Development of respiratory control instability in heart failure: a novel approach to dissect the pathophysiological mechanisms

Observational data suggest that periodic breathing is more common in subjects with low   F _ETCO2  , high apnoeic thresholds or high chemoreflex sensitivity. It is, however, difficult to determine the individual effect of each variable because they are intrinsically related. To distinguish the effect of isolated changes in chemoreflex sensitivity, mean   F _ETCO2  and apnoeic threshold, we employed a modelling approach to break their obligatory in vivo interrelationship. We found that a change in mean CO₂ fraction from 0.035 to 0.045 increased loop gain by 70 ± 0.083% ( P < 0.0001), irrespective of chemoreflex gain or apnoea threshold. A 100% increase in the chemoreflex gain (from 800 l min⁻¹ (fraction CO₂)⁻¹) resulted in an increase in loop gain of 275 ± 6% ( P < 0.0001) across a wide range of values of steady state CO₂ and apnoea thresholds. Increasing the apnoea threshold   F _ETCO2  from 0.02 to 0.03 had no effect on system stability. Therefore, of the three variables the only two destabilizing factors were high gain and high mean CO₂; the apnoea threshold did not independently influence system stability. Although our results support the idea that high chemoreflex gain destabilizes ventilatory control, there are two additional potentially controversial findings. First, it is high (rather than low) mean CO₂ that favours instability. Second, high apnoea threshold itself does not create instability. Clinically the apnoea threshold appears important only because of its associations with the true determinants of stability: chemoreflex gain and mean CO₂.     

Change in the peripheral CO2 chemoreflex from rest to exercise

A single-breath CO₂ test of peripheral chemosensitivity has recently been described, and elaborated based on model simulations. This study was designed to measure the peripheral CO₂ chemoreflex at rest and during heavy exercise to see if carotid chemosensitivity to CO₂ increased. Ten healthy, adult males performed an incremental exercise test to determine their ventilatory anaerobic threshold (VAT), and 20 minutes of steady-state exercise at a pre-determined power output above VAT. Arterialized venous blood was obtained during each minute of incremental exercise to verify development of metabolic acidosis. Carotid chemosensitivity was tested repeatedly at rest and in steady-state exercise by the ventilatory response to a single breath of 13% CO₂ in air. The peripheral chemoreflex for CO₂ for the group of subjects doubled from rest to exercise (mean 0.0961 · s^–1 · kPa^–1) with all subjects showing an increase. We conclude that the gain of the carotid CO₂ chemoreflex increases from rest to exercise at work above the VAT.     

Estimation of peripheral chemoreflex gain from spontaneous sigh responses

A method is proposed for quantifying the responsiveness of the peripheral chemoreflex loop to CO₂ by utilizing the natural fluctuations in ventilation and endtidal P_CO2 which occur subsequent to the appearance of spontaneous sighs. The advantage of this method lies in its simplicity and noninvasiveness: the need for administering inhaled mixtures with high CO₂ content is eliminated. Using autoregressive moving-average (ARMA) analysis, we demonstrate that post-sigh responses can be adequately described by a simple chemoreflex model that contains first order dynamics and a pure time delay. The effective gain of this model is shown to reflect peripheral chemosensitivity closely when the estimation procedure is applied to ‘data’ obtained from computer simulations of the respiratory control system. Although central chemosensitivity affects the absolute values of effective gain, the slope of the linear correlation between effective and peripheral gains remains unchanged. Application of the procedure to spontaneously breathing anesthetized dogs shows that, in every case, effective gain increased with the induction of hypoxia, which is known to enhance peripheral chemosensitivity.     

Tolerance induction towards cardiac allografts under costimulation blockade is impaired in CCR7-deficient animals but can be restored by adoptive transfer of syngeneic plasmacytoid dendritic cells

Deficiency of transplant recipients for the chemokine receptor CCR7 was originally described to slightly increase the survival time of vascularized solid organ grafts, probably due to a reduced priming of alloreactive T cells. Using a model of allotolerance induction by donor-specific splenocyte transfusion (DST) in combination with anti-CD40L mAb-mediated costimulation blockade (CSB), we show here a striking failure of CCR7-deficient (CCR7(-/-) ) recipients to tolerate cardiac allografts. Furthermore, in addition to the recently described lack of Treg, CCR7(-/-) mice were found to harbor significantly reduced numbers of plasmacytoid dendritic cells (pDCs) within peripheral as well as mesenteric lymph nodes (LNs), but not the bone marrow or spleen. pDCs had previously been suggested to function as tolerogenic APC during allograft transplantation, and a single transfer of syngeneic WT pDCs, but not conventional DCs, was indeed sufficient to rescue graft survival in DST+CSB-treated CCR7(-/-) recipients in a dose-dependent manner. We therefore conclude that the nearly complete absence of pDCs within LNs of CCR7(-/-) mice prevents the successful induction of DST+CSB-mediated allotolerance, leading to the observed acute rejection of cardiac allografts under tolerizing conditions.     

