Approximate entropy of motoneuron firing patterns during a motor preparation task.

The aim of this study was to test whether approximate entropy (ApEn) analysis provides a suitable method of detecting differences induced by a motor preparation task in time-ordered inter-spike intervals (ISIs) recorded in tonically firing motoneurons. Unlike classical methods of analyzing neuronal discharge variability, in which serial order is no taken into account, the approximate entropy (ApEn) was proposed by Pincus [Pincus SM. Approximate entropy as a measure of system complexity. Proc Natl Acad Sci USA 1991;88:2297-301] to analyze ordered series. ApEn statistic is a number assigned to an ordered series, where higher values correspond to greater serial irregularity. In the present study, the activity of 31 single motor units (SMUs) was recorded in human extensor carpi radialis muscles and the ISI durations were analyzed during the performance of a pre-cueing reaction time motor task involving a 3-s preparatory period. ApEn values were computed for each SMU during three steps of the preparatory period and during the preceding control period. Lower ApEn values, were found during preparatory period. The decrease in ApEn values, i.e., the increase in serial regularity, was monotonic from the control to the end of the preparatory period. These results show that ApEn model-independent statistics are a relevant means of detecting changes related to motor preparation in the regularity of time-ordered inter-spike intervals (ISIs).

Anticipatory changes in human motoneuron discharge patterns during motor preparation.

The influence of motor preparation on human motoneuron activity was studied by combining single motor unit recording techniques with reaction-time (RT) methods. The tonic activity of wrist extensor motor units associated with voluntary isometric contractions was analysed during preparation for a ballistic wrist extensor muscle contraction, using a time preparation procedure. Two durations of the preparatory period elapsing between the warning signal and the response signal were used in separate blocks of trials: a short preparatory period (1 s) allowing optimum time preparation, and a longer, non-optimum one (3 s). Changes in motoneuron tonic discharge patterns not associated with any changes in the force output were observed during the preparatory period, which suggests that these changes were subtle enough to prevent any changes in muscle contraction from occurring before the forthcoming movement. The changes observed were a lengthening of the mean interspike interval (ISI) and a decrease in the ISI variability. These data confirm that inhibitory mechanisms are activated during motor preparation and suggest that spinal inhibitory mechanisms are involved in the preparatory processes. The mechanisms possibly involved, such as presynaptic inhibition, disfacilitation processes or AHP conductance changes, are discussed. The fact that the preparation-induced effects on motoneuron activity were particularly prominent during the last part of the 3 s preparatory period suggests that they were probably related to the neural processes underlying temporal estimation. The anticipatory changes in motoneuron activity observed here during preparation for action provide evidence that central influences act on spinal motoneurons well before it is time to act.

Mecp2 deficiency disrupts norepinephrine and respiratory systems in mice.

Rett syndrome is a severe X-linked neurological disorder in which most patients have mutations in the methyl-CpG binding protein 2 (MECP2) gene and suffer from bioaminergic deficiencies and life-threatening breathing disturbances. We used in vivo plethysmography, in vitro electrophysiology, neuropharmacology, immunohistochemistry, and biochemistry to characterize the consequences of the MECP2 mutation on breathing in wild-type (wt) and Mecp2-deficient (Mecp2-/y) mice. At birth, Mecp2-/y mice showed normal breathing and a normal number of medullary neurons that express tyrosine hydroxylase (TH neurons). At approximately 1 month of age, most Mecp2-/y mice showed respiratory cycles of variable duration; meanwhile, their medulla contained a significantly reduced number of TH neurons and norepinephrine (NE) content, even in Mecp2-/y mice that showed a normal breathing pattern. Between 1 and 2 months of age, all unanesthetized Mecp2-/y mice showed breathing disturbances that worsened until fatal respiratory arrest at approximately 2 months of age. During their last week of life, Mecp2-/y mice had a slow and erratic breathing pattern with a highly variable cycle period and frequent apneas. In addition, their medulla had a drastically reduced number of TH neurons, NE content, and serotonin (5-HT) content. In vitro experiments using transverse brainstem slices of mice between 2 and 3 weeks of age revealed that the rhythm produced by the isolated respiratory network was irregular in Mecp2-/y mice but could be stabilized with exogenous NE. We hypothesize that breathing disturbances in Mecp2-/y mice, and probably Rett patients, originate in part from a deficiency in noradrenergic and serotonergic modulation of the medullary respiratory network.

MafB deficiency causes defective respiratory rhythmogenesis and fatal central apnea at birth.

The genetic basis for the development of brainstem neurons that generate respiratory rhythm is unknown. Here we show that mice deficient for the transcription factor MafB die from central apnea at birth and are defective for respiratory rhythmogenesis in vitro. MafB is expressed in a subpopulation of neurons in the preBötzinger complex (preBötC), a putative principal site of rhythmogenesis. Brainstems from Mafb(-/-) mice are insensitive to preBötC electrolytic lesion or stimulation and modulation of rhythmogenesis by hypoxia or peptidergic input. Furthermore, in Mafb(-/-) mice the preBötC, but not major neuromodulatory groups, presents severe anatomical defects with loss of cellularity. Our results show an essential role of MafB in central respiratory control, possibly involving the specification of rhythmogenic preBötC neurons.

