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1Department of Neurobiology, and 4Brain Research Institute, University of California at Los Angeles, Los Angeles, California 90095-1763; 2Department of Anatomy and Histology, University of Sydney, Sydney, NSW 2006, Australia; and 3Department of Radiology, University of Arizona, Tucson, Arizona 85724
Submitted 12 August 2003 ; accepted in final form 13 October 2003
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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heart rate; respiration; blood pressure; baroreflex; barodenervation
Functional neuroanatomic techniques such as c-fos or 2-de-oxyglucose procedures have been used to determine neural responses to blood pressure manipulations, but these possess significant disadvantages. Typically, only one time-related value during the challenge can be obtained, the preparation must be killed for examination after one trial, and activity changes can be evaluated only after a prolonged period from the initial study. Functional magnetic resonance imaging (fMRI) procedures, however, allow repeated evaluation of activity changes during challenges over the entire brain at relatively high temporal resolution and with minimal invasion. The technique has been effectively used to demonstrate human forebrain and cerebellar involvement to manipulations that modify blood pressure (27). The temporal pattern of responses from certain forebrain areas that exert control over sympathetic and parasympathetic outflow, such as the insular cortex (36), is of particular interest because those areas exhibit damage in human syndromes with high tonic sympathetic outflow or cardiovascular pathologies, such as heart failure (17), and certain neurological conditions, including stroke (36).
In this study, we used fMRI techniques in adult cats to visualize brain regions that responded to pharmacological pressor and depressor challenges. The objective was to identify neural sites recruited in response to blood pressure challenges and describe the temporal sequence of the recruitment. We hypothesized that 1) both transitory and late-developing responses would arise from ventral medullary sites, in congruence with previous optical imaging data (42); 2) right insular regions would show increased activity to pressor challenges to suppress sympathetic outflow and restore blood pressure homeostasis, and diminished activity to depressor challenges to allow compensatory enhancement of sympathetic action; and 3) cerebellar structures would show altered activity patterns to pressor and depressor challenges for compensatory somatomotor and autonomic actions.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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Pressor responses were elicited by intravenous injection of phenylephrine (PE; 5 µg/kg) and depressor responses by injections of sodium nitroprusside (NTP; 5 µg/kg). Each injection was delivered as a 0.25-ml bolus followed by a 1-ml saline flush over 
8 s (2 volumes). Images were also collected during an equivalent volume of a normal saline control dose. In each animal, up to six separate injections of PE, NTP, and saline were delivered, with at least 13 min between injections.
All MRI experiments were performed on a 4.7-T Bruker (Billerica, MA) Biospec imager. Blood oxygen level-dependent (BOLD) fMRI was performed by using the gradient-echo echo-planar imaging (EPI) technique (9) to visualize rapid brain signal changes to the challenges. A volume of standard T2-weighted images was collected before functional imaging. The EPI protocol consisted of 60 gradient-echo volumes (4 s each) with 16 coronal slices collected per volume. Images were acquired with the following parameters: repetition time = 1,000 ms; matrix size = 128 x 128; phase encode steps/segment = 32; echo time = 12 ms; effective echo time = 128 ms; flip angle = 90°; field of view = 7 x 7 cm; and no interslice gap. Voxel sizes were 0.55 x 0.55 x 2.25 mm. Images were acquired continuously during an initial 60-s baseline and subsequent 180-s challenge conditions, with the total series lasting 240 s (no delays between image volumes). Each series was separated by a rest period (13-20 min), which allowed adequate recovery from the challenge as monitored by physiological parameters [i.e., heart rate (HR), respiratory rate, and AP]. At completion of the studies, animals were euthanized with an overdose of pentobarbital sodium (50 mg/kg).
The first five scans in each series were excluded from analysis due to signal intensity stabilization time, which left 55 image volumes per challenge for analysis. The SPM99 (11) software package, together with custom-designed software, was used to analyze all image sets. Brain movements were visualized by animation of successive images and by plotting displacement and rotation over time, as determined by a realignment algorithm. The head stabilization device effectively prevented movement, and thus motion correction was unnecessary. The regions surrounding the brain were manually removed, and the image volumes were corrected for acquisition time. One EPI volume from each cat was then spatially normalized to the T2 image volume from one cat. The resulting normalized EPI volumes were then averaged and smoothed [full width at half maximum (FWHM) = 2.7 mm]. With the use of this mean image as a template, all EPI volumes were spatially normalized. The image sets were then smoothed (FWHM = 2.7 mm), intensity normalized, and temporally smoothed (FWHM = 8 s).
