Neuron Pool Research Articles

Transplantation of embryonic spinal motor neurons into peripheral nerves enables functional reconstruction of a denervated diaphragm

Respiratory muscle paralysis due to trauma or neurodegenerative diseases can have devastating consequences. Only a few studies have investigated the reconstruction of motor function in denervated diaphragms caused by such conditions. Here, we studied the efficacy of transplanting E14 embryonic spinal motor neurons (SMNs) into peripheral nerve grafts for functionally reconstructing a denervated diaphragm in a rat model. The diaphragms of 8-week-old male Fischer 344 rats were first denervated by transecting the phrenic nerves. Subsequently, peripheral nerve grafts taken from the lower limb were used for neurotization of the denervated diaphragms. One week later, fetal E14 SMNs were transplanted into the peripheral nerve grafts. After 3 months, we observed functional contraction of the diaphragm following neuromuscular electrical stimulation (NMES) of the peripheral nerve graft. Additionally, we confirmed that SMN transplantation into the peripheral nerve graft had an inhibitory effect on diaphragm muscle atrophy. The SMNs transplanted into the peripheral nerve grafts formed a structure similar to the spinal cord, and the neuromuscular junction of the denervated diaphragm was reinnervated. These findings suggest the establishment of an ectopic motor neuron pool in the peripheral nerve graft. Free peripheral intra-nerve SMN transplantation in combination with NMES, which can be applied for diaphragmatic pacing, offers novel insights into the development of neuroregenerative therapies for treating life-threatening and intractable respiratory muscle paralysis caused by severe nerve damage and degenerative diseases.

Beta bursts in the parkinsonian cortico-basal ganglia network form spatially discrete ensembles

Defining spatial synchronisation of pathological beta oscillations is important, given that many theories linking them to parkinsonian symptoms propose a reduction in the dimensionality of the coding space within and/or across cortico-basal ganglia structures. Such spatial synchronisation could arise from a single process, with widespread entrainment of neurons to the same oscillation. Alternatively, the partially segregated structure of cortico-basal ganglia loops could provide a substrate for multiple ensembles that are independently synchronized at beta frequencies. Addressing this question requires an analytical approach that identifies groups of signals with a statistical tendency for beta synchronisation, which is unachievable using standard pairwise measures. Here, we utilized such an approach on multichannel recordings of background unit activity (BUA) in the external globus pallidus (GP) and subthalamic nucleus (STN) in parkinsonian rats. We employed an adapted version of a principle and independent component analysis-based method commonly used to define assemblies of single neurons (i.e., neurons that are synchronized over short timescales). This analysis enabled us to define whether changes in the power of beta oscillations in local ensembles of neurons (i.e., the BUA recorded from single contacts) consistently covaried over time, forming a “beta ensemble”. Multiple beta ensembles were often present in single recordings and could span brain structures. Membership of a beta ensemble predicted significantly higher levels of short latency (<5 ms) synchrony in the raw BUA signal and phase synchronisation with cortical beta oscillations, suggesting that they comprised clusters of neurons that are functionally connected at multiple levels, despite sometimes being non-contiguous in space. Overall, these findings suggest that beta oscillations do not comprise of a single synchronisation process, but rather multiple independent activities that can bind both spatially contiguous and non-contiguous pools of neurons within and across structures. As previously proposed, such ensembles provide a substrate for beta oscillations to constrain the coding space of cortico-basal ganglia circuits.

A spatial-temporal map of glutamatergic neurogenesis in the murine embryonic cerebellar nuclei uncovers a high degree of cellular heterogeneity.

