Jason R. Carter

Neurovascular responses to mental stress

The effects of mental stress (MS) on muscle sympathetic nerve activity (MSNA) and limb blood flows have been studied independently in the arm and leg, but they have not been studied collectively. Furthermore, the cardiovascular implications of postmental stress responses have not been thoroughly addressed. The purpose of the current investigation was to comprehensively examine concurrent neural and vascular responses during and after mental stress in both limbs. In Study 1, MSNA, blood flow (plethysmography), mean arterial pressure (MAP) and heart rate (HR) were measured in both the arm and leg in 12 healthy subjects during and after MS (5 min of mental arithmetic). MS significantly increased MAP (Δ15 ± 3 mmHg; P < 0.01) and HR (Δ19 ± 3 beats min−1; P < 0.01), but did not change MSNA in the arm (14 ± 3 to 16 ± 3 bursts min−1; n= 6) or leg (14 ± 2 to 15 ± 2 bursts min−1; n= 8). MS decreased forearm vascular resistance (FVR) by −27 ± 7% (P < 0.01; n= 8), while calf vascular resistance (CVR) did not change (−6 ± 5%; n= 11). FVR returned to baseline during recovery, whereas MSNA significantly increased in the arm (21 ± 3 bursts min−1; P < 0.01) and leg (19 ± 3 bursts min−1; P < 0.03). In Study 2, forearm and calf blood flows were measured in an additional 10 subjects using Doppler ultrasound. MS decreased FVR (−27 ± 10%; P < 0.02), but did not change CVR (5 ± 14%) as in Study 1. These findings demonstrate differential vascular control of the arm and leg during MS that is not associated with muscle sympathetic outflow. Additionally, the robust increase in MSNA during recovery may have acute and chronic cardiovascular implications.

Sympathetic neural responses to mental stress: responders, nonresponders and sex differences

Mental stress consistently increases heart rate (HR) and blood pressure (BP) in humans, despite inconsistent sympathetic neural responses that include increases, decreases, or no change in muscle sympathetic nerve activity (MSNA). The purpose of the present study was to examine associations between MSNA, BP, and HR responses to mental stress. Leg MSNA, BP, HR, and perceived stress levels were recorded during 3-5 min of mental arithmetic in 82 subjects (53 men and 29 women). Subjects were divided into positive responders (>or=Delta3 bursts/min; n = 40), negative responders (<or=Delta-3 bursts/min; n = 9), and nonresponders (n = 33). Mental stress increased MSNA in positive responders (Delta6 +/- 1 bursts/min), decreased MSNA in negative responders (Delta-6 +/- 1 bursts/min), and did not change MSNA in nonresponders (Delta1 +/- 1 bursts/min). Mental stress increased mean BP and HR similarly in positive responders (Delta15 +/- 1 mmHg and Delta16 +/- 1 beats/min; P < 0.001), nonresponders (Delta15 +/- 1 mmHg and Delta19 +/- 2 beats/min; P < 0.001), and negative responders (Delta12 +/- 2 mmHg and Delta19 +/- 3 beats/min; P < 0.001). Perceived stress levels and sex distributions were similar across responders and nonresponders; thus, perceived stress and sex do not appear to influence MSNA during mental stress. However, men demonstrated higher increases of mean BP during mental stress when compared with women (Delta16 +/- 1 vs. Delta12 +/- 1 mmHg; P < 0.05), despite no differences in MSNA responses. In conclusion, our results demonstrate marked differences in MSNA responses to mental stress and a disassociation between MSNA and BP responses to mental stress, suggesting complex patterns of vascular responsiveness during mental stress.

Sympathetic Responses to Vestibular Activation in Humans

Activation of sympathetic neural traffic via the vestibular system is referred to as the vestibulosympathetic reflex. Investigations of the vestibulosympathetic reflex in humans have been limited to the past decade, and the importance of this reflex in arterial blood pressure regulation is still being determined. This review provides a summary of sympathetic neural responses to various techniques used to engage the vestibulosympathetic reflex. Studies suggest that activation of the semicircular canals using caloric stimulation and yaw rotation do not modulate muscle sympathetic nerve activity (MSNA) or skin sympathetic nerve activity (SSNA). In contrast, activation of the otolith organs appear to alter MSNA, but not SSNA. Specifically, head-down rotation and off-vertical axis rotation increase MSNA, while sinusoidal linear accelerations decrease MSNA. Galvanic stimulation, which results in a nonspecific activation of the vestibule, appears to increase MSNA if the mode of delivery is pulse trained. In conclusion, evidence strongly supports the existence of a vestibulosympathetic reflex in humans. Furthermore, attenuation of the vestibulosympathetic reflex is coupled with a drop in arterial blood pressure in the elderly, suggesting this reflex may be important in human blood pressure regulation.

