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J Appl Physiol 100: 266-273, 2006. First published August 25, 2005; doi:10.1152/japplphysiol.00588.2005
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Neural sites involved in the sustained increase in muscle sympathetic nerve activity induced by inspiratory capacity apnea: a fMRI study

V. G. Macefield,1 S. C. Gandevia,1 and L. A. Henderson2

1Prince of Wales Medical Research Institute and University of New South Wales, and 2Department of Anatomy and Histology, University of Sydney, Sydney, New South Wales, Australia

Submitted 19 May 2005 ; accepted in final form 22 August 2005


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
A maximal inspiratory breath hold (inspiratory capacity apnea) against a closed glottis evokes a large and sustained increase in muscle sympathetic nerve activity (MSNA). Because of its dependence on a high intrathoracic pressure, it has been suggested that this maneuver causes unloading of the low-pressure baroreceptors, known to increase MSNA. To determine the central origins of this sympathoexcitation, we used functional magnetic resonance imaging to define the loci and time course of activation of different brain areas. We hypothesized that, as previously shown for the Valsalvsa maneuver, discrete but widespread regions of the brain would be involved. In 15 healthy human subjects, a series of 90 gradient echo echo-planar image sets was collected during three consecutive 40-s inspiratory capacity apneas using a 3-T scanner. Global signal intensity changes were calculated and subsequently removed by using a detrending technique, which eliminates the global signal component from each voxel's signal intensity change. Whole brain correlations between changes in signal intensity and the known pattern of MSNA during the maneuver were performed on a voxel-by-voxel basis, and significant changes were determined by using a random-effects analysis procedure (P < 0.01, uncorrected). Significant signal increases emerged in multiple areas, including the rostral lateral medulla, cerebellar nuclei, anterior insula, dorsomedial hypothalamus, anterior cingulate, and lateral prefrontal cortexes. Decreases in signal intensity occurred in the dorsomedial and caudal lateral medulla, cerebellar cortex, hippocampus, and posterior cingulate cortex. Given that many of these sites have roles in cardiovascular control, the sustained increase in MSNA during an inspiratory capacity apnea is likely to originate from a distributed set of discrete areas.

cardiopulmonary receptors; sympathetic activity; paraventricular nucleus; medulla

DESPITE THE HIGH PREVALENCE of disease states characterized by serious alterations in autonomic function, the central neural sites responsible for controlling the autonomic nervous system in humans remain largely unexplored. The advent of functional brain imaging has made the exploration of cortical function in humans more accessible, and a large number of investigators have studied cortical involvement during sensory and motor tasks. To date, only a few investigations have used functional brain imaging to study cerebral sites involved in autonomic control (11, 12, 14). These studies have reported discrete, yet widespread, sites of activation during such tasks as the cold-pressor test and the Valsalva maneuver, both of which evoke increases in muscle sympathetic (vasoconstrictor) nerve activity (MSNA). As the cold-pressor test is also often painful, and the autonomic changes associated with the Valsalva maneuver are complex, in this study we used a "simpler" maneuver that elicits a consistent change in MSNA, a voluntary breath hold at maximal lung volume [inspiratory capacity apnea (19, 20)].

An inspiratory capacity apnea causes a sustained and pronounced increase in MSNA (20). It has been suggested that this increase results from unloading of the low-pressure (cardiopulmonary) baroreceptors (19). In addition, unlike the Valsalva maneuver, which is maintained by active expiratory effort, an inspiratory capacity apnea requires muscular effort only during the inflation phase: the lungs are maintained inflated by closure of the glottis while the inspiratory muscles relax.

Low-pressure baroreceptors are located in the atria and pulmonary veins and respond to low-level changes in absolute venous pressure. They detect changes in right atrial filling and, as a result, are almost certainly responsible for producing the changes in sympathetic activity that accompany conditions such as congestive heart failure (16). Despite this, little is known about the reflex circuitry involved in producing the changes in muscle vasoconstrictor drive. This investigation used functional magnetic resonance imaging (fMRI) in humans to define the brain regions involved in the increased muscle vasoconstrictor drive during an inspiratory capacity apnea.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Subjects.   Fifteen healthy subjects (8 men, 7 women; mean age 32 ± 3 yr, range 23–49 yr) participated in the study. No subjects exhibited a history of autonomic dysfunction or were currently on cardiovascular-altering medications. All procedures were carried out with the understanding and written consent of the subjects, and the study was approved by the Human Research Ethics Committee of the University of New South Wales and the Scientific Advisory Board of the Mayne Clinical Research Imaging Centre.

