Dilation of the oropharynx via selective stimulation of the hypoglossal nerve

Obstructive sleep apnea (OSA) is caused by the retraction of the tongue to occlude the upper airway (UAW). Electrical stimulation of the tongue protrudor and retractor muscle has been demonstrated as an effective technique to alleviate UAW obstructions and is considered to be a potential treatment for OSA. Recent studies have shown that selective stimulation of the hypoglossal nerve (HG) to activate tongue muscles using a single implantable device presents an attractive approach for treating OSA. In this study, the functional outcome of selective hypoglossal nerve stimulation with a multi-contact peripheral nerve electrode was studied by imaging the airway in anesthetized beagles. A pulse train of varying amplitude was applied through each one of the tripolar contact sets of the nerve electrode while the pharyngeal images were acquired via a video grabber into a computer. For the open mouth positions, the tongue activation patterns were also viewed and videotaped with a digital camcorder through the mouth. The percent dilation of the pharyngeal opening for each contact was calculated. The images show that stimulations delivered through the electrode contacts placed around the HG nerve trunk can generate several different activation patterns of the tongue muscles. Some of these patterns translate into a substantial increase in the oropharyngeal size, while others do not have any effect on the pharynx. The activation patterns vary as a function of the head position and the lower jaw. These results suggest that selective nerve stimulation can be a useful technique to maximize the effects of HG nerve stimulation in removing the obstructions in sleep apnea patients

Intralingual and Intrapleural AAV Gene Therapy Prolongs Survival in a SOD1 ALS Mouse Model

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that results in death from respiratory failure. No cure exists for this devastating disease, but therapy that directly targets the respiratory system has the potential to prolong survival and improve quality of life in some cases of ALS. The objective of this study was to enhance breathing and prolong survival by suppressing superoxide dismutase 1 (SOD1) expression in respiratory motor neurons using adeno-associated virus (AAV) expressing an artificial microRNA targeting the SOD1 gene. AAV-miR(SOD1) was injected in the tongue and intrapleural space of SOD1(G93A) mice, and repetitive respiratory and behavioral measurements were performed until the end stage. Robust silencing of SOD1 was observed in the diaphragm and tongue as well as systemically. Silencing of SOD1 prolonged survival by approximately 50 days, and it delayed weight loss and limb weakness in treated animals compared to untreated controls. Histologically, there was preservation of the neuromuscular junctions in the diaphragm as well as the number of axons in the phrenic and hypoglossal nerves. Although SOD1 suppression improved breathing and prolonged survival, it did not ameliorate the restrictive lung phenotype. Suppression of SOD1 expression in motor neurons that underlie respiratory function prolongs survival and enhances breathing until the end stage in SOD1(G93A) ALS mice

Sex, stress and sleep apnoea: decreased susceptibility to upper airway muscle dysfunction following intermittent hypoxia in females

Obstructive sleep apnoea syndrome (OSAS) is a devastating respiratory control disorder more common in men than women. The reasons for the sex difference in prevalence are multifactorial, but are partly attributable to protective effects of oestrogen. Indeed, OSAS prevalence increases in post-menopausal women. OSAS is characterized by repeated occlusions of the pharyngeal airway during sleep. Dysfunction of the upper airway muscles controlling airway calibre and collapsibility is implicated in the pathophysiology of OSAS, and sex differences in the neuro-mechanical control of upper airway patency are described. It is widely recognized that chronic intermittent hypoxia (CIH), a cardinal feature of OSAS due to recurrent apnoea, drives many of the morbid consequences characteristic of the disorder. In rodents, exposure to CIH-related redox stress causes upper airway muscle weakness and fatigue, associated with mitochondrial dysfunction. Of interest, in adults, there is female resilience to CIH-induced muscle dysfunction. Conversely, exposure to CIH in early life, results in upper airway muscle weakness equivalent between the two sexes at 3 and 6 weeks of age. Ovariectomy exacerbates the deleterious effects of exposure to CIH in adult female upper airway muscle, an effect partially restored by oestrogen replacement therapy. Intriguingly, female advantage intrinsic to upper airway muscle exists with evidence of substantially greater loss of performance in male muscle during acute exposure to severe hypoxic stress. Sex differences in upper airway muscle physiology may have relevance to human OSAS. The oestrogen–oestrogen receptor α axis represents a potential therapeutic target in OSAS, particularly in post-menopausal women

