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Cardiovascular modulation of central neuronal activity
Brain Research, 105 (1976) 333-336
333
© Elsevier Scientific Publishing Company, Amsterdam - Printed in The Netherlands
Cardiovascular modulation of central neuronal activity
A L A N FORSTER AND T R E V O R W. STONE
Department of Physiology, University of Aberdeen, Marischal College, Aberdeen AB9 1AS (Great Britain) (Accepted December 15th, 1975)
Although the generally accepted 'text-book' explanation of the physiological tremor which normally accompanies muscle movement is that it is due to oscillation in the stretch reflex servo-loopS,6A 0-12, several groups have produced evidence that the tremor originates from cardiovascular activity. Thus Brumlik 1 noted a marked similarity between finger tremor and the ballistocardiogram and showed that neuromuscular blockade did not abolish the tremor. Marsden et al. 13 observed tremor in a surgically deafferented limb, and Yap and Boshes 16 have reported that physiological tremor can be summated by an averaging computer triggered by the electrocardiogram. In the present experiments we have tried to assess further the influence of the cardiovascular system on finger tremor. Thirty-nine subjects (aged 17-22 years) were instructed to keep the index finger approximately horizontal in the path of a light beam directed onto a photodiode. The photodiode output was amplified in a Fenlow AD55 amplifier and then passed to a Devices Pen Recorder. The output was also displayed on a Telequipment oscilloscope and on a Biomac 1000 averaging computer. The QRS spike of the electrocardiogram (lead II) was used to trigger the Biomac sweep. The Biomac was usually programmed for 128 sweeps of 1.28 sec duration to allow examination of a complete cardiac cycle in each sweep. Summated records from the Biomac were taken out on punched tape or on a Telsec pen recorder. Subjects were seated with the arm resting horizontally in front of the body. The a r m was supported to the metacarpals and was clamped firmly from the elbow to the wrist to reduce gross movements and ballistic effects on the arm. To completely prevent any ballistic effects affecting movement of the finger itself some recordings were made during the inflation of a cuff around the upper arm to 220 m m Hg. In this case finger movements were summated for 30 sec after which the cuff was deflated, the arm allowed to recover for 2 min and then the process was repeated until the 128 Biomac sweeps had been reached. The arrival of the finger-tip pulse was monitored directly using a M I E M k liB photoelectric pulse monitor. A direct recording of normal tremor is shown in Fig. la. After arterial occlusion the tremor declined in amplitude until it had virtually disappeared after about 3 min.
334
a
Ao
Fig. 1. Direct pen recordings of finger tremor, a: normal tremor, b: tremor recorded immediately after arterial occlusion of the upper arm using a cuff inflated to 220 mm Hg. Note the failure of such occlusion to abolish the tremor. The basic tremor at approximately 8 Hz is actually clarified. The amplitude of the tremor decreased slowly after occlusion and was virtually abolished after 3 min. Time: I sec. N o waves definitely related to the heartbeat were seen in direct recordings and it was f o u n d that t r e m o r did n o t s u m m a t e in the Q R S triggered Biomac (Fig. 2a). However, the s u m m a t e d recordings revealed a wave b e g i n n i n g 200 ± 33 msec (S.D.) after the Q R S spike a n d reaching a peak 317 ± 53 msec after QRS. Arterial occlusion immediately abolished this wave (Fig. 2b), which has been labelled the B wave to indicate a presumed ballistic origin. Arterial occlusion also clarified the second wave, labelled N in Fig. 2b. This wave had initial a n d peak latencies o f 497 ± 68 msec a n d 591 ± 55 msec respectively from the Q R S spike. W i t h c o n t i n u e d arterial occlusion the N wave declined in amplitude with a similar time course to the reduction of directly recorded tremor. The latency of arrival of the systolic pulse at the finger-tip was recorded directly as 230 ± 26 msec after the Q R S spike.