Menstrual cycle alters sympathetic neural responses to orthostatic stress in young, eumenorrheic women

Sympathetic baroreflex sensitivity (BRS) and muscle sympathetic nerve activity (MSNA) responses during early follicular (EF) and midluteal (ML) phases of the menstrual cycle are controversial. We hypothesize an augmented sympathetic BRS and MSNA response to orthostatic stress during the ML phase of the menstrual cycle. MSNA, mean arterial pressure (MAP), and heart rate (HR) were recorded during progressive lower body negative pressure (LBNP) (-5, -10, -15, -20, -30, and -40 mmHg; 3 min/stage) in 13 healthy, eumenorrheic women (age 21 +/- 1 yr). Sympathetic BRS was assessed by examining relations between spontaneous fluctuations of diastolic arterial pressure and MSNA at rest and during progressive LBNP. Plasma estradiol (42 +/- 6 vs. 112 +/- 12 pg/ml; P < 0.01) and progesterone (2 +/- 0 vs. 10 +/- 2 ng/ml; P < 0.04) were elevated during the ML phase. Resting MSNA (8 +/- 1 vs. 11 +/- 1 bursts/min), MAP (79 +/- 2 vs. 78 +/- 2 mmHg), and HR (58 +/- 2 vs. 60 +/- 2 beats/min) were not different during EF and ML phases. MSNA and HR increased during progressive LBNP (P < 0.001), and the increases in MSNA burst frequency (bursts/min) and HR were similar during both phases. In contrast, increases in total MSNA (arbitrary units) during progressive LBNP were augmented during the ML phase (P < 0.04), but this response does not appear to be linked to differences in sympathetic BRS. Progressive LBNP did not change MAP during either phase. Our results demonstrate an augmentation of the MSNA response to progressive LBNP during the ML phase of the menstrual cycle. These findings suggest that hormonal fluctuations of eumenorrheic women may influence sympathoexcitation during an orthostatic challenge, but not through sympathetic baroreflex-mediated pathways.

Sympathetic neural responses to 24-hour sleep deprivation in humans: sex differences

Sleep deprivation has been linked to hypertension, and recent evidence suggests that associations between short sleep duration and hypertension are stronger in women. In the present study we hypothesized that 24 h of total sleep deprivation (TSD) would elicit an augmented pressor and sympathetic neural response in women compared with men. Resting heart rate (HR), blood pressure (BP), and muscle sympathetic nerve activity (MSNA) were measured in 30 healthy subjects (age, 22 ± 1; 15 men and 15 women). Relations between spontaneous fluctuations of diastolic arterial pressure and MSNA were used to assess sympathetic baroreflex function. Subjects were studied twice, once after normal sleep and once after TSD (randomized, crossover design). TSD elicited similar increases in systolic, diastolic, and mean BP in men and women (time, P < 0.05; time × sex, P > 0.05). TSD reduced MSNA in men (25 ± 2 to 16 ± 3 bursts/100 heart beats; P = 0.02), but not women. TSD did not alter spontaneous sympathetic or cardiovagal baroreflex sensitivities in either sex. However, TSD shifted the spontaneous sympathetic baroreflex operating point downward and rightward in men only. TSD reduced testosterone in men, and these changes were correlated to changes in resting MSNA (r = 0.59; P = 0.04). Resting HR, respiratory rate, and estradiol were not altered by TSD in either sex. In conclusion, TSD-induced hypertension occurs in both sexes, but only men demonstrate altered resting MSNA. The sex differences in MSNA are associated with sex differences in sympathetic baroreflex function (i.e., operating point) and testosterone. These findings may help explain why associations between sleep deprivation and hypertension appear to be sex dependent.

