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In a randomized trial, pulsed field ablation was noninferior to cryoballoon ablation with respect to the incidence of a first recurrence of atrial tachyarrhythmia, as assessed by continuous rhythm monitoring.

Spinal cord injuries often occur at the cervical level above the phrenic motor pools, which innervate the diaphragm. The effects of impaired breathing are a leading cause of death from spinal cord injuries, underscoring the importance of developing strategies to restore respiratory activity. Here we show that, after cervical spinal cord injury, the expression of chondroitin sulphate proteoglycans (CSPGs) associated with the perineuronal net (PNN) is upregulated around the phrenic motor neurons. Digestion of these potently inhibitory extracellular matrix molecules with chondroitinase ABC (denoted ChABC) could, by itself, promote the plasticity of tracts that were spared and restore limited activity to the paralysed diaphragm. However, when combined with a peripheral nerve autograft, ChABC treatment resulted in lengthy regeneration of serotonin-containing axons and other bulbospinal fibres and remarkable recovery of diaphragmatic function. After recovery and initial transection of the graft bridge, there was an unusual, overall increase in tonic electromyographic activity of the diaphragm, suggesting that considerable remodelling of the spinal cord circuitry occurs after regeneration. This increase was followed by complete elimination of the restored activity, proving that regeneration is crucial for the return of function. Overall, these experiments present a way to markedly restore the function of a single muscle after debilitating trauma to the central nervous system, through both promoting the plasticity of spared tracts and regenerating essential pathways. Axonal regeneration after spinal injury Patients with spinal cord injuries in the neck area often need mechanical ventilators to help them breathe, and impaired breathing is a leading cause of death in these patients. Two factors combine to make recovery difficult. First, an injury above the fourth cervical vertebra disrupts the passage of nerve impulses from the respiratory centre in the brainstem to the phrenic motor nuclei in the spinal cord, and second, in the event of injury, adult spinal cord axons tend not to regenerate. Working in a rat model of spinal cord injury, Jerry Silver and colleagues have identified an upregulation of extracellular matrix molecules that impairs axonal regeneration following injury. Using a strategy of specific extracellular component digestion with chondroitinase, combined with peripheral nerve autografting across the damaged section of the spinal cord, the authors demonstrate a significant recovery of respiratory activity after axon regeneration. This study suggests that regeneration and restoration of diaphragm function may be possible after some types of spinal cord trauma.

Cholesterol is one of the major components of plasma membrane, where its distribution is nonhomogeneous and it participates in lipid raft formation. In skeletal muscle cholesterol and lipid rafts seem to be important for excitation-contraction coupling and for neuromuscular transmission, involving cholesterol-rich synaptic vesicles. In the present study, nerve and muscle stimulation-evoked contractions were recorded to assess the role of cholesterol in contractile function of mouse diaphragm. Exposure to cholesterol oxidase (0.2 U/ml) and cholesterol-depleting agent methyl-β-cyclodextrin (1 mM) did not affect markedly contractile responses to both direct and indirect stimulation at low and high frequency. However, methyl-β-cyclodextrin at high concentration (10 mM) strongly decreased the force of both single and tetanus contractions induced by phrenic nerve stimulation. This decline in contractile function was more profoundly expressed when methyl-β-cyclodextrin application was combined with phrenic nerve activation. At the same time, 10 mM methyl-β-cyclodextrin had no effect on contractions upon direct muscle stimulation at low and high frequency. Thus, strong cholesterol depletion suppresses contractile function mainly due to disturbance of the neuromuscular communication, whereas muscle fiber contractility remains resistant to decline.

