratory Function in Amyotrophic Lateral Sclerosis.

ObjectiveTo evaluate the usefulness of thoracic excursion as a biomarker in patients with amyotrophic lateral sclerosis (ALS).MethodsWe measured the forced the vital capacity (FVC), thoracic excursion, baseline-to-peak diaphragmatic compound muscle action potential (DCMAP) amplitude, diaphragm thickness at full inspiration (DTfi), Medical Research Council (MRC) sum score for muscle strength, and arterial partial pressures of oxygen and carbon dioxide and administered the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) and modified Medical Research Council (mMRC) Dyspnea Scale. The test–retest reliability of thoracic excursion was determined.Results and ConclusionsThirty-four patients with ALS and 26 age- and sex-matched healthy participants were enrolled. Thoracic excursion measurement had excellent test–retest reliability (intraclass coefficient: 0.974). Thoracic excursion was more strongly correlated with FVC (r = 0.678, p < 0.001) than DCMAP amplitude (r = 0.501, p = 0.003) and DTfi (r = 0.597, p < 0.001). It was also correlated with ALSFRS-R score (r = 0.610, p < 0.001), MRC sum score (r = 0.470, p = 0.005), and mMRC Dyspnea Scale score (r = −0.446, p = 0.008) and was the most sensitive parameter for assessing dyspnea and FVC. Thoracic excursion decreased as FVC declined in the early and late stages, there were no differences in DCMAP amplitude and DTfi between the early and late stages, and ALSFRS-R score and MRC sum score decreased only in the late stage. Thoracic excursion was well correlated with respiratory function and is useful for predicting respiratory and general dysfunction in patients with ALS regardless of stage.

The Amplitude of Diaphragm Compound Muscle Action Potential Correlates With Diaphragmatic Excursion on Ultrasound and Pulmonary Function After Supraclavicular Brachial Plexus Block.

ObjectiveThis prospective, double-blind, randomized study assessed (1) the associations between diaphragm compound muscle action potential (CMAP), hemidiaphragmatic excursion, and pulmonary function after supraclavicular brachial plexus block (SCBPB) and (2) diagnostic efficacy of pulmonary function for hemidiaphragmatic paralysis evidenced by diaphragm CMAP as an assessment of diaphragm strength was evaluated.MethodsEighty-six patients were scheduled for the removal of hardware after healing of a right upper limb fracture distal to the shoulder who were randomly assigned in a 1:1 ratio to two groups: Group A (diaphragmatic excursion), or Group B (pulmonary function). Phrenic nerve conduction studies (PNCSs), M-mode ultrasonography of the diaphragm, and pulmonary function tests (PFTs) were performed before and 30 min after SCBPB. PNCSs were used to determine the latency and amplitude of diaphragm CMAP. Ultrasonography of the diaphragm was performed with patients in a supine position using a low-frequency probe over the subcostal space at the midclavicular line. The diaphragmatic excursion was measured during quiet breathing and deep breathing. Pulmonary function, i.e., forced vital capacity (FVC), predicted value of FVC, and forced expiratory flow in the first second (FEV1), was measured with spirometry. Receiver Operating Characteristic (ROC) curve analysis was used to assess the diagnostic efficacy of pulmonary function for hemidiaphragmatic paralysis evidenced by diaphragm CMAP as an assessment of diaphragm strength.ResultsThere were significant associations between the reduction in amplitude of diaphragm CMAP and reductions in diaphragmatic excursion during quiet breathing (r = 0.70, p < 0.01) and deep breathing (r = 0.63, p < 0.01) when expressed as a percentage of baseline values. There were significant associations between the reduction in amplitude of diaphragm CMAP and reductions in FVC (r = 0.67, p < 0.01), FVC% (r = 0.67, p < 0.01), and FEV1 (r = 0.62, p < 0.01), when expressed as percentage of baseline values. The area under the ROC curve for FVC was 0.86. A decrease of >8.4% in FVC compared to pre-block predicted hemidiaphragmatic paralysis (determined by diaphragm CMAP) with sensitivity and specificity of 79.2 and 100%, respectively.ConclusionsThe relative reduction in diaphragm CMAP amplitude after SCBPB was correlated with relative reductions in diaphragmatic excursion and pulmonary function. FVC has potential as a useful diagnostic indicator of hemidiaphragmatic paralysis, evidenced by diaphragm CMAP, after SCBPB. These data establish diaphragm CMAP as a direct and objective index of diaphragmatic paralysis after SCBPB.