Nerve recording and analysis.   MSNA was recorded from fascicles of the common peroneal nerve supplying the pretibial flexors via tungsten microelectrodes (FHC, Bowdoinham, ME) inserted percutaneously at the level of the fibular head in eight subjects. Neural activity was amplified (gain 20,000, band pass 0.3–5.0 kHz) using an isolated amplifier (ISO-80, WPI, Sarasota, FL) and stored on computer (10-kHz sampling) using a PowerLab 16s data-acquisition system and Chart 5 software (AD Instruments, Castle Hill, NSW, Australia). Small manual adjustments of the microelectrode tip were undertaken until spontaneous, pulse-synchronous, multiunit bursts of MSNA were encountered. ECG (0.3 Hz–1 kHz; sampling 3.2 kHz) was recorded with Ag-AgCl surface electrodes placed bilaterally anterolaterally over the fifth to sixth ribs. Respiration (sampling 0.4 kHz) was recorded via a strain gauge band wrapped around the chest (PneumoTrace, UFI, Morro Bay, CA) and continuous blood pressure (sampling 0.4 kHz) via radial arterial tonometry (CBM-7000, Colin Corp, Kamaki City, Japan). Sustained increases in MSNA were evoked by instructing subjects to inhale to maximal capacity and to hold for 40 s, which they did by closure of the glottis. Mean burst amplitudes at rest and during the static phase of the apnea were calculated from R-wave-triggered averages of the root-mean-square-processed nerve signal (100-ms time constant). Equal numbers of triggers were used in the rest and maneuver conditions. The average time profile of MSNA was used to construct a model for subsequent use in analysis of the fMRI data (see below). High-pass filtering (100 Hz) and root-mean-square processing (100-ms time constant) of the ECG signal recorded from the chest wall allowed the electromyographic activity of the intercostal muscles to be observed during the inspiratory capacity apnea.

Image collection and analysis.   Subjects lay supine on the MRI scanner bed with foam pads placed on either side of the head to minimize head movement. Noninverting mirrors allowed subjects to view a display that provided instructions during the challenge period. There were four conditions, each represented by a static schematic picture of chest expansion: 1) relaxed, quiet breathing, 2) inhale, 3) maintain (at the maximal lung volume), and 4) exhale. Brain images were collected with a 3-T whole body scanner (Intera, Philips, The Netherlands) by using a SENSE head coil. Signal intensity changes were measured by using gradient echo echo-planar imaging sensitive to blood oxygen level-dependent (BOLD) contrast (17, 26). Two series of 90 image volumes (time to repetition = 4 s, time to echo = 50 ms, flip angle = 90°, field of view = 220 mm) were collected continuously over two separate 360-s periods. The first series covered the entire brain (voxel size = 1.72 x 1.9 x 4.0 mm thick, slice gap = 0.4 mm), whereas the second series covered the brain stem and cerebellum only (voxel size = 1.72 x 1.9 x 2.0 mm thick, slice gap = 0.2 mm). Each scanning period was divided into an initial 40-s baseline (10 volumes) followed by a 40-s inspiratory capacity apnea (10 volumes) and a 40-s recovery period (10 volumes). This sequence was then repeated twice so that a total of three inspiratory capacity apneas were recorded. A three-dimensional T1-weighted anatomical image covering the entire brain (voxel size = 0.4 x 0.4 x 0.9 mm) and a T2-weighted anatomical image covering the brain stem and cerebellum only (voxel size = 0.4 x 0.4 x 2.2 mm) were also collected.

fMRI images were processed by using SPM2 and custom-built software (10). The whole brain image volumes were realigned, spatially normalized, and segmented into gray, white, and cerebrospinal fluid images. The gray images were then used for analysis. Two subjects' images were subsequently removed from further analysis due to excessive head movement (>0.5 mm in any direction). The remaining 13 subject's gray matter images were spatially smoothed [5-mm full width at half maximum (FWHM)], and they were detrended using the method described by Macey et al. (23) and temporally smoothed (8-s FWHM). The detrending method removes signal intensity changes that match the individual subject's global signal intensity change on a voxel-by-voxel basis. This method ensures that no significant activations occur as a result of global signal intensity changes.

