Cervical Magnetic Stimulation Research Articles

Inspiratory Muscle Dysfunction Mediates and Predicts a Disease Continuum of Hypercapnic Failure in Chronic Obstructive Pulmonary Disease.

Advanced chronic obstructive pulmonary disease (COPD) is associated with chronic hypercapnic failure. The present work aimed to comprehensively investigate inspiratory muscle function as a potential key determinant of hypercapnic respiratory failure in patients with COPD. Prospective patient recruitment encompassed 61 stable subjects with COPD across different stages of respiratory failure, ranging from normocapnia to isolated nighttime hypercapnia and daytime hypercapnia. Arterialized blood gas analyses and overnight transcutaneous capnometry were used for patient stratification. Assessment of respiratory muscle function encompassed body plethysmography, maximum inspiratory pressure (MIP), diaphragm ultrasound, and transdiaphragmatic pressure recordings following cervical magnetic stimulation of the phrenic nerves (twPdi) and a maximum sniff manoeuvre (Sniff Pdi). Twenty patients showed no hypercapnia, 10 had isolated nocturnal hypercapnia, and 31 had daytime hypercapnia. Body plethysmography clearly distinguished patients with and without hypercapnia but did not discriminate patients with isolated nocturnal hypercapnia from those with daytime hypercapnia. In contrast to ultrasound parameters and transdiaphragmatic pressures, only MIP reflected the extent of hypercapnia across all three stages. MIP values below -48 cmH2O predicted nocturnal hypercapnia (area under the curve = 0.733, p = 0.052). In COPD, inspiratory muscle dysfunction contributes to progressive hypercapnic failure. In contrast to invasive tests of diaphragm strength only MIP fully reflects the pathophysiological continuum of hypercapnic failure and predicts isolated nocturnal hypercapnia.

Sex differences in quadriceps and inspiratory muscle fatigability following high-intensity cycling.

As females have been hypothesized to have more fatigue resistant inspiratory muscles, this study aimed to compare the development of inspiratory and leg muscle fatigue between males and females following high-intensity cycling. Cross-sectional comparison. 17 healthy young males (27 ± 6 years, V̇O2peak 55 ± 10 ml･min-1･kg-1) and females (25 ± 4 years, V̇O2peak 45 ± 7 ml･min-1･kg-1) cycled until exhaustion at 90% of the peak power output achieved during an incremental test. Changes in quadriceps and inspiratory muscle function were assessed via maximal voluntary contractions (MVC) and assessments of contractility via electrical stimulation of the femoral nerve and cervical magnetic stimulation of the phrenic nerves. Time to exhaustion was similar between sexes (p = 0.270, 95% CI -2.4 - 0.7 min). MVC of the quadriceps was lower after cycling for males (83.9 ± 11.5% vs. 94.0 ± 12.0% of baseline for females, p = 0.018). Reductions in twitch forces were not different between sexes for the quadriceps (p = 0.314, 95% CI -5.5 - 16.6 percent-points) or inspiratory muscles (p = 0.312, 95% CI -4.0 - 2.3 percent-points). Changes in inspiratory muscle twitches were unrelated to the different measures of quadriceps fatigue. Females incur similar peripheral fatigue in the quadriceps and inspiratory muscles compared with men following high-intensity cycling, despite smaller reduction in voluntary force. This small difference alone does not seem sufficient to warrant different training strategies to be recommended for women.

Voluntary activation of the diaphragm after inspiratory pressure threshold loading.

After a bout of isolated inspiratory work, such as inspiratory pressure threshold loading (IPTL), the human diaphragm can exhibit a reversible loss in contractile function, as evidenced by a decrease in transdiaphragmatic twitch pressure (PDI,TW ). Whether or not diaphragm fatigability after IPTL is affected by neural mechanisms, measured through voluntary activation of the diaphragm (D-VA) in addition to contractile mechanisms, is unknown. It is also unknown if changes in D-VA are similar between sexes given observed differences in diaphragm fatigability between males and females. We sought to determine whether D-VA decreases after IPTL and whether this was different between sexes. Healthy females (n=11) and males (n=10) completed an IPTL task with an inspired duty cycle of 0.7 and targeting an intensity of 60% maximal transdiaphragmatic pressure until task failure. PDI,TW and D-VA were measured using cervical magnetic stimulation of the phrenic nerves in combination with maximal inspiratory pressure maneuvers. At task failure, PDI,TW decreased to a lesser degree in females vs. males (87 ± 15 vs. 73 ± 12% baseline, respectively, p=0.016). D-VA decreased after IPTL but was not different between females and males (91 ± 8 vs. 88 ± 10% baseline, respectively, p=0.432). When all participants were pooled together, the decrease in PDI,TW correlated with both the total cumulative diaphragm pressure generation (R2 =0.43; p=0.021) and the time to task failure (TTF, R2 = 0.40; p = 0.30) whereas the decrease in D-VA correlated only with TTF (R2 =0.24; p=0.041). Our results suggest that neural mechanisms can contribute to diaphragm fatigability, and this contribution is similar between females and males following IPTL.