The nuclei are the main output structures of the cerebellum. Each and every cerebellar cortical computation reaches several areas of the brain by means of cerebellar nuclei processing and integration. Nevertheless, our knowledge of these structures is still limited compared to the cerebellar cortex. Here, we present a mouse genetic inducible fate-mapping study characterizing rhombic lip-derived glutamatergic neurons of the nuclei, the most conspicuous family of long-range cerebellar efferent neurons. Glutamatergic neurons mainly occupy dorsal and lateral territories of the lateral and interposed nuclei, as well as the entire medial nucleus. In mice, they are born starting from about embryonic day 9.5, with a peak between 10.5 and 12.5, and invade the nuclei with a lateral-to-medial progression. While some markers label a heterogeneous population of neurons sharing a common location (BRN2), others appear to be lineage specific (TBR1, LMX1a, and MEIS2). A comparative analysis of TBR1 and LMX1a distributions reveals an incomplete overlap in their expression domains, in keeping with the existence of separate efferent subpopulations. Finally, some tagged glutamatergic progenitors are not labeled by any of the markers used in this study, disclosing further complexity. Taken together, our results obtained in late embryonic nuclei shed light on the heterogeneity of the excitatory neuron pool, underlying the diversity in connectivity and functions of this largely unexplored cerebellar territory. Our findings contribute to laying the groundwork for a comprehensive functional analysis of nuclear neuron subpopulations.

Muscle contractile properties directly influence shared synaptic inputs to spinal motor neurons.

Alpha band oscillations in shared synaptic inputs to the alpha motor neuron pool can be considered an involuntary source of noise that hinders precise voluntary force production. This study investigated the impact of changing muscle length on the shared synaptic oscillations to spinal motor neurons, particularly in the physiological tremor band. Fourteen healthy individuals performed low-level dorsiflexion contractions at ankle joint angles of 90° and 130°, while high-density surface electromyography (HDsEMG) was recorded from the tibialis anterior (TA). We decomposed the HDsEMG into motor units spike trains and calculated the motor units' coherence within the delta (1-5Hz), alpha (5-15Hz), and beta (15-35Hz) bands. Additionally, force steadiness and force spectral power within the tremor band were quantified. Results showed no significant differences in force steadiness between 90° and 130°. In contrast, alpha band oscillations in both synaptic inputs and force output decreased as the length of the TA was moved from shorter (90°) to longer (130°), with no changes in delta and beta bands. In a second set of experiments (10 participants), evoked twitches were recorded with the ankle joint at 90° and 130°, revealing longer twitch durations in the longer TA muscle length condition compared to the shorter. These experimental results, supported by a simple computational simulation, suggest that increasing muscle length enhances the muscle's low-pass filtering properties, influencing the oscillations generated by the Ia afferent feedback loop. Therefore, this study provides valuable insights into the interplay between muscle biomechanics and neural oscillations. KEY POINTS: We investigated whether changes in muscle length, achieved by changing joint position, could influence common synaptic oscillations to spinal motor neurons, particularly in the tremor band (5-15Hz). Our results demonstrate that changing muscle length from shorter to longer induces reductions in the magnitude of alpha band oscillations in common synaptic inputs. Importantly, these reductions were reflected in the oscillations of muscle force output within the alpha band. Longer twitch durations were observed in the longer muscle length condition compared to the shorter, suggesting that increasing muscle length enhances the muscle's low-pass filtering properties. Changes in the peripheral contractile properties of motor units due to changes in muscle length significantly influence the transmission of shared synaptic inputs into muscle force output. These findings prove the interplay between muscle mechanics and neural adaptations.

The neural implausibility of the diffusion decision model doesn't matter for cognitive psychometrics, but the Ornstein-Uhlenbeck model is better.

