Influence of central command on cerebral blood flow at the onset of exercise in women

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1 Exp Physiol pp Experimental Physiology Research Paper Influence of central command on cerebral blood flow at the onset of exercise in women Kohei Sato, Mayumi Moriyama and Tomoko Sadamoto Research Institute of Physical Fitness, Japan Women s College of Physical Education, Tokyo, Japan This study evaluated the role of central command in the regulation of common carotid artery blood flow ( Q CCA ) and middle cerebral artery mean flow velocity (V MCA ) at the onset of arm exercise. Eleven young women performed 2 min voluntary elbow flexion and extension exercise with no load (VOL) that was considered to activate both central command and the muscle mechanoreflex, and 2 min passive elbow flexion and extension exercise (PAS) that was considered to activate only the muscle mechanoreflex. Immediately before the onset of VOL, Q CCA and V MCA began to increase from the baseline and peaked 5 s thereafter (mean ± s.d.; 20 ± 5and14± 5%, respectively; P < 0.05). Also, VOL increased heart rate (9 ± 2%; P < 0.05) and cardiac output (16± 3%;P < 0.05). Indexes of the cerebrovascular resistance (MAP/ Q CCA and MAP/V MCA ) were reduced at the onset of VOL ( 13 ± 4and 12 ± 4%, respectively; P < 0.05). However, there were no significant changes in these parameters during PAS. These results suggest that central command plays an important role in the increase of cerebral blood flow at the onset of voluntary exercise. (Received 4 May 2009; accepted after revision 30 July 2009; first published online 31 July 2009) Corresponding author K. Sato: Research Institute of Physical Fitness, Japan Women s College of Physical Education, Kita-Karasuyama, Setagaya-ku, Tokyo, , Japan. ksato@jwcpe.ac.jp The cardiorespiratory response to the onset of exercise is considered to be mediated by both central and peripheral neural mechanisms (Mitchell, 1990; Kaufman & Forster, 1996). Central neural mechanisms include feedforward control of signals descending from higher brain centres (central command), which may influence the cardiorespiratory responses even before the start of voluntary exercise (Krogh & Lindhard, 1917; Goodwin et al. 1972; Mitchell, 1990; Kaufman & Forster, 1996). Feedback control includes peripheral neural reflexes arising from group III and IV mechanically and metabolically sensitive fibres in the exercising muscles (Sinoway et al. 1993; Kaufman & Forster, 1996; Gladwell & Coote, 2002). Since it may take some 15 s to activate the muscle metaboreflex, central command and the muscle mechanoreflex are considered to be responsible for the initial changes in cardiorespiratory variables in response to voluntary exercise (Herr et al. 1999; Matsukawa et al. 2007). Regional cerebral blood flow (CBF) increases during static and especially dynamic exercise, and this increase diminishes after local anaesthesia of muscle afferents (Friedman et al. 1991, 1992; Jørgensen et al. 1993), suggesting that the CBF response to exercise is predominantly controlled by peripheral neural reflexes arising from the working muscles (Jørgensen et al. 1992a,b, 1993). In addition, a previous study reported that the exercise-mediated increase in V MCA could not be maintained during postexercise muscle ischaemia, which may mainly stimulate the muscle metaboreflex (Jørgensen et al. 1992a). Thus, the increase in CBF during exercise is thought to depend primarily on the muscle mechanoreflex (Jørgensen et al. 1992a,b, 1993). However, the cardiovascular adjustment to exercise is redundant and depends on the experimental conditions and specific autonomic response examined (Mitchell, 1990). It is important to bear in mind that the contribution of central command during voluntary exercise is assessed under non-invasive conditions, since some anxiety and discomfort accompanying invasive procedures may affect the cardiovascular responses. Indeed, in experimental designs with imagined exercise (Williamson et al. 2002) and attempted movement in spinal cord-injured subjects (Nowak et al. 2005), neuroimaging studies have suggested that the higher brain structures, including insular and anterior cingulate cortex, are involved in the autonomic control of cardiovascular functions. Based on these considerations, it was hypothesized that central command DOI: /expphysiol