Effects of hypoxia on exercise-induced diaphragm fatigue in healthy males and females.

Following high-intensity, normoxic exercise there is evidence to show that healthy females, on average, exhibit less fatigue of the diaphragm relative to males. In the present study, we combined hypoxia with exercise to test the hypothesis that males and females would develop a similar degree of diaphragm fatigue following cycle exercise at the same relative exercise intensity. Healthy young participants (n=10 male; n=10 female) with a high aerobic capacity (120% predicted) performed two time-to-exhaustion (TTE; ~85% maximum) cycle tests on separate days breathing either a normoxic or hypoxic (FiO2 =0.15) gas mixture. Fatigue of the diaphragm was assessed in response to cervical magnetic stimulation prior to, immediately post-exercise, 10-, 30-, and 60-min post-exercise. Males and females had similar TTE durations in normoxia (males: 690 ± 181 s; females: 852 ± 401 s) and hypoxia (males: 381 ± 160 s; females: 400 ± 176 s) (p > 0.05). Cycling time was significantly shorter in hypoxia versus normoxia in both males and females (p < 0.05) and did not differ on the basis of sex (p > 0.05). Following the hypoxic TTE tests, males and females experienced a similar degree of diaphragm fatigue compared to normoxia as shown by 20%-25% reductions in transdiaphragmatic twitch pressure. This occurred despite the fact that exercise time in hypoxia was substantially shorter relative to normoxia and the cumulative diaphragm work was lower. We also observed that females did not fully recover from diaphragm fatigue in hypoxia, whereas males did (p < 0.05). Sex differences in the rate of diaphragm contractility recovery following exercise in hypoxia might relate to sex-based differences in substrate utilization or diaphragm blood flow.

Altering magnetic field strength impacts the assessment of diaphragmatic function using cervical magnetic stimulation

Quantifying diaphragm neuromuscular function using cervical magnetic stimulation (CMS) typically uses only a single stimulator (1-Stim) which may be inadequate to maximally stimulate the phrenic nerves. We questioned if using two stimulators (2-Stim) together alters diaphragm neuromuscular function at baseline and following inspiratory pressure threshold loading. Six (n = 3 female) healthy young participants were instrumented with esophageal and gastric balloon tipped catheters and electrodes over the 7–8th intercostal space. With either 1-Stim or 2-Stim an incremental protocol, where the stimulator intensity was progressively increased was completed prior to a series of potentiated twitches. The inspiratory threshold loading test consisted of loaded breathing to failure. Compared to 1-Stim, 2-Stim resulted in significantly greater unpotentiated Pditw and M-waves during the incremental protocol (both p < 0.01). Similarly, 2-Stim resulted in greater potentiated Pditw (31 ± 8 vs. 41 ± 9 cmH2O; p = 0.02) and M-waves (6.4 ± 2.9 vs. 8.6 ± 2.4 V; p = 0.02). Our findings suggest that CMS using 1-Stim is unlikely to generate a sufficient magnetic field to maximally stimulate the phrenic nerves and may underestimate diaphragm function.

Role of Cervical Spinal Magnetic Stimulation in Improving Posture and Functional Ambulation of Patients with Relapsing Remitting Multiple Sclerosis

Balance impairment is one of the hallmarks of early MS. Proprioceptive deficit was found to be one of the main causes of this imbalance. The cervical enlargement has a strong proprioceptive system, with its projections to the reticular formation and the central pattern generators, helping in rhythmic pattern generation and alternate leg movements. Repetitive trans-spinal magnetic stimulation (rTSMS) is a noninvasive technique, which can trigger massive proprioceptive afferents. Therefore, it has the potential of improving proprioceptive deficits and motor control. Objective. To determine the effectiveness of repetitive cervical magnetic stimulation in improving functional ambulation of patients with relapsing remitting multiple sclerosis (RRMS). Design. Prospective sequential clinical trial. Setting. University and academic hospital. Participants. A total of 32 participants (N = 32) with RRMS. Interventions. Outpatient rehabilitation. The 32 patients received 10 sessions over two weeks of 20 Hz cervical spinal magnetic stimulation (SMS). Both groups were assessed at baseline, after 2 weeks, then one month later. Patients were enrolled as a control group at first and received Sham SMS, and then a wash out period of one month was done for all the patients, followed by a baseline assessment. Second, the same 32 patients rejoined as the active group, which received real magnetic stimulation. Both groups performed an intensive physical therapy program with the spinal magnetic stimulation. Main Outcome Measures. Extended Disability status score (EDSS), Timed up and Go test (TUG), Mini-Best test, dynamic posturography sensory organization composite score, and motor composite score. Results. Thirty-two RRMS patients with EDSS range from 1.5 to 6. They showed statistically significant difference between active and control groups in Mini-Best test score. We divided our patients according to EDSS into 3 subgroups: (a) mild: ≤2.5, (b) moderate: 3-5.5, and (c) severe: ≥6. Mild cases showed significant differences in EDSS score, TUG test, Mini-Best test, and dynamic posturography sensory composite scale. The effect size between the different patient subgroups was also measured and showed highly significant improvements in all measured parameters among our mild patients, indicating that this subgroup could be the best responders to cervical repetitive high-frequency magnetic stimulation. Moderate cases showed highly significant improvement in TUG score and Mini-Best test and significant change in EDSS score and the dynamic posturography sensory composite score. Severe cases showed only significant improvements in TUG, Mini-Best test, and sensory composite score. Conclusion. Cervical repetitive magnetic stimulation can help improve balance and functional ambulation and decreases the risk of falls in RRMS patients, especially in the mild, low disability cases.