Regional cortical thickness changes accompanying generalized tonic-clonic seizures

OBJECTIVE: Generalized tonic-clonic seizures are accompanied by cardiovascular and respiratory sequelae that threaten survival. The frequency of these seizures is a major risk factor for sudden unexpected death in epilepsy (SUDEP), a leading cause of untimely death in epilepsy. The circumstances accompanying such fatal events suggest a cardiovascular or respiratory failure induced by unknown neural processes rather than an inherent cardiac or lung deficiency. Certain cortical regions, especially the insular, cingulate, and orbitofrontal cortices, are key structures that integrate sensory input and influence diencephalic and brainstem regions regulating blood pressure, cardiac rhythm, and respiration; output from those cortical regions compromised by epilepsy-associated injury may lead to cardiorespiratory dysregulation. The aim here was to assess changes in cortical integrity, reflected as cortical thickness, relative to healthy controls. Cortical alterations in areas that influence cardiorespiratory action could contribute to SUDEP mechanisms. METHODS: High-resolution T1-weighted images were collected with a 3.0-Tesla MRI scanner from 53 patients with generalized tonic-clonic seizures (Mean age ± SD: 37.1 ± 12.6 years, 22 male) at Case Western Reserve University, University College London, and the University of California at Los Angeles. Control data included 530 healthy individuals (37.1 ± 12.6 years; 220 male) from UCLA and two open access databases (OASIS and IXI). Cortical thickness group differences were assessed at all non-cerebellar brain surface locations (P < 0.05 corrected). RESULTS: Increased cortical thickness appeared in post-central gyri, insula, and subgenual, anterior, posterior, and isthmus cingulate cortices. Post-central gyri increases were greater in females, while males showed more extensive cingulate increases. Frontal and temporal cortex, lateral orbitofrontal, frontal pole, and lateral parietal and occipital cortices showed thinning. The extents of thickness changes were sex- and hemisphere-dependent, with only males exhibiting right-sided and posterior cingulate thickening, while females showed only left lateral orbitofrontal thinning. Regional cortical thickness showed modest correlations with seizure frequency, but not epilepsy duration. SIGNIFIANCE: Cortical thickening and thinning occur in patients with generalized tonic-clonic seizures, in cardiovascular and somatosensory areas, with extent of changes sex- and hemisphere-dependent. The data show injury in key autonomic and respiratory cortical areas, which may contribute to dysfunctional cardiorespiratory patterns during seizures, as well as to longer-term SUDEP risk

Loss of FHL1 induces an age-dependent skeletal muscle myopathy associated with myofibrillar and intermyofibrillar disorganization in mice

Recent human genetic studies have provided evidences that sporadic or inherited missense mutations in four-and-a-half LIM domain protein 1 (FHL1), resulting in alterations in FHL1 protein expression, are associated with rare congenital myopathies, including reducing body myopathy and Emery–Dreifuss muscular dystrophy. However, it remains to be clarified whether mutations in FHL1 cause skeletal muscle remodeling owing to gain- or loss of FHL1 function. In this study, we used FHL1-null mice lacking global FHL1 expression to evaluate loss-of-function effects on skeletal muscle homeostasis. Histological and functional analyses of soleus, tibialis anterior and sternohyoideus muscles demonstrated that FHL1-null mice develop an age-dependent myopathy associated with myofibrillar and intermyofibrillar (mitochondrial and sarcoplasmic reticulum) disorganization, impaired muscle oxidative capacity and increased autophagic activity. A longitudinal study established decreased survival rates in FHL1-null mice, associated with age-dependent impairment of muscle contractile function and a significantly lower exercise capacity. Analysis of primary myoblasts isolated from FHL1-null muscles demonstrated early muscle fiber differentiation and maturation defects, which could be rescued by re-expression of the FHL1A isoform, highlighting that FHL1A is necessary for proper muscle fiber differentiation and maturation in vitro. Overall, our data show that loss of FHL1 function leads to myopathy in vivo and suggest that loss of function of FHL1 may be one of the mechanisms underlying muscle dystrophy in patients with FHL1 mutations