Fig. 2. Computer averaged recordings of tremor triggered by the QRS spike of the electrocardiogram. a: normal finger, b: finger movement during the first 30 sec of arterial occlusion, c: the electrocardiogram taken simultaneously with b. A total of 128 sweeps were averaged for each trace. Note that the B wave seen in a disappeared on arterial occlusion but that a late wave (N) was revealed by this procedure. Time: 500 msec. R and T are ECG waves.
335 The 8-12 Hz finger tremor does not appear to be due to cardiovascular activity, since it cannot be summated by QRS triggering and it continues for some time after arterial occlusion. The eventual decline of tremor amplitude with continued ischaemia is probably due to the developing hypoxia of the excitable tissues of the arm4,14. A previous report that tremor could be summated by ECG triggering probably resulted from the use of the unsupported arm, since gross movements of the arm would certainly follow the cardiac pulse 16. Our use of the rigidly clamped arm has excluded this artifact. The B wave seen on averaged records, however, was clearly related to the heartbeat; it disappeared on arterial occlusion of the arm and it coincided in time with the directly recorded finger-tip pulse. It is probable that the B wave is a residual movement of the finger due to the transitory engorgement of the finger following the cardiac pulse. The N wave is most interesting since this feature of summated records persisted for some time after arterial occlusion but declined in amplitude in parallel with directly recorded tremor. We would, therefore, suggest that the N wave is neurally mediated and that its decline with ischaemia is due to the hypoxia of excitable tissues, as is the decline of gross tremor 4,14. Since the N wave is clearly related to the QRS spike an extension of this conclusion is that the N wave is a reflection of an effect of the cardiac pulse on the central nervous system. The pulse pressure wave could well modulate the excitability of central neurones by a piezo-electric effect on neuronal membranes. From the long latency of the N wave we would suggest that such an effect might be felt primarily by interneurones, or the small gamma-motoneurones, rather than the larger alphamotoneurones. The enhanced excitability of gamma-motoneurones would cause an increased activation of intrafusal fibres and a stretch reflex (of the finger) would be initiated as a result. The conduction times, central reflex time and twitch time would amount to some 100-150 msec. We envisage a pulse pressure wave latency of about 300 msec after the QRS spike to the small spinal cord arterioles (Kelman, personal communication, see ref. 7). The total latency of the resulting finger movement would approximate the observed N wave latency. An alternative to the suggestion of a piezo-electric effect is that neuronal excitability varies with the changing oxygen/carbon dioxide tensions in the microcirculation during a cardiac cycle. It is known that developing hypoxia or asphyxia lead to neuronal depolarisation2,9,15. Whether or not either of our suggested explanations are proved correct, it seems clear that somehow the cardiovascular system does exert a synchronising effect on central neurones. Our observations may explain hitherto puzzling facts such as the ventilatory cycle beginning at a certain preferred point or points during the cardiac cyclea,s. This may be due to an effect of the cardiac pulse pressure wave on the inspiratory neurone pool.
336 1 BRUML1K, J., On the nature of normal tremor, Neurology (Minneap.), 12 (1962) 159-179. 2 COLLEWUN, H., AND VAN HARREVELD, A., Intracellular recording from cat spinal motoneurones during acute asphyxia, J. Physiol. (Lond.), 185 (1966) 1-14. 3 ENGEL, P., JAEGER, A., UND HILDEBRANDT, G., l~ber die Beinflussung der Frequenz- und Phasenkoordination zwischen Herzschlag und Atmung durch verschiedene Narkotika, ArzneimittelForsch., 22 (1972) 1460-1468. 4 HALUDAY, A. M., AND REDFEARN, J. W. T., The effect of ischaemia on finger tremor, J. Physiol. (Lond.), 123 (1954) 23-24P. 5 HALLIDAY, A. M., AND REDVEARN, J. W. T., An analysis of the frequencies of finger tremor in healthy subjects, J. Physiol. (Lond.), 134 (1956) 600-611. 6 HALHDAY, A. M., AND REDFEARN, J. W. T., Finger tremor in tabetic patients and its bearing on the mechanism producing the rhythm of physiological tremor, J. Neurol. Neurosurg. Psychiat., 21 (1958) 101-108. 