PHRENIC NERVE CONDUCTION STUDY IN HEALTHY POPULATION

The phrenic nerve provides the primary motor supply to the diaphragm Phrenic nerve conduction study provides a sensitive indicator of phrenic nerve function when the nerve is affected either by local lesions or by generalized neuropathies. Percutaneous phrenic nerve stimulation is an easy and rapid procedure that achieves successful stimulation of the nerve. It is associated with little or no discomfort. Amplitude, latency, area, and duration are measures used to evaluate phrenic nerve integrity. Only limited data has however been published on normative data of phrenic nerve conduction study. Aim of the work The aim of this study was to determine normative values of phrenic nerve conduction parameters in healthy population.Subjects & Methods • Seventy-three healthy individuals (47 men and 26 women) aged from 18 to 61 years participated in the study. • Motor conduction studies of the phrenic nerve were performed bilaterally both during inspiration and expiration. The phrenic nerve was stimulated at the posterior border of the sternocleidomastoid muscle at the level of the cricoid cartilage. Recording was made from both sternal and costal diaphragm. • Measured parameters were latency, amplitude, area and duration of the diaphragmatic compound muscle action potential )DCMAP( at each recording site. Side-side differences were determined.

Characteristics of respiratory muscle involvement in myotonic dystrophy type 1

The pathophysiology of respiratory muscle weakness in myotonic dystrophy type 1 (DM1) remains incompletely understood. 21 adult patients with DM1 (11 men, 42 ± 13 years) and 21 healthy matched controls underwent spirometry, manometry, and diaphragm ultrasound. In addition, surface electromyography of the diaphragm and the obliquus abdominis muscle was performed following cortical and posterior cervical magnetic stimulation (CMS) of the phrenic nerves or magnetic stimulation of the lower thoracic nerve roots. Magnetic stimulation was combined with invasive recording of the twitch transdiaphragmatic and gastric pressure (twPdi and twPgas) in 10 subjects per group. The following parameters were reduced in DM1 patients compared to control subjects: maximum inspiratory pressure (MIP; 40.3 ± 19.2 vs. 95.8 ± 28.5 cmH2O, p < 0.01), diaphragm thickening ratio (DTR; 2.0 ± 0.4 vs. 2.7 ± 0.6, p < 0.01), twPdi following CMS (10.8 ± 8.3 vs. 21.4 ± 10.1 cmH2O, p = 0.03), and amplitude of diaphragm compound muscle action potentials (0.10 ± 0.25 vs. 0.46 ± 0.35 mV; p = 0.04). MIP and DTR were significantly correlated with the muscular impairment rating scale (MIRS) score. Maximum expiratory pressure (MEP) was reduced in DM1 patients compared to controls (41.3 ± 13.4 vs. 133.8 ± 28.0 cmH2O, p < 0.01) and showed negative correlation with the MIRS score. Pgas following a maximum cough was markedly lower in patients than in controls (71.9 ± 43.2 vs. 102.4 ± 35.5 cmH2O) but without statistical significance (p = 0.06). In DM1, respiratory muscle weakness relates to clinical disease severity and involves inspiratory and probably expiratory muscle strength. Axonal phrenic nerve pathology may contribute to diaphragm dysfunction.

Respiratory muscle weakness in facioscapulohumeral muscular dystrophy.

The purpose of this study was to comprehensively evaluate respiratory muscle function in adults with facioscapulohumeral muscular dystrophy (FSHD). Fourteen patients with FSHD (9 men, 53 ± 16 years of age) and 14 matched controls underwent spirometry, diaphragm ultrasound, and measurement of twitch gastric and transdiaphragmatic pressures (twPgas and twPdi; n = 10) after magnetic stimulation of the lower thoracic nerve roots and the phrenic nerves. The latter was combined with recording of diaphragm compound muscle action potentials (CMAPs; n = 14). The following parameters were significantly lower in patients vs controls: forced vital capacity (FVC); maximum inspiratory and expiratory pressure; peak cough flow; diaphragm excursion amplitude; and thickening ratio on ultrasound, twPdi (11 ± 5 vs 20 ± 6 cmH2 O) and twPgas (7 ± 3 vs 25 ± 20 cmH2 O). Diaphragm CMAP showed no group differences. FVC correlated inversely with the clinical severity scale score (r = -0.63, P = .02). In FSHD, respiratory muscle weakness involves both the diaphragm and the expiratory abdominal muscles.

