MRI-related anxiety can induce slow BOLD oscillations coupled with cardiac oscillations.

OBJECTIVE: Although about 1-2% of MRI examinations must be aborted due to anxiety, there is little research on how MRI-related anxiety affects BOLD signals in resting states. METHODS: We re-analyzed cardiac beat-to beat interval (RRI) and BOLD signals of 23 healthy fMRI participants in four resting states by calculation of phase-coupling in the 0.07-0.13 Hz band and determination of positive time delays (pTDs; RRI leading neural BOLD oscillations) and negative time delays (nTDs; RRI lagging behind vascular BOLD oscillations). State anxiety of each subject was assigned to either a low anxiety (LA) or a high anxiety (HA, with most participants exhibiting moderate anxiety symptoms) category based on the inside scanner assessed anxiety score. RESULTS: Although anxiety strongly differed between HA and LA categories, no significant difference was found for nTDs. In contrast, pTDs indicating neural BOLD oscillations exhibited a significant cumulation in the high anxiety category. CONCLUSIONS: Findings may suggest that vascular BOLD oscillations related to slow cerebral blood circulation are of about similar intensity during low/no and elevated anxiety. In contrast, neural BOLD oscillations, which might be associated with a central rhythm generating mechanism (pacemaker-like activity), appear to be significantly intensified during elevated anxiety. SIGNIFICANCE: The study provides evidence that fMRI-related anxiety can activate a central rhythm generating mechanism very likely located in the brain stem, associated with slow neural BOLD oscillation.

Subchronic alpha- and beta-adrenergic regulation of cardiac gap junction protein expression.

Gap junction channels are essential for intercellular electrical communication in the heart. The most important cardiac gap junction proteins are connexin43 (predominantly) (Cx43), connexin40 (Cx40), and in early developmental stages connexin45. Since catecholamines play an important role in cardiac (patho)physiology, we wanted to elucidate whether catecholamines may affect expression of Cx43 and Cx40. Cultured neonatal rat cardiomyocytes were exposed for 24 h to increasing concentrations of noradrenaline (1-10000 nM) (physiological agonist at alpha and beta-adrenoceptors), resulting in significantly increased Cx43-expression, while Cx40 was unaffected. In further experiments cells were incubated with either phenylephrine (alpha-adrenergic agonist) or isoproterenol (beta-adrenergic agonist) (0.1-1000 nM) for 24 h. Both catecholamines lead to a concentration-dependent increase in Cx43 protein and mRNA expression (EC50: 10-20 nM). Inhibition experiments showed that the phenylephrine effect was transduced via PKC, while the isoproterenol effect was mediated by PKA. Dual whole-cell voltage clamp demonstrated that increased Cx43-expression was accompanied by significant increases in gap junction current. In additional in vivo experiments, adult rats were subjected to 24-h infusion of isoproterenol or phenylephrine showing again significant increase in Cx43 but not Cx40. Adrenergic stimulation of cardiomyocytes can enhance Cx43 expression thereby increasing cellular coupling, indicating a possible role for catecholamines in the regulation of cardiac gap junction expression in cardiac disease.

Cardiac remodeling after long term norepinephrine treatment in rats.