7 HARPER, D. R., KELMAN, G. R., MAYOR, G. E., WALKER, M. G., AND WATSON, A. W. S., Time interval between ECG R wave and peak flow velocity in leg arteries of normal humans, J. Physiol. (Lond.), 239 (1974) 21-22P. 8 H1LDEBRANDT,G., UND DAUMANN, F.-J., Die Koordination von Puls und Atemrhythmus bei Arbeit, Int. Z. angew. PhysioL, 21 (1965) 27-48. 9 KOLMODIN, G. M., AND SKOGLUND, C. R., Influence of asphyxia on membrane potential level and action potentials of spinal moto- and interneurones, Acta physiol, scand., 45 (1959) 1-18. 10 LIPPOLD, O. C. J., Oscillation in the stretch reflex arc and the origin of the rhythmical 8-12 Hz component of physiological tremor, J. Physiol. (Lond.), 206 (1970) 359-382. 11 LIPPOLD, O. C. J., REDFEARN, J. W. T., AND VUCO, J., The relation between the stretch reflex and the electrical and mechanical rhythmicity in human voluntary muscle, J. PhysioL (Lond.), 138 (1957) 14-15P. 12 LIPPOLD, O. C. J., REDEEARN, J. W. T., AND Vuco, J., The rhythmical activity of groups of motor units in the voluntary contraction of muscle, J. Physiol. (Lond.), 137 (1957) 473-487. 13 MARSDEN, C. D., MEADOWS, J. C., LANGE, G. W., AND WATSON, R. S., Effect of deafferentation on human physiological tremor, Lancet, ii (1967) 700-702. 14 MARSDEN, C. D., MEADOWS, J. C., LANGE, G. W., AND WATSON, R. S., The role of the ballistocardiographic impulse in the genesis of physiological tremor, Brain, 92 (1969) 647-662. 15 VAN HARREVELD,A., Asphyxial depolarization in the spinal cord, Amer. J. Physiol., 147 (1946) 669-684. 16 YAP, C. B., AND BOSHES, B., The frequency and pattern of normal tremor, Electroenceph. clin. Neurophysiol., 22 (1967) 197-203.
333
© Elsevier Scientific Publishing Company, Amsterdam - Printed in The Netherlands
Cardiovascular modulation of central neuronal activity
A L A N FORSTER AND T R E V O R W. STONE
Department of Physiology, University of Aberdeen, Marischal College, Aberdeen AB9 1AS (Great Britain) (Accepted December 15th, 1975)
Although the generally accepted 'text-book' explanation of the physiological tremor which normally accompanies muscle movement is that it is due to oscillation in the stretch reflex servo-loopS,6A 0-12, several groups have produced evidence that the tremor originates from cardiovascular activity. Thus Brumlik 1 noted a marked similarity between finger tremor and the ballistocardiogram and showed that neuromuscular blockade did not abolish the tremor. Marsden et al. 13 observed tremor in a surgically deafferented limb, and Yap and Boshes 16 have reported that physiological tremor can be summated by an averaging computer triggered by the electrocardiogram. In the present experiments we have tried to assess further the influence of the cardiovascular system on finger tremor. Thirty-nine subjects (aged 17-22 years) were instructed to keep the index finger approximately horizontal in the path of a light beam directed onto a photodiode. The photodiode output was amplified in a Fenlow AD55 amplifier and then passed to a Devices Pen Recorder. The output was also displayed on a Telequipment oscilloscope and on a Biomac 1000 averaging computer. The QRS spike of the electrocardiogram (lead II) was used to trigger the Biomac sweep. The Biomac was usually programmed for 128 sweeps of 1.28 sec duration to allow examination of a complete cardiac cycle in each sweep. Summated records from the Biomac were taken out on punched tape or on a Telsec pen recorder. Subjects were seated with the arm resting horizontally in front of the body. The a r m was supported to the metacarpals and was clamped firmly from the elbow to the wrist to reduce gross movements and ballistic effects on the arm. To completely prevent any ballistic effects affecting movement of the finger itself some recordings were made during the inflation of a cuff around the upper arm to 220 m m Hg. In this case finger movements were summated for 30 sec after which the cuff was deflated, the arm allowed to recover for 2 min and then the process was repeated until the 128 Biomac sweeps had been reached. The arrival of the finger-tip pulse was monitored directly using a M I E M k liB photoelectric pulse monitor. A direct recording of normal tremor is shown in Fig. la. After arterial occlusion the tremor declined in amplitude until it had virtually disappeared after about 3 min.