The combined use of subcostal ultrasonography and respiratory manometry represents a novel, integrative method for quantifying diaphragm contractile function (force, velocity and power). We evaluated the technical feasibility, construct validity and within‐day test–retest reliability of this method during non‐volitional, volitional and reflexive respiratory perturbations in healthy adults. Two independent cohorts were studied. In Experiment 1 (n = 10), diaphragm excursion (subcostal ultrasonography) and transdiaphragmatic pressure (Pdi, manometry) were measured during unilateral magnetic phrenic nerve stimulation (non‐potentiated and potentiated twitches, paired stimuli at 10–100 Hz) and maximal sniffs. In Experiment 2 (n = 8), the same measurements were obtained during progressive CO2 rebreathing. All protocols were repeated after 20 min of rest. Diaphragm velocity and power were calculated as excursion/time and Pdi × velocity, respectively. Ultrasound analysis was successful in >95% of cases. Potentiated twitches elicited greater Pdi, excursion and power than non‐potentiated twitches, with responses increasing at higher stimulation frequencies. Reliability improved with potentiation and high‐frequency stimulation and was moderate to excellent for peak responses during sniffs and CO2 rebreathing (ICC3,k = 0.70–0.94) but poor for slope‐based measures (ICC3,k ≤ 0.20). During CO2 rebreathing, excursion and velocity correlated strongly with inspiratory tidal volume (r = 0.83, P < 0.001) and mean inspiratory flow (r = 0.69, P < 0.001), respectively. These findings demonstrate that subcostal ultrasonography combined with manometry is a feasible, valid and reliable method for assessing diaphragm contractile function across non‐volitional, volitional and reflexive perturbations. With further refinement, this integrated method has translational potential for mechanistic research and clinical application. What is the central question of this study? Does subcostal ultrasonography combined with respiratory manometry provide a feasible, valid and reliable means of assessing of diaphragm contractile properties (force, velocity and power) during non‐volitional, volitional and reflexive respiratory perturbations in healthy humans? What is the main finding and its importance? The combined method was technically feasible, demonstrated strong construct validity, and showed acceptable test–retest reliability for most indices during unilateral magnetic phrenic nerve stimulation, maximal sniffs and CO2 rebreathing. This method enables comprehensive assessment of diaphragm function across a range of contractile states and has translational potential for mechanistic research and clinical evaluation.

Objective: This study aimed to analyze the cases of phrenic nerve injury caused by the percutaneous microwave ablation of lung tumors conducted at our center and to explore the risk factors. Materials and Methods: The data of 455 patients who underwent the percutaneous microwave ablation of lung tumors at the Department of Interventional Radiology, First Affiliated Hospital of Fujian Medical University from July 2017 to October 2021, were retrospectively analyzed. The cases of phrenic nerve injury after the percutaneous ablation were reported to analyze the risk factors involved, such as the shortest distance between tumor margin and phrenic nerve, tumor size, and ablation energy. The groups were divided based on the shortest distance between the tumor edge and the phrenic nerve into group 1, d ≤ l cm; group 2, 1 < d ≤2 cm; and group 3, d >2 cm. Lesions with a distance ≤2 cm were compared in terms of tumor size and ablation energy. Results: Among the 455 patients included in this study, 348 had primary lung cancer, and 107 had oligometastatic cancer. A total of 579 lesions were detected, with maximum diameter of 1.27 ± 0.55 cm, and the ablation energy was 9,000 (4,800-72,000) J. Six patients developed phrenic nerve injury, with an incidence of 1.32%. For these six patients, the shortest distance from the lesion edge to the phrenic nerve was 0.75 ± 0.48 cm, and the ablation energy was 10,500 (8,400-34,650) J. There were statistically significant differences in phrenic nerve injury among groups 1, 2, and 3 (P < 0.05). In patients with a distance (d) ≤ 2 cm, there were no significant differences in tumor diameter and energy between the phrenic nerve injury group and the non-injury group (P = 0.80; P = 0.41). In five out of six patients, the diaphragm level completely recovered to the pre-procedure state, and the recovery time of the phrenic nerve was 9.60 ± 5.60 months. Another one was re-examined 11 months after the procedure, and the level of the diaphragm on the affected side had partially recovered. Conclusions: Phrenic nerve injury is a rare but not negligible complication of thermal ablation and is more likely to occur in lesions with a distance ≤2 cm from the phrenic nerve.