A design of an artificial control system of the cardiac output

Summary An automatic control system of the cardiac output of a dog was designed by a method where a cardiac vagus and the heart were involved in the feedback system. The cardiac output was measured at the ascending aorta by a sine wave electromagnetic flowmeter. The output voltage of the flowmeter was compared with a controllable reference voltage. The error voltage was amplified or integrated, and converted to pulses of the frequencies which was proportional to the input of the AD convertor. A peripheral cut end of a vagus was stimulated by an electric stimulator triggered by those pulses. Vagal stimuli decrease the cardiac output by their negative chronotropic and inotropic action. The error approximated zero when the feedback loop gain was more than about 10 or an integral control was used. Complete stability could not be achieved with a zero error and an unstable oscillation of the smoothed cardiac output signal with a period of several seconds was observed. However, the instability was slight and did not disturb its application. Effects of disturbances such as change of venous return and peripheral resistance were sufficiently reduced.     

Retrotrapezoid nucleus and central chemoreception

The 'distributed chemoreception theory' attributes the central chemoreflex (the stimulation of breathing by CNS acidification) to the cumulative effects of pH on multiple classes of respiratory neurons as well as on their tonic sources of drive. Opinions differ as to how many classes of pH-sensitive neurons contribute to the central chemoreflex but the number of candidates is high and growing fast. The 'specialized chemoreceptor theory', endorsed here, attributes the chemoreflex to a limited number of specialized neurons. These neurons (the central chemoreceptors) would drive a respiratory pattern generator that is not or minimally activated by acidification. In this review we first describe the properties of the retrotrapezoid nucleus (RTN) and argue that this nucleus may contain the most important central chemoreceptors. Next, we subject the assumptions that underlie the distributed chemoreception theory to a critical analysis. We propose several explanations for the apparent contradiction between the two competing theories of central chemoreception. We attribute much of the current controversy to premature extrapolations of the effects of acidification on neurons recorded in vitro (chemosensitivity) and to a semantic confusion between chemosensitivity and chemoreception (the mechanism by which CO₂ or pH activates breathing in vivo ).     

A theoretical study of the effect of circadian rhythms on sleep-induced periodic breathing and apnoea

This study employed a mathematical model of the respiratory control system to test the plausibility of the hypothesis that circadian rhythms in respiratory control can significantly influence respiratory stability at sleep onset. Computer simulations utilized a standardized "normal" sleep onset effect, superimposed upon systematic changes in chemoreflex parameters that mimicked the peaks and troughs of normal and high amplitude circadian rhythms. The analysis predicted that circadian influences may augment sleep-induced periodic breathing in nocturnal sleep compared with daytime naps. Furthermore, increased circadian amplitude of chemoreflex threshold, or absence of a circadian rhythm in peripheral chemosensitivity, each acted to stabilize respiration during daytime sleep onset and promote periodic breathing during nocturnal sleep onset. High amplitude circadian rhythms in respiratory control were predicted to cause an increasing number and duration of obstructive apnoeas from early to late night. It is suggested that the circadian timing system creates a nocturnal window of respiratory vulnerability and that abnormal circadian rhythms could potentially induce nocturnal sleep apnoea, even in individuals with normal sleep mechanisms.     