334
a
Ao
Fig. 1. Direct pen recordings of finger tremor, a: normal tremor, b: tremor recorded immediately after arterial occlusion of the upper arm using a cuff inflated to 220 mm Hg. Note the failure of such occlusion to abolish the tremor. The basic tremor at approximately 8 Hz is actually clarified. The amplitude of the tremor decreased slowly after occlusion and was virtually abolished after 3 min. Time: I sec. N o waves definitely related to the heartbeat were seen in direct recordings and it was f o u n d that t r e m o r did n o t s u m m a t e in the Q R S triggered Biomac (Fig. 2a). However, the s u m m a t e d recordings revealed a wave b e g i n n i n g 200 ± 33 msec (S.D.) after the Q R S spike a n d reaching a peak 317 ± 53 msec after QRS. Arterial occlusion immediately abolished this wave (Fig. 2b), which has been labelled the B wave to indicate a presumed ballistic origin. Arterial occlusion also clarified the second wave, labelled N in Fig. 2b. This wave had initial a n d peak latencies o f 497 ± 68 msec a n d 591 ± 55 msec respectively from the Q R S spike. W i t h c o n t i n u e d arterial occlusion the N wave declined in amplitude with a similar time course to the reduction of directly recorded tremor. The latency of arrival of the systolic pulse at the finger-tip was recorded directly as 230 ± 26 msec after the Q R S spike.
Fig. 2. Computer averaged recordings of tremor triggered by the QRS spike of the electrocardiogram. a: normal finger, b: finger movement during the first 30 sec of arterial occlusion, c: the electrocardiogram taken simultaneously with b. A total of 128 sweeps were averaged for each trace. Note that the B wave seen in a disappeared on arterial occlusion but that a late wave (N) was revealed by this procedure. Time: 500 msec. R and T are ECG waves.
335 The 8-12 Hz finger tremor does not appear to be due to cardiovascular activity, since it cannot be summated by QRS triggering and it continues for some time after arterial occlusion. The eventual decline of tremor amplitude with continued ischaemia is probably due to the developing hypoxia of the excitable tissues of the arm4,14. A previous report that tremor could be summated by ECG triggering probably resulted from the use of the unsupported arm, since gross movements of the arm would certainly follow the cardiac pulse 16. Our use of the rigidly clamped arm has excluded this artifact. The B wave seen on averaged records, however, was clearly related to the heartbeat; it disappeared on arterial occlusion of the arm and it coincided in time with the directly recorded finger-tip pulse. It is probable that the B wave is a residual movement of the finger due to the transitory engorgement of the finger following the cardiac pulse. The N wave is most interesting since this feature of summated records persisted for some time after arterial occlusion but declined in amplitude in parallel with directly recorded tremor. We would, therefore, suggest that the N wave is neurally mediated and that its decline with ischaemia is due to the hypoxia of excitable tissues, as is the decline of gross tremor 4,14. Since the N wave is clearly related to the QRS spike an extension of this conclusion is that the N wave is a reflection of an effect of the cardiac pulse on the central nervous system. The pulse pressure wave could well modulate the excitability of central neurones by a piezo-electric effect on neuronal membranes. From the long latency of the N wave we would suggest that such an effect might be felt primarily by interneurones, or the small gamma-motoneurones, rather than the larger alphamotoneurones. The enhanced excitability of gamma-motoneurones would cause an increased activation of intrafusal fibres and a stretch reflex (of the finger) would be initiated as a result. The conduction times, central reflex time and twitch time would amount to some 100-150 msec. We envisage a pulse pressure wave latency of about 300 msec after the QRS spike to the small spinal cord arterioles (Kelman, personal communication, see ref. 7). The total latency of the resulting finger movement would approximate the observed N wave latency. An alternative to the suggestion of a piezo-electric effect is that neuronal excitability varies with the changing oxygen/carbon dioxide tensions in the microcirculation during a cardiac cycle. It is known that developing hypoxia or asphyxia lead to neuronal depolarisation2,9,15. Whether or not either of our suggested explanations are proved correct, it seems clear that somehow the cardiovascular system does exert a synchronising effect on central neurones. Our observations may explain hitherto puzzling facts such as the ventilatory cycle beginning at a certain preferred point or points during the cardiac cyclea,s. This may be due to an effect of the cardiac pulse pressure wave on the inspiratory neurone pool.