Two analysis procedures were used: fixed effects and volume-of-interest (VOI) analyses. Fixed effects analysis used a voxel-by-voxel procedure to search for regions in which signal intensity changes matched the changes in AP after NTP and PE administration. VOI analysis used anatomically defined regions to explore changes in signal intensity irrespective of the pattern of change. Multiple trials of the same drug in each animal (2-3 trials) were averaged so that only one image set and one set of physiology traces per animal were used for analysis.
With the use of SPM99, the processed image sets for each animal were analyzed with fixed-effects procedures. Patterns of signal intensity change were determined by using a model of mean AP, which was convolved with a standard hemodynamic response function. The resulting statistical maps were constructed with a threshold (P < 0.001, corrected for multiple comparisons) and overlaid onto the mean of all spatially normalized T2 image volumes. The statistical maps were overlaid onto a mean functional image volume to verify the location of significant voxels. For selected clusters of significant voxels, the mean (±SE) signal intensity at each time point was plotted by group. The trend plots were drawn for sites showing significant clusters of signal change, which are traditionally associated with aspects of cardiovascular control or have recently been implicated in such control. Other trend plots were drawn from regions of significant alterations not usually suggested as mediating baroreflex action but were of interest because they showed potential to affect cardiovascular processes, as indicated by recent literature (14).
VOIs, including regions of known cardiorespiratory function, were selected from the functional images by using anatomic landmarks on an animal-by-animal basis. These VOIs included regions in the medulla [NTS, caudal ventrolateral medulla (CVLM), RVLM, caudal midline medulla, inferior olivary nucleus (IO)], cerebellum (vermis, fastigial, and dentate/interpositis nuclei), pons (dorsolateral pons), midbrain [ventrolateral periaqueductal gray matter (vlPAG)], diencephalon [amygdala, dorsal and ventral hypothalamus, and supraoptic nucleus (SON)], and cerebral cortex (insula). With the use of custom-designed software, the average voxel intensity of the VOI in each volume was calculated, resulting in a time trend for each animal. For both VOI and cluster time trends, signal intensity changes were evaluated relative to baseline at each time point by using repeated-measures ANOVA. Significance threshold was set at P < 0.01.
In three animals, a barodenervation was performed. Briefly, the animals were removed from the scanner (after multiple recording periods), and the carotid sinus was exposed bilaterally. The carotid sinus, aortic depressor, vagus, and glossopharyngeal nerves were isolated and cut. A 10% phenol solution was applied to the carotid sinus to further ensure barodenervation. Animals were placed into the scanner, and the PE, NTP, and saline challenges were repeated (2-3 trials). The image sets from these challenges were processed as described above.
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RESULTS |
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Mean baseline values of AP and HR in all cats before each challenge were 101 ± 5 mmHg and 195 ± 11 beats/min, respectively. Intravenous injection of saline evoked no change in AP or HR (Fig. 1).
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NTP administration evoked profound, short-latency onset (within 2-5 s) falls in AP (mean = -45 ± 3%; nadir = 45 s), combined with increases in HR (mean = 3 ± 1%). Intravenous PE delivery evoked substantial short-latency increases in AP (mean = 24 ± 4%; peak = 20 s) and reflexive decreases in HR (mean = -3 ± 1%).
BOLD signal intensity changes
NTP. After NTP administration, fixed-effects analysis revealed significant decreases in signal intensity within the ventrolateral and dorsomedial medulla, both medial and lateral deep cerebellar nuclei (after an initial, transient rise), pons, and midbrain tegmentum. Increases in signal intensity occurred in a discrete area of the ventral hypothalamus and in the right frontal/parietal cortex (Fig. 2). VOI analysis revealed gradual decreases in signal intensity (range 0.5-1%) in the caudal and intermediate levels of the NTS, the RVLM, IO, dentate/interpositus deep cerebellar nuclei, cerebellar vermis, dorsolateral pons, and the right insular cortex (Fig. 3). The declines in signal intensity in the cerebellar vermis, right insula, and dorsolateral pons were steeper and reached significance earlier. A decline in signal also occurred in the region of the CVLM; however, this decline was preceded by a transient increase in signal at the onset of the challenge. A late onset, transient decline in signal intensity occurred in the fastigial nucleus of the cerebellum. Significant increases in signal intensity (range 0.5-1%) occurred in the region of the ventral hypothalamus, SON, and amygdala.
