Journal of Applied Physiology Journal of Applied Physiology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

J Appl Physiol 97: 1897-1907, 2004. First published July 16, 2004; doi:10.1152/japplphysiol.00359.2004
8750-7587/04 $5.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow All Versions of this Article:
97/5/1897    most recent
00359.2004v1
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (10)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Macey, K. E.
Right arrow Articles by Harper, R. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Macey, K. E.
Right arrow Articles by Harper, R. M.

fMRI signal changes in response to forced expiratory loading in congenital central hypoventilation syndrome

K. E. Macey,1 P. M. Macey,1 M. A. Woo,3 R. K. Harper,1 J. R. Alger,2 T. G. Keens,4 and R. M. Harper1

1Departments of Neurobiology and 2Radiology, and 3School of Nursing, University of California, Los Angeles 90095; and 4Childrens Hospital, Los Angeles, California 90027

Submitted 5 April 2004 ; accepted in final form 2 July 2004


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Congenital central hypoventilation syndrome (CCHS) patients show impaired ventilatory responses to CO2 and hypoxia and reduced drive to breathe during sleep but retain appropriate breathing patterns in response to volition or increased exercise. Breath-by-breath influences on heart rate are also deficient. Using functional magnetic resonance imaging techniques, we examined responses over the brain to voluntary forced expiratory loading, a task that CCHS patients can perform but that results in impaired rapid heart rate variation patterns normally associated with the loading challenge. Increased signals emerged in control (n = 14) over CCHS (n = 13; ventilator dependent during sleep but not waking) subjects in the cingulate and right parietal cortex, cerebellar cortex and fastigial nucleus, and basal ganglia, whereas anterior cerebellar cortical sites and deep nuclei, dorsal midbrain, and dorsal pons showed increased signals in the patient group. The dorsal and ventral medulla showed delayed responses in CCHS patients. Primary motor and sensory areas bordering the central sulcus showed comparable responses in both groups. The delayed responses in medullary sensory and output regions and the aberrant reactions in cerebellar and pontine sensorimotor coordination areas suggest that rapid cardiorespiratory integration deficits in CCHS may stem from defects in these sites. Additional autonomic and perceptual motor deficits may derive from cingulate and parietal cortex aberrations.

Ondine's curse; cerebellum; insula; functional magnetic resonance imaging

PATIENTS WITH congenital central hypoventilation syndrome (CCHS) show impaired ventilatory responses to CO2 and O2 (7, 42, 46), a reduced drive to breathe during sleep (21), and impaired emotional responses to challenges that normally induce dyspnea (46, 53), with a resulting loss of drive to breathe from absence of affect. However, several aspects of breathing control remain relatively intact. Affected patients are able to breathe on command (51), increase respiratory efforts to meet metabolic needs when exercising (45, 52, 55), and maintain adequate ventilation to cyclic movement of the foot (19), even if the lower extremity movement is passively induced and occurs during sleep (20). CCHS patients retain at least some components of peripheral chemoreception (18) and arouse to hypercapnia from sleep (38), indicating that some aspects of chemosensitive afferent processes are operating, although integration with appropriate breathing output may be lacking. A substantial proportion of CCHS patients carry a heterozygous PHOX2B gene mutation (2); the gene governs autonomic nervous system development in mice, and alterations may modify interactions between autonomic and respiratory motor output.

The collective evidence suggests retention of voluntary breathing mechanisms and automatic respiratory synchronization processes associated with lower limb motion, long described in normal breathing control (11), as well as intact slower cardiovascular responses accompanying chemoreceptor processes (36). Deficiencies apparently remain in rapid integration of chemoreceptor input with breathing, rapid heart rate and breathing interactions, affective drive to breathe during waking, and automatic breathing during sleep. To investigate aberrant neural processes responsible for these patterns, we subjected CCHS and control children to forced expiratory loading and examined response patterns over the brain using functional magnetic resonance imaging (fMRI) techniques. We hypothesized that CCHS children would share common "voluntary" motor site activity with control subjects, but structures mediating rapid cardiovascular and breathing integration (breath-by-breath changes in heart rate) would differ in responses. Both control and CCHS children successfully accomplished the forced expiratory effort task, and both groups showed nearly comparable slower heart rate variability patterns accompanying the breathing efforts (26); however, more rapid heart rate variation was deficient in the affected children. Examination of differing neural response patterns through functional imaging should reveal mechanisms underlying these deficiencies.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Thirteen children with a diagnosis of CCHS (7 boys, 6 girls) and 14 controls (7 boys, 7 girls) participated. Thirteen pairs were age and gender matched; the remaining control subject was matched with one CCHS subject (age in yr: mean 10.9; range 8–15; standard deviation: controls 2.2, CCHS 2.3). Diagnosis was based on standard criteria (1). Patients were ventilated via tracheostomy only during sleep, but not during waking, and showed a clear reduction in ventilatory responses to hypercapnia. The syndrome is associated with a range of breathing deficiencies, including patients who are ventilator dependent 24 h a day, but subjects with such severe respiratory characteristics were not included in the study for practical reasons of ventilation during the challenges. Patients with Hirschsprung's disease were also excluded, as were patients with indications of cardiac disease or any indication of primary pulmonary or neuromuscular disease.

Subjects lay supine in an MRI scanner and breathed through a two-way nonrebreather valve. Tracheostomy openings were closed throughout the studies. Masking tape across the forehead and foam pads on either side of the head were used to minimize head movement. Measurements of airflow and the ECG were recorded simultaneously with the fMRI signal (26). Each subject underwent two scanning periods, the first consisting of a 150-s baseline and the second a 30-s baseline followed without pause by a 120-s challenge. The challenge consisted of voluntary expiratory efforts against a closed glottis. Subjects were instructed to "bear down" as if performing a bowel movement during the challenge. During the 120-s challenge, subjects generally performed five to nine inspiratory efforts of 1–2 s during otherwise continuous expiratory exertion.