The brain stem-only image volumes were processed in a slightly different manner. The images from the 13 subjects used in the entire brain analysis were initially realigned, and two subjects' images were removed due to excessive head movement. A brain stem template was then created by spatially normalizing each subject's T2 anatomical image to one subject's T2 anatomical image. The resulting anatomical images from each subject (n = 11) were then averaged and smoothed to create a brain stem template. Each subject's BOLD images were normalized to their own T2 anatomical image. The parameters used to spatially normalize each subject's T2 anatomical image to the brain stem template were then used to spatially normalize each individual's BOLD images. These normalized images were then spatially smoothed (5-mm FWHM), detrended, and temporally smoothed (8-s FWHM).

In both the entire brain and brain stem-only images, a model of mean MSNA evoked by the inspiratory capacity apnea was constructed, in which each 4-s volume was assigned a normalized mean MSNA amplitude. This was used to determine significant changes in signal intensity on a voxel-by-voxel basis. Statistical maps were threshold (random effects, uncorrected P < 0.01) and overlaid onto an average anatomical image, calculated from all of the subjects. To reduce the risk of false-positive activations, a minimum cluster threshold of 10 voxels was employed. Percent BOLD signal intensity changes from baseline of significant clusters of voxels were calculated and averaged (±SE) across subjects.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Physiological changes.   A typical example of the changes in MSNA, electrocardiogram, blood pressure, and respiration during a breath hold at maximal lung volume (inspiratory capacity apnea) is shown in Fig. 1. As described previously (19, 20), the maneuver causes an initial inhibition of spontaneous MSNA during the inflation phase but a large increase during the transient fall in systolic and diastolic pressures. Subsequently, diastolic pressure returns to control levels, and a sustained increase in MSNA occurs until the deflation phase, when it is inhibited. Measurements of intercostal electromyography show that these inspiratory muscles are active during the inflation phase. However, the inspiratory muscles are virtually silent during the static phase of the maneuver, when the subject relaxes the effort but maintains the high lung volume by closure of the glottis.



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  		Fig. 1. Muscle sympathetic nerve activity (MSNA), shown in the filtered and root-mean-square-processed neurograms in the top two traces, electrocardiogram (ECG), blood pressure (BP), and respiration during an inspiratory capacity apnea in 1 subject. Intercostal eletromyogram (EMG) was derived from the ECG record. The dashed line in the blood pressure trace indicates that diastolic pressure remained above normal after the initial fall early in the maneuver.

 
fMRI signal changes.   The locations of significant changes in BOLD signal intensity are shown in Table 1 and Figs. 2 and 3. Within 4 s (one brain volume) of the start of each inspiratory apnea, signal intensity began to increase in the rostral lateral medulla, deep cerebellar nuclei, hypothalamus, and anterior insula cortex. These increases in signal intensity remained significantly above baseline for the entire period of apnea, returning to baseline levels between each apnea. Short-onset (within 4 s) signal intensity decreases occurred in the caudal dorsomedial medulla, caudal lateral medulla, posterior cingulate cortex, and the hippocampus. The decreases in signal intensity within the hippocampus were the largest of all signal changes, declining ~3% during each inspiratory apnea.


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  		Table 1. Significant changes in blood oxygen level-dependent signal intensity during inspiratory capacity apnea

 


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  		Fig. 2. Significant blood oxygen level-dependent signal intensity (SI) changes correlated to mean MSNA overlaid onto an average T1-weighted anatomical image set. The hot color scale (coded for t-value) indicates regional signal increases during each inspiratory capacity apnea. The cool color scale indicates regional signal decreases during each inspiratory capacity apnea. Slice positions are indicted in the bottom right inset and by Montreal Neurological Institute (MNI) coordinates at the top left of each image.