Corrigendum: Pressure measurement characteristics of a micro‐transducer and balloon catheters

Physiological ReportsVolume 10, Issue 21 e15500 ERRATUMOpen Access Corrigendum: Pressure measurement characteristics of a micro-transducer and balloon catheters This article corrects the following: Pressure measurement characteristics of a micro-transducer and balloon catheters William MacAskill, Ben Hoffman, Michael A. Johnson, Graham R. Sharpe, Dean E. Mills, Volume 9Issue 8Physiological Reports First Published online: May 2, 2021 First published: 02 November 2022 https://doi.org/10.14814/phy2.15500AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL The authors of the article by William MacAskill et al. (2021) noticed an error in the figure legends of their article. The correct figure legends are as follows: Figure 2. Experiment 1 – in vitro: Ensemble average waveforms (each from 100 waves) from the micro-transducer catheter (MC), balloon catheter (BC) and reference (RP) pressures in response to chamber pressures of 25, 50, 75 and 100 cmH2O with a constant pressurisation time of 0.2 s. Figure 3. Experiment 2 – in vivo: Representative oesophageal, gastric and transdiaphragmatic pressure characteristics for the balloon catheters and micro-transducer catheter following cervical magnetic stimulation at 100% of stimulator power output. Three repeated twitches from one participant are shown superimposed. Stimulation artefacts are marked with an arrow (↑). Figure 4. Experiment 2 – in vivo: Oesophageal, gastric and transdiaphragmatic pressure amplitudes (top panels) and areas (bottom panels) for balloon catheters and micro-transducer catheter following cervical magnetic stimulation at increasing stimulation intensities. Data are mean ± SD and pooled from visits 1 and 2. Significant difference between catheters (*P < 0.05; **P < 0.01). Figure 5. Bland–Altman plots of oesophageal, gastric and transdiaphragmatic pressure amplitudes (top panels) and areas (bottom panels) between balloon catheters (BC) and micro-transducer catheter (MC) following cervical magnetic stimulation at increasing stimulation intensities. Bias is represented by the solid line and the limits of agreement by the dotted lines (± 1.96 SD). Each participant has one datapoint per stimulation power and each datapoint was calculated as the mean value from visits 1 and 2. REFERENCE MacAskill, W., Hoffman, B., Johnson, M. A., Sharpe, G. R., & Mills, D. E. (2022). Pressure measurement characteristics of a micro-transducer and balloon catheters. Physiol Rep, 10, e14831. https://doi.org/10.14814/phy2.14831 Volume10, Issue21November 2022e15500 ReferencesRelatedInformation

Diaphragm Voluntary Activation After Inspiratory Pressure Threshold Loading In Healthy Humans

Inspiratory pressure threshold loading (IPTL) elicits a reduction in diaphragm contractile function (transdiaphragmatic twitch pressure; PDI,TW). It is unknown if diaphragm fatigability after IPTL is also mediated by neural mechanisms (diaphragm voluntary activation; D-VA) or if it differs on the basis of sex. PURPOSE: We sought to determine if D-VA decreases after IPTL and whether this was different between sexes. METHODS: Healthy participants (11F; 10 M) performed IPTL to task failure with an inspired duty cycle of 0.7 at 60% PDI,MAX. Cervical magnetic stimulation of the phrenic nerves was used to assess PDI,TW and D-VA. The relationship between fatigability outcomes (PDI,TW and D-VA), time to task failure, and cumulative diaphragm work were tested to explore how each factor contributes to diaphragm fatigability. RESULTS: Main effects of time (p < 0.001) and sex (p = 0.030), along with an interaction effect (p = 0.007) were observed when examining the changes in PDI,TW after IPTL. Specifically, immediately following IPTL, the decrease in PDI,TW was greater in males compared to females (24 ± 17 vs. 13 ± 15%points; p = 0.016). D-VA was 91 ± 8%baseline in males and 88 ± 11%baseline in females immediately following IPTL. We observed main effects of time, (p < 0.001) but neither the effect of sex (p = 0.177) nor the interaction between sex and time (p = 0.304) were significant, suggesting that D-VA decreases after IPTL similarly in males and females. The decrease in PDI,TW correlated with both the total cumulative diaphragm work (R2 = 0.43; p = 0.021) and time to task failure (R2 = 0.40; p = 0.030), whereas the decrease in D-VA was significantly correlated with time to task failure (R2 = 0.24; p = 0.041) and not cumulative diaphragm work (R2 = 0.19; p = 0.079). CONCLUSION: Our results indicate that neural mechanisms contribute to diaphragm fatigability and this contribution is similar between females and males after IPTL. A decrease in contractile function can be partially explained by both the amount of work performed and the total time of the IPTL task. Decreases in D-VA appear to be influenced primarily by the total time spent performing the IPTL task rather than the amount of work performed. Moreover, these contributing factors appear to be independent of sex. Supported by the Natural Sciences and Engineering Research Council of Canada.