In cognitive psychometrics, the parameters of cognitive models are used as measurements of the processes underlying observed behavior. In decision making, the diffusion decision model (DDM) is by far the most commonly used cognitive psychometric tool. One concern when using this model is that more recent theoretical accounts of decision-making place more emphasis on neural plausibility, and thus incorporate many assumptions not found in the DDM. One such model is the Ising Decision Maker (IDM), which builds from the assumption that two pools of neurons with self-excitation and mutual inhibition receive perceptual input from external excitatory fields. In this study, we investigate whether the lack of such mechanisms in the DDM compromises its ability to measure the processes it does purport to measure. We cross-fit the DDM and IDM, and find that the conclusions of DDM would be mostly consistent with those from an analysis using a more neurally plausible model. We also show that the Ornstein-Uhlenbeck Model (OUM) model, a variant of the DDM that includes the potential for leakage (or self-excitation), reaches similar conclusions to the DDM regarding the assumptions they share, while also sharing an interpretation with the IDM in terms of self-excitation (but not leakage). Since the OUM is relatively easy to fit to data, while being able to capture more neurally plausible mechanisms, we propose that it be considered an alternative cognitive psychometric tool to the DDM.

A latent pool of neurons silenced by sensory-evoked inhibition can be recruited to enhance perception

To investigate which activity patterns in sensory cortex are relevant for perceptual decision-making, we combined two-photon calcium imaging and targeted two-photon optogenetics to interrogate barrel cortex activity during perceptual discrimination. We trained mice to discriminate bilateral whisker deflections and report decisions by licking left or right. Two-photon calcium imaging revealed sparse coding of contralateral and ipsilateral whisker input in layer 2/3, with most neurons remaining silent during the task. Activating pyramidal neurons using two-photon holographic photostimulation evoked a perceptual bias that scaled with the number of neurons photostimulated. This effect was dominated by optogenetic activation of non-coding neurons, which did not show sensory or motor-related activity during task performance. Photostimulation also revealed potent recruitment of cortical inhibition during sensory processing, which strongly and preferentially suppressed non-coding neurons. Our results suggest that a pool of non-coding neurons, selectively suppressed by network inhibition during sensory processing, can be recruited to enhance perception.

Neurodegeneration Biomarkers in Adult Spinal Muscular Atrophy (SMA) Patients Treated with Nusinersen.

The objective of this study is to evaluate biomarkers for neurodegenerative disorders in adult SMA patients and their potential for monitoring the response to nusinersen. Biomarkers for neurodegenerative disorders were assessed in plasma and CSF samples obtained from a total of 30 healthy older adult controls and 31 patients with adult SMA type 2 and 3. The samples were collected before and during nusinersen treatment at various time points, approximately at 2, 6, 10, and 22 months. Using ELISA technology, the levels of total tau, pNF-H, NF-L, sAPPβ, Aβ40, Aβ42, and YKL-40 were evaluated in CSF samples. Additionally, plasma samples were used to measure NF-L and total tau levels using SIMOA technology. SMA patients showed improvements in clinical outcomes after nusinersen treatment, which were statistically significant only in walkers, in RULM (p = 0.04) and HFMSE (p = 0.05) at 24 months. A reduction in sAPPβ levels was found after nusinersen treatment, but these levels did not correlate with clinical outcomes. Other neurodegeneration biomarkers (NF-L, pNF-H, total tau, YKL-40, Aβ40, and Aβ42) were not found consistently changed with nusinersen treatment. The slow progression rate and mild treatment response of adult SMA types 2 and 3 may not lead to detectable changes in common markers of axonal degradation, inflammation, or neurodegeneration, since it does not involve large pools of damaged neurons as observed in pediatric forms. However, changes in biomarkers associated with the APP processing pathway might be linked to treatment administration. Further studies are warranted to better understand these findings.