Electrophysiological Properties of the Human Diaphragm Assessed by Magnetic Phrenic Nerve Stimulation: Normal Values and Theoretical Considerations in Healthy Adults

This study determined normal values for motor evoked potentials (MEPs) and compound muscle action potentials (CMAPs) of the diaphragm following cortical and cervical magnetic stimulation (COMS and CEMS) of the phrenic nerves in healthy adults. Using surface electrodes, diaphragmatic MEP and CMAP were recorded in 70 subjects (34 ± 13 years, 25 men) following supramaximal cortical magnetic stimulation and CEMS at functional residual capacity and using a standardized inspiratory pressure trigger (-0.5 kPa). All healthy volunteers underwent standard spirometry and measurement of maximum inspiratory and expiratory pressure. At functional residual capacity, upper limit of normal for MEP latency was 25 ms in men and 23 ms in women (p < 0.05), and upper limit of normal for CMAP latency was 6 ms. In contrast to MEP and CMAP amplitude, corresponding latencies showed little interindividual and intraindividual variability. Use of an inspiratory pressure trigger enhanced reproducibility and amplitude of diaphragm MEP. Diaphragm responses to both cortical and cervical magnetic stimulation were symmetrical and independent of age (in our cohort), with higher values for latency and amplitude in men (each p < 0.05). Diaphragm CMAP amplitude showed weak-moderate correlations with forced vital capacity (r = 0.47; p < 0.01), maximum inspiratory pressure (r = 0.39; p < 0.01), and maximum expiratory pressure (r = 0.32; p < 0.01). Combination of cortical magnetic stimulation and CEMS of the phrenic nerves is feasible and allows noninvasive assessment of both central and peripheral conductivity of the diaphragm and the inspiratory pathway.

Phrenic nerve involvement and respiratory muscle weakness in patients with Charcot-Marie-Tooth disease 1A.

Diaphragm weakness in Charcot-Marie-Tooth disease 1A (CMT1A) is usually associated with severe disease manifestation. This study comprehensively investigated phrenic nerve conductivity, inspiratory and expiratory muscle function in ambulatory CMT1A patients. Nineteen adults with CMT1A (13 females, 47 ± 12 years) underwent spiromanometry, diaphragm ultrasound, and magnetic stimulation of the phrenic nerves and the lower thoracic nerve roots, with recording of diaphragm compound muscle action potentials (dCMAP, n = 15), transdiaphragmatic and gastric pressures (twPdi and twPgas, n = 12). Diaphragm motor evoked potentials (dMEP, n = 15) were recorded following cortical magnetic stimulation. Patients had not been selected for respiratory complaints. Disease severity was assessed using the CMT Neuropathy Scale version 2 (CMT-NSv2). Healthy control subjects were matched for age, sex, and body mass index. The following parameters were significantly lower in CMT1A patients than in controls (all P < .05): forced vital capacity (91 ± 16 vs 110 ± 15% predicted), maximum inspiratory pressure (68 ± 22 vs 88 ± 29 cmH2 O), maximum expiratory pressure (91 ± 23 vs 123 ± 24 cmH2 O), and peak cough flow (377 ± 135 vs 492 ± 130 L/min). In CMT1A patients, dMEP and dCMAP were delayed. Patients vs controls showed lower diaphragm excursion (5 ± 2 vs 8 ± 2 cm), diaphragm thickening ratio (DTR, 1.9 [1.6-2.2] vs 2.5 [2.1-3.1]), and twPdi (8 ± 6 vs 19 ± 7 cmH2 O; all P < .05). DTR inversely correlated with the CMT-NSv2 score (r = -.59, P = .02). There was no group difference in twPgas following abdominal muscle stimulation. Ambulatory CMT1A patients may show phrenic nerve involvement and reduced respiratory muscle strength. Respiratory muscle weakness can be attributed to diaphragm dysfunction alone. It relates to neurological impairment and likely reflects a disease continuum.