2 1140 K. Sato and others Exp Physiol pp may influence CBF at the onset of exercise. In the present study, we use the classical definition of the term central command as a feedforward mechanism involving both anticipation/arousal and parallel activation of motor and cardiovascular centres, although a new concept has been proposed in recent studies (Williamson et al. 2006). Cerebrovascular responses to voluntary arm exercise (VOL) were compared with those elicited by similar passive exercise (PAS) to evaluate whether central command influences not only heart rate (HR) and blood pressure at the onset of exercise but also CBF as assessed by the common carotid artery (CCA) blood flow ( Q CCA )and the middle cerebral artery mean flow velocity (V MCA ). In prior reports on this topic, three studies suggested that the reflex arising from the exercising muscles was a primary cause of the changes in the CBF responses because the CBF responses were similar between voluntary (active) exercise and motor-driven passive exercise (Weiller et al. 1996; Doering et al. 1998; Matteis et al. 2001). However, these studies only assessed the CBF changes in the later period of exercise and did not focus on the rapid adjustment of CBF at the beginning of exercise. It therefore remains unknown whether central command plays an important role at the onset of exercise. Methods Eleven young women (means ± S.D.: 23.5 ± 0.7 years, ± 5.2 cm and 56.2 ± 7.6 kg) participated in this study after written informed consent was obtained according to the guidelines of the Ethics Committee of Japan Women s College of Physical Education, and the study was conducted in accordance with the Declaration of Helsinki. The subjects were requested to abstain from consuming caffeinated beverages for 6 h and physical activity for 12 h before any experimental session. Before the experimental day, the subjects visited the laboratory for familiarization with the elbow flexor extensor computer-controlled multifunctional dynamometer (VINE, Tokyo, Japan) and practised the exercise protocols. We also recorded the subjects medical history and performed a physical examination. Voluntary and passive exercise The subject was seated, while the right upper arm was maintained at 45 deg on a padded rest and the wrist was attached to the arm lever of the dynamometer by a Velcro strap. In VOL, the subject was instructed to move her forearm to elbow angles between 50 and 90 deg (0 deg is full extension) at 90 deg s 1 in synchronization with a sound played by a tape-recorder. The dynamometer was not loaded, and the onset of VOL was signalled by a 10 s countdown;at0,thesubjectflexedherarmandexercise continued for 2 min. The PAS was established by a motor-driven lever arm that rotated at constant velocity to cover the same range of movement, angular velocity and frequency as VOL. The subjects were requested to relax and not resist the movement, which continued for 2 min. All variables were recorded during a 2 min resting period, during the 2 min of VOL or PAS and during 2 min of recovery. The VOL and PAS were performed in random order. The dynamometer used for the VOL and PAS comprised a force transducer that was mounted on the metal lever arm. Online signals from the force transducer were displayed on a cathode ray tube (Fig. 1) to ensure that the force production was standardized (a given constant amplitude and frequency of force) during VOL and PAS exercises. After experiments, it was verified by offline analysis that the mechanical stimulus was equivalent in VOL and PAS exercises. Common carotid artery blood flow The Q CCA was examined using a high-resolution ultrasound system (LOGIQ5; GE Medical Systems, Tokyo, Japan) equipped with an 8.8 MHz linear transducer. For the examination of the left CCA, the subject s neck was turned slightly to the right. The site for measuring the vessel diameter and blood flow velocity was 2 3cm proximal to the carotid bifurcation using an insonation angle as low as possible and always < 60 deg (Fig. 2A). The systolic and diastolic diameters of the CCA were measured using a pulsed-wave Doppler signal. The mean CCA diameter (D CCA ) was calculated in relation to the blood pressure curve as follows: D CCA = (systolic diameter 1/3) + (diastolic diameter 2/3) Figure 1. The mean force production during voluntary and passive exercise The diameter was obtained in B-mode with the cursor set perpendicular to the vessel wall and presented as the average of at least three measurements. The Q CCA was