Changes in chemoreflex characteristics following acute carbonic anhydrase inhibition in humans at rest

The effect of carbonic anhydrase (CA) inhibition with acetazolamide (ACZ, 10 mg kg(-1) I.V.) on the peripheral and central chemosensitivity and breathing pattern was investigated in four women and three men aged 25 +/- 3 years using a modified version of Read's rebreathing technique. Subjects were exposed to dynamic increases in CO2 in hypoxic and hyperoxic backgrounds during control conditions and following acute CA inhibition. All manoeuvres were repeated twice and averaged for data analysis. The central chemoreflex sensitivities, estimated from the slopes of the ventilatory response to CO2 during hyperoxic rebreathing, increased following acute CA inhibition (control vs. ACZ treatment: 1.87 +/- 0.66 vs. 4.07 +/- 1.03 l x min(-1) (mmHg CO2)(-1), P < 0.05). The increased slope was reflected by an increase in the rate of rise of tidal volume and breathing frequency. Furthermore with ACZ, there was a left-ward shift of the ventilation vs. end-tidal PCO2 curve during hyperoxic hypercapnia but not hypoxic hypercapnia. The peripheral chemoreflex sensitivity was isolated by subtracting the hyperoxic slope (central only) from the hypoxic slope (central and peripheral). Following ACZ administration, the peripheral chemosensitivity was blunted (control vs. ACZ treatment: 3.66 +/- 0.92 vs. 1.33 +/- 0.46 l x min(-1) (mmHg CO2)(-1), P < 0.05). In conclusion, acute CA inhibition enhanced the central chemosensitivity to CO2 but diminished the peripheral chemosensitivity.     

Chemoreflexes – physiology and clinical implications

The chemoreflexes are important modulators of sympathetic activation. The peripheral chemoreceptors located in the carotid bodies respond primarily to hypoxaemia. Central chemoreceptors located in the region of the brainstem respond to hypercapnia. Activation of either the hypoxic or hypercapnic chemoreflex elicits both hyperventilation and sympathetic activation. During apnoea, when the inhibitory influence of stretch of the pulmonary afferents is eliminated, there is a potentiation of the sympathetic response to both hypoxia and hypercapnia. This inhibitory influence of the pulmonary afferents is more marked on the sympathetic response to peripheral compared with central chemoreceptor activation. The arterial baroreflexes also have a powerful inhibitory influence on the chemoreflexes. This inhibition is again more marked with respect to the peripheral compared with central chemoreflexes. In patients with hypertension, there is a marked increase in the sympathetic and ventilatory response to hypoxaemia. During apnoea, with elimination of the inhibitory influence of breathing, the sympathetic response in untreated mild hypertensive patients is strikingly greater than that seen in matched normotensive controls. This potentiated peripheral chemoreflex sensitivity in hypertension may be explained in part by impaired baroreflex function in these patients. Enhanced peripheral chemoreflex sensitivity is also evident in patients with obstructive sleep apnoea. This peripheral chemoreflex enhancement is not explained by obesity, as obese individuals have a selective potentiation of the central chemoreceptors with peripheral chemoreflex responses similar to those seen in lean controls. Increased sensitivity to hypoxaemia has important implications in patients with obstructive sleep apnoea who experience repetitive and severe hypoxaemic stress. Tonic activation of the chemoreflex may also contribute to the high levels of sympathetic activity evident even during normoxic daytime wakefulness in sleep apnoea patients. Administration of 100% oxygen in patients with sleep apnoea results in reductions in heart rate, blood pressure and central sympathetic outflow. In patients with heart failure, the central chemoreflex response to hypercapnia is markedly and selectively enhanced. This increased central chemoreflex sensitivity may contribute to the development of central sleep apnoea in heart failure patients. Administration of 100% oxygen does not lower sympathetic activity in patients with heart failure, providing further evidence against any peripheral chemoreflex potentiation. The peripheral and central chemoreflexes have powerful effects on sympathetic activity in both health and disease and may contribute importantly to disease pathophysiology, particularly in conditions such as hypertension, obstructive sleep apnoea and heart failure.     