Impaired respiratory motor output contributes to morbidity and mortality in many neurodegenerative diseases and neurologic injuries. We investigated if expressing designer receptors exclusively activated by designer drugs (DREADDs) in the mid-cervical spinal cord could effectively stimulate phrenic motor output to increase diaphragm activation. Two primary questions were addressed: (1) does effective DREADD-mediated diaphragm activation require focal expression in phrenic motoneurons (vs. non-specific mid-cervical expression), and (2) can this method produce a sustained increase in inspiratory tidal volume? Wild-type (C57Bl/6) and ChAT-Cre mice received bilateral intraspinal (C4) injections of an adeno-associated virus (AAV) encoding the hM3D(Gq) excitatory DREADD. In wild-type mice, this produced non-specific DREADD expression throughout the mid-cervical ventral horn. In ChAT-Cre mice, a Cre-dependent viral construct was used to drive neuronal DREADD expression in the C4 ventral horns, targeting phrenic motoneurons. Diaphragm electromyograms (EMG) were recorded in isoflurane-anesthetized spontaneously breathing mice at 4–9 weeks post-AAV delivery. The DREADD ligand JHU37160 (J60) caused a bilateral, sustained (>1 hr) increase in inspiratory EMG bursting in both groups; the relative increase was greater in ChAT-Cre mice. Additional experiments in ChAT-Cre rats were conducted to determine if spinal DREADD activation could increase inspiratory tidal volume during spontaneous breathing, assessed using whole-body plethysmography without anesthesia. Three to four months after intraspinal (C4) injection of AAV driving Cre-dependent hM3D(Gq) expression, intravenous J60 resulted in a sustained (>30 min) increase in tidal volume. Subsequently, phrenic nerve recordings performed under urethane anesthesia confirmed that J60 evoked a >200% increase in inspiratory output. We conclude that targeting mid-cervical spinal DREADD expression to the phrenic motoneuron pool enables ligand-induced, sustained increases in phrenic motor output and tidal volume. Further development of this technology may enable application to clinical conditions associated with impaired diaphragm activation and hypoventilation.

Thoracic surgery rapidly induces weakness in human diaphragm fibers. The dysfunction is thought to arise from combined effects of the surgical procedures and inactivity. This project tested whether brief bouts of intraoperative hemidiaphragm stimulation would mitigate slow and fast fiber loss of force in the human diaphragm. We reasoned that maintenance of diaphragm activity with brief bouts of intraoperative phrenic stimulation would mitigate diaphragm fiber weakness and myofilament protein derangements caused by thoracic surgery. Nineteen adults (9 females, age 59 ± 12 years) with normal inspiratory strength or spirometry consented to participate. Unilateral phrenic twitch stimulation (twitch duration 1.5 ms, frequency 0.5 Hz, current 2x the motor threshold, max 25 mA) was applied for one minute, every 30 minutes during cardiothoracic surgery. Thirty minutes following the last stimulation bout, biopsies were obtained from the hemidiaphragms for single fiber force mechanics and quantitation of myofilament proteins (abundance and phosphorylation) and compared by a linear mixed model and paired t-test, respectively. Subjects underwent 6 ±  2 hemidiaphragm stimulations at 17 ±  6 mA, during 278 ±  68 minutes of surgery. Longer-duration surgeries were associated with a progressive decline in diaphragm fiber force (p < 0.001). In slow-twitch fibers, phrenic stimulation increased absolute force (+25%, p <  0.0001), cross-sectional area (+16%, p < 0.0001) and specific force (+7%, p < 0.0005). Stimulation did not alter contractile function of fast-twitch fibers, calcium-sensitivity in either fiber type, and abundance and phosphorylation of myofilament proteins. In adults without preoperative weakness or lung dysfunction, unilateral phrenic stimulation mitigated diaphragm slow fiber weakness caused by thoracic surgery, but had no effect on myofilament protein abundance or phosphorylation.