Whole Body Vibration's Potential to Improve Balance and Function in Cerebral Palsy in Weight and Non-Weight Bearing Positions: A Hypothesis Study

Cerebral palsy is one of the most prevalent neurological conditions in children. It has classical features of spasticity, poor balance and coordination, muscle weakness, proprioception, and inter-limb coordination. The primary cause is brain damage which affects certain circuits of the central nervous system. It has been reported that D1 inhibition is affected by cerebral palsy. The corticospinal and somatosensory pathways are also affected in the central nervous system along with abnormal activation of the motor neuron pool. There is abnormal presynaptic inhibition and post-activation depression of Ia afferents, while Group II facilitation is strongly enhanced. There are various therapies available to treat the symptoms of cerebral palsy, among which whole-body vibration therapy is considered to change the spinal transmission and somatosensory input. WBVT is typically administered in a weight bearing stance, targeting the lower extremities only. To the best of our knowledge, there is no research available exploring the cross-training effect of WBVT applied to upper and lower extremities, both weight and non-weight bearing positions, either alone on altogether. Hence, we propose that administering the WBVT across various configurations, incorporating weight and non-weight bearing positions for both upper and lower extremities could induce neural plasticity through cross training effect. We expect that by engaging all extremities in weight bearing positions may yield more significant outcomes compared to focusing solely on either upper or lower extremities.

The synaptic drive of central pattern-generating networks to leg motor neurons of a walking insect is motor neuron pool specific.

Rhythmic locomotor activity, such as flying, swimming, or walking, results from an interplay between higher-order centers in the central nervous system, which initiate, maintain, and modify task-specific motor activity, downstream central pattern-generating neural circuits (CPGs) that can generate a default rhythmic motor output, and, finally, feedback from sense organs that modify basic motor activity toward functionality.1,2,3 In this context, CPGs provide phasic synaptic drive to motor neurons (MNs) and thereby support the generation of rhythmic activity for locomotion. We analyzed the synaptic drive that the leg MNs supplying the three main leg joints receive from CPGs in pharmacologically activated and deafferented preparations of the stick insect (Carausius morosus). We show that premotor CPGs pattern the tonic activity of five of the six leg MN pools by phasic inhibitory synaptic drive. These are the antagonistic MN pools supplying the thoraco-coxal joint and the femur-tibial joint4,5 and the levator MN pool supplying the coxa-trochanteral (CTr) joint. In contrast, rhythmic activity of the depressor MN pool supplying the CTr joint was found to be primarily based on a phasic excitatory drive. This difference is likely related to the pivotal role of the depressor muscle in generating leg stance during any walking situation. Thus, our results provide evidence for qualitatively differing mechanisms to generate rhythmic activity between MN pools in the same locomotor system.

Nerve Tracing in Juvenile Rats: A Feasible Model for the Study of Brachial Plexus Birth Palsy and Cocontractions?

Brachial plexus birth injuries cause diminished motor function in the upper extremity. The most common sequel is internal rotation contracture. A number of these patients also suffer from cocontractions, preventing the use of an otherwise good passive range of motion in the shoulder. One theory behind the co-contracture problem is that injured nerve fibers grow into distal support tissue not corresponding to the proximal support tissue, resulting in reinnervation of the wrong muscle groups. To further elucidate this hypothesis, we used rat neonates to investigate a possible model for the study of cocontractions in brachial plexus birth injuries. Five-day-old rats were subjected to a crush injury to the C5-C6 roots. After a healing period of 4 weeks, the infraspinatus muscle was injected with Fluoro-Gold. A week later, the animals were perfused and spinal cords harvested and sectioned. Differences in the uptake of Fluoro-Gold and NeuN positive cells of between sides of the spinal cord were recorded. We found a larger amount of Fluoro-Gold positive cells on the uninjured side, while the injured side had positive cells dispersed over a longer area in the craniocaudal direction. Our findings indicate that the method can be used to trace Fluoro-Gold from muscle through a neuroma. Our results also indicate that a neuroma in continuity somewhat prevents the correct connection from being established between the motor neuron pool in the spinal cord and target muscle and that some neurons succumb to a crushing injury. We also present future research ideas.

Fractal Neurodynamics.