OBJECTIVE: In this study we have tested the hypothesis that degradation of collagen by matrix metalloproteinase 2 (MMP-2) precedes the deposition of extracellular matrix (ECM) after long term norepinephrine (NE) treatment. METHODS: Female Sprague-Dawley rats received continuous i.v. infusion of NE (0.1 mg/kg.h) for 1, 2, 3, 4 and 14 days. Heart function and weight as well as expression of cardiac colligin and of collagen I and III were examined. Furthermore, we have assessed the degradation pathway of collagen by measuring the mRNA and activity of myocardial MMP-2 and tissue inhibitor of metalloproteinase 2 (TIMP-2) as well as the protein level of TIMP-2. RESULTS: NE induced hypertrophy predominantly of the left ventricle (LV) in a time-dependent manner. It increased the mRNAs of colligin, collagen I and III, and of MMP-2 and TIMP-2 as well as MMP-2 activity in two phases: In the initial phase, at 3 and 4 days, the mRNA of colligin and of collagen I and III was elevated predominantly in the LV, MMP-2 and TIMP-2 mRNA, as well as TIMP-2 protein and MMP-activity were increased in both ventricles. The second phase, after 14 days, was characterized by a less pronounced increase in colligin, collagen I and III and in MMP-2 activity which occurred exclusively in the LV. Finally, long-term treatment with NE induced a 37% increase in interstitial fibrosis which was shown to occur exclusively in the LV after 14 days. CONCLUSION: NE treatment induced fibrosis exclusively in the LV which was associated with hypertrophy predominantly of the LV. The elevated MMP-2 activity seems to be necessary for the ECM to adapt to the enlargement of myocytes and to reduce overproduction of collagen.

Interactions of breathing with the postural regulation of the fingers.

OBJECTIVES: The present study was performed to detect the interactions between breathing and the postural motor control of the fingers. A previous study revealed a scattering in the intraindividual motor responses which resembled a grouping. It is hypothesized to result from the influence of breathing. METHODS: Torque impulses and torque steps at two intensities were applied to 17 healthy volunteers, to the II-IV fingers of their right hand. The subjects had to compensate for these additional torque loads that were triggered by a breathing-related signal and elicited at 4 different moments within a breath. RESULTS: We demonstrated mutual influences between breathing and the regulation of finger posture. The reaction to a torque load was faster at the beginning of inspiration but more precise when the torque load was applied in mid-expiration. The motor response to torque loads was accompanied by changes in the breathing time course, particularly when the torque load was elicited during inspiration. The effects were most pronounced when torque steps were applied. The intensity of torque loads had no significant influence. Additionally, we observed that the respiratory phase-transitions often coincided with the end of the applied torque steps. CONCLUSIONS: The results correspond well with the interactions existing between breathing and single or rhythmical movements. Further investigations of motor functions should consider this interdependence with breathing.

Mutual nervous influences between breathing and precision finger movements.

The precision of short-term finger tracking flexions has been shown to vary with the respiratory cycle. In the present study, we analysed the mutual effects between breathing and short-term finger tracking movements (SFTM)--both flexions and extensions. Moreover, we investigated the preferred phase relationships between breathing and spontaneous single finger flexions and extensions. Two types of experiments were carried out. Fifteen volunteers participated in the finger tracking experiments. In one experimental session, a square-wave function served as a tracking signal that required a rapid finger flexion, and in another session it required a finger extension. In the second type of experiment, 14 volunteers performed spontaneous short-term finger flexions and extensions of a pre-defined amplitude, with the starting point chosen at their convenience. SFTM were associated with modulations in the time course of the respiratory cycle. These were more pronounced for finger flexions than for extensions. Likewise, the precision of finger flexions, but not extensions, showed significant respiratory-phase-dependent differences. The largest tracking errors occurred at the end of expiration in finger flexions and at the end of inspiration in finger extensions. Spontaneous finger flexions tended to start at around the respiratory phase transitions. Spontaneous extensions, however, tended to start at early expiration (12.5-37.5% of expiration time). The results demonstrate that both spontaneous and tracking finger flexions and extensions are influenced by different stages of a breath. However, spontaneous finger movements did not tend to start at the stages of breaths that were associated with the highest movement precision in the tracking tests. Moreover, these results suggest that finger flexions are more closely related to the respiratory rhythm than are finger extensions.

Coordination-related changes in the rhythms of breathing and walking in humans.