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PE. After PE administration, fixed-effects analysis revealed significant increases in signal intensity within the dorsal and ventral medulla, thalamus, and right insular cortex. Declines in signal intensity were found in the left lateral cerebellar cortex and the region of the hippocampus (Fig. 4). VOI analysis revealed signal increases in the caudal NTS, RVLM, dorsolateral pons, right insula, and SON (Fig. 3). A transient decrease occurred in the CVLM, and a late-onset decrease occurred in the ventral hypothalamus.
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No significant change in signal intensity occurred after either NTP or PE administration in the regions of the caudal midline medulla, dorsal hypothalamus, vlPAG, or left insula.
Temporal Patterns
Time courses of significant mean signal intensity changes, grouped by early, intermediate, and late onset responses, are shown in Fig. 5. In general, after NTP administration, short-onset (within 20 s, before any increase in HR) changes in signal intensity occurred in rostral brain structures as well as the cerebellar vermis. Shortly after the onset of these signal changes, and at approximately the nadir of the AP response, signal intensity began to decline in medullary regions. The onset of these declines also matched the onset of the HR increase. Late decreases in signal intensity emerged in deep cerebellar nuclei.
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As with NTP, PE administration resulted in signal intensity changes in medullary regions that coincided with HR decreases. Late responses occurred in the pons and rostral brain structures. In contrast to NTP-evoked signal intensity changes, PE did not evoke any signal change in deep cerebellar nuclei.
Lateralization
The recruitment of structures showed a propensity for lateralization in multiple areas to the pressor or depressor challenges. In addition to the insula and cerebellar cortex, these areas included the left dorsal and right ventral medulla, the right parietal cortex, right thalamus, and an area near and including the left hippocampus. The lateralization emerged as a greater number of significant voxels on one side, a higher significance, or as an unilateral recruitment.
Barodenervation
Physiology. Even though PE administration resulted in similar AP increases in the barointact and barodenervated preparations (mean intact = 30 ± 5%; mean barodenervated = 39 ± 16%), the reflexive fall in HR was completely blocked by barodenervation, and a small increase in HR occurred (mean fall intact = -3 ± 2%; mean increase barodenervated = 1 ± 1%). NTP administration evoked similar declines in AP (mean before and after barodenervation = -49 ± 3%) and only slightly smaller increases in HR after barodenervation (mean intact = 4 ± 2%; mean barodenervated = 3 ± 2%) (Fig. 6A).
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BOLD signal intensity changes. Despite the similar AP changes before and after barodenervation, changes in signal intensities within the NTS, CVLM, and RVLM differed strikingly (Fig. 6B). In intact animals, AP decreases evoked signal intensity declines within the NTS, RVLM, and CVLM, with a brief increase in CVLM signal at the challenge onset. After barodenervation, the same fall in AP evoked increases in signal intensity in the NTS and CVLM and no change in the RVLM. After PE administration, AP increases evoked increased signal intensity in the NTS, RVLM, and CVLM (after a brief fall at the onset) before baroreceptor denervation. After barodenervation, these changes were reduced, with no significant change in signal intensity in the NTS and only brief, transient changes in the CVLM and RVLM. In addition, signal intensity changes in rostral brain structures, such as the ventral hypothalamus and SON, showed similar changes in signal intensity before and after barodenervation (data not shown).
Saline
Intravenous saline delivery resulted in no significant change in signal intensity in most brain sites (Fig. 7). In the fastigial nucleus, dorsolateral pons, and left insula, small increases in signal intensity emerged.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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Medullary Structures
Baroreceptors located in the aortic arch and carotid sinus whose afferents terminate in the NTS increase firing rates in response to increased AP. The increase in NTS activity, in turn, increases CVLM GABAergic activity, which further inhibits the tonically active pressor region of the RVLM (47). Because BOLD signal intensity apparently reflects synaptic activity, as opposed to neuronal firing (1, 30), we expected that NTS signal intensity (inferred synaptic activity) would decrease as the baroreceptors were unloaded (depressor responses) and increase during pressor responses. Furthermore, signal intensity within the RVLM would decrease during depressor challenges (baroreceptor unloading results in reduced synaptic inhibition from the CVLM and thus increased sympathetic outflow from the RVLM). The expected changes in synaptic activity within these regions are supported by both c-fos and optical imaging studies (16, 41, 42), although the optical data are available only from surface recordings. Pharmacological AP elevation or lowering decreases or increases neuronal discharge, respectively, on the RVLM surface both in anesthetized and initially in sleep-waking states; hypovolemia significantly increases activity over large areas of the RVLM surface (15, 18). From the perspective that fMRI signal intensities reflect synaptic activity and not neuronal firing, the signal changes found in the RVLM were expected from known microelectrode and optical imaging findings.