Chemoreflexes--physiology and clinical implications

The chemoreflexes are important modulators of sympathetic activation. The peripheral chemoreceptors located in the carotid bodies respond primarily to hypoxaemia. Central chemoreceptors located in the region of the brainstem respond to hypercapnia. Activation of either the hypoxic or hypercapnic chemoreflex elicits both hyperventilation and sympathetic activation. During apnoea, when the inhibitory influence of stretch of the pulmonary afferents is eliminated, there is a potentiation of the sympathetic response to both hypoxia and hypercapnia. This inhibitory influence of the pulmonary afferents is more marked on the sympathetic response to peripheral compared with central chemoreceptor activation. The arterial baroreflexes also have a powerful inhibitory influence on the chemoreflexes. This inhibition is again more marked with respect to the peripheral compared with central chemoreflexes. In patients with hypertension, there is a marked increase in the sympathetic and ventilatory response to hypoxaemia. During apnoea, with elimination of the inhibitory influence of breathing, the sympathetic response in untreated mild hypertensive patients is strikingly greater than that seen in matched normotensive controls. This potentiated peripheral chemoreflex sensitivity in hypertension may be explained in part by impaired baroreflex function in these patients. Enhanced peripheral chemoreflex sensitivity is also evident in patients with obstructive sleep apnoea. This peripheral chemoreflex enhancement is not explained by obesity, as obese individuals have a selective potentiation of the central chemoreceptors with peripheral chemoreflex responses similar to those seen in lean controls. Increased sensitivity to hypoxaemia has important implications in patients with obstructive sleep apnoea who experience repetitive and severe hypoxaemic stress. Tonic activation of the chemoreflex may also contribute to the high levels of sympathetic activity evident even during normoxic daytime wakefulness in sleep apnoea patients. Administration of 100% oxygen in patients with sleep apnoea results in reductions in heart rate, blood pressure and central sympathetic outflow. In patients with heart failure, the central chemoreflex response to hypercapnia is markedly and selectively enhanced. This increased central chemoreflex sensitivity may contribute to the development of central sleep apnoea in heart failure patients. Administration of 100% oxygen does not lower sympathetic activity in patients with heart failure, providing further evidence against any peripheral chemoreflex potentiation. The peripheral and central chemoreflexes have powerful effects on sympathetic activity in both health and disease and may contribute importantly to disease pathophysiology, particularly in conditions such as hypertension, obstructive sleep apnoea and heart failure.     

Chemical control stability in the elderly

The prevalence of central apnoea and periodic breathing is increased in the elderly. This implies that the chemical control of breathing might become less stable with ageing. To investigate this, we measured loop gain in healthy elderly individuals using proportional assist ventilation. Loop gain is an engineering term that describes the stability of a system controlled by feedback loops, such as the respiratory control system. A loop gain close to zero indicates a stable system, whereas a loop gain close to or greater than one indicates an unstable system. Eleven healthy elderly subjects were studied with a mean ± s.d. age and body mass index (BMI) of 71 ± 5 years and 25 ± 3 kg m⁻², respectively. We also studied a small group of elderly individuals with obstructive sleep apnoea (OSA) for comparison ( n = 3, age 68 ± 1 years, BMI 32 ± 11 kg m⁻²). Comparisons were made with previously studied young individuals (age 27 ± 4 years, BMI 23 ± 1 kg m⁻²). We found significantly lower loop gains in the healthy elderly group (loop gain ≤ 0.25) compared with the young group (loop gain ≤ 0.47, P = 0.001). Also, we found quite low loop gains in the elderly OSA group (loop gain ≤ 0.26). We conclude that the chemical control of breathing does not become unstable with ageing and is thus an unlikely cause of central (and possibly obstructive) apnoeas in this population.     

SHIV-XJ02170在中国恒河猴体内传代过程中env基因变异研究

目的 研究SHIV-XJ02170在中国恒河猴体内传代过程中env基因序列变异的特点.方法 应用聚合酶链反应(PCR)和逆转录聚合酶链反应(RT-PCR)分别对各代动物SHIV-XJ02170病毒载量峰值时间点全血前病毒DNA gp160基因和血浆病毒RNA gp120基因进行扩增.GP160基因PCR产物直接进行测序分析,gp120 RNA扩增产物连接T载体后每份样品挑选18个克隆测序,分析传代过程中病毒的基因距离(divergence,diversity)的变化规律及病毒基因进化的特点.结果 SHIV-XJ02170在传代过程中基因连续进化并且进化的方向和病毒传代的顺序完全一致,基因距离总体上表现为逐步扩大的趋势,病毒传代早期存在明显的"瓶颈效应".氨基酸序列分析发现V3环顶端四肽和辅助受体在传代过程中未发生改变.结论 SHIV-XJ02170经过中国恒河猴体内传代后基因距离出现明显扩大过程,且按照传代的顺序发生连续的基因进化.这从分子水平上部分解释了 SHIV-XJ02170经猴体传代出现毒力增强的原因.     