Neurophysiological Correlates in Patients with Syringomyelia and Chiari Malformation: The Cortico-Diaphragmatic Involvement.

Purpose. Brainstem syndromes have frequently been reported in Chiari syndrome and in syringobulbia; previous studies have shown that determining the central motor conduction time (CMCT) along the circuit of the phrenic nerve makes the assessment of the voluntary control of the respiratory pathway possible. In our study, we evaluated the transcranial magnetic stimulation (TMS) of the phrenic nerve in patients affected by Chiari syndrome and/or syringomyelia (Syr) with the aim of identifying subclinical neurophysiological alterations. Methods. One hundred patients (75 females; average age: 51 ± 13.08 SD; range: 18–76) affected by Chiari syndrome and/or Syr without dyspnea were selected. The magnetic stimulation of the second motor neuron correlating with the phrenic nerve was performed using cervical magnetic stimulation (C5-MEP); the cortical MEP after magnetic stimulation (Cz-MEP) was recorded by magnetic stimulation of the motor cortex (areas corresponding to the diaphragm). The CMCT was calculated. The differences between the patients and controls were calculated (Student’s t test). Results. In 13% of the patients, the Cz-MEP were absent bilaterally, and the CMCT was not evaluable. In all these cases, bulbar/cervical Syr was present at MRI; in 10 of them, this was associated with CM1. A bilateral response was obtained in all the other patients (87%), and the CMCTs were normal. All the patients with alterations/absence of Cz-MEP presented bulbar/cervical Syr at MRI. The C5-MEP latency was prolonged or absent in 48%; of these, 84% presented bulbar/cervical Syr associated with CM1 at MRI. The C5-MEP latency values were significantly higher in the group of patients. Conclusions. Neurophysiological alterations of the diaphragmatic pathway were recorded in a group of Chiari syndrome and, particularly, in bulbar/cervical Syr. Future studies with larger cohorts of patients are needed to further assess the specific role of the TMS of the phrenic nerve in CM/Syr patients.

Acute intermittent hypercapnic-hypoxia elicits central neural respiratory motor plasticity in humans.

Acute intermittent hypoxia (AIH) elicits long-term facilitation (LTF) of respiration. Although LTF is observed when CO2 is elevated during AIH in awake humans, the influence of CO2 on corticospinal respiratory motor plasticity is unknown. Thus, we tested the hypotheses that acute intermittent hypercapnic-hypoxia (AIHH): (1) enhances cortico-phrenic neurotransmission (reflecting volitional respiratory control); and (2) elicits ventilatory LTF (reflecting automatic respiratory control). Eighteen healthy adults completed four study visits. Day 1 consisted of anthropometry and pulmonary function testing. On Days 2, 3 and 4, in a balanced alternating sequence, participants received: AIHH, poikilocapnic AIH, and normocapnic-normoxia (Sham). Protocols consisted of 15, 60s exposures with 90s normoxic intervals. Transcranial (TMS) and cervical (CMS) magnetic stimulation were used to induce diaphragmatic motor-evoked potentials and compound muscle action potentials, respectively. Respiratory drive was assessed via mouth occlusion pressure (P0.1 ), and minute ventilation measured at rest. Dependent variables were assessed at baseline and 30-60min after exposures. Increases in TMS-evoked diaphragm potential amplitudes were observed following AIHH vs. Sham (+28±41%, P=0.003), but not after AIH. No changes were observed in CMS-evoked diaphragm potential amplitudes. Mouth occlusion pressure also increased after AIHH (+21±34%, P=0.033), but not after AIH. Ventilatory LTF was not observed after any treatment. We demonstrate that AIHH elicits central neural mechanisms of respiratory motor plasticity and increases resting respiratory drive in awake humans. These findings may have important implications for neurorehabilitation after spinal cord injury and other neuromuscular disorders compromising breathing. KEY POINTS: The occurrence of respiratory long-term facilitation following acute exposure to intermittent hypoxia is believed to be dependent upon CO2 regulation - mechanisms governing the critical role of CO2 have seldom been explored. We tested the hypothesis that acute intermittent hypercapnic-hypoxia (AIHH) enhances cortico-phrenic neurotransmission in awake healthy humans. The amplitude of diaphragmatic motor-evoked potentials induced by transcranial magnetic stimulation was increased after AIHH, but not the amplitude of compound muscle action potentials evoked by cervical magnetic stimulation. Mouth occlusion pressure (P0.1 , an indicator of neural respiratory drive) was also increased after AIHH, but not tidal volume or minute ventilation. Thus, moderate AIHH elicits central neural mechanisms of respiratory motor plasticity, without measurable ventilatory long-term facilitation in awake humans.