The neuronal ongoing electrical activity in the brain network, the neurodynamics, reflects the structure and functionality of generating neuronal pools. The activity of neurons due to their excitatory and inhibitory projections is associated with specific brain functions. Here, the purpose was to investigate if the local ongoing electrical activity exhibits its characteristic spectral and fractal features in wakefulness and sleep across and within subjects. Moreover, we aimed to show that measures typical of complex systems catch physiological features missed by linear spectral analyses. For this study, we concentrated on the evaluation of the power spectral density (PSD) and Higuchi fractal dimension (HFD) measures. Relevant clinical impact of the specific features of neurodynamics identification stands primarily in the potential of classifying cortical parcels according to their neurodynamics as well as enhancing the effectiveness of neuromodulation interventions to cure symptoms secondary to neuronal activity unbalances.

A computational model of surface electromyography signal alterations after spinal cord injury

Objective. Spinal cord injury (SCI) can cause significant impairment and disability with an impact on the quality of life for individuals with SCI and their caregivers. Surface electromyography (sEMG) is a sensitive and non-invasive technique to measure muscle activity and has demonstrated great potential in capturing neuromuscular changes resulting from SCI. The mechanisms of the sEMG signal characteristic changes due to SCI are multi-faceted and difficult to study in vivo. In this study, we utilized well-established computational models to characterize changes in sEMG signal after SCI and identify sEMG features that are sensitive and specific to different aspects of the SCI. Approach. Starting from existing models for motor neuron pool organization and motor unit action potential generation for healthy neuromuscular systems, we implemented scenarios to model damages to upper motor neurons, lower motor neurons, and the number of muscle fibers within each motor unit. After simulating sEMG signals from each scenario, we extracted time and frequency domain features and investigated the impact of SCI disruptions on sEMG features using the Kendall Rank Correlation analysis. Main results. The commonly used amplitude-based sEMG features (such as mean absolute values and root mean square) cannot differentiate between injury scenarios, but a broader set of features (including autoregression and cepstrum coefficients) provides greater specificity to the type of damage present. Significance. We introduce a novel approach to mechanistically relate sEMG features (often underused in SCI research) to different types of neuromuscular alterations that may occur after SCI. This work contributes to the further understanding and utilization of sEMG in clinical applications, which will ultimately improve patient outcomes after SCI.

Intermediate gray matter interneurons in the lumbar spinal cord play a critical and necessary role in coordinated locomotion.

Locomotion is a complex task involving excitatory and inhibitory circuitry in spinal gray matter. While genetic knockouts examine the function of individual spinal interneuron (SpIN) subtypes, the phenotype of combined SpIN loss remains to be explored. We modified a kainic acid lesion to damage intermediate gray matter (laminae V-VIII) in the lumbar spinal enlargement (spinal L2-L4) in female rats. A thorough, tailored behavioral evaluation revealed deficits in gross hindlimb function, skilled walking, coordination, balance and gait two weeks post-injury. Using a Random Forest algorithm, we combined these behavioral assessments into a highly predictive binary classification system that strongly correlated with structural deficits in the rostro-caudal axis. Machine-learning quantification confirmed interneuronal damage to laminae V-VIII in spinal L2-L4 correlates with hindlimb dysfunction. White matter alterations and lower motoneuron loss were not observed with this KA lesion. Animals did not regain lost sensorimotor function three months after injury, indicating that natural recovery mechanisms of the spinal cord cannot compensate for loss of laminae V-VIII neurons. As gray matter damage accounts for neurological/walking dysfunction in instances of spinal cord injury affecting the cervical or lumbar enlargement, this research lays the groundwork for new neuroregenerative therapies to replace these lost neuronal pools vital to sensorimotor function.