3 Exp Physiol pp Cerebral blood flow at the onset of exercise 1141 calculated by multiplying the cross-sectional area of the CCA [area = π (diameter/2) 2 ] by the CCA mean blood flow velocity (V CCA ;inms 1 ), as follows: Q CCA = V CCA area 60 (ml min 1 ) Middle cerebral artery blood flow velocity The V MCA was measured using an ultrasound system (VIVID7; GE Medical Systems) equipped with a 2.0 MHz sector transducer. We used colour-mode imaging to visualize the left MCA (Fig. 2B), with identification of the real-time Doppler velocity spectrum in PW-mode. The V MCA was obtained with the sample volume set at 7 8 mm and with the vector of the cursor positioned at the centre of the bloodstream. The time-averaged mean flow velocity obtained in the automatic-calculation mode was defined as V MCA. VOL and PAS were compared by the Kolmogorov Smirnov test for normality. If the data were normally distributed, Student s paired t test was used. Otherwise, Wilcoxon s signed-rank test was performed (SPSS 12.0; SPSS, Tokyo, Japan), and P < 0.05 was considered to indicate a significant difference. Results The resting cardiorespiratory and cerebrovascular variables are summarized in Table 1. There was no significant difference in these variables between the two conditions. The force produced during VOL and PAS was Heart rate and blood pressure Mean arterial pressure (MAP) was measured with photoelectric plethysmography (Finapres Medical Systems BV, Arnhem, The Netherlands). The HR, stroke volume (SV), hence the cardiac output (CO), were determined from the blood pressure waveform using the Modelflow software program (Beat Scope 1.1; Finapres Medical Systems BV), factored by sex, age, height and weight of the subjects, with CO being SV HR. Ventilation Ventilatory variables were determined breath by breath from expired air using a face mask. The gas fractions were analysed using a mass spectrometer (ARCO-1000; Arco System, Chiba, Japan) that was calibrated before each test. Expired gas volume was measured using a Fleisch pneumotachometer (WLSU-5201; Westron, Tokyo, Japan), and data were analysed using customized software (PC-9821; NEC, Tokyo, Japan), with expiratory minute ventilation ( V E ) and end-tidal partial pressure of CO 2 (P ETCO2 ) being calculated. Data processing and statistical analysis We calculated the ratios of MAP/V MCA and MAP/ Q CCA as indexes of cerebrovascular resistance. All variables were averaged over 5 s and, to estimate changes from rest, averaged from 1.5 to 2.5 min before the beginning of VOL and PAS. Values are expressed as means ± S.D.Inordertoevaluate whether VOL and PAS influenced the variables, Dunnett s t test and a two-way analysis of variance (ANOVA) with repeated measures were used. Differences between Figure 2. A, Doppler ultrasound image showing the common carotid artery (CCA) with its Doppler-flow waveform. B, middle cerebral artery (MCA) with Doppler-flow waveform.

4 1142 K. Sato and others Exp Physiol pp Table 1. Resting cardiorespiratory and cerebrovascular variables VOL PAS MAP (mmhg) 84 ± 5 83 ± 6 HR (beats min 1 ) 64 ± 5 64 ± 6 SV (ml) 79 ± 7 78 ± 7 CO (l min 1 ) 4.9 ± ± 0.6 P ETCO2 (mmhg) 37.5 ± ± 3.8 V E (l min 1 ) 6.4 ± ± 1.3 Q CCA (ml min 1 ) 378 ± ± 43 D CCA (cm) 0.58 ± ± 0.06 V CCA (cm s 1 ) 23.9 ± ± 3.2 V MCA (cm s 1 ) 40.8 ± ± 3.8 Data are means ± S.D. Abbreviations: MAP, mean arterial pressure; HR, heart rate; SV, stroke volume; CO, cardiac output; P ETCO2, end-tidal partial pressure of CO 2 ; V E, minute ventilation; Q CCA, mean blood blood flow in CCA; D CCA, mean diameter of CCA; V CCA, mean blood flow velocity in CCA; and V MCA, mean blood flow velocity in MCA. similar and within a standardized range of ±1.0 kg as shown in Fig. 1. Figures 3 and 4 show the cardiorespiratory and cerebral blood flow variables during VOL and PAS. Figure 5 shows the cardiorespiratory and cerebrovascular responses to the initial period of VOL and PAS on an expanded time scale. The HR and CO responses to VOL began to increase before its onset and continued to increase thereafter (Fig. 5). In contrast, both HR and CO were unchanged from rest at the onset of PAS. The MAP in VOL increased before the onset of exercise and transiently decreased belowtherestinglevel 15 s after the onset, which was followed by a gradual increase to the resting value. The MAPresponses35saftertheonsetofexercisewerehigher in VOL than