 


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  		Fig. 3. Significant blood oxygen level-dependent SI changes ({Delta}) in the medulla and cerebellum, obtained from the brain stem-specific scans (see METHODS) overlaid onto an average T2-weighted anatomical image set. Ventral is at the base of each image. The hot and cool color scales (coded for t-value) indicate regional signal increases and decreases, respectively. Slice positions (MNI space) are indicted in the top right of each image. To the right are 3 graphs showing the mean (±SE) percent changes in SI over time for 3 significant clusters. Shaded bars indicate each of the 3 inspiratory capacity apnea periods. {Delta}, Change.

 
In addition to short-onset signal intensity changes, three brain regions displayed signal changes that began well after the increase in sympathetic nerve activity, i.e., ~16 s following the apnea onset. Late-onset signal increases were seen in the anterior cingulate and lateral prefrontal cortexes, whereas a signal decline occurred in the cerebellar cortex (Figs. 4A and 5).



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  		Fig. 4. A: mean (±SE) percent change in SI over time for 8 clusters that displayed significant changes in SI. Shaded bars indicate each of the 3 inspiratory capacity apnea periods. To the left of each trace, the significant cluster is indicated by a white arrow. B: individual subject percent SI changes in the deep cerebellar nuclei during 3 inspiratory capacity apnea periods. Note the consistency in the SI changes between subjects and during each inspiratory capacity apnea.

 


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  		Fig. 5. Summary of regional SI changes, functional magnetic resonance imaging (fMRI) model, sympathetic nerve activity, AP, and respiration during one inspiratory capacity apnea. The regional SI changes are divided into 2 groups: short and long onset latency. PF, prefrontal.

 
Figure 4B shows the signal intensity changes in the deep cerebellar nuclei for each subject during the three inspiratory capacity apneas. Despite the use of a random-effects analysis with an uncorrected threshold, it is clear that the patterns of signal intensity change were consistent both between subjects and during each of the three apnea periods.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
An inspiratory capacity apnea evokes a sustained elevation in MSNA. During the static phase of the maneuver, in which the inspiratory pump muscles are quiescent and only the laryngeal constrictors are active, intrathoracic pressure remains high because of the elastic recoil of the lungs and chest wall against a closed glottis. Accordingly, the sustained increase in MSNA is probably due to unloading of the low-pressure baroreceptors (19, 20). Inspiratory capacity apneas elicit discrete fMRI signal intensity changes over multiple brain regions. These changes were located primarily in regions that have been implicated in autonomic control in animals and humans. In addition to signal intensity increases in the rostral lateral medulla, signal increases were found in the deep cerebellar nuclei, anterior insula, dorsomedial hypothalamus, and anterior cingulate cortex. Furthermore, decreases in signal intensity were evoked by the challenge in the dorsomedial and caudal lateral medulla, hippocampus, and cerebellar and posterior cingulate cortexes.

Limitations.   While subjects found it easy to hold their breath at maximal lung volume for 40 s, there would have been an increase in CO2. It is well-established that hypercapnia evokes cerebral vasodilation and increases cerebral blood flow. During the inspiratory capacity apnea, following an initial transient increase (2 scan volumes, i.e., 8 s), global signal intensity gradually decreased below baseline and then increased above baseline approximately two volumes before the end of the apnea period. This pattern of global signal change did not resemble either the sustained increase in MSNA (which was the model used to search for significant changes in BOLD signal intensity) or the signal intensity changes in those areas that we suggested were responding to the "urge to breathe," i.e., cingulate, prefrontal, and cerebellar cortexes. Despite this, in an attempt to eliminate the influence of global signal intensity changes, we used gray matter-only images for analysis. It has been previously shown that hypercapnia evokes significantly different global signal intensity changes in gray and white matter (21), and, as a result, false positives can arise if whole brain images are used for analysis. We then detrended the gray matter images using a newly developed technique, specifically designed for eliminating global changes like those evoked by hypercapnia (23). This detrending technique removes the global signal intensity component from each voxel's signal intensity change and eliminates the risk of false-positive activations due to global signal intensity changes.