Noninvasive Prediction of Twitch Transdiaphragmatic Pressure: Insights from Spirometry, Diaphragm Ultrasound, and Phrenic Nerve Stimulation Studies

Background: Twitch transdiaphragmatic pressure (twPdi) following magnetic stimulation (MS) of the phrenic nerves is the gold standard for non-volitional assessment of diaphragm strength. Expiratory muscle function can be investigated using MS of the abdominal muscles and measurement of twitch gastric pressure (twPgas). Objectives: To investigate whether twitch pressures following MS of the phrenic and lower thoracic nerve roots can be predicted noninvasively by diaphragm ultrasound parameters and volitional tests of respiratory muscle strength. Methods: Sixty-three healthy subjects underwent standard spirometry, measurement of maximum inspiratory (PI_max) and expiratory pressure (PE_max), and diaphragm ultrasound. TwPdi following cervical MS of the phrenic nerve roots and twPgas after lower thoracic MS (twPgas-Thor) were measured using esophageal and gastric balloon catheters inserted transnasally. Using surface electrodes, compound muscle action potentials (CMAP) were simultaneously recorded from the diaphragm or obliquus abdominis muscles, respectively. Results: Forced expiratory flow (FEF_25–75) was significantly correlated with twPdi (r = 0.37; p = 0.003) and its components (twPgas and twitch esophageal pressure, twPes). Diaphragm excursion velocity during tidal breathing was correlated to twPes (r = 0.44; p = 0.02). No prediction of twitch pressures was possible from CMAP amplitude, forced vital capacity (FVC), or PI_max. TwPgas-Thor was correlated with FEF_25–75 (r = 0.46; p = 0.05) and diaphragm thickness at total lung capacity (r = 0.38; p = 0.04) but could not be predicted from CMAP amplitude, FVC, or PE_max. Conclusions: TwPdi and twPgas-Thor cannot be predicted from volitional measures of respiratory muscle strength, diaphragm and abdominal CMAP, or diaphragm ultrasound. Invasive recording of esophageal and gastric pressures following MS remains indispensable for objective assessment of respiratory muscle strength.

Phrenic Nerve Conduction in Healthy Subjects.

Assessment of diaphragm compound muscle action potential by noninvasive phrenic nerve stimulation at the neck is well described. However, normal values in a large cohort of healthy subjects are lacking. Our objective was to determine reference values of phrenic nerve conduction in healthy subjects. We recruited 155 healthy subjects (25-79 years old) and measured mean amplitude (PhrenAmp) and latency (PhrenLat) of motor responses according to Bolton's method. The lower limit for PhrenAmp was 0.28 and 0.25 mV and the upper limit for PhrenLat was 8.41 and 8.56 ms for right and left side, respectively. PhrenLat was correlated with age. PhrenAmp, PhrenLat and area were significantly higher in men. Tolerance to phrenic nerve stimulation was excellent. Our study provides normative values of phrenic nerve motor responses in a large cohort of healthy subjects and identifies age and sex as factors of variation. Muscle Nerve 59:451-456, 2019.

Effect of local anesthetic volume (20 mL vs 30 mL ropivacaine) on electromyography of the diaphragm and pulmonary function after ultrasound-guided supraclavicular brachial plexus block: a randomized controlled trial

Background and objectivesDiaphragmatic paralysis following supraclavicular brachial plexus block (SCBPB) is ascribed to phrenic nerve palsy. This study investigated the effect of 2 volumes of 0.375% ropivacaine on efficacy of...

Prospective Hospital-Based Clinical and Electrophysiological Evaluation of Acute Organophosphate Poisoning.

Introduction:Acute organophosphate (OP) poisoning is one of the most common poisoning causing significant morbidity and mortality in developing countries. Acute cholinergic manifestations predominate with many patients requiring intensive care management and ventilator support. Nerve conduction studies including repetitive nerve stimulation can evaluate the altered neuromuscular transmission and peripheral nerve function by OPs.Objective:To evaluate the electrophysiological abnormalities in patients with acute OP poisoning and correlate with clinical status.Materials and Methods:Patients with acute OP poisoning admitted from August 2016 to August 2017 were prospectively studied. Nerve conduction studies including phrenic nerve conduction were performed within 24 h of admission. Repetitive nerve stimulation was performed at 3 and 30 Hz. Nerve conduction findings were compared with data from age-matched healthy controls.Results:Thirty patients were included (18 men and 12 women) in the study. Their age ranged from 16 to 47 years (30 ± 9.2). The first assessment revealed a mild reduction of compound muscle action potential (CMAP) amplitude and reduced F-wave persistence. Eleven patients had repetitive CMAPs suggesting cholinergic excess. Seven among the 11 patients requiring mechanical ventilation had decrement–increment response with 30 Hz stimulation and reduced diaphragmatic CMAP amplitude (P = 0.02).Conclusion:The presence of repetitive CMAPs, decrement–increment response to tetanic stimulation and reduced diaphragmatic CMAP amplitude in OP poisoning patients correlate with neuromuscular paralysis and need for mechanical ventilation.