Ovarian Cycle and Sympathoexcitation in Premenopausal Women

The influence of the ovarian cycle on muscle sympathetic nerve activity (MSNA) remains controversial. Some studies report an increase of resting MSNA during the mid luteal (ML) phase of the ovarian cycle compared with the early follicular phase, whereas other studies do not. These inconsistent findings may be attributable, in part, to the variable surges in estradiol and progesterone. We tested the hypothesis that the degree of sympathoexcitation during the ML phase (&Dgr;MSNA) is associated with changes in estradiol (&Dgr;E2) and progesterone (&Dgr;P). Multiple regression analysis of data from previous studies with complete recordings of mean arterial pressure, MSNA, E2, and P during both early follicular and ML phases were available from 30 eumenorrheic women (age, 28±1 years; body mass index, 23±0 kg/m2). ML phase increased E2 (37±2 to 117±9 pg/mL; P<0.001), P (1±0 to 11±1 ng/mL; P<0.001), and MSNA (12±1 to 15±1 bursts/min; P=0.02), but did not alter mean arterial pressure (83±2 to 83±2 mm Hg; P=0.91). &Dgr;MSNA was correlated with &Dgr;E2 (r=−0.50, P=0.003) and &Dgr;E2/&Dgr;P (r=−0.52, P=0.002) but not &Dgr;P (r=0.21, P=0.13). There was no association between &Dgr;mean arterial pressure and &Dgr;E2 (r=−0.13, P=0.49), &Dgr;P (r=−0.04, P=0.83), or &Dgr;E2/&Dgr;P (r<0.01, P=0.98). In conclusion, sympathoexcitation during the ML phase of the ovarian cycle seems to be dependent, in part, on the degree of sex steroid surges. This dynamic interaction among E2, P, and MSNA likely explains previously reported inconsistencies in the field; it remains possible that other sex steroids, such as testosterone, might explain further variance.

Effects of the menstrual cycle on sympathetic neural responses to mental stress in humans

The influence of the menstrual cycle on resting muscle sympathetic nerve activity (MSNA) remains controversial, and the effect of the menstrual cycle on MSNA responses to mental stress is unknown. We examined MSNA, mean arterial pressure (MAP), and heart rate (HR) responses to mental stress (via mental arithmetic) in 11 healthy females during the early follicular (EF) and mid‐luteal (ML) phases of the menstrual cycle. The menstrual cycle did not alter resting MSNA (EF, 13 ± 3 bursts min−1versus ML, 13 ± 2 bursts min−1), MAP (EF, 79 ± 3 mmHg versus ML, 81 ± 2 mmHg) and HR (EF, 66 ± 3 beats min−1versus ML, 64 ± 2 beats min−1). 5 min of mental stress increased MSNA, MAP and HR during both the EF (Δ4 ± 2 bursts min−1, Δ12 ± 2 mmHg, Δ18 ± 2 beats min−1; P < 0.05) and ML (Δ4 ± 2 bursts min−1, Δ13 ± 3 mmHg and Δ20 ± 2 beats min−1; P < 0.05) phases. These responses were not different between phases. In contrast, MSNA responses were different between phases during the 10 min recovery from mental stress. MSNA remained elevated during the initial 5 min of recovery in both the EF (Δ6 ± 1 bursts min−1; P < 0.01) and ML (Δ7 ± 1 bursts min−1; P < 0.01) phases, but only remained elevated during the ML phase (Δ6 ± 1 bursts min−1; P < 0.01) during the final 5 min of recovery. Our results demonstrate that MSNA, MAP and HR responses at rest or during mental stress are not different during the EF and ML phases of the menstrual cycle in young, healthy females. However, MSNA activation during recovery from mental stress is prolonged during the ML phase compared to the EF phase.