Sex Differences in Diaphragm Voluntary Activation after Exercise.

The female diaphragm develops less fatigue after high-intensity exercise compared with males. Diaphragm fatigability is typically defined as a decrease in transdiaphragmatic twitch pressure (Pdi,TW) and represents the contractile function of the muscle. However, it is unclear whether this sex difference persists when examining changes in voluntary activation, which represents a neural mechanism contributing to fatigability. This study aimed to determine if high-intensity cycling results in a decrease in diaphragm voluntary activation (D-VA) and to explore if the decrease in D-VA is different between sexes. Twenty-five participants (15 females) completed a single bout of high-intensity constant load cycling. D-VA and Pdi,TW were measured before and after exercise using cervical magnetic stimulation of the phrenic nerves to assess diaphragm fatigability. Participants were of similar aerobic fitness when expressed relative to predicted values (females: 114% ± 25% predicted, males: 111% ± 11% predicted; P = 0.769). Pdi,TW decreased relative to baseline to 85.2% ± 16.7% and 70.3% ± 12.4% baseline (P = 0.012) in females and males, respectively, immediately after exercise. D-VA also decreased in both females and males immediately after exercise. The decrease in D-VA was less in females compared with males (95.4% ± 4.9% baseline vs 87.4% ± 10.8% baseline, respectively; P = 0.018). D-VA decreases after whole-body exercise in both females and males, although the magnitude of the decrease is not as large in females compared with males. The findings of this study suggest that the female diaphragm is more resistant to both contractile and neural mechanisms of fatigability after whole-body exercise.

Rostral-Caudal Effect of Cervical Magnetic Stimulation on the Diaphragm Motor Evoked Potential after Cervical Spinal Cord Contusion in the Rat.

The present study was designed to investigate the rostral-caudal effect of spinal magnetic stimulation on diaphragmatic motor-evoked potentials after cervical spinal cord injury. The diaphragm electromyogram was recorded in rats that received a laminectomy or a left midcervical contusion at the acute (1 day), subchronic (2 weeks), or chronic (8 weeks) injury stages. The center of a figure-eight coil was placed at 30 mm lateral to bregma on the left side, and the effect of magnetic stimulation was evaluated by stimulating the rostral, middle, and caudal cervical regions in spontaneously breathing rats. The results demonstrated that cervical magnetic stimulation induced intensity-dependent motor-evoked potentials in the bilateral diaphragm in both uninjured and contused rats; however, the left diaphragm exhibited a higher amplitude and earlier onset than the right diaphragm. Moreover, the intensity-response curve was shifted upward in the rostral-to-caudal direction of magnetic stimulation, suggesting that caudal cervical magnetic stimulation produced more robust diaphragmatic motor-evoked potentials compared with rostral cervical magnetic stimulation. Interestingly, the diaphragmatic motor-evoked potentials were similar between uninjured and contused rats during cervical magnetic stimulation despite weaker inspiratory diaphragmatic activity in contused rats. In addition, in contused animals but not uninjured animals, diaphragmatic motor-evoked potential amplitudes were greater at the chronic stage than during earlier injury stages. These results demonstrated that cervical magnetic stimulation can excite the residual phrenic motor circuit to activate the diaphragm in the presence of a significant lesion in the cervical spinal cord. These findings indicate that this non-invasive approach is effective for modulating diaphragmatic excitability after cervical spinal cord injury.

Diaphragm Motor-Evoked Potential Induced by Cervical Magnetic Stimulation following Cervical Spinal Cord Contusion in the Rat.