Coordination of the respiratory rhythm with the rhythm of limb movements has often been observed during rhythmical exercise (e.g. in locomotion). It is usually associated with changes in the respiratory time course, but not in the locomotor rhythm. Therefore, we hypothesised that in walking, the extent of coordination-related changes (CRC) in respiratory parameters would increase with closer coordination. With respect to the controversially discussed question of a possible energetic advantage due to coordination, we devoted particular interest to the CRC in oxygen uptake (VO2). In addition, we investigated the incidence and the extent of CRC in the stepping rhythm. We examined 18 volunteers walking on a treadmill at three different workload levels, which were adjusted by altering either the velocity or slope of the treadmill. Each walking test was carried out twice, once with spontaneous breathing and once with breathing paced by a step-related acoustic signal to enhance the coordination between breathing and walking. No correlation was found between the CRC in the analysed parameters and the degree of coordination. However, the extent of CRC of ventilation and VO2 decreased with increasing workload. With the transition to coordination, increases and decreases of VO2 occurred about equally often. From this we conclude that energetic economisation in walking, as reflected by a reduction in VO2, is rather a side-effect of coordination, and is probably due to a more precise regulation of the breathing pattern. The economisation was more pronounced at higher work loads than at lower work loads. Our results revealed that coordination is also associated with changes in the stepping rate, which occurred more frequently when the variability of breathing was restricted by acoustic pacing of the breathing rhythm. This finding suggests that the choice of walking rhythm is not completely free, but can be influenced by the breathing rhythm. CRC in the walking rhythm might contribute to the avoidance of excessive CRC in the respiratory time course, which would entail an inefficient breathing pattern and thus, an energetic disadvantage.

Analysis of coordination between breathing and walking rhythms in humans.

We investigated the coordination between breathing and walking in humans to elucidate whether the coordination degree depends more on metabolic load or on breathing or stride frequencies and whether coordination causes energetic economization expressed by reduction of oxygen uptake (VO2). Eighteen healthy volunteers walked on a treadmill at three load levels realized by different velocities and slopes. We analyzed the time intervals between step onset and the onset of inspiration or expiration related to stride duration (relative phase, phi) and computed the relative-phase histogram to assess the degree of coordination. The degree of coordination between breathing and stepping enhanced with increasing walking speed. Increased work load achieved by slope at constant walking speed improved coordination only slightly. No significant VO2 reduction due to coordination was found. VO2 was more strongly related to ventilation variations occurring during coordination. Also the sympathetic tone reflected by the spectral power of heart rate variability was not reduced during coordination. We conclude that during walking the coordination degree increases with increasing stride frequency and that coordination does not necessarily cause energetic economization.

Coordination between breathing and forearm movements during sinusoidal tracking.

Time relationships (coordination) between breathing and rhythmical limb movements were analyzed during sinusoidal tracking movements of the forearm in 11 healthy subjects. The tracking rate was varied systematically between 0.1 and 1.0 Hz in 0.1-Hz steps. The aim of the study was to elucidate whether rhythmical tracking movements can entrain breathing, and whether this entrainment depends upon the movement rate. Subjects exhibited coordination between tracking movements and breathing at various rate ratios (1:1, 1:2, 1:3). At tracking rates of between 0.2 and 0.6 Hz, 1:1 coordination occurred with a maximum at 0.3 Hz; this rate range was called the 1:1 entrainment band. Coordination of 1:2 occurred at between 0.5 and 1. 0 Hz (the 1:2 coordination band) with a maximum at 0.7 Hz. Coordination of 1:3 could be detected at between 0.5 and 1.0 Hz. Different subjects showed 1:n entrainment bands at similar locations but different widths of the rate range studied. The breathing rate during tracking was significantly higher than at rest, and it was correlated positively with tracking rate. This correlation, however, depended upon the width of the entrainment bands. Breathing rates varied between 0.2 and 0.6 Hz for all coordination patterns. We conclude that the occurrence of fixed time relationships is an expression of the strength of central nervous system coupling between the two processes. The frequency of coordination between breathing and rhythmical tracking movements depends critically upon the movement rate.