In humans, striato-pallido-thalamic projections are largely segregated by their origin in either the striosome-like or matrix-like compartments

Cortico-striato-thalamo-cortical (CSTC) loops are fundamental organizing units in mammalian brains. CSTCs process limbic, associative, and sensorimotor information in largely separated but interacting networks. CTSC loops pass through paired striatal compartments, striosome (aka patch) and matrix, segregated pools of medium spiny projection neurons with distinct embryologic origins, cortical/subcortical structural connectivity, susceptibility to injury, and roles in behaviors and diseases. Similarly, striatal dopamine modulates activity in striosome and matrix in opposite directions. Routing CSTCs through one compartment may be an anatomical basis for regulating discrete functions. We used differential structural connectivity, identified through probabilistic diffusion tractography, to distinguish the striatal compartments (striosome-like and matrix-like voxels) in living humans. We then mapped compartment-specific projections and quantified structural connectivity between each striatal compartment, the globus pallidus interna (GPi), and 20 thalamic nuclei in 221 healthy adults. We found that striosome-originating and matrix-originating streamlines were segregated within the GPi: striosome-like connectivity was significantly more rostral, ventral, and medial. Striato-pallido-thalamic streamline bundles that were seeded from striosome-like and matrix-like voxels transited spatially distinct portions of the white matter. Matrix-like streamlines were 5.7-fold more likely to reach the GPi, replicating animal tract-tracing studies. Striosome-like connectivity dominated in six thalamic nuclei (anteroventral, central lateral, laterodorsal, lateral posterior, mediodorsal-medial, and medial geniculate). Matrix-like connectivity dominated in seven thalamic nuclei (centromedian, parafascicular, pulvinar-anterior, pulvinar-lateral, ventral lateral-anterior, ventral lateral-posterior, ventral posterolateral). Though we mapped all thalamic nuclei independently, functionally-related nuclei were matched for compartment-level bias. We validated these results with prior thalamostriate tract tracing studies in non-human primates and other species; where reliable data was available, all agreed with our measures of structural connectivity. Matrix-like connectivity was lateralized (left &amp;gt; right hemisphere) in 18 thalamic nuclei, independent of handedness, diffusion protocol, sex, or whether the nucleus was striosome-dominated or matrix-dominated. Compartment-specific biases in striato-pallido-thalamic structural connectivity suggest that routing CSTC loops through striosome-like or matrix-like voxels is a fundamental mechanism for organizing and regulating brain networks. Our MRI-based assessments of striato-thalamic connectivity in humans match and extend the results of prior tract tracing studies in animals. Compartment-level characterization may improve localization of human neuropathologies and improve neurosurgical targeting in the GPi and thalamus.

Maximal Fusion Capacity and Efficient Replenishment of the Dense Core Vesicle Pool in Hippocampal Neurons.

Neuropeptides and neurotrophins, stored in dense core vesicles (DCVs), are together the largest currently known group of chemical signals in the brain. Exocytosis of DCVs requires high-frequency or patterned stimulation, but the determinants to reach maximal fusion capacity and for efficient replenishment of released DCVs are unknown. Here, we systematically studied fusion of DCV with single vesicle resolution on different stimulation patterns in mammalian CNS neurons. We show that tetanic stimulation trains of 50-Hz action potential (AP) bursts maximized DCV fusion, with significantly fewer fusion event during later bursts of the train. This difference was omitted by introduction of interburst intervals but did not increase total DCV fusion. Interburst intervals as short as 5 s were sufficient to restore the fusion capacity. Theta burst stimulation (TBS) triggered less DCV fusion than tetanic stimulation, but a similar fusion efficiency per AP. Prepulse stimulation did not alter this. However, low-frequency stimulation (4 Hz) intermitted with fast ripple stimulation (200 APs at 200 Hz) produced substantial DCV fusion, albeit not as much as tetanic stimulation. Finally, individual fusion events had longer durations with more intense stimulation. These data indicate that trains of 50-Hz AP stimulation patterns triggered DCV exocytosis most efficiently and more intense stimulation promotes longer DCV fusion pore openings.SIGNIFICANCE STATEMENT Neuropeptides and neurotrophins modulate multiple regulatory functions of human body like reproduction, food intake or mood. They are packed into dense core vesicles (DCVs) that undergo calcium and action potential (AP) fusion with the plasma membrane. In order to study the fusion of DCVs in vitro, techniques like perfusion with buffer containing high concentration of potassium or electric field stimulation are needed to trigger the exocytosis of DCVs. Here, we studied the relationship between DCVs fusion properties and different electric field stimulation patterns. We used six different stimulation patterns and showed that trains of 50-Hz action potential bursts triggered DCV exocytosis most efficiently and more intense stimulation promotes longer DCV fusion pore openings.