Temporal stability of the hemodynamics of cardiovascular reactivity

Cardiovascular responses to a competitive reaction-time task were monitored in 13 male subjects tested twice, 3 months apart. The temporal stability of blood pressure responses was in line with previous reports. However, in this study impedance cardiography permitted the investigation of the hemodynamic adjustments underlying the observed blood pressure responses. Analyses revealed that cardiac output and total peripheral resistance responses displayed temporal stability, indicating that subjects' blood pressure responses on the two occasions were the result of similar hemodynamic responses. These data thus extend the literature by demonstrating that the hemodynamic response pattern itself represents a stable individual difference variable.     

Computational model of the role of sensory disorganization in focal task-specific dystonia

We present a new computational model for the development of task-specific focal dystonia. The purpose of the model is to explain how altered sensory representations can lead to abnormal motor behavior. Dystonia is described as the result of excessive gain through a sensorimotor loop. The gain is determined in part by the sensory cortical area devoted to each motor function, and behaviors that lead to abnormal increases in sensory cortical area are predicted to lead to dystonia. Properties of dystonia including muscular co-contraction, overflow movements, and task specificity are predicted by properties of a linear approximation to the loop transformation. We provide simulations of several different mechanisms that can cause the gain to exceed 1 and the motor activity to become sustained and uncontrolled. The model predicts that normal plasticity mechanisms may contribute to worsening of symptoms over time.     

Neonatal stress increases respiratory instability in rat pups

Neonatal maternal separation (NMS) is a form of stress that has persistent, sex-specific effects on respiratory control development. In adult male (but not female) rats, NMS increases the hypoxic ventilatory response and augments respiratory instability during sleep; however, the effects of NMS on respiratory control prior to puberty are unknown. This study tested the hypothesis that NMS augments respiratory instability and the O(2) chemosensitivity in 12 days old rats. Pups subjected to NMS were placed in an incubator 3h/day from P3 to P12. Controls were undisturbed. Breathing and apnea index were measured in normoxia with plethysmography. The ventilatory chemoreflex was assessed by measuring the increase in breathing frequency upon brief exposure to a hypoxic challenge ( [Formula: see text]; 5 min). In normoxia, NMS augments the coefficient of variation (CV; an index of respiratory instability) of respiratory frequency and the number of apneas; this effect was more pronounced in male pups. We conclude that disruption of respiratory regulation by NMS is already apparent at P12. Based on results showing that plasma corticosterone levels of NMS pups were still elevated one day after the last NMS episode and the lack of effect of NMS on the O(2) chemoreflex index, we propose that disruption of hypothalamic regulation contributes to respiratory instability in NMS pups.     

Normal and hypertrophic growth of the rat heart: changes in cell dimensions and number.

The length and width of enzymatically isolated individual rat cardiac myocytes were concurrently measured during normal and stimulated cardiac growth. In normal rats weighing between 75 and 750 g the length and width increased by 64 and 68% while their ratio remained constant (ca. 5.3). The cell volume, calculated on the basis of a cylindrical model, increased almost 5 times. The rates of increase in the volume of an average myocyte and in left ventricular mass were found to be similar, indicating that normal myocardial growth could be explained by hypertrophy of existing myocytes and no proliferation would be required. In cardiomegaly induced by aortic constriction in the adult rat, an increase in cell volume was observed while no significant changes in the length-to-width ratios could be detected. The cell volumes of the hypertrophic hearts corresponded to those observed in hearts of similar weight obtained from larger normal rats and the stimulated cardiac growth could also be explained solely by hypertrophy of existing cells.     

Relationship between productive HIV-1 infection of macrophages and CCR5 utilization

HIV-1 isolates exhibit specificity for infection of immortalized T-cell lines and macrophages. The distinct cellular tropisms have been attributed to expression of coreceptors CXCR4 or CCR5, respectively. However, it is unclear whether or not other tissue-specific determinants regulate entry. The current study uses a panel of viruses to analyze the relationship between CCR5 utilization and macrophage infection. Only chimeric viruses with the entire V3 loop from macrophage-tropic isolates, ADA or SF162, were able to infect macrophages. In contrast, chimeric viruses with smaller portions of the ADA V3 loop or the V3 loop of SF2, sufficient to allow CCR5 use, were insufficient for macrophage infection. PCR analysis showed that the defect in macrophage infection of the latter viruses was due to a defect in entry. Moreover, strains capable of infecting macrophages showed relative resistance to neutralization by anti-CCR5 antibody, 2D7, compared to strains which utilize CCR5 but are incapable of macrophage infection.     