those in PAS, although the MAP in PAS was unchanged from the resting level during exercise. The P ETCO2 during both VOL and PAS was not different from rest. In VOL, Q CCA began to increase before the onset of exercise and peaked at 5 s (increase of 20 ± 5%; P < 0.05) thereafter and then gradually returned to the resting level. In contrast, during PAS, Q CCA was stable throughout, at the resting level. Thus, at the onset of VOL, Q CCA washigher(p < 0.05) than the corresponding values for PAS. We observed similar differences between V MCA for VOL and PAS; values of V MCA at the 5, 25 and 50 s time points duringvolwerehigher(p < 0.05) than those during PAS. The MAP/ Q CCA ratio decreased for 15 s after the onset of VOL and reached a minimum of 13 ± 5% below rest. The MAP/V MCA values at the onset of VOL also decreased in a similar manner. In contrast, these indices of vascular resistance did not significantly change during Figure 3. Circulatory and ventilatory variables recorded before, during and after no-load voluntary and passive exercise The dotted line at time 0 indicates the onset of exercise and the dotted line at 120 s indicates its termination. Abbreviations: MAP, mean arterial pressure; HR, heart rate; SV, stroke volume; CO, cardiac output; P ETCO2, end-tidal CO 2 ;and V E,expiratory minute ventilation. Values are means ± SD.

5 Exp Physiol pp Cerebral blood flow at the onset of exercise 1143 PAS. Thus, a difference between VOL and PAS was detected after 10 s for MAP/ Q CCA and after 5 s for MAP/V MCA (P < 0.05). Discussion Cerebrovascular responses to VOL were compared with those elicited by PAS to evaluate whether central command influences the CBF at the onset of exercise. The major findings were that Q CCA, V MCA, HR and CO began to increase before the onset of VOL, with a parallel transient decrease in cerebrovascular resistance (MAP/ Q CCA and MAP/V MCA ). In contrast, there were no significant changes in these parameters during PAS and, consequently, variables were different between VOL and PAS before and immediately after the onset of each exercise bout. We take these observations to indicate that the rapid adjustment in the cerebrovascular responses at the onset of voluntaryexerciseisprobablymediatedbytheinfluence of central command descending from the higher brain centres. This interpretation is in line with the previous work in consciously exercising cats (Matsukawa et al. 1991, 2007) andhumans (Goodwinet al. 1972; Williamson et al. 2002) showing that the initial cardiovascular adjustments at the onset of exercise are more related to central command rather than contractile force. However, our finding is inconsistent with the previous literature of Jørgensen et al. (1992b, 1993). Our data are also different from earlier work which suggested that there was a similar increase in V MCA (Doering et al. 1998; Matteis et al. 2001) and regional CBF for the motor and sensorimotor cortexes (Weiller et al. 1996) betweenvoluntary (active) andmotordriven (passive) elbow flexion exercises and, thereby, indicating an essential contribution of peripheral reflex for CBF. The discrepancy between the previous reports and this study was firstly due to the different time of exercise examined. The previous studies, which reported the critical role of muscle mechanoreflex, focus on the CBF changes in the later period of exercise without specifically addressing the onset of exercise (Jørgensen et al. 1992b, 1993; Doering et al. 1998; Matteis et al. 2001). We, in contrast, provide data for the rapid adjustment in CBF at the onset of exercise. Indeed, if we had compared the V MCA responses in the later period of exercise, such as at s of exercise shown in Fig. 4, there was no significant difference between VOL and PAS, as mentioned in the previous studies. Other reasons for the differences are not entirely clear but may relate to the differences in the experimental design and methodologies used in experiments. For instance, the invasive conditions with neuromuscular blockade (Jørgensen et al. 1993), eyeclosed conditions (Matteis et al. 2001) and conditions with the spine position (Weiller et al. 1996; Doering Figure 4. Cerebrovascular variables before, during and after voluntary and passive exercise Abbreviations: Q CCA, mean blood flow in CCA; V MCA, mean blood flow velocity in MCA; D CCA, mean diameter of CCA; and V CCA, mean blood flow velocity in CCA. Values are means ± S.D.