Neurovascular responses to mental stress in the supine and upright postures

The purpose of this study was to determine neurovascular responses to mental stress (MS) in the supine and upright postures. MS was elicited in 23 subjects (26 +/- 1 yr) by 5 min of mental arithmetic. In study 1 (n = 9), Doppler ultrasound was used to measure mean blood flow velocity in the renal (RBFV) and superior mesenteric arteries (SMBFV), and venous occlusion plethysmography was used to measure forearm blood flow (FBF). In study 2 (n = 14), leg blood flow (LBF; n = 9) was measured by Doppler ultrasound, and muscle sympathetic nerve activity (MSNA; n = 5) was measured by microneurography. At rest, upright posture increased heart rate and MSNA and decreased LBF, FBF, RBFV, and SMBFV and their respective conductances. MS elicited similar increases in mean arterial blood pressure ( approximately 12 mmHg) and heart rate ( approximately 17 beats/min), regardless of posture. MS in both postures elicited a decrease in RBFV, SMBFV, and their conductances and an increase in LBF, FBF, and their conductances. Changes in blood flow were blunted in the upright posture in all vascular beds examined, but the pattern of the vascular response was the same as the supine posture. MS did not change MSNA in either posture (change: approximately 1 +/- 3 and approximately 3 +/- 3 bursts/min, respectively). In conclusion, the augmented sympathetic activity of the upright posture does not alter heart rate, mean arterial blood pressure, or MSNA responses to MS. MS elicits divergent vascular responses in the visceral and peripheral vasculature. These results indicate that, although the upright posture attenuates vascular responses to MS, the pattern of neurovascular responses does not differ between postures.

Neural and cardiovascular responses to emotional stress in humans

Sympathetic neural responses to mental stress are well documented but controversial, whereas sympathetic neural responses to emotional stress are unknown. The purpose of this study was to investigate neural and cardiovascular responses to emotional stress evoked by negative pictures and reexamine the relationship between muscle sympathetic nerve activity (MSNA) and perceived stress. Mean arterial pressure (MAP), heart rate (HR), MSNA, and perceived stress levels were recorded in 18 men during three randomized trials: 1) neutral pictures, 2) negative pictures, and 3) mental stress. MAP and HR increased during mental stress (Delta14 +/- 2 mmHg and Delta15 +/- 2 beats/min, P < 0.001) but did not change during viewing of negative or neutral pictures. MSNA did not change during viewing of neutral (Delta1 +/- 1 burst/min, n = 16) or negative (Delta0 +/- 1 burst/min, n = 16) pictures or during mental stress (Delta1 +/- 2 burst/min, n = 13). Perceived stress levels were higher during mental stress (3 +/- 0 arbitrary units) than during viewing negative pictures (2 +/- 0 arbitrary units, P < 0.001). Perceived stress levels were not correlated to changes in MSNA during negative pictures (r = 0.10, P = 0.84) or mental stress (r = 0.36, P = 0.23). In conclusion, our results demonstrate robust increases in MAP and HR during mental stress, but not during emotional stress evoked by negative pictures. Although the influence of mental stress on MSNA remains unresolved, our findings challenge the concept that perceived stress levels modulate MSNA during mental stress.

Central modulation of exercise‐induced muscle pain in humans

The purpose of the current study was to determine if exercise‐induced muscle pain is modulated by central neural mechanisms (i.e. higher brain systems). Ratings of muscle pain perception (MPP) and perceived exertion (RPE), muscle sympathetic nerve activity (MSNA), arterial pressure, and heart rate were measured during fatiguing isometric handgrip (IHG) at 30% maximum voluntary contraction and postexercise muscle ischaemia (PEMI). The exercise trial was performed twice, before and after administration of naloxone (16 mg intravenous; n= 9) and codeine (60 mg oral; n= 7). All measured variables increased with exercise duration. During the control trial in all subjects (n= 16), MPP significantly increased during PEMI above ratings reported during IHG (6.6 ± 0.8 to 9.5 ± 1.0; P < 0.01). However, MSNA did not significantly change compared with IHG (7 ± 1 to 7 ± 1 bursts (15 s)−1), whereas mean arterial blood pressure was slightly reduced (104 ± 4 to 100 ± 3 mmHg; P < 0.05) and heart rate returned to baseline values during PEMI (83 ± 3 to 67 ± 2 beats min−1; P < 0.01). These responses were not significantly altered by the administration of naloxone or codeine. There was no significant relation between arterial blood pressure and MSNA with MPP during either IHG or PEMI. A second study (n= 8) compared MPP during ischaemic IHG to MPP during PEMI. MPP was greater during PEMI as compared with ischaemic IHG. These findings suggest that central command modulates the perception of muscle pain during exercise. Furthermore, endogenous opioids, arterial blood pressure and MSNA do not appear to modulate acute exercise‐induced muscle pain.