Phase-dependence of breathing and finger tracking movements during normocapnia and hypercapnia.

The coordination between breathing and other motor activities usually implies that the respiratory rhythm has become entrained by the rhythm of the simultaneous movement. Our hypothesis was that by increasing the respiratory drive, e.g. by hypercapnia, we would be able to reduce the subordination of breathing to other movements and, on the other hand, enhance effects of breathing on those movements. We investigated interactions between breathing and finger flexion movements in a visually controlled step-tracking procedure which allowed us to distinguish the mutual effects and to detect the dependence of these effects on the phase-relationship between breathing and movement. In contrast to our hypothesis, we found no large increase of the respiratory influences on finger movements during hypercapnia. A noteworthy difference to normocapnia was a shortening of the finger flexion time during the final stage of expiration which was associated with an increased frequency of coincidence between the end of flexion time and the transition from expiration to inspiration. On the other hand, the response of breathing to the finger movement increased when the tracking signal was presented at the beginning of inspiration. The results of the study disproved our hypothesis and demonstrated that, during hypercapnia, breathing can be even more susceptible to influences originating from motor control. Thus, they are in agreement with the findings of a previous study that the coordination between breathing and rhythmic limb movements becomes closer during hypercapnia.

[Effect of central coordination in the sense of v. Holst on the control of breathing and limb movements in humans]. / Einfluss zentralnervöser Koordination im Sinne v. HOLSTs auf die Steuerung von Atem- und Extremitätenmotorik des Menschen.

We found modulations in the time-course of breathing during rhythmic abduction-adduction movements in shoulder and hip joints which can be interpreted as phenomena of central coordination in the sense of v. Holst. They occurred in more than 75% of the recorded breaths. The strength of this coordination depends on number and kind of limbs moving rhythmically and on the use of an acoustic trigger signal ("Zeitgeber") for the limb rhythm as well. Our findings indicate that reactions of the respiratory apparatus cannot be regarded only in connection with its homeostatic function and with mechanical influences. Breathing control appears integrated in the whole organism's "motor control system". Therefore, an influence of breathing movements on other motor processes is possible as well. Coordination leads to a stable temporal order between breathing and additional movements. Its possible advantage could be an energetic economization as may be concluded from analogous phenomena in coupled non-linear oscillators.

Coordination Between Breathing and Finger Tracking in Man.

Arm and leg movements are known to produce temporal pattern changes of breathing. This can be interpreted as coordination, as defined by von Holst (1939). The aim of the present study was to find whether breathing exerts an influence in a reverse direction on a nonrespiratory movement as well. A pursuit tracking test was used, and test individuals (N = 19) were instructed to track a visually presented step function by flexion or extension of their right index finger. Velocity and precision of the step responses proved to be dependent on their relation to the breathing time course; the differences between inspiratory and expiratory responses were smaller than those within each half-cycle. The movements were performed more rapidly and more precisely in about the middle of each half-cycle than immediately after the respiratory phase transition or during the second half of each inspiration or expiration. Discontinuous short-lasting motor actions exerted a coordinative influence on respiration comparablewith that of periodical events: Breaths coinciding with step responses were shortened, preferably when the preset step was given early in the inspiration. It was hypothesized that the reciprocal effect between both motor actions changes periodically. In the first part of each respiratory half-cycle, the respiratory rhythm exerts only a weak influence on additional movements, but it can be altered easily by simultaneous motor processes. Toward the respiratory phase-switching, the respiratory rhythm behaves more stably against coordinative influences and becomes capable of impairing an additional movement.

Breathing--homeostatic function and voluntary motor activity.