Short-onset BOLD signal changes.   In contrast to the high-pressure arterial baroreceptor reflex, the brain circuitry responsible for relaying low-pressure cardiopulmonary baroreceptor information has received little attention. Cardiopulmonary baroreceptors are located in the atria and pulmonary veins and respond to low-level changes in absolute venous pressure. Like the arterial baroreceptors, cardiopulmonary baroreceptors are unloaded by falls in pressure and project via the vagus nerve to the nucleus of the solitary tract (NTS). This is consistent with the signal intensity changes in this study, as cardiopulmonary baroreceptor unloading evoked a decrease in signal intensity in the region encompassing the NTS. Despite these similarities, the cardiopulmonary reflex circuit does not appear to be the same as the arterial baroreflex circuit, i.e., the well-described NTS-caudal ventrolateral medulla (CVLM)-rostral ventrolateral medulla (RVLM) pathway. Although, in rabbits, cardiopulmonary baroreceptor activation results in excitation of NTS and CVLM neurons, these activated neurons do not project to the RVLM (31). Thus cardiopulmonary baroreceptor information must travel from the NTS to the RVLM via an alternate, probably extramedullary, pathway. Furthermore, unlike the arterial baroreceptor reflex, in which unloading evokes increased RVLM activity via decreased tonic CVLM GABAergic synaptic input, unloading of cardiopulmonary baroreceptors may increase RVLM activity via increased excitatory synaptic input. Indeed, this latter possibility is supported by the current investigation as BOLD signal intensity [a measure of synaptic activity (18)] increased in the region of the rostral lateral medulla (encompassing the RVLM) during the inspiratory capacity apnea.

There are multiple pathways through which cardiopulmonary baroreceptor information can reach the RVLM from the NTS. Three regions, the dorsomedial hypothalamus, the anterior insular cortex, and the deep cerebellar nuclei, all displayed signal intensity changes that were very similar to that of the RVLM, i.e., an early-onset increase in signal intensity. The dorsomedial hypothalamus encompasses the paraventricular nucleus of the hypothalamus (PVN), a region with a well-established role in autonomic control. The PVN receives afferents from the NTS, projects directly to the RVLM (30), evokes sympathoexcitation upon chemical activation (37), and contains neurons that are activated during volume unloading (1). Furthermore, both lesions and chemical inhibition of the PVN prevent the sympathoinhibition elicited by cardiac mechanoreceptor activation (13, 38), suggesting that the PVN is a critical relay in the cardiopulmonary baroreflex. In contrast, although PVN stimulation alters arterial baroreceptor sensitivity (6), lesions of the PVN do not abolish the arterial baroreceptor reflex (7). Using fMRI, our laboratory has previously shown that, during a Valsalva maneuver in humans or during arterial baroreceptor unloading in cats, BOLD signal intensity in the region encompassing the PVN region remains unchanged (14, 15). Therefore, it is likely that, during an inspiratory capacity apnea, cardiac unloading results in decreased NTS activity, which in turn produces an increase in drive onto PVN neurons. This increase in PVN activity may then directly activate RVLM premotor neurons, producing an increased muscle sympathetic drive.

The insula is being increasingly regarded as an important cortical region in cardiovascular regulation. Electrical stimulation of the anterior insula can elicit changes in arterial pressure, heart rate, and sympathetic activity (5), and we have previously reported signal increases in the anterior insula during cardiorespiratory challenges, including Valsalva maneuvers, cold pressor tests, and loaded breathing (12, 14, 22). The precise route via which the insula alters sympathetic outflow remains unknown, although the insula does not project directly to the RVLM (29). Despite this, electrical stimulation of the insula excites some RVLM sympathoexcitatory neurons (32) and, therefore, must achieve this via a polysynaptic pathway.