336 1 BRUML1K, J., On the nature of normal tremor, Neurology (Minneap.), 12 (1962) 159-179. 2 COLLEWUN, H., AND VAN HARREVELD, A., Intracellular recording from cat spinal motoneurones during acute asphyxia, J. Physiol. (Lond.), 185 (1966) 1-14. 3 ENGEL, P., JAEGER, A., UND HILDEBRANDT, G., l~ber die Beinflussung der Frequenz- und Phasenkoordination zwischen Herzschlag und Atmung durch verschiedene Narkotika, ArzneimittelForsch., 22 (1972) 1460-1468. 4 HALUDAY, A. M., AND REDFEARN, J. W. T., The effect of ischaemia on finger tremor, J. Physiol. (Lond.), 123 (1954) 23-24P. 5 HALLIDAY, A. M., AND REDVEARN, J. W. T., An analysis of the frequencies of finger tremor in healthy subjects, J. Physiol. (Lond.), 134 (1956) 600-611. 6 HALHDAY, A. M., AND REDFEARN, J. W. T., Finger tremor in tabetic patients and its bearing on the mechanism producing the rhythm of physiological tremor, J. Neurol. Neurosurg. Psychiat., 21 (1958) 101-108. 7 HARPER, D. R., KELMAN, G. R., MAYOR, G. E., WALKER, M. G., AND WATSON, A. W. S., Time interval between ECG R wave and peak flow velocity in leg arteries of normal humans, J. Physiol. (Lond.), 239 (1974) 21-22P. 8 H1LDEBRANDT,G., UND DAUMANN, F.-J., Die Koordination von Puls und Atemrhythmus bei Arbeit, Int. Z. angew. PhysioL, 21 (1965) 27-48. 9 KOLMODIN, G. M., AND SKOGLUND, C. R., Influence of asphyxia on membrane potential level and action potentials of spinal moto- and interneurones, Acta physiol, scand., 45 (1959) 1-18. 10 LIPPOLD, O. C. J., Oscillation in the stretch reflex arc and the origin of the rhythmical 8-12 Hz component of physiological tremor, J. Physiol. (Lond.), 206 (1970) 359-382. 11 LIPPOLD, O. C. J., REDFEARN, J. W. T., AND VUCO, J., The relation between the stretch reflex and the electrical and mechanical rhythmicity in human voluntary muscle, J. PhysioL (Lond.), 138 (1957) 14-15P. 12 LIPPOLD, O. C. J., REDEEARN, J. W. T., AND Vuco, J., The rhythmical activity of groups of motor units in the voluntary contraction of muscle, J. Physiol. (Lond.), 137 (1957) 473-487. 13 MARSDEN, C. D., MEADOWS, J. C., LANGE, G. W., AND WATSON, R. S., Effect of deafferentation on human physiological tremor, Lancet, ii (1967) 700-702. 14 MARSDEN, C. D., MEADOWS, J. C., LANGE, G. W., AND WATSON, R. S., The role of the ballistocardiographic impulse in the genesis of physiological tremor, Brain, 92 (1969) 647-662. 15 VAN HARREVELD,A., Asphyxial depolarization in the spinal cord, Amer. J. Physiol., 147 (1946) 669-684. 16 YAP, C. B., AND BOSHES, B., The frequency and pattern of normal tremor, Electroenceph. clin. Neurophysiol., 22 (1967) 197-203.