Neural drive and motor unit characteristics after anterior cruciate ligament reconstruction: implications for quadriceps weakness.

The purpose of this investigation was to compare the quality of neural drive and recruited quadriceps motor units' (MU) action potential amplitude (MUAPAMP) and discharge rate (mean firing rate (MFR)) relative to recruitment threshold (RT) between individuals with anterior cruciate ligament reconstruction (ACLR) and controls. Fourteen individuals with ACLR and 13 matched controls performed trapezoidal knee extensor contractions at 30%, 50%, 70%, and 100% of their maximal voluntary isometric contraction (MVIC). Decomposition electromyography (dEMG) and torque were recorded concurrently. The Hoffmann reflex (H-reflex) and central activation ratio (CAR) were acquired bilaterally to detail the proportion of MU pool available and volitionally activated. We examined MUAPAMP-RT and MFR-RT relationships with linear regression and extracted the regression line slope, y-intercept, and RT range for each contraction. Linear mixed effect modelling used to analyze the effect of group and limb on regression line slope and RT range. Individuals with ACLR demonstrated lower MVIC torque in the involved limb compared to uninvolved limb. There were no differences in H-reflex or CAR between groups or limbs. The ACLR involved limb demonstrated smaller mass-normalized RT range and slower MU firing rates at high contraction intensities (70% and 100% MVIC) compared to uninvolved and control limbs. The ACLR involved limb also demonstrated larger MU action potentials in the VM compared to the contralateral limb. These differences were largely attenuated with relative RT normalization. These results suggest that persistent strength deficits following ACLR may be attributable to a diminished quadriceps motor neuron pool and inability to upregulate the firing rate of recruited MUs.

Modeling Long-Term Facilitation of Respiration During Interval Exercise in Humans

Long-term facilitation (LTF) of respiration has been mainly initiated by intermittent hypoxia and resultant chemoreceptor stimulation in humans. Comparable levels of chemoreceptor stimulation can occur in combined exercise and carbon dioxide (CO2) inhalation and lead to LTF. This possibility was supported by data collected during combined interval exercise and 3% inhaled CO2 in seven normal subjects. These data were further analyzed based on the dynamics involved using mathematical models in this study. Previously estimated peripheral chemoreceptor sensitivity during light exercise (40 W) with air or 3% inhaled CO2 approximately doubled resting sensitivity. Ventilation after a delay increased by 17.0 ± 2.48 L/min (p < 0.001) during recovery following 45% maximal oxygen uptake (VO2max\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$V_{{{\ ext{O}}_{2} \\max }}$$\\end{document}) exercise consistent with LTF which exceeded what can be achieved with intermittent hypoxia. Model fitting of the dynamic responses was used to separate neural from chemoreceptor-mediated CO2 responses. Exercise of 45% VO2max\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$V_{{{\ ext{O}}_{2} \\max }}$$\\end{document} was followed by ventilation augmentation following initial recovery. Augmentation of LTF developed slowly according to second-order dynamics in accordance with plasticity involving a balance between self-excitatory and self-inhibitory neuronal pools.