In a magnitude production test, subjects of both sexes rated their breath depth under different conditions. In the first group, 50 subjects were examined at rest in the supine position and breathing spontaneously or assisted by a respirator. The second group, consisting of 33 subjects, was tested in the sitting position at rest and during mild bicycle exercise (females 35 W, males 40 W). Subjectively quantified breath depths and corresponding tidal volumes were compared and their relations were described by Stevens power function. The assessment of breath depth in spontaneous breathing at rest was remarkably precise (mean Stevens exponent 0.94 +/- 0.02). During assisted ventilation, rating was less accurate and tended to underestimate breath depth. Noticeable under both conditions was a tendency to overestimate voluntary tidal volume reductions. This was more pronounced in young (up to 35 years) women than in men or elderly women. During exercise, the subjects (men and women) overestimated both increases and reductions of tidal volume. Each voluntary tidal volume modification was accompanied immediately by involuntary changes of inspiration and expiration times, thus, partially compensating disturbances of ventilation. In addition, voluntarily reduced tidal volumes were quantitatively compensated within the first breath subsequent to the voluntary manoeuver. We conclude that breath depth sensation is more strongly related to proprioceptive signals than to visceroceptive signals and is influenced by the autonomous respiratory drive. Furthermore, proprioception is assumed to participate in the control of the autonomous respiratory drive.

[Effect of surgical positioning and spinal anesthesia on lung function]. / Der Einfluss von Operationslagerungen und Spinalanästhesie auf die Lungenfunktion.

BACKGROUND: Various surgical positions, e.g., lithotomy, prone, or head-down positions influence respiratory mechanics. The aim of the present paper was to investigate whether particular surgical positions (lithotomy, lithotomy with head-down tilt, prone, prone with a roller placed under the abdomen) as well as spinal anaesthesia in lithotomy position impair the pulmonary function to a greater extent than supine position and whether they have to be considered as increasing the perioperative risk in elderly patients and patients with ventilatory disorders. METHODS: In two separate experimental series, we examined a) the influence of the surgical positions on the pulmonary function in 45 subjects (25 without and 20 with ventilatory disorders) and b) the effects of spinal anaesthesia in 25 urologic patients (9 without and 16 with ventilatory disorders). Static and dynamic lung function parameters were determined. Under spinal anaesthesia, the arterial O2 saturation and the end-expiratory partial pressure of CO2 were measured additionally. RESULTS: The most pronounced lung function decrease occurred with the transition from seated to supine position. Lithotomy and prone positions impaired the respiratory function only slightly. In elderly persons and in patients with ventilatory disorders, the spirometric changes tended to be stronger than in young persons, but were not considered to increase the perioperative pulmonary risk. A combination of lithotomy position and spinal anaesthesia did likewise not remarkably impair the respiratory function. CONCLUSIONS: Lithotomy and prone positions as well as spinal anaesthesia are not considered to be an additional risk factor for pulmonary function.

[The prognostic relevance of preoperative pulmonary function tests]. / Die prognostische Relevanz präoperativer Lungenfunktionsdiagnostik.