Objective: To report a new patient friendly and convenient technique for phrenic nerve conduction with alternative sites of stimulation and recording. Methods: Phrenic nerve conduction was performed in forty volunteers and ten patients of peripheral neuropathy. Active recording electrode was placed in tenth intercostal space 2.5 cm away from para-spinal muscles (mid-scapular line), reference electrode in eighth intercostal space just medial to subcostal margin with ground between stimulating and recording electrode. Stimulation was done at the level of crico-thyroid space near or under the posterior margin of sternocleidomastoid muscle. This new method was compared with existing ones. Analysis: Data was analysed using SPSS 23 version. Correlation between height, weight, body mass index, age, and chest expansion was done using bi-variate correlation. Mean latency and amplitude of the study method were compared with other methods using MANNOVA test. Results: Total of forty subjects were studied. Thirty-seven were male subjects. Mean age was 28.03 ± 9.63 years, height 168.0 ± 9.60 cm and chest expansion 3.53 ± 0.64 cm. Right sided phrenic nerve mean latency was 5.99 ± 0.629 ms and amplitude 1.088 ± 0.178 mV. Left sided phrenic nerve conductions showed mean latency of 6.02 ± 1.82 ms, amplitude of 1.092 ± 0.2912 mV. These standard deviations were smaller than what were observed with other methods suggesting increased consistency of our results. There was no correlation between phrenic nerve conduction with age, height, gender or chest expansion. Conclusion: This study method gave a better as well as consistent morphology, higher amplitude and required lower amount of current strength. It was superior to previously reported methods in consistency of normative data.

Interscalene brachial plexus block (ISB) frequently causes phrenic nerve palsy. This study investigated whether ultrasound-guided saline injection around the C5 phrenic nerve could lessen diaphragmatic paralysis during shoulder surgery. A randomized controlled trialrandomized 120 patients into either a saline or control group. The saline group received 10 mL of normal saline around the C5 phrenic nerve before the routine ISB; the control group received the standard ISB alone. The primary endpoint was the incidence of diaphragmatic paralysis, while secondary endpoints included analgesic effectiveness, respiratory complications, and patient satisfaction. Compared with the conventional ISB group, the saline group showed a markedly lower rate of complete diaphragmatic paralysis (13. % vs. 83. %, P  < 0.001) and partial paralysis (13. % vs. 75. %, P  < 0.001) after injection. Additionally, the saline group experienced faster onset of sensory and motor blockade ( P  < 0.001) and a longer block duration. Post-operative VAS scores were lower, respiratory complications were fewer, and patient satisfaction were higher in the saline group (all P  < 0.001). Thus, saline injection around the C5 phrenic nerve reduces ISB-induced diaphragmatic paralysis, improves anaesthetic performance, and diminishes postoperative respiratory complications, thereby underscoring its clinical value. Clinical trial number:  The study was registered with chictr.org.cn (ChiCTR2400094577) by Jing Zhao on December 25, 2024.

A rare but important complication after lung transplantation (LTx) is postoperative phrenic nerve dysfunction (PND). Diaphragmatic plication (DP) is a well-established treatment option for PND, however, the long-term effect of PND and DP on lung function parameters and survival after LTx are currently unknown. We retrospectively reviewed 1400 LTx recipients transplanted at Medical University of Vienna between 01/2003 and 12/2022. Fluoroscopy and/or phrenic nerve conduction studies confirmed PND when chest radiographs after extubation showed a unilateral heightened diaphragm. We identified 25 patients with post-operative PND, of whom 12 underwent DP. The remaining 1,375 patients served as a control group. Median ICU-stay and hospital-stay were significantly longer in the PND groups (DP: 20 and 57 days; non-DP: 27 and 43 days; control group: 7 and 25 days; P = 0.001/ P < 0.001). PND led to consistently lower %TLC in lung function tests performed within the first three years after LTx. DP was associated with lower %FEV1.0 early after LTx but it aligned to %FEV1.0 of the other groups during follow-up. Although PND significantly affected postoperative recovery after LTx, it did not impair long-term survival outcomes.