Perinatal maturation of the mouse respiratory rhythm-generator: in vivo and in vitro studies.

In vivo (plethysmography) and in vitro (en bloc preparations) experiments were performed from embryonic day 16 (E16) to postnatal day 9 (P9) in order to analyse the perinatal maturation of the respiratory rhythm-generator in mice. At E16, delivered foetuses did not ventilate and survive but at E18 they breathed at about 110 cycles/min with respiratory cycles of variable individual duration. From E18 to P0-P2, the respiratory cycles stabilised without changes in the breathing parameters. However, these increased several-fold during the next days. Hypoxia increased breathing frequency from E18-P5 and only significantly affected ventilation from P3 onwards. At E16, in vitro medullary preparations (pons resection) produced rhythmic phrenic bursts at a low frequency (about 5 cycles/min) with variable cycle duration. At E18, their frequency doubled but cycle duration remained variable. After birth, the frequency did not change although cycle duration stabilised. At E18 and P0-P2, the in vitro frequency decreased by around 50% under hypoxia, increased by 40-50% under noradrenaline or substance P and was permanently depressed by the pontine A5 areas. At E16 however, hypoxia had no effects, both noradrenaline and substance P drastically increased the frequency and area A5 inhibition was not expressed at this time. At E18 and P0-P2, electrical stimulation and electrolytic lesion of the rostral ventrolateral medulla affected the in vitro rhythm but failed to induce convincing effects at E16. Thus, a major maturational step in respiratory rhythmogenesis occurs between E16-E18, in agreement with the concept of multiple rhythmogenic mechanisms.

The murine neurokinin NK1 receptor gene contributes to the adult hypoxic facilitation of ventilation.

Substance P and neurokinin-1 receptors (NK1) modulate the respiratory activity and are expressed early during development. We tested the hypothesis that NK1 receptors are involved in prenatal development of the respiratory network by comparing the resting respiratory activity and the respiratory response to hypoxia of control mice and mutant mice lacking the NK1 receptor (NK1-/-). In vitro and in vivo experiments were conducted on neonatal, young and adult mice from wild-type and NK1-/- strains. In the wild strain, immunohistological, pharmacological and electrophysiological studies showed that NK1 receptors were expressed within medullary respiratory areas prior to birth and that their activation at birth modulated central respiratory activity and the membrane properties of phrenic motoneurons. Both the membrane properties of phrenic motoneurons and the respiratory activity generated in vitro by brainstem-spinal cord preparation from NK1-/- neonate mice were similar to that from the wild strain. In addition, in vivo ventilation recordings by plethysmography did not reveal interstrain differences in resting breathing parameters. The facilitation of ventilation by short-lasting hypoxia was similar in wild and NK1-/- neonates but was significantly weaker in adult NK1-/- mice. Results demonstrate that NK1 receptors do appear to be necessary for a normal respiratory response to short-lasting hypoxia in the adult. However, NK1 receptors are not obligatory for the prenatal development of the respiratory network, for the production of the rhythm, or for the regulation of breathing by short-lasting hypoxia in neonates.

Evaluation of left ventricular filling pressure by transthoracic Doppler echocardiography in the intensive care unit.

OBJECTIVE: To determine whether Doppler transmitral and pulmonary venous flow pattern is related to left ventricular filling pressures in critically ill patients. DESIGN: Prospective clinical investigation. SETTING: Medical intensive care unit of a university hospital. PATIENTS: Fifty-four mechanically ventilated patients (age, 63 +/- 16 yrs) were investigated via transthoracic echocardiography and Doppler. Main diagnoses were pneumonia (31%), acute exacerbation of chronic obstructive pulmonary disease (24%), congestive heart failure (11%), and poisoning (11%). INTERVENTIONS: Doppler examinations were performed simultaneously with measurements of pulmonary artery occlusion pressure via a right heart catheter. MEASUREMENTS AND MAIN RESULTS: Pulmonary artery occlusion pressure correlated with transmitral peak E-wave velocity (r =.46) and E/A ratio (r =.55). Pulmonary artery occlusion pressure inversely correlated with deceleration time of the transmitral E-wave (r = -.52), pulmonary venous peak S-wave velocity (r = -.37), and systolic fraction of the pulmonary forward flow (r = -.56). An E/A ratio >2 predicted a pulmonary artery occlusion pressure >18 mm Hg with a positive predictive value of 100%. A duration of pulmonary venous A-wave reversal flow exceeding the duration of the transmitral A-wave forward flow predicted a pulmonary artery occlusion pressure >15 mm Hg with a positive predictive value of 83%. A systolic fraction of the pulmonary venous forward flow <0.4 predicted a pulmonary artery occlusion pressure >12 mm Hg with a positive predictive value of 100%. CONCLUSION: Transmitral and pulmonary venous flow patterns measured by transthoracic Doppler echocardiography can be used to estimate the left ventricular filling pressure in critically ill patients.