Cervical spinal injury is typically associated with respiratory impairments due to damage to bulbospinal respiratory pathways and phrenic motoneurons. Magnetic stimulation is a non-invasive approach for the evaluation and modulation of the nervous system. The present study was designed to examine whether cervical magnetic stimulation can be applied to evaluate diaphragmatic motor outputs in a pre-clinical rat model of cervical spinal injury. The bilateral diaphragm was monitored in anesthetized rats using electromyogram at the acute, subchronic, and chronic stages following left mid-cervical contusion. The center of a figure-of-eight coil was placed 20 mm caudal to bregma to stimulate the cervical spinal cord. The results demonstrated that a single magnetic stimulation can evoke significant motor-evoked potentials in the diaphragms of uninjured animals when the animal's head was placed 30 mm right or left from the center of the coil. The spontaneous bursting of the diaphragm was significantly attenuated by contusion injury at all-time-points post-injury. However, the threshold of the diaphragmatic motor-evoked potential was reduced, and the amplitude of the diaphragmatic motor-evoked potential was enhanced in response to cervical magnetic stimulation at the acute injury stage. Moreover, the motor-evoked potentials of the bilateral diaphragm in animals with contusions were generally larger when the coil was placed at the left spinal cord at the subchronic and chronic injury stages. These results suggested that cervical magnetic stimulation can be used to examine the excitability of phrenic motor outputs post-injury, and magnetic stimulation applied more laterally may be more effective for triggering diaphragmatic motor-evoked potentials.

Diaphragm motor evoked potential induced by cervical magnetic stimulation following cervical spinal cord contusion in the rat

Cervical spinal cord injury is usually associated with respiratory impairments due to damage of bulbospinal respiratory pathways and cervical phrenic motoneurons. The magnetic stimulation is a non-invasive and safe approach to evaluate and modulate the central and peripheral nervous system. The purpose of the present study was to examine whether cervical magnetic stimulation can be applied to evaluate the diaphragmatic motor outputs in a pre-clinical rodent model of cervical spinal cord injury. The bilateral diaphragm electromyogram was measured in anesthetized rats at the acute, subchronic and chronic stage following left mid-cervical spinal cord contusion. The center of figure-of-eight coil was placed 20 mm caudal to the Bregma to stimulate the cervical spinal cord. The results demonstrated that cervical magnetic stimulation can evoke a significant diaphragm motor evoked potential in uninjured animals when the coil was placed at the lateral position (3 cm right or left to the midline). The spontaneous bursting of diaphragm was significantly attenuated by cervical spinal cord contusion at all-time points post-injury. However, the threshold of diaphragm motor evoked potential was reduced and the amplitude of diaphragm motor evoked potential was augmented in response to cervical magnetic stimulation at the acute injured stage. In addition, the motor evoked potential of bilateral diaphragm in contused animals was generally greater when the coil was placed at the left spinal cord at the subchronic and chronic injured stages. These results suggested that cervical magnetic stimulation can be used to examine the excitability of phrenic motor outputs, and the lateral cervical magnetic stimulation may be more effective to trigger the diaphragm motor evoked potential.

Effect of acute intermittent hypoxia on cortico-diaphragmatic conduction in healthy humans

Acute intermittent hypoxia (AIH) is a strategy to improve motor output in humans with neuromotor impairment. A single AIH session increases the amplitude of motor evoked potentials (MEP) in a finger muscle (first dorsal interosseous), demonstrating enhanced corticospinal neurotransmission. Since AIH elicits phrenic/diaphragm long-term facilitation (LTF) in rodent models, we tested the hypothesis that AIH augments diaphragm MEPs in humans. Eleven healthy adults (7 males, age = 29 ± 6 years) were tested. Transcranial and cervical magnetic stimulation were used to induce diaphragm MEPs and compound muscle action potentials (CMAP) recorded by surface EMG, respectively. Stimulus-response curves were generated prior to and 30–60 min after AIH. Diaphragm LTF was assessed by measurement of integrated EMG burst amplitude and frequency during eupnoeic breathing before and after AIH. Following baseline measurements, AIH was delivered from an oxygen generator connected to a facemask under poikilocapnic conditions (15 one minute episodes of 9% inspired oxygen with one minute room air intervals). There were no detectable changes in MEP (−1.5 ± 12.1%, p = 0.96) or CMAP (+0.1 ± 7.8%, p = 0.97) amplitudes across the stimulus-response curve. At stimulation intensities approximating 50% of the difference between minimum and maximum baseline amplitudes, MEP and CMAP amplitudes were also unchanged (p > 0.05). Further, no AIH effect was observed on diaphragm EMG activity during eupnoea post-AIH (p > 0.05). We conclude that unlike hand muscles, poikilocapnic AIH does not enhance diaphragm MEPs or produce diaphragm LTF in healthy humans.

Diaphragm Dysfunction as a Determinant of Persisting Dyspnoea in Patients One Year after Invasive Mechanical Ventilation Due to COVID-19 Related ARDS

