Mantilla, Carlos B

The neuromotor control of the diaphragm muscle (DIAm) in response to hypercapnia is not well understood. We show that both the number of motor units recruited and their discharge rates increase with hypercapnia, consistent with increased respiratory drive during hypercapnia. Potentially in response to this increased drive, the greatest effect of hypercapnia is on during the postinspiratory (descending) ramp of DIAm EMG activity, which shortens to facilitate higher respiratory rates.

The heterogeneity of diaphragm muscle (DIAm) activity in awake animals reflects real motor behavior diversity but makes assessments of eupneic breathing challenging. The present article uses an unsupervised machine learning model to identify eupneic breathing amidst a deluge of different DIAm electromyography (EMG) burst patterns in awake rats. This technique offers a scalable and reliable tool that improves efficiency of DIAm EMG analysis and minimizes potential sources of bias.

The diaphragm muscle is essential for breathing, and its dysfunctions can be fatal. Many disorders affect the diaphragm, including muscular dystrophies. Despite the clinical relevance of targeting the diaphragm, there have been few studies evaluating diaphragm function following a given experimental treatment, with most of these involving anti-inflammatory drugs or gene therapy. Cell-based therapeutic approaches have shown success promoting muscle regeneration in several mouse models of muscular dystrophy, but these have focused mainly on limb muscles. Here we show that transplantation of as few as 5000 satellite cells directly into the diaphragm results in consistent and robust myofiber engraftment in dystrophin- and fukutin-related protein-mutant dystrophic mice. Transplanted cells also seed the stem cell reservoir, as shown by the presence of donor-derived satellite cells. Force measurements showed enhanced diaphragm strength in engrafted muscles. These findings demonstrate the feasibility of cell transplantation to target the diseased diaphragm and improve its contractility.

We characterized three phases of neuromotor control—motor unit recruitment, sustained activity, and derecruitment—based on statistical assessments of stationarity of the diaphragm muscle (DIAm) EMG activity in awake rats. Our findings may allow indirect estimates of the contribution of motor unit recruitment and frequency coding toward generating force and provide novel insights about the temporal aspects of DIAm neuromotor control and descending respiratory drive in unanesthetized animals.

Recent findings suggest that autophagy plays a role in the development of aging-related neuromuscular dysfunction; however, the contribution of autophagy impairment to the maintenance of diaphragm force generation in old age is unknown. This study shows that in old mice, chloroquine administration decreases maximal transdiaphragmatic pressure generation. These chloroquine effects suggest a susceptibility to impairments in autophagy in old age.

Type S and FR motor units, comprising smaller phrenic motor neurons (PhMNs) are regularly activated to perform indefatigable ventilatory requirements. By contrast, type FF motor units, comprising larger PhMNs, are infrequently activated to perform expulsive straining and airway defense maneuvers. This difference in activation history is mirrored in the mitochondrial volume density (MVD), with smaller PhMNs having higher MVD than larger PhMNs. In proximal dendrites, this trend was reversed, with larger PhMNs having higher MVD than smaller PhMNs, likely due to the maintenance requirements for the larger dendritic arbor of FF PhMNs.

Neurotrophin brain-derived neurotrophic factor (BDNF) enhances neuromuscular transmission via activation of tropomyosin-related kinase receptor B (TrkB). Rat phrenic nerve-diaphragm muscle preparations were used to determine the rapid effect of BDNF on synaptic quantal release during repetitive stimulation. BDNF treatment significantly enhanced quantal release at all fiber types. BDNF increased synaptic vesicle cycling (measured using FM4-64 fluorescence uptake); conversely, inhibiting BDNF/TrkB signaling decreased FM4-64 uptake.

