J. Kevin Shoemaker

MRI Measures of Middle Cerebral Artery Diameter in Conscious Humans During Simulated Orthostasis

BACKGROUND AND PURPOSE The relationship between middle cerebral artery (MCA) flow velocity (CFV) and cerebral blood flow (CBF) is uncertain because of unknown vessel diameter response to physiological stimuli. The purpose of this study was to directly examine the effect of a simulated orthostatic stress (lower body negative pressure [LBNP]) as well as increased or decreased end-tidal carbon dioxide partial pressure (P(ET)CO(2)) on MCA diameter and CFV. METHODS Twelve subjects participated in a CO(2) manipulation protocol and/or an LBNP protocol. In the CO(2) manipulation protocol, subjects breathed room air (normocapnia) or 6% inspired CO(2) (hypercapnia), or they hyperventilated to approximately 25 mm Hg P(ET)CO(2) (hypocapnia). In the LBNP protocol, subjects experienced 10 minutes each of -20 and -40 mm Hg lower body suction. CFV and diameter of the MCA were measured by transcranial Doppler and MRI, respectively, during the experimental protocols. RESULTS Compared with normocapnia, hypercapnia produced increases in both P(ET)CO(2) (from 36+/-3 to 40+/-4 mm Hg, P<0.05) and CFV (from 63+/-4 to 80+/-6 cm/s, P<0.001) but did not change MCA diameters (from 2.9+/-0.3 to 2.8+/-0.3 mm). Hypocapnia produced decreases in both P(ET)CO(2) (24+/-2 mm Hg, P<0.005) and CFV (43+/-7 cm/s, P<0.001) compared with normocapnia, with no change in MCA diameters (from 2.9+/-0.3 to 2.9+/-0.4 mm). During -40 mm Hg LBNP, P(ET)CO(2) was not changed, but CFV (55+/-4 cm/s) was reduced from baseline (58+/-4 cm/s, P<0.05), with no change in MCA diameter. CONCLUSIONS Under the conditions of this study, changes in MCA diameter were not detected. Therefore, we conclude that relative changes in CFV were representative of changes in CBF during the physiological stimuli of moderate LBNP or changes in P(ET)CO(2).

Ventral medial prefrontal cortex and cardiovagal control in conscious humans.

The autonomic nervous system plays a critical role in regulating the cardiovascular responses to mental and physical stress. Recent neuroimaging studies have demonstrated that sympathetic outflow to the heart is modulated by the activity of the anterior cingulate cortex (ACC). However, the cortical modulation of cardiovagal activity is still unclear in humans. The present study used functional MRI to investigate the cortical network involved in cardiovagal control. Seventeen healthy individuals performed graded handgrip exercise while heart rate (HR) and cortical activity were recorded. Muscle sympathetic nerve activity (MSNA), mean arterial pressure (MAP) and HR were measured while participants repeated the same protocol in a parallel experiment session. The handgrip exercise elevated HR and MAP without concurrent elevations in MSNA supporting earlier conclusions that the cardiovascular responses are mainly modulated by vagal withdrawal. The imaging data showed activation in the insular cortex, thalamus, parietal cortices and cerebellum during the exercise period. Consistently across all the participants, the HR response correlated with the deactivation in the ventral medial prefrontal cortex (vMPFC), which has substantial anatomical connection with the subcortical autonomic structures. The deactivation of the vMPFC was independent of the motor control and was observed commonly in both left and right hand exercise. Stronger vMPFC deactivation was observed when participants completed a higher intensity exercise that elicited a larger HR response. Our findings support the hypothesis that the vMPFC is involved in modulating the vagal efferent outflow to the heart and the suppression of its activity elevates cardiovascular arousal in conscious humans.