6 1144 K. Sato and others Exp Physiol pp et al. 1998) may modulate the cerebrovascular responses, owing to a higher arousal level with some anxiety and discomfort or a lower arousal level with less sensory input and less sympathoexcitation. In addition, the different methods, i.e. use of positron emission tomography (PET; Weiller et al. 1996) or the Doppler ultrasound system, might yield dissimilar flow responses because PET and the Doppler ultrasound system have respective strengths and weaknesses for CBF measurements. Of note, the rapid increases in Q CCA and V MCA occurred in parallel with the increase in CO at the onset of VOL. This finding suggests an important role for CO in the CBF regulation during exercise. This interpretation is supported by the previous reports that the V MCA response during dynamic exercise is clearly dependent on CO in both patients (Ide et al. 1999) and healthy subjects (Ide et al. 1998, 2000; Ogohet al. 2005). Furthermore, it should be noted that the rapid increase in Q CCA and V MCA could not be maintained from 15 s after the onset of exercise even though central command would be operating at this time. This evidence suggests that the initial adjustment at the onset of exercise was mediated by a feedforward mechanism of central command which is associated with anticipation, arousal and preparation but not with parallel activation in both motor and cardiovascular centres in the brain (Williamson et al. 2006). Although the study could not describe any anatomical or physiological properties of central command responsible for the increase in Q CCA and V MCA at the onset of VOL, neuroimaging studies have proposed a neural network for central command in the central nervous system, including the insular cortex, anterior cingulate cortex, medial prefrontal region and thalamic regions (Williamson et al. 1997; King et al. 1999; Nowak et al. 1999, 2005; Thornton et al. 2001; Williamson et al. 2001, 2002, 2006). A similar central command network might Figure 5. The cardiorespiratory and cerebral blood flow variables at the onset of voluntary and passive exercise Changes are expressed relative to rest. Variables are from 30 s before to 60 s after the onset of exercise. Abbreviations: Q CCA, common carotid artery mean blood flow; V MCA, middle cerebral artery mean blood flow velocity; HR, heart rate; CO, cardiac output; MAP, mean arterial pressure; P ETCO2, end-tidal CO 2 tension; MAP/ Q CCA, index of common carotid artery resistance; and MAP/V MCA, index of middle cerebral artery resistance. Values are means ± S.D. P < 0.05 different from the rest; P < 0.05 difference between the voluntary and passive exercise.

7 Exp Physiol pp Cerebral blood flow at the onset of exercise 1145 also play a role in the rapid cerebrovascular adjustment at the onset of VOL in the present study. Given the lack of spatial resolution of the Doppler measurements of V MCA, we should caution that the interpretation of changes in CBF relies on the assumption of a constant diameter of the MCA (Secher et al. 2008), although previous studies have indicated a constancy of MCA diameter during various environments in humans (Giller et al. 1993; Serrador et al. 2000). In the present study, the possible doubt of V MCA as an index of CBF was evaluated by an assessment of the CCA blood flow instead of evaluation of the internal carotid artery (ICA) blood flow. Since the insonation position for ICA could not avoid the helical flow patterns known to prevail in the area near to the carotid bulb owing to the short neck size in our female subjects, we chose to assess the CCA instead of the ICA. However, our pilot experiments and previous study found similar and parallel changes of blood flow in the ICA and CCA during light static handgrip exercise (T. Sadamoto, M. Moriyama & K. Sato, unpublished observations) and dynamic light exercise (Hellström et al. 1996). It was also shown that the CCA blood flow measured by the Doppler ultrasound system reflects the overall CBF measured by computed tomography scanning at rest (Uematsu et al. 1983; Chu et al. 2000). We acknowledge the limitation of application of noload exercise and passive movement. Gladwell & Coote (2002) indicated that rhythmic passive stretch would have stimulated muscle spindle afferents and Golgi tendon organs, which did not elicit any cardiovascular responses, rather than group III muscle mechanoreceptors. If so, we cannot rule out a possible role for muscle mechanoreflex involvement in CBF at the onset of exercise. 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