The impact of spasticity on diaphragm contraction: Electrophysiological assessment

ObjectiveWe aimed to evaluate diaphragm spasticity by measuring diaphragm compound muscle action potentials (CMAPs) to phrenic nerve stimulation at end-expiration (exp) and at full-inspiration (insp) in amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS) and aged-matched controls. We also compared diaphragmatic responses of ALS patients with and without spasticity. MethodsDiaphragm CMAPs were recorded from 111 ALS patients, 15 PLS patients and 36 controls. Percentage of change (%insp-exp) was calculated for each neurophysiological measure. Clinical evaluation included: functional ALS scale, spasticity and forced vital capacity. ResultsDiaphragmatic exp and insp CMAPs in ALS patients had longer latency, lower peak-to-peak amplitude and smaller negative-peak area (all p < 0.05). ANCOVA analysis for %insp-exp differences across groups, taking into account end-expiration values, revealed a group effect for peak-to-peak amplitude (all p < 0.001) and negative-peak area (all p < 0.01). For both measures, the change in ALS and PLS patients was smaller than controls (all p < 0.05). Among ALS patients, those without spasticity (74%) had longer latency, lower peak-to-peak amplitude and smaller negative-peak area (all p < 0.05). ConclusionsUpper motor neuron involvement changes physiological variability of diaphragmatic CMAPs, likely due to decreased muscle shortening and mobility. SignificanceSpasticity impacts on diaphragm electrophysiology, with potential implications in respiratory function.

Phrenic nerve stimulation is more sensitive than ultrasound measurement of diaphragm thickness in assessing early ALS progression

To compare the assessment of respiratory decline with conventional tests, measurement of diaphragm compound muscle action potential (CMAP) to phrenic nerve stimulation and diaphragm thickness to ultrasound (US) investigation in amyotrophic lateral sclerosis (ALS) patients followed for a short period of time. We evaluated in 40 consecutive ALS patients, the clinical functional scale (ALSFRS-R), forced vital capacity (FVC), maximal voluntary ventilation (MVV), maximal inspiratory (MIP) and expiratory (MEP) pressures, sniff nasal inspiratory pressure (SNIP), Diaphragm-CMAP (latency and amplitude) and diaphragm US (maximal and minimal diaphragm thickness during full inspiration and expiration, respectively). Patients were evaluated at study entry and 4 months later. Clinical functional assessment (ALSFRS-R), MEP, SNIP, and Diaphragm-CMAP amplitude declined significantly. Conversely, FVC, MVV, MIP, and diaphragm thickness showed a non-significant decline. We found significant correlations between all variables measured at both evaluation times. In this study, we included patients who might be potentially eligible for a clinical trial and re-evaluated them within 4 months. In this short time, diaphragm thickness as assessed by US is not sensitive to detect changes. However, Diaphragm-CMAP amplitude was confirmed to be a sensitive non-volitional method to measure respiratory function in ALS.

Altered activation of the diaphragm in late-onset Pompe disease

Pompe disease is an inherited neuromuscular disorder that affects respiratory function and leads to dependence on external ventilatory support. We studied the activation of the diaphragm using bilateral phrenic magnetic stimulation and hypothesized that diaphragm compound muscle action potential (CMAP) amplitude and evoked transdiaphragmatic pressure (Twitch PDI) would correlate to disease severity. Eight patients with late onset Pompe disease (LOPD, aged 14–48 years) and four healthy control subjects completed the tests. Maximal Twitch PDI responses were progressively reduced in patients with LOPD compared to control subjects (1.4–17.1cm H2O, p<0.001) and correlated to voluntary functional tests (p<0.05). Additionally, CMAP amplitude (mA) was lower in the patients who used nighttime or fulltime ventilatory support, when compared to controls and patients who used no ventilatory support (p<0.005). However, the normalized (%peak) Twitch PDI and CMAP responses were similar between patients and controls. This suggests a loss of functional phrenic motor units in patients, with normal recruitment of remaining motor units.