At Leipzig University, preoperative pulmonary function testing has been performed for about 3 years in order to detect and classify patients at high pulmonary risk. During the postoperative period, the risk of developing pulmonary complications is particularly high due to factors influencing respiratory mechanics such as the supine position, pain, residual effects of narcotic drugs, etc. It has often been emphasised that an underlying ventilatory disturbance such as obstructive lung disease or smoking may enhance the postoperative pulmonary risk, although the extent of the influence of preoperative pulmonary diseases on the postoperative complication rate is still controversial. The prediction of postoperative lung function from preoperative spirometric values is complicated by factors such as patient cooperation, pulmonary complications secondary to aspiration, infection, peritonitis, etc., and by differing and therefore non-comparable postoperative care. For this reason, the criteria for assessing pulmonary risk vary widely. METHODS. We examined 339 patients (mean age 59.3 years) preoperatively by quiet and forced spirometry; in most cases we also measured airway resistance and functional residual capacity. We estimated the postoperative lung function using the quadrant scheme of Miller and compared this risk class with our spirometric diagnosis and the postoperative clinical course. RESULTS. According to our results, Miller's classification seems inadequately differentiated for patients with mild to moderate ventilatory disturbances. A relatively high percentage of these patients were considered to have normal postoperative lung function. Some patients with severely diminished pulmonary function were classified as having sufficient postoperative lung function. The number and severity of pulmonary complications also corresponded better with the spirometric diagnosis, which was made using all spirometric parameters and not only vital capacity (VC) and 1-s forced expiratory volume (FEV1). We found that the percentage of primary respiratory complications increased with deterioration of the preoperative spirometric values. To provide a prognostic model combining both the advantages of using only a few parameters (FEV1, VC) and appropriate risk assessment, we propose a modification of the Miller scheme consisting of five risk classes. The analysis of the respiratory therapy regimen was unsatisfactory because of discrepancies between the predicted pulmonary risk, the use of respiratory therapy, and the occurrence of pulmonary complications. CONCLUSIONS. For minimising perioperative pulmonary complications, respiratory care (prophylaxis and therapy) adequate for the functional risk of the patient is necessary. We assume that intensive pre- and postoperative respiratory care and therapy in patients with underlying reductions in ventilatory function can help to avoid or reduce respiratory complications. The modification of Miller's scheme proposed after evaluating the postoperative course of our patients provides a differentiated prognostic model that allows the establishment of an appropriate and economical therapeutic regimen of perioperative pulmonary care.

Transient pleural effusion in norepinephrine-stimulated rats.

Transient pleural effusions occurred in rats receiving continuous intravenous infusion of norepinephrine (NE, 0.1 mg/kg/h). We hypothesized that these pleural effusions result from a NE-induced increase in right ventricular systolic pressure (RVSP) and total peripheral resistance (TPR). NE was administered over time intervals between 20 min and 72 h. It induced an immediate doubling in RVSP whereas LVSP remained at the control level. TPR increased with a delay of 6 h. At this time, pleural effusions occurred in NE-treated animals, reached their maximum after 8h and disappeared after 24 h of NE stimulation. Combining NE with the alpha-blocker prazosin normalized TPR and prevented pleural effusions. Therefore, we interpret the pleural effusion as a consequence of pulmonary venous congestion, mainly caused by an increased TPR. LV hypertrophy which developed after 24 h of NE stimulation is considered to compensate for the hemodynamic disturbance due to the NE-induced elevation in TPR. This is reflected in the disappearance of pleural effusion.

Norepinephrine-induced interleukin-6 increase in rat hearts: differential signal transduction in myocytes and non-myocytes.

Continuous i.v. infusion of norepinephrine in rats has been shown to induce early interleukin (IL)-6 mRNA expression in the left ventricle (LV) which was followed by hypertrophy and fibrosis. In this study, two approaches were used. In the first, NE (0.1 mg/kg per hour) was infused i.v. in rats for several time periods, and freshly obtained ventricular myocardium was dissociated into myocyte (MC) and non-myocyte (NMC) fractions. Second, isolated adult MCs and fibroblasts were treated with NE (10 microM). NE infusion (4 h, in vivo) caused an 11-fold increase in IL-6 mRNA in both cell populations. In vitro treatment of isolated adult MCs for 2 h and of fibroblasts for 1 h with NE induced a 3.5- and 23-fold maximum increase, respectively, in IL-6 mRNA. After in vivo NE treatment, the expression of the mRNA of the transcriptional factor of IL-6, C/EBP-beta, was elevated earlier (after 45 min of NE infusion) than IL-6 mRNA (after 4 h) and was seen in MCs and NMCs. The mRNAs of both receptors of IL-6, the soluble IL6R and gp130, were increased subsequently to IL-6 mRNA. Gp130 was elevated after 24 h and, like IL6R, predominantly in NMCs. In contrast, the IL6R protein and the downstream regulator STAT3 were increased only in MCs after 24 h of NE infusion. The mRNA of C/EBP-delta, which is regulated by STAT3, was elevated only in myocytes.