Although over a half a century has passed since the first report demonstrating an autonomic role for the cerebellum (25), most investigations of cerebellar function relate to its role in motor control. Electrical and chemical stimulation of the deep cerebellar nuclei have been shown to modify blood pressure, heart rate, and vasopressin release (4, 8). Indeed, the deep cerebellar nuclei project directly to the PVN, and stimulation of the interpositus nucleus elicits short-latency excitation of PVN neurons (34). It is possible that the increases in signal intensity within both the deep cerebellar nuclei and the PVN are directly related to the release of vasopressin. In support of this, during lower body negative pressure (which, like the inspiratory capacity apnea, also unloads low-pressure baroreceptors), vasopressin release increases significantly as sympathetic activity increases and arterial pressure remains stable (36).

Two regions that displayed short-latency signal intensity decreases were the hippocampus and the posterior cingulate cortex. In fact, the hippocampal signal changes were the largest and most robust of all signal changes. We have previously shown that, during a Valsalva maneuver, hippocampal signal intensity increases transiently at the onset of each maneuver and suggested that this transient increase is related to inspiration (14). Given that the hippocampal signal change during the inspiratory capacity apnea is sustained during the entire maneuver (which is maintained passively by closure of the glottis and relaxation of inspiratory muscles), it is unlikely that this prolonged signal change is driven by respiratory muscle contraction but instead is involved in producing or modulating sympathetic activity. The hippocampus projects indirectly to sympathetic targets, including the adrenal gland and stellate ganglion (35). Furthermore, microinjection of opiates into the hippocampus reduces arterial pressure and heart rate (33), and the destruction of opiate-producing hippocampal neurons increases blood pressure (28). It is possible that, during cardiopulmonary baroreceptor unloading, decreased opiate drive within the hippocampus further enhances the resultant increase in sympathetic drive. The specific pathway via which the hippocampus can alter sympathetic activity has not been established, although alterations in hippocampal activity can change hypothalamic activity (24).

Long-onset BOLD signal changes.   Approximately 15 s after the start of the maneuver, signal intensity began to increase within the anterior cingulate and lateral prefrontal cortexes and to decrease in the cerebellar cortex. Given this late onset, we speculate that these two regions are not directly involved in producing the sympathoexcitation evoked by cardiopulmonary unloading. Brain imaging studies have revealed that signal intensity increases within the anterior insula and lateral prefrontal cortexes and decreases in the cerebellar cortex during dyspnea (2, 9, 27). During a breath hold at the end of a normal expiration, the urge to breath begins after ~10 s (3). Furthermore, after ~40 s, the urge to breath is about one-half the level of that at the breaking point. While subjects found it easy to hold their breath at maximal inflation for 40 s, it is possible that the signal intensity changes within the cingulate, prefrontal, and cerebellar cortexes are directly related to the voluntary suppression of breathing.

The inspiratory capacity apnea recruits neural structures throughout the rostrocaudal extent of the brain. Early-onset recruitment occurs within the medulla, deep cerebellum, hypothalamus, hippocampus, and insula. These sites are likely involved in initiating and maintaining the profound increase in sympathetic activity that occurs during the maneuver. Delayed signal intensity changes were found in cerebellar, anterior cingulated, and lateral prefrontal cortexes, sites that are likely recruited in response to increases in the urge to breathe, which develops as the apnea is sustained. These findings emphasize the discrete activation pattern of a simple autonomic challenge and suggest that the timing of signal changes can provide information as to the relative contribution of each brain region.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
ACKNOWLEDGMENTS
 REFERENCES
 
This work was supported by National Health and Medical Research Council of Australia Grant 350889 to V. G. Macefield and L. A. Henderson.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
REFERENCES
 
We thank Kathy M. Hughes for advice and technical assistance in all imaging procedures and Dr. Paul Macey for help with the image analysis software. Scans were performed at the Mayne Clinical Research Imaging Centre, Prince of Wales Medical Research Institute.


   FOOTNOTES
 

Address for reprint requests and other correspondence: L. A. Henderson, Dept. of Anatomy and Histology, Univ. of Sydney, Sydney, NSW 2006, Australia (e-mail: lukeh{at}anatomy.usyd.edu.au)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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 DISCUSSION
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 ACKNOWLEDGMENTS
 REFERENCES
 

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