Background: Some patients with coronavirus disease 2019 (COVID-19) experience prolonged fatigue and dyspnoea without objective impairment of pulmonary or cardiac function. This study determined diaphragm function and its central voluntary activation as a possible pathophysiological correlate after severe COVID-19 acute respiratory distress syndrome (ARDS).Methods:Ten patients with severe COVID-19 ARDS treated with invasive mechanical ventilation (IMV) (6 female, age 56±14 years, 63±45 days of IMV) and ten matched healthy controls underwent pulmonary function tests (PFTs), 6-minute walk test, echocardiography, diaphragm ultrasound, and invasive recording of twitch transdiaphragmatic pressure (twPdi) following magnetic diaphragm stimulation. Twitch interpolation was used to determine the diaphragm voluntary activation index (DVAI); reflecting central diaphragm activation.Findings: One year post discharge, neither PFTs nor echocardiography were indicative of significant abnormalities in severe COVID-19 survivors. However, six patients reported persisting dyspnoea on exertion (severe in two, moderate in four). On ultrasound, the diaphragm thickening ratio was lower in patients versus controls (1.87±0.37 vs. 2.76±0.72; pInterpretation: Inspiratory muscle dysfunction with impaired central voluntary activation of the diaphragm is present one year after severe COVID-19 ARDS treated with IMV, and relates to dyspnoea.Trial Registration: This prospective case-control study was registered with number, (NCT04854863)Funding: None to declare. Declaration of Interest: The authors have no conflicts of interest to disclose.Ethical Approval: This study was approved by the local ethics committee (Ethikkommission an der Medizinischen Fakultät der Rheinisch-Westfälischen Technischen Hochschule Aachen, CTCA-A-Nr. 20-515, AZ EK 443/20).

Sex differences in diaphragmatic fatigue: Effects of hypoxia during inspiratory loading.

Under normoxic conditions, both healthy female and male diaphragms fatigue at a similar degree when matched for absolute diaphragmatic work during inspiratory loading. We investigated whether similarities in diaphragm fatigability persist under acute hypoxic conditions. We found that, in acute hypoxia, fatigue of the diaphragm is greater in women compared to men, whereas the magnitude of fatigue in normoxia did not differ between sexes. When matched for maximal diaphragm strength, women and men had a similar pressor response to work-matched inspiratory loading, independent of oxygen availability. In normoxia, women and men display a comparable magnitude of diaphragmatic fatigue (DF) after work-matched inspiratory loading. Whether these sex similarities are maintained under acute hypoxic conditions is unknown. We investigated the influence of acute hypoxia during work-matched inspiratory pressure-threshold loading (PTL) on DF in healthy women (n=8) and men (n=8). Two 5min isocapnic PTL tasks targeting a transdiaphragmatic pressure (Pdi ) of 92cmH2 O in normoxia and hypoxia (8% O2 ) were performed on separate days (≥48h). DF was quantified by twitch Pdi (Pdi,tw ) via cervical magnetic stimulation post-PTL. Women and men had similar maximal Pdi (Pdi,max ; women: 171±16, men: 178±20cmH2 O) and relative target workload (women: 54±5%, men: 53±6% Pdi,max ). The absolute cumulative diaphragmatic work did not differ between sexes in normoxia (women: 12,653±1796cmH2 Os-1 , men: 13,717±1231cmH2 Os-1 ; P=0.202) or hypoxia (women: 11,624±1860cmH2 Os-1 , men: 12 722±1502cmH2 Os-1 ; P=0.189). In normoxia, the magnitude of reduction in Pdi,tw post-PTL was similar between sexes (women: -21.1±8.4%, men: -22.5±4.9 %; P=0.193); however, a higher degree of DF was observed in women compared to men following PTL in acute hypoxia (women: -27.6±7.7%, men: -23.4±9.6%, P=0.019). We conclude that the female diaphragm is more susceptible to fatigue after inspiratory loading under acute hypoxic conditions. This finding may be related to sex differences in diaphragm muscle metabolism, such as fibre type composition, contractile properties, substrate utilisation and blood perfusion.

Heart Failure Results in Inspiratory Muscle Dysfunction Irrespective of Left Ventricular Ejection Fraction

Background: Exercise intolerance in heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF) results from both cardiac dysfunction and skeletal muscle weakness. Respiratory muscle dysfunction with restrictive ventilation disorder may be present irrespective of left ventricular ejection fraction and might be mediated by circulating pro-inflammatory cytokines. Objective: To determine lung and respiratory muscle function in patients with HFrEF/HFpEF and to determine its associations with exercise intolerance and markers of systemic inflammation. Methods: Adult patients with HFrEF (n = 22, 19 male, 61 ± 14 years) and HFpEF (n = 8, 7 male, 68 ± 8 years) and 19 matched healthy control subjects underwent spirometry, measurement of maximum mouth occlusion pressures, diaphragm ultrasound, and recording of transdiaphragmatic and gastric pressures following magnetic stimulation of the phrenic nerves and the lower thoracic nerve roots. New York Heart Association (NYHA) class and 6-min walking distance (6MWD) were used to quantify exercise intolerance. Levels of circulating interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) were measured using ELISAs. Results: Compared with controls, both patient groups showed lower forced vital capacity (FVC) (p < 0.05), maximum inspiratory pressure (PI_max), maximum expiratory pressure (PE_max) (p < 0.05), diaphragm thickening ratio (p = 0.01), and diaphragm strength (twitch transdiaphragmatic pressure in response to supramaximal cervical magnetic phrenic nerve stimulation) (p = 0.01). In patients with HFrEF, NYHA class and 6MWD were both inversely correlated with FVC, PI_max, and PE_max. In those with HFpEF, there was an inverse correlation between amino terminal pro B-type natriuretic peptide levels and FVC (r = −0.77, p = 0.04). In all HF patients, IL-6 and TNF-α were statistically related to FVC. Conclusions: Irrespective of left ventricular ejection fraction, HF is associated with respiratory muscle dysfunction, which is associated with increased levels of circulating IL-6 and TNF-α.