Ultrasonographic diaphragm thickness correlates with compound muscle action potential amplitude and forced vital capacity

Noninvasive evaluation of respiratory function in patients with various neuromuscular disorders is important for predicting life expectancy. We performed B-mode ultrasonography (USG) and nerve conduction studies in 37 patients (16 had amyotrophic lateral sclerosis; 11, myopathy; and 10, neuropathy) and 10 controls. USG of the diaphragm was performed in the supine position using a linear probe over the intercostal space at the anterior axillary line. Diaphragm muscle thickness was measured at end-expiration. The amplitude of diaphragm compound muscle action potentials (CMAP) was obtained by phrenic nerve stimulation with a surface electrode. Respiratory function was measured with standard pulmonary function tests including forced vital capacity (FVC). Diaphragm thickness was significantly correlated with FVC (r = 0.74) and CMAP amplitude (r = 0.53). Diaphragm USG is useful for objective evaluation of pulmonary function in neuromuscular disorders without requiring undue patient effort or cooperation.

GLT1 overexpression in SOD1G93A mouse cervical spinal cord does not preserve diaphragm function or extend disease

Amyotrophic lateral sclerosis (ALS) is characterized by relatively rapid degeneration of both upper and lower motor neurons, with death normally occurring 2–5years following diagnosis primarily due to respiratory paralysis resulting from phrenic motor neuron (PhMN) loss and consequent diaphragm denervation. In ALS, cellular abnormalities are not limited to MNs. For example, decreased levels and aberrant functioning of the major central nervous system (CNS) glutamate transporter, GLT1, occur in spinal cord and motor cortex astrocytes of both humans with ALS and in SOD1G93A rodents, a widely studied ALS animal model. This results in dysregulation of extracellular glutamate homeostasis and consequent glutamate excitotoxicity, a primary mechanism responsible for MN loss in ALS animal models and in the human disease. Given these observations of GLT1 dysfunction in areas of MN loss, as well as the importance of testing therapeutic strategies for preserving PhMNs in ALS, we evaluated intraspinal delivery of an adeno-associated virus type 8 (AAV8)–Gfa2 vector to the cervical spinal cord ventral horn of SOD1G93A ALS mice for focally restoring intraspinal GLT1 expression. AAV8 was specifically injected into the ventral horn bilaterally throughout the cervical enlargement at 110days of age, a clinically-relevant time point coinciding with phenotypic/symptomatic disease onset. Intraspinal delivery of AAV8–Gfa2–GLT1 resulted in robust transduction primarily of GFAP+ astrocytes that persisted until disease endstage, as well as a 2–3-fold increase in total intraspinal GLT1 protein expression in the ventral horn. Despite this robust level of astrocyte transduction and GLT1 elevation, GLT1 overexpression did not protect PhMNs, preserve histological PhMN innervation of the diaphragm NMJ, or prevent decline in diaphragmatic respiratory function as assessed by phrenic nerve–diaphragm compound muscle action potential (CMAP) recordings compared to control AAV8–Gfa2–eGFP injected mice. In addition, AAV–Gfa2–GLT1 did not delay forelimb disease onset, extend disease duration (i.e. time from either forelimb or hindlimb disease onsets to endstage) or prolong overall animal survival. These findings suggest that focal restoration of GLT1 expression in astrocytes of the cervical spinal cord using AAV delivery is not an effective therapy for ALS.

Esophageal versus surface recording of diaphragm compound muscle action potential.

Repeated diaphragm compound muscle action potential (CMAP) recordings may help to understand the pathophysiology of respiratory muscle weakness. Neurally adjusted ventilator assist (NAVA) uses esophageal EMG electrodes to drive the ventilator. We evaluated the feasibility of CMAP recordings using these electrodes and established normal values. Bilateral cervical phrenic nerve electrical stimulation was performed in 15 healthy volunteers. CMAP recordings with esophageal NAVA electrodes were compared with surface electrode recordings during inspiratory and expiratory pause. Compared with surface recordings, esophageal CMAP amplitudes were higher with increased latencies. Differences between the 2 techniques were most prominent in inspiration. For both recording techniques, amplitudes were higher, and latencies were longer during inspiration. Latencies were also longer when measured on the left side. Diaphragm CMAPs can be measured using the commercially available esophageal NAVA probe. This may facilitate repeated diaphragm CMAP studies in mechanically ventilated patients.