Transpulmonary pressure and lung volume of the cat and the newborn: removal of cardiac effects with a digital filter

Dynamic lung compliance is a measure of the elastic properties of the lungs in the normal breathing range and is measured as the relationship between the transpulmonary pressure changes and the corresponding changes in lung volume. This relationship is given as a pressure-volume loop, from which the compliance is calculated as the slope of the line joining the end points of the loop. Owing to cardiac interference, which is superimposed on the normal pressure and volume signals, the compliance loops are often severely distorted, making it difficult to establish the end points in the loop. Therefore it is necessary to preprocess the measured data so that the superimposed cardiac pulsations are eliminated. In the investigations that are described in this paper, we have applied digital filtering techniques to recover compliance loops resulting solely from respiratory origin. The design method of a digital filter based on ‘windowing’ technique is discussed. The method is applied for filtering transpulmonary-pressure and lung-volume data obtained from experiments with cats and neonates. The effectiveness of digital filtering in recovering the compliance loops which are contaminated by the presence of cardiac pulsations is shown.     

Postmortem cardiomegaly and echocardiographic measurements of left ventricular size and function in children infected with the human immunodeficiency virus. The Prospective P2C2 HIV Multicenter Study.

BACKGROUND: Cardiomegaly, seen postmortem in over 50% of HIV-infected children, may occur in the absence of clinical or histopathologic cardiac disease. Premortem echocardiography has also demonstrated clinical and subclinical cardiac disease, including increased left ventricular mass (LVM) and functional abnormalities. No studies have compared these echocardiographic measures of heart size and function with postmortem findings in this population. We sought to determine the postmortem prevalence, clinicopathologic relationships and importance of cardiomegaly in HIV-infected children. METHODS: We reviewed clinical and postmortem cardiac findings in 30 HIV-infected children who were part of the Prospective P(2)C(2) HIV Study. Postmortem heart weight was compared with clinical measures of heart size and function, with cardiac pathology and with clinical measures reflecting chronic effects of HIV disease. RESULTS: Postmortem cardiomegaly (heart weight z score >/=2) was identified in 53% of the children. Children with cardiomegaly had increased LVM, increased heart rate, more frequent clinical chronic heart disease and a higher prevalence of postmortem pericardial effusions compared to children without cardiomegaly (P相似文献   

Thresholds of cortical activation of muscle spindles and α motoneurones of the baboon''s hand

1. Much current thinking about voluntary movement assumes that the segmental gamma loops can function as a servomechanism operated by the brain. However, the alpha motoneurones of the baboon's hand receive a powerful monosynaptic (CM) projection from the precentral gyrus. If servo-driving from the same cortical area is to be possible, it must project independently to the fusimotor neurones and have sufficient power to increase the afferent signalling from the muscle spindles. The cortical thresholds for contraction of m. extensor digitorum communis and for acceleration of the discharges of its muscle spindles have therefore been compared.2. Significant results in this context require that the spindles studied be coupled in parallel with the responding extrafusal muscle fibres. Many spindles were not unloaded by the submaximal contractions evoked by cortical stimulation, although all so tested were unloaded by maximal motor nerve twitches. Reasons are given for thinking that such apparent lack of parallel coupling is an artifact of complex intramuscular anatomy and limitation of shortening by ;isometric' myography.3. A brief burst of corticospinal volleys at 500/sec, which is specially effective in exciting alpha motoneurones over the CM projection, failed to excite spindle afferents at or below the threshold for a cortical ;twitch'.4. In a few epileptiform discharges, bursts of spindle acceleration occurred independently of the clonic contractions. A relatively direct and independent cortico-fusimotor (CF) projection may therefore exist.5. Prolonged near-threshold stimulation at 50-100/sec, which allows time for temporal summation in the less direct projections (e.g. cortico-interneuronal, cortico-rubro-spinal) and does not cause frequency-potentiation at CM synapses, gives abundant evidence of independent alpha and fusimotor projections, whose actions hardly outlast the stimulation period.6. Although independent CF projections would permit servo-driving in natural movements of the hand (given adequate loop gain), there has been no evidence of servo-driving by cortical stimulation or in the spontaneous contractions of light anaesthesia.7. Independent projections would provide for controlled alphagamma co-excitation in the servo-governing of natural movements (Matthews, 1964).8. Evidence is reviewed that the CM projection itself may be part of an important control loop for voluntary movement in primates. A corollary would be a diminished importance of CF projections for segmental loops and an increased importance for maintaining the spindle input to cortical loops.