Ultrafast ultrasound coupled with cervical magnetic stimulation for non-invasive and non-volitional assessment of diaphragm contractility.

Twitch transdiaphragmatic pressure elicited by cervical magnetic stimulation of the phrenic nerves is a fully non-volitional method for assessing diaphragm contractility in humans, yet it requires invasive procedures such as oesophageal and gastric catheter balloons. Ultrafast ultrasound enables a very high frame rate allowing the capture of transient events, such as muscle contraction elicited by nerve stimulation (twitch). Whether indices derived from ultrafast ultrasound can be used as an alternative to the invasive measurement of twitch transdiaphragmatic pressure is unknown. Our findings demonstrate that maximal diaphragm tissue velocity assessed using ultrafast ultrasound following cervical magnetic stimulation is reliable, sensitive to change in cervical magnetic stimulation intensity, and correlates to twitch transdiaphragmatic pressure. This approach provides a novel fully non-invasive and non-volitional tool for the assessment of diaphragm contractility in humans. Measuring twitch transdiaphragmatic pressure (Pdi,tw ) elicited by cervical magnetic stimulation (CMS) is considered as a reference method for the standardized evaluation of diaphragm function. Yet, the measurement of Pdi requires invasive oesophageal and gastric catheter-balloons. Ultrafast ultrasound is a non-invasive imaging technique enabling frame rates high enough to capture transient events such as evoked muscle contractions. This study investigated relationships between indices derived from ultrafast ultrasound and Pdi,tw , and how these indices might be used to estimate Pdi,tw . CMS was performed in 13healthy volunteers from 30% to 100% of maximal stimulator intensity in units of 10% in a randomized order. Pdi,tw was measured and the right hemidiaphragm was imaged using a custom ultrafast ultrasound sequence with 1kHz framerate. Maximal diaphragm axial velocity (Vdi ,max ) and diaphragm thickening fraction (TFdi,tw ) were computed. Intra-session reliability was assessed. Repeated-measures correlation (R) and Spearman correlation coefficients (ρ) were used to assess relationships between variables. Intra-session reliability was strong for Pdi,tw and Vdi,max and moderate for TFdi,tw . Vdi,max correlated with Pdi,tw in all subjects (0.64<ρ<1.00, R=0.75; all P < 0.05). TFdi,tw correlated with Pdi,tw in eight subjects only (0.85<ρ<0.93, R=0.69; all P<0.05). Coupling ultrafast ultrasound and CMS shows promise for the non-invasive and fully non-volitional assessment of diaphragm contractility. This approach opens up the prospect of both diagnosis and follow-up of diaphragm contractility in clinical populations.

Reliability of diaphragm voluntary activation measurements in healthy adults

Voluntary activation can be used to assess central fatigue of the diaphragm after tasks such as exercise or inspiratory muscle loading. Cervical magnetic stimulation (CMS) of the phrenic nerves elicits an involuntary contraction, or twitch, of the diaphragm. This twitch is quantified based on a measure of transdiaphragmatic pressure and can be used to evaluate diaphragm contractile function and diaphragm voluntary activation (diaphragm-VA). The test-retest reliability of diaphragm-VA using CMS is currently unknown. Thirteen participants (4 male, 9 female; aged 25 ± 3 years) performed a series of interpolated twitch manoeuvres, which included a maximal inspiratory effort against a semi-occluded mouthpiece and 2 CMS-stimuli, 1 during the inspiratory manoeuvre and 1 after when the participant returned to functional residual capacity to quantify diaphragm-VA. Intraclass correlation coefficients (ICCs) and standard error of measurement (SEM) measured between-day and within-session reliability of diaphragm-VA, respectively. Maximal diaphragm-VA values were 91% (SD: 6; SEM: 3.9) and 92% (SD: 5; SEM: 2.2) during visits 1 and 2 (p = 0.68), respectively, and displayed "good" between-day reliability (ICC: 0.88; 95% confidence interval: 0.67-0.95; SEM: 2.7). Our results suggest that assessing diaphragm-VA using CMS is reliable in young healthy adults. Measuring diaphragm-VA may provide additional insight into the consequences and mechanisms of diaphragm fatigue. Novelty: Magnetic stimulation of the phrenic nerves can reliably measure voluntary activation of the diaphragm. Diaphragm voluntary activation can be used to provide additional insight into fatigability of the diaphragm.