Comparison of filtering methods for real-time extraction of the volitional EMG component in electrically stimulated muscles

ObjectiveRecorded electromyograms (EMG) of electrically stimulated muscles can contain both an exogenous-evoked potential (M-wave) and an endogenous, or volitional, component. This study evaluated the effectiveness of three filtering methods (i.e., high-pass, adaptive, and comb), commonly used in neurorehabilitation, in extracting the volitional component of simulated and experimental EMG during upper-limb tasks. MethodsVolitional EMG and M-wave were simulated through a physiological model of muscle recruitment, comprising of a motor neuron pool and associated muscle fibres, superimposed to a stimulation artefact. Experimental EMG data during different levels of volitional muscle contraction in isometric and dynamic tasks were recorded from five unimpaired individuals. Electrical stimulation artefact was removed with different techniques (i.e., none, removing samples, blanking, and interpolation) to assess filter performance across time and frequency domains, and information content (i.e., Kolmogorov-Smirnov D-value). ResultsThe experimental results agreed with the simulations, wherein the adaptive filter outperformed the other filters when using no artefact removal or removing artefact samples from the signal, while for the blanking and interpolation artefact removal methods, the adaptive and comb filters outperformed the high-pass filter. ConclusionThe adaptive and comb filters best estimated volitional muscle activity in electrically stimulated muscles. SignificanceResults from this study will enable the enhanced design of real-time neuroprosthesis control.

Beyond ℓ1 sparse coding in V1.

Growing evidence indicates that only a sparse subset from a pool of sensory neurons is active for the encoding of visual stimuli at any instant in time. Traditionally, to replicate such biological sparsity, generative models have been using the ℓ1 norm as a penalty due to its convexity, which makes it amenable to fast and simple algorithmic solvers. In this work, we use biological vision as a test-bed and show that the soft thresholding operation associated to the use of the ℓ1 norm is highly suboptimal compared to other functions suited to approximating ℓp with 0 ≤ p < 1 (including recently proposed continuous exact relaxations), in terms of performance. We show that ℓ1 sparsity employs a pool with more neurons, i.e. has a higher degree of overcompleteness, in order to maintain the same reconstruction error as the other methods considered. More specifically, at the same sparsity level, the thresholding algorithm using the ℓ1 norm as a penalty requires a dictionary of ten times more units compared to the proposed approach, where a non-convex continuous relaxation of the ℓ0 pseudo-norm is used, to reconstruct the external stimulus equally well. At a fixed sparsity level, both ℓ0- and ℓ1-based regularization develop units with receptive field (RF) shapes similar to biological neurons in V1 (and a subset of neurons in V2), but ℓ0-based regularization shows approximately five times better reconstruction of the stimulus. Our results in conjunction with recent metabolic findings indicate that for V1 to operate efficiently it should follow a coding regime which uses a regularization that is closer to the ℓ0 pseudo-norm rather than the ℓ1 one, and suggests a similar mode of operation for the sensory cortex in general.

Mesenchymal stem cell attenuates spinal cord injury by inhibiting mitochondrial quality control-associated neuronal ferroptosis

Ferroptosis is a newly discovered form of iron-dependent oxidative cell death and drives the loss of neurons in spinal cord injury (SCI). Mitochondrial damage is a critical contributor to neuronal death, while mitochondrial quality control (MQC) is an essential process for maintaining mitochondrial homeostasis to promote neuronal survival. However, the role of MQC in neuronal ferroptosis has not been clearly elucidated. Here, we further demonstrate that neurons primarily suffer from ferroptosis in SCI at the single-cell RNA sequencing level. Mechanistically, disordered MQC aggravates ferroptosis through excessive mitochondrial fission and mitophagy. Furthermore, mesenchymal stem cells (MSCs)-mediated mitochondrial transfer restores neuronal mitochondria pool and inhibits ferroptosis through mitochondrial fusion by intercellular tunneling nanotubes. Collectively, these results not only suggest that neuronal ferroptosis is regulated in an MQC-dependent manner, but also fulfill the molecular mechanism by which MSCs attenuate neuronal ferroptosis at the subcellular organelle level. More importantly, it provides a promising clinical translation strategy based on stem cell-mediated mitochondrial therapy for mitochondria-related central nervous system disorders.