The CVLM showed an early transient increase during AP falls and a transient decrease during AP rises. Several c-fos studies show that, although many RVLM-projecting CVLM neurons are activated by AP increases or decreases (39), not all activated CVLM neurons project to the RVLM, and a significant proportion of these neurons provide a major source of input onto vasopressin-secreting neurons in the supraoptic and paraventricular nuclei (6) and are inhibited by increases and excited by decreases in AP (25). Thus the initial increase in CVLM signal found during hypotension likely represents the summation of decreased synaptic drive onto GABAergic RVLM-projecting neurons and increased drive onto paraventricular/supraoptic-projecting neurons, and vice versa in pressor cases. This hypothesis is supported by the findings that signal intensity in the hypothalamus increased during hypotensive challenges and decreased during hypertensive challenges. Furthermore, during hypotensive challenges after barodenervation, CVLM signal intensity increased and remained increased during the challenge period. This signal intensity increase likely reflects increased synaptic input to those hypothalamic projecting neurons, because both the signal intensity response (data not shown) and c-fos expression (40) in the hypothalamus are unaffected by barodenervation. The initial transient response in the CVLM before AP reached a nadir likely reflects input onto regions that trigger hormonal releases in response to AP changes (hypothalamus). As HR begins to decline, signal intensity in the CVLM, NTS, and RVLM also decline. These responses may represent neural activity changes in the NTS-CVLM-RVLM network to directly influence sympathetic output.
Cerebellum and Cerebellar-Related Structures
Hypotensive challenges elicited large signal intensity decreases in all deep cerebellar nuclei, the cerebellar vermis, and the inferior olivary nucleus. The responses emphasize a role for cerebellar areas in cardiovascular regulation and further call attention to a potential role for those structures in compensation for large AP fluctuations, particularly hypotension. The pressor challenges did not alter signals in deep cerebellar sites (only the lateral cerebellar cortex), suggesting specificity of the cerebellar response to the pharmacologically induced blood pressure fall; cold pressor, Valsalva, and other respiratory pressor challenges induce deep cerebellar nuclei activity changes in humans (14, 17).
Studies demonstrating an autonomic role for the cerebellum date to the 1940s (33). Electrical and chemical stimulations of the fastigial nucleus modifies AP, vasopressin release (7), and baroreceptor reflex sensitivity (22), and fastigial nucleus lesions prevent adequate compensatory efforts during hemorrhagic shock, resulting in a fatal outcome (31). In this study, signal changes in the IO, the principal afferent supply to the fastigial nucleus, paralleled those of the fastigial nucleus during AP decreases, with a phase lead (48 s). The IO raises AP on chemical stimulation (49), and c-fos expression increases after hypovolemia (8). The IO may modify fastigial nucleus activity to dampen extreme swings in AP. Similarly, the dentate and interpositus nuclei showed declines in signal intensity during the hypotensive challenges and may contribute to such a dampening role. Unlike the deep cerebellar nuclei, the cerebellar vermis responded early (and profoundly) to the challenge, presumably to initiate appropriate reflexive respiratory reactions while deeper nuclei are recruited when more extreme hypotensive levels are reached. Preferential responses of deep nuclei to extreme AP levels, rather than to momentary, smaller changes, have been reported by others (31).
Pontine/Midbrain Sites
The parabrachial region showed decreased signal intensity during AP falls and increased intensity during AP elevations, patterns consistent with c-fos and electrophysiological studies (24, 40). The parabrachial nucleus receives projections from the central nucleus of the amygdala (21), the fastigial nucleus, and the NTS (37, 48). The timing of parabrachial signal intensity changes was similar to that of the NTS and may reflect NTS input or a baroreceptor relay role (13).
Despite reports that the vlPAG activation alters AP, HR, and baroreceptor sensitivity and expresses c-fos after changes in AP (23, 34), we found no change in signal intensity in this region during either depressor or pressor challenges. The absence of signal change may be a consequence of the inherent low spatial resolution of fMRI, making alterations in neural activity in small regions difficult to detect.