Cortical regions associated with autonomic cardiovascular regulation during lower body negative pressure in humans

The purpose of the present study was to determine the cortical structures involved with integrated baroreceptor‐mediated modulation of autonomic cardiovascular function in conscious humans independent of changes in arterial blood pressure. We assessed the brain regions associated with lower body negative pressure (LBNP)‐induced baroreflex control using functional magnetic resonance imaging with blood oxygen level‐dependent (BOLD) contrast in eight healthy male volunteer subjects. The levels of LBNP administered were 5, 15 and 35 mmHg. Heart rate (HR; representing the cardiovascular response) and LBNP (representing the baroreceptor activation level) were simultaneously monitored during the scanning period. In addition, estimated central venous pressure (CVP), arterial blood pressure (ABP) and muscle sympathetic nerve activity were recorded on a separate session. Random effects analyses (SPM2) were used to evaluate significant (P < 0.05) BOLD signal changes that correlated separately with both LBNP and HR (15‐ and 35‐mmHg versus 5‐mmHg LBNP). Compared to baseline, steady‐state LBNP at 15 and 35 mmHg decreased CVP (from 7 ± 1 to 5 ± 1 and 4 ± 1 mmHg, respectively) and increased MSNA (from 12 ± 1 to 23 ± 3 and 36 ± 4 bursts min−1, respectively, both P < 0.05 versus baseline). Furthermore, steady‐state LBNP elevated HR from 54 ± 2 beats min−1 at baseline to 64 ± 2 beats min−1 at 35‐mmHg suction. Both mean arterial and pulse pressure were not different between rest and any level of LBNP. Cortical regions demonstrating increased activity that correlated with higher HR and greater LBNP included the right superior posterior insula, frontoparietal cortex and the left cerebellum. Conversely, using the identical statistical paradigm, bilateral anterior insular cortices, the right anterior cingulate, orbitofrontal cortex, amygdala, midbrain and mediodorsal nucleus of the thalamus showed decreased neural activation. These data corroborate previous investigations highlighting the involved roles of the insula, anterior cingulate cortex and amygdala in central autonomic cardiovascular control. In addition, we have provided the first evidence for the identification of the cortical network involved specifically with baroreflex‐mediated autonomic cardiovascular function in conscious humans.

Cerebral blood flow velocity underestimates cerebral blood flow during modest hypercapnia and hypocapnia

To establish the accuracy of transcranial Doppler ultrasound (TCD) measures of middle cerebral artery (MCA) cerebral blood flow velocity (CBFV) as a surrogate of cerebral blood flow (CBF) during hypercapnia (HC) and hypocapnia (HO), we examined whether the cross-sectional area (CSA) of the MCA changed during HC or HO and whether TCD-based estimates of CBFV were equivalent to estimates from phase contrast (PC) magnetic resonance imaging. MCA CSA was measured from 3T magnetic resonance images during baseline, HO (hyperventilation at 30 breaths/min), and HC (6% carbon dioxide). PC and TCD measures of CBFV were measured during these protocols on separate days. CSA and TCD CBFV were used to calculate CBF. During HC, CSA increased from 5.6 ± 0.8 to 6.5 ± 1.0 mm(2) (P < 0.001, n = 13), while end-tidal carbon dioxide partial pressure (PETCO2) increased from 37 ± 3 to 46 ± 5 Torr (P < 0.001). During HO, CSA decreased from 5.8 ± 0.9 to 5.3 ± 0.9 mm(2) (P < 0.001, n = 15), while PetCO2 decreased from 36 ± 4 to 23 ± 3 Torr (P < 0.001). CBFVs during baseline, HO, and HC were compared between PC and TCD, and the intraclass correlation coefficient was 0.83 (P < 0.001). The relative increase from baseline was 18 ± 8% greater (P < 0.001) for CBF than TCD CBFV during HC, and the relative decrease of CBF during HO was 7 ± 4% greater than the change in TCD CBFV (P < 0.001). These findings challenge the assumption that the CSA of the MCA does not change over modest changes in PETCO2.

The effect of hypoxia on pulmonary O2 uptake, leg blood flow and muscle deoxygenation during single-leg knee-extension exercise.