Intensity of respiratory cortical arousals is a distinct pathophysiologic feature and is associated with disease severity in obstructive sleep apnea patients

Background: We investigated whether the number, duration and intensity of respiratory arousals (RA) on C3-electroencephalographic (EEG) recordings correlate with polysomnography (PSG)-related disease severity in obstructive sleep apnea (OSA) patients. We also investigated if every patient might have an individual RA microstructure pattern, independent from OSA-severity. Methods: PSG recordings of 20 OSA patients (9 female; age 27–80 years) were analyzed retrospectively. Correlation coefficients were calculated between RA microstructure (duration, EEG-intensity) and RA number and respiratory disturbance index (RDI), oxygen desaturation index (ODI) and arousal index (AI). Intraclass correlations (ICC) for both RA duration and intensity were calculated. Sleep stage-specific and apnea- and hypopnea-specific analyses were also done. The probability distributions of duration and intensity were plotted, interpolated with a kernel which fits the distribution. A Bayesian posterior distribution analysis and pair-wise comparisons of each patient with all other 19 patients were performed. Results: Of the analyzed 2600 RA, strong positive correlations were found between average RA intensity and both RDI and AI. The number of PSG-recorded RA was strongly positively correlated with RDI. Significant correlations between average RA intensity in REM, NREM2 and NREM3 sleep stages and total ODI were identified. No sleep stage-specific correlations of arousal microstructure with age, sex, RDI or AI were identified. Although between-subjects ICC values were 0.7 (all p < 0.05). While apnea-related RA duration did not differ from hypopnea-related RA duration, RA intensity was significantly higher (p = 0.00135) in hypopneas than in apneas. A clear individual pattern of arousal duration for each patient was made distinct. For arousal intensity, a Gaussian distribution was identified in most patients. The Bayesian statistics regarding the arousal microstructure showed significant differences between each pair of patients. Conclusions: Each individual patient with OSA might have an individual pattern of RA intensity and duration indicating a distinct individual pathophysiological feature. Arousal intensity was significantly higher in hypopneic than in apneic events and may be related causally to the diminished (compared to apneas) respiratory distress associated with hypopneas. RA intensity in REM, NREM2 and NREM3 strongly correlated with ODI

The clavicular part of the pectoralis major: a true entity of the upper limb on anatomical, phylogenetic, ontogenetic, functional and clinical bases. Case report and review of the literature

The pectoralis major consists of three parts: clavicular, sternocostal and abdominal. The first is usually separated from the deltoid by a deltopectoral triangular space, and often from the sternocostal part by another triangular space. The clavicular part is a new acquisition in Anthropoids, to optimize stabilization of the upper limb to the thorax thus permitting an increased limb mobility in Primates. It is synergetic with the deltoid in arm flexion and even more in adduction. This action is important in Humans, as the coracobrachialis becomes smaller in Mammals. Among non human Primates, those having cranially displaced shoulder joint show a significant clavicular origin of the pectoralis major. The clavicular origin might be necessary in flexion of the forelimb, when the humeral insertion of the muscle is on the same transverse plane as, or cranial to, the sternal manubrium. As to the blood and nerve supply, occurrence in Humans of a neuro-vascular pedicle for the clavicular part, shared with the deltoid, indicates a relatively morpho-functional independence of this part from the rest of the muscle. Under this regard, the width of the lateral pectoral nerve, which supplies the clavicular part of the muscle, may be related to a greater functional ability. Many manoeuvres for plastic and reconstructive surgery are performed by isolating the clavicular part of the pectoralis major. Indeed, this part may be considered as a true, self-standing anatomical entity. In fact, it has morphological individuality, peculiar bony attachments and functional autonomy, so that it is simply adjacent to the sternocostal part. Moreover, according to phylogenesis, this topographic relation develops secondarily, in parallel with the development of the clavicle. Therefore, it may be regarded not only as a simple part of an extrinsic muscle of the thorax, but also as an intrinsic muscle of the upper limb