Amygdala, Hypothalamus, and Insula
The insular cortex exhibited lateralized changes in signal intensity; on the right side only, signals decreased during depressor challenges and increased during pressor challenges. The right insula is tonically active (3, 4), contains baroreceptor responsive neurons, and produces changes in AP and HR on activation (50, 51). Human syndromes, which exhibit increased basal sympathetic tone [e.g., heart failure (10), obstructive sleep apnea (19), and stroke (36)], show abnormalities in the right insula. The decrease in right insula signal intensity after NTP administration likely represents a release of insular inhibition of tonic sympathetic drive, resulting in increased sympathetic activity and a return of AP toward baseline.
Signal intensity within the amygdala increased significantly during falls in AP and showed no change during AP rises. Electrophysiology, chemical stimulation, cold blockade, and c-fos investigations demonstrate that the amygdala is involved in both reflex and behaviorally coupled cardiovascular control (5, 12). We found that the amygdala is preferentially involved in compensatory responses to AP falls rather than AP rises.
The hypothalamus and SON exhibited significant signal increases during induced hypotension and decreases during hypertensive challenges. The signal changes during AP decreases are consistent with findings of increased c-fos expression in vasopressin-secreting neurons in the hypothalamus and SON after NTP infusion (29). Unlike this previous report, however, fMRI revealed decreases in both regions during pressor challenges. The changes in BOLD signal in the SON and hypothalamus likely reflect their roles in regulating secretion of vasopressin and adrenocorticotropin from the pituitary gland.
Saline
The majority of regions did not exhibit changes in signal during saline administration. A few regions showed small, transient signal changes, which were likely elicited by volume loading.
Autoregulation and Perfusion
Severe alterations in AP have the potential to alter overall brain perfusion and thereby the BOLD signal. Such a global signal change might lead to erroneous interpretation of signals corresponding to neural activity. During AP challenges, we observed signal intensity changes in areas of the brain known to contribute to cardiovascular regulation, with the location of changes remarkably similar to the extent of c-fos activation to comparable challenges (40). Furthermore, changes in regions such as the insular cortex were lateralized. However, despite these findings, we removed the baroreceptors and repeated the AP challenges. The barodenervated animals showed changes in signal intensity in certain medullary cardiovascular regions that differed from those of the intact animal. Hence, the regional changes in signal intensity in intact animals resulted from specific actions of the drug-induced changes in AP on baroreceptors and not from global changes in cerebral blood flow.
Limitations
The scanning protocol was optimized to provide rapid temporal resolution while evaluating signal changes over as wide an area of the brain as possible. The necessity for high temporal resolution precluded examination of signals through the entire brain. Thus frontal areas, including the frontal cortex, known to be involved in AP regulation (27) were not examined. The spatial resolution is inherently limited in this imaging technique. Each voxel may contain functionally distinct neuronal populations whose activity may alter in opposing directions.
The data were collected while the animals were anesthetized with isoflurane; an anesthetized preparation was necessary to minimize movement and reduce unacceptable stresses, which would be imposed on a conscious animal. Previous studies have shown that volatile anesthetics such as isoflurane depress baroreflex control of HR (2, 28, 45). However, the depressive effects of isoflurane anesthesia on the basal levels of AP, HR, sympathetic nerve activity, and baroreflex sensitivity are less significant compared with other volatile anesthetics, such as sevoflurane or enflurane (43). The precise sites at which isoflurane alters baroreflex sensitivity are unknown, although it was recently reported that, in the rat, removal of all structures above the midbrain did not affect baroreceptor sensitivity during isoflurane anesthesia (28). Given this evidence, it is possible that signal changes elicited in neural sites caudal to the midbrain during baroreceptor stimulation may differ from those observed in an unanesthetized condition or under a different anesthetic agent.
In summary, blood pressure elevation or lowering elicits widespread participation of multiple brain areas that are often lateralized and respond with unique timing sequences. Recruitment of brain areas follows patterns expected from the perspective of early hormonal release, reflexive HR responses, and late compensation for extreme levels of blood pressure. The regional responses to blood pressure manipulation do not derive from global effects exerted by overall perfusion changes because barodenervation results in site-specific signal differences from intact animals in the presence of comparable blood pressure alterations. Responses in the right insula, an area frequently found damaged in human syndromes associated with high sympathetic tone, support a tonic sympathetic inhibitory role for this structure. Vermal cerebellar signal changes suggest participation in early reflexive responses, whereas deep cerebellar and inferior olive patterns indicate late compensatory roles.
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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ACKNOWLEDGMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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FOOTNOTES |
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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.
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