The effect of hypoxic breathing on pulmonary O2 uptake (VO2p), leg blood flow (LBF) and O2 delivery and deoxygenation of the vastus lateralis muscle was examined during constant‐load single‐leg knee‐extension exercise. Seven subjects (24 ± 4 years; mean ±s.d.) performed two transitions from unloaded to moderate‐intensity exercise (21 W) under normoxic and hypoxic (PETO2= 60 mmHg) conditions. Breath‐by‐breath VO2p and beat‐by‐beat femoral artery mean blood velocity (MBV) were measured by mass spectrometer and volume turbine and Doppler ultrasound (VingMed, CFM 750), respectively. Deoxy‐(HHb), oxy‐, and total haemoglobin/myoglobin were measured continuously by near‐infrared spectroscopy (NIRS; Hamamatsu NIRO‐300). VO2p data were filtered and averaged to 5 s bins at 20, 40, 60, 120, 180 and 300 s. MBV data were filtered and averaged to 2 s bins (1 contraction cycle). LBF was calculated for each contraction cycle and averaged to 5 s bins at 20, 40, 60, 120, 180 and 300 s. VO2p was significantly lower in hypoxia throughout the period of 20, 40, 60 and 120 s of the exercise on‐transient. LBF (l min−1) was approximately 35% higher (P > 0.05) in hypoxia during the on‐transient and steady‐state of KE exercise, resulting in a similar leg O2 delivery in hypoxia and normoxia. Local muscle deoxygenation (HHb) was similar in hypoxia and normoxia. These results suggest that factors other than O2 delivery, possibly the diffusion of O2, were responsible for the lower O2 uptake during the exercise on‐transient in hypoxia.

Functional neuroanatomy of autonomic regulation

Considerable effort has been put into animal studies establishing the sites in the brain that are responsible for control of the autonomic nervous system. These studies relied on an electrophysiological or neurochemical response to the activation of peripheral autonomic receptors or chemical or electrical stimulation of central sites. A large number of excellent reviews summarize the results of these studies. More recently, functional imaging has been used to not only confirm the electrophysiological and anatomical studies in animals, but has allowed a more complete understanding of how the brain responds as a whole for effecting autonomic control. The earliest studies to examine forebrain control during functional imaging utilized tests that involved active participation of the subjects and included maximal inspiration, Valsalva manoeuvre, isometric handgrip and cold compress application. There were a few issues that arose from these studies. First, they involved areas of the brain that included active decision making, they were more prone to inducing movement artefact, and some of these tests could activate noxious regions in the brain in addition to autonomic sites. In fact, this dual modality activation represented a more severe complication for investigators determining nociceptive sites in the brain, since virtually all of their stimuli had concomitant autonomic responses. More recent investigations attempted to resolve these issues with more selective passive and active stimuli. In spite of the very different approaches taken to visceral activation in functional imaging studies, a consistent picture of the key areas involved in autonomic control has emerged.

Early mobilization in the critical care unit: A review of adult and pediatric literature.

Early mobilization of critically ill patients is beneficial, suggesting that it should be incorporated into daily clinical practice. Early passive, active, and combined progressive mobilizations can be safely initiated in intensive care units (ICUs). Adult patients receiving early mobilization have fewer ventilator-dependent days, shorter ICU and hospital stays, and better functional outcomes. Pediatric ICU data are limited, but recent studies also suggest that early mobilization is achievable without increasing patient risk. In this review, we provide a current and comprehensive appraisal of ICU mobilization techniques in both adult and pediatric critically ill patients. Contraindications and perceived barriers to early mobilization, including cost and health care provider views, are identified. Methods of overcoming barriers to early mobilization and enhancing sustainability of mobilization programs are discussed. Optimization of patient outcomes will require further studies on mobilization timing and intensity, particularly within specific ICU populations.

Hypercapnic vs. hypoxic control of cardiovascular, cardiovagal, and sympathetic function