The role of frontal cortex-reticular interactions in performance and extinction of the classically conditioned nictitating membrane response in the rabbit

In order to investigate the behavioral role of interactions between frontal cortex and reticular nuclei, we examined the effects of single and combined lesions of these structures on the classically conditioned nictitating membrane response (NMR) of rabbits. Lesions of frontal cortex decreased latencies of the conditioned NMRs in reacquisition and retarded extinction of the conditioned response. Lesions of nucleus reticularis pontis oralis (NRPO) produced similar effects. In contrast, lesions of nucleus reticularis tegmenti (NRT) increased NMR latencies during reacquisition. The opposite effects of frontal cortex and NRT lesions were abolished when the two lesions were combined, indicating that the two lesion effects summed. In contrast, the deficits due to frontal and NRPO lesions did not sum; combined frontal--NRPO lesions produced deficits very similar in magnitude and time course to those of the NRPO lesions alone. These findings suggest that frontal cortex may exert its inhibitory effects on behavior not by directly interacting with NRT, but by facilitating NRPO, which in turn may inhibit the nucleus of the VIth nerve, the final common pathway to the NMR. NRT may facilitate the motor pathway by modulating the inhibitory effect of NRPO on the VIth nerve nucleus.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/23959/1/0000208.pd

The Effects of Variable Quadriceps and Hamstring Loading Configurations on Knee Joint Kinematics During In Vitro Testing

Previous studies have highlighted the importance of the hamstrings and quadriceps muscles on knee joint mechanics and the effects of their pathologies. It is crucial that the resultant force of theses musculature be accurately represented in in vitro simulation. This study has two objectives to be examined during a deep knee squat: 1) measure the patellofemoral kinematics as a function of different loading configurations of the extensor mechanism and 2) measure the changes in tibiofemoral kinematics after including a direct hamstrings load. Fourteen fresh frozen cadavers were tested using a custom designed muscle loading rig. The rig can statically load the individual heads of the quadriceps and the hamstrings in their anatomical orientation using dead weights or directly drive the rectus femoris quadriceps muscle using a stepper motor. Patellofemoral flexion and shift were the only kinematics that changed significantly between the single line and the physiological based distributed loading configuration of the extensor mechanism, with the largest difference of 2.8° and 0.9 mm at 15° and 45° knee flexion respectively. A weak vastus medialis induced an average lateral shift of 1.5 mm and an external rotation of 0.8° while a 0.9 mm medial shift and 0.6° internal rotation was seen when simulating a weak vastus lateralis relative to the physiological based distributed configuration. The change in patellofemoral kinematics was caused by the non-parallel forces to the axis of the femur generated from the vastus medialis and the vastus lateralis. The flexion moment generated from these forces in the sagittal plane decreased patellar flexion. The vastus lateralis load was larger than that of the vastus medialis causing the resultant force in the frontal plane to be more externally rotated. When the hamstrings were loaded throughout the flexion cycle, the femoral lateral condyle lowest point was more anterior with the largest difference of 1.1 mm at 80° knee flexion. For the iv medial femoral condyle lowest point, loading the hamstrings shifted the lowest point 0.9 mm posterior until 40° flexion. At this flexion angle, the medial lowest point became more anterior for the rest of the flexion cycle (0.9 mm on average). The hamstrings also decreased the medial and lateral lowest point range of motion by 1.7 mm and 0.9 mm respectively. The change in tibia femoral kinematics was larger in deeper knee flexion when the hamstrings were loaded which is due to the increase in the hamstrings moment arm, but it is unclear at this point whether the reduction in tibial internal rotation is due to the isometric loading configuration of the hamstrings. The results from this study demonstrated that different muscle loading configurations of the extensor mechanism and muscle weakness significantly influence patellofemoral shift and tilt while increasing the co-contraction between the quadriceps and hamstrings significantly reduces tibial anterior translation and internal rotation. The study has aided in describing the effects of different muscle loading configurations on knee joint kinematics from simulations and provided important experimental data to investigate changes to improve dynamic simulations using the Kansas Knee Simulator