Background: Debate surrounds the issue of whether peripheral nerve blockade or periarticular infiltration (PAI) should be employed within a contemporary, comprehensive multimodal analgesia pathway for total hip arthroplasty. We hypothesized that patients treated with a continuous posterior lumbar plexus block (PNB) would report less pain and consume less opioid medication than those treated with PAI. Methods: This investigator-initiated, independently funded, 3-arm randomized clinical trial (RCT) performed at a single high-volume institution compared postoperative analgesia interventions for elective, unilateral primary total hip arthroplasty: (1) PNB; (2) PAI with ropivacaine, ketorolac, and epinephrine (PAI-R); and (3) PAI with liposomal bupivacaine, ketorolac, and epinephrine (PAI-L) using computerized randomization. The primary outcome was maximum pain during the morning (06:00 to 12:00) of the first postoperative day (POD) on an ascending numeric rating scale (NRS) from 0 to 10. Pairwise treatment comparisons were performed using the rank-sum test, with a p value of <0.017 indicating significance (Bonferroni adjusted). A sample size of 150 provided 80% power to detect a difference of 2.0 NRS units. Results: We included 159 patients (51, 54, and 54 patients in the PNB, PAI-R, and PAI-L groups, respectively). No significant differences were found with respect to the primary end point on the morning of the first POD (median, 3.0, 4.0, and 3.0, respectively; p > 0.033 for all). Opioid consumption was low and did not differ across groups at any intervals. Median maximum pain on POD 1 was 5.0, 5.5, and 4.0, respectively, and was lower for the PAI-L group than for the PAI-R group (p = 0.006). On POD 2, maximum pain (median, 3.5, 5.0, and 3.5, respectively) was lower for the PNB group (p = 0.014) and PAI-L group (p = 0.016) compared with the PAI-R group. The PAI-L group was not significantly different from the PNB group with respect to any outcomes: postoperative opioid use including rescue intravenous opioid medication, length of stay, and hospital adverse events, and 3-month follow-up data including any complication. Conclusions: In this RCT, we found a modest improvement with respect to analgesia in patients receiving PNB compared with those receiving PAI-R, but not compared with those who had PAI-L. Secondary analyses suggested that PNB or PAI-L provides superior postoperative analgesia compared with PAI-R. For primary total hip arthroplasty, a multimodal analgesic regimen including PNB or PAI-L provides opioid-limiting analgesia. Level of Evidence: Therapeutic Level I . See Instructions for Authors for a complete description of levels of evidence.

AbstractThe diaphragm muscle comprises various types of motor units that are recruited in an orderly fashion governed by the intrinsic electrophysiological properties (membrane capacitance as a function of somal surface area) of phrenic motor neurons (PhMNs). Glutamate is the main excitatory neurotransmitter at PhMNs and acts primarily via fast acting AMPA and N‐methyl‐D‐aspartic acid (NMDA) receptors. Differences in receptor expression may also contribute to motor unit recruitment order. We used single cell, multiplex fluorescence in situ hybridization to determine glutamatergic receptor mRNA expression across PhMNs based on their somal surface area. In adult male and female rats (n = 9) PhMNs were retrogradely labeled for analyses (n = 453 neurons). Differences in the total number and density of mRNA transcripts were evident across PhMNs grouped into tertiles according to somal surface area. A ~ 25% higher density of AMPA (Gria2) and NMDA (Grin1) mRNA expression was evident in PhMNs in the lower tertile compared to the upper tertile. These smaller PhMNs likely comprise type S motor units that are recruited first to accomplish lower force, ventilatory behaviors. In contrast, larger PhMNs with lower volume densities of AMPA and NMDA mRNA expression presumably comprise type FInt and FF motor units that are recruited during higher force, expulsive behaviors. Furthermore, there was a significantly higher cytosolic NMDA mRNA expression in small PhMNs suggesting a more important role for NMDA‐mediated glutamatergic neurotransmission at smaller PhMNs. These results are consistent with the observed order of motor unit recruitment and suggest a role for glutamatergic receptors in support of this orderly recruitment. image Cover Image for this issue: doi: 10.1111/jnc.14747.