We compared the integrated cardiovascular and autonomic responses to hypercapnia and hypoxia to test the hypothesis that these stimuli differentially affect muscle sympathetic nerve activity (MSNA) discharge patterns and cardiovagal and sympathetic baroreflex function in a manner related to ventilatory chemoreflex sensitivity. Six males and six females underwent 5 min of hypoxia (end-tidal Po2 = 45 Torr) and 5 min of hypercapnia (end-tidal Pco2 = +8 Torr from baseline), causing similar ventilatory responses. A downward right shift in cardiovagal set point was observed during both conditions, which was strongly related to the change in inspiratory time (Ti) from baseline to hypercapnia (r2 = 0.67, P = 0.007) and hypoxia (r2 = 0.79, P < 0.001). Cardiovagal baroreflex gain was decreased during hypoxia (20.1 +/- 6.9 vs. 8.9 +/- 5.1 ms/mmHg, P < 0.001) but not hypercapnia (26.7 +/- 12.7 vs. 23.0 +/- 9.1 ms/mmHg). Both hypoxia and hypercapnia increased MSNA burst amplitude, whereas hypoxia, but not hypercapnia, also increased in MSNA burst frequency (21 +/- 9 vs. 28 +/- 7 bursts/min, P = 0.03) and total MSNA (4.56 +/- 3.07 vs. 7.37 +/- 3.26 mV/min, P = 0.002). However, neither hypercapnia nor hypoxia affected sympathetic burst probability or baroreflex gain. Hypoxia also caused a greater reduction in total peripheral resistance (P = 0.04), a greater increase in heart rate (P = 0.002), and a trend for a greater cardiac output response (P = 0.06) compared with hypercapnia. Nonetheless, central venous pressure remained unchanged during either condition. These results suggest that hypercapnia and hypoxia exert differential effects on cardiovagal, but not sympathetic, baroreflex gain and set point in a manner not related to ventilatory chemoreflex sensitivity. Furthermore, the data suggest that the individuals respiratory pattern to hypoxia or hypercapnia, as reflected in the inspiratory time, was a strong determinant of cardiovagal baroreflex set- point rather than the total ventilatory chemoreflex gain per se.

Sympathetic neural activation: an ordered affair

Is there an ordered pattern in the recruitment of postganglionic sympathetic neurones? Using new multi‐unit action potential detection and analysis techniques we sought to determine whether the activation of sympathetic vasomotor neurones during stress is governed by the size principle of recruitment. Multi‐unit postganglionic sympathetic activity (fibular nerve) was collected from five male subjects at rest and during periods of elevated sympathetic stress (end‐inspiratory apnoeas; 178 ± 37 s(mean ± S.D.)). Compared to baseline (0.24 ± 0.04 V), periods of elevated stress resulted in augmented sympathetic burst size (1.34 ± 0.38 V, P < 0.05). Increased burst size was directly related to both the number of action potentials within a multi‐unit burst of postganglionic sympathetic activity (r= 0.88 ± 0.04, P < 0.001 in all subjects), and the amplitude of detected action potentials (r= 0.88 ± 0.06, P < 0.001 in all subjects). The recruitment of larger, otherwise silent, neurons accounted for approximately 74% of the increase in detected action potentials across burst sizes. Further, action potential conduction velocities (inverse of latencies) were increased as a function of action potential size (R2= 0.936, P= 0.001). As axon diameter is positively correlated with action potential size and conduction velocity, these data suggest that the principle of ordered recruitment based on neuronal size applies to postganglionic sympathetic vasomotor neurones. This information may be pertinent to our understanding of reflex‐specific recruitment strategies in postganglionic sympathetic nerves, patterns of vasomotor control during stress, and the malleability of sympathetic neuronal properties and recruitment in health and disease.

Human cardiovascular and gustatory brainstem sites observed by functional magnetic resonance imaging.

The reflex control and relay to higher brain sites of visceral sensory information within the central nervous system is mediated via discrete sites in the brainstem. Anatomical characterization of these sites in humans has been limited due to the invasive nature of such research. The present study employed 4 Tesla functional magnetic resonance imaging (fMRI) to characterize brainstem sites involved in autonomic control in the human. Eight subjects performed tasks that activate the general visceral (the isometric hand‐grip, maximal inspiration, Valsalva maneuver) or special visceral sensory systems (sucrose administration to the tongue). Activation of the nucleus of the solitary tract and parabrachial nucleus was consistently observed with all general visceral tasks. Periaqueductal gray area activation was observed during the maximal inspiration and Valsalva maneuver conditions and raphe activation was present in response to isometric hand‐grip and maximal inspiration tasks. The activation in the nucleus of the solitary tract was consistently more rostral in the medulla during sucrose administration than during performance of the other experimental tasks. This finding is consistent with what has been previously demonstrated in animals. This is the first study to image the human brainstem with respect to visceral control and demonstrates the feasibility of using high‐resolution fMRI to study the functional organization of the human brainstem. J. Comp. Neurol. 471:446–461, 2004.