Images were collected by use of a 1.5-Tesla scanner (General Electric Signa, Milwaukee, WI). For each 150-s scanning period, 25 volumes of 20 oblique image slices were collected by using a gradient echo echo-planar imaging (EPI) protocol [repetition time (TR) = 6 s, time to echo (TE) = 60 ms, flip angle = 90°, field of view (FOV) 30 x 30 cm, no interslice gap, and voxel size 2.3 x 2.3 x 5 mm]. The EPI protocol used the blood oxygen level-dependent (BOLD) intrinsic contrast to highlight changes in neural activity during the challenge. Conventional spin-echo T1-weighted images (TR = 500 ms, TE = 9 ms, FOV = 30 x 30 cm, no interslice gap, voxel size 1.2 x 1.2 x 5 mm) were collected at the same location and orientation to aid in anatomical identification.

The images were preprocessed by use of a statistical parametric mapping package, SPM (16), and custom software. Volumes were corrected for differences in the timing of slice acquisition, motion corrected, spatially normalized, and smoothed. Global changes were removed (35), and the images were subsequently analyzed for significant signal changes.

Two types of analyses were performed on the preprocessed images: 1) volume-of-interest (VOI) analysis using custom routines, and 2) cluster analysis using SPM. VOI analysis used a priori defined regions, manually outlined on a subject-by-subject basis to account for individual variation, within which the voxel intensities were averaged for each subject. Repeated-measures ANOVA (RMANOVA) was used to assess both differences from baseline for each group and response differences between the groups (29). The global BOLD signal, i.e., the average intensity across the entire brain volume at each time point, was analyzed in a similar manner before detrending. Cluster analysis was performed over the entire brain on a voxel-by-voxel basis, comparing the time course of each voxel to a parametric boxcar model [step function from baseline (off) to challenge (on)], convolved with a standard hemodynamic response function. Such a model was calculated for each subject, with resulting estimates of the contribution of the boxcar pattern at each voxel recorded. Clusters of voxels in which group differences between CCHS and control subjects approximately matched this boxcar pattern were identified by performing a two-sample t-test of the boxcar estimates at each voxel (described in the fMRI literature as a population or "random effects" analysis). Cluster analysis was used to provide an overview of areas in which response patterns differed between groups. Strict modeling to the boxcar pattern, however, has the potential to result in false negative indications of differences, because some patterns may occur early and transiently or others may emerge late in the challenge and be undetected by the procedure. For that reason, we used cluster analysis with less conservative statistical criteria (P < 0.1, false discovery rate correction for multiple comparisons) and applied RMANOVA to the time trends from the clusters, rejecting clusters with RMANOVA P ≥ 0.05. For selected clusters, the average time courses of all voxels within that cluster were extracted and plotted for the two groups.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Physiology.   Physiological characteristics of the breathing challenge have been described earlier (26). Briefly, during baseline, CCHS patients showed overall reduced heart rate variability, but slower variation (<0.1 Hz) was much better preserved than more rapid variation, i.e., breath-by-breath changes in heart rate. In response to the challenge, heart rates initially decreased in both control and CCHS patients; however, heart rates of the CCHS group increased after 30 s, a pattern not followed by the control group. The change in breath-by-breath heart rate variation in response to the challenge was significantly reduced in CCHS patients.

Global BOLD signal.   The global BOLD signal declined in both groups later in the challenge, but no group differences emerged (Fig. 1); detrending removed all global effects (35).



View larger version (27K):
[in this window]
[in a new window]
  		Fig. 1. Mean global signal (average intensity per volume across time) for congenital central hypoventilation syndrome (CCHS) and control groups (±SE) during baseline and challenge series. Time periods of significant decrease [repeated-measures ANOVA (RMANOVA) P < 0.05] relative to baseline occurred later in the challenge, as indicated above and below the plots (key at bottom). No time periods were significantly different between groups.

 
VOI analysis.   Areas selected for VOI analysis are shown in Fig. 2, and time trends from those areas are shown in Fig. 3. Table 1 summarizes the results. Significantly different patterns between groups were often lateralized (e.g., dentate and lentiform nuclei, amygdala) or developed early (dorsal and ventral medulla) or transiently (left insula, vermis, right lentiform nucleus, dorsal pons). In the dorsal and ventral medulla, the control response was an early transient decline in signal; however, signals declined only after a 20-s delay in CCHS patients. Responses in the dorsal pons were transiently higher in CCHS but lower in controls. In the hippocampus, signals from control subjects declined, but no change emerged in CCHS. The right dentate nucleus showed an early transient decline in control subjects but a significant and sustained elevation in CCHS patients. Areas of sustained differences in responses emerged in the head of the caudate (rise in controls, decline in CCHS), ventral pons, and dorsal and ventral midbrain (rise in CCHS, decline in controls).



View larger version (47K):
[in this window]
[in a new window]
  		Fig. 2. Examples of voxel of interest (VOI) areas, in white overlaid onto individual T1 images, from which time trends were calculated.

 


View larger version (36K):
[in this window]
[in a new window]
  		Fig. 3. Signal time trends of VOI from control and CCHS subjects in selected areas during baseline periods and during the short baseline and challenge. Time points of group difference are indicated by * above the plots (RMANOVA, P < 0.05); time points of significant increase or decrease within each group are indicated by bars above or below plots (key at bottom of figure).

 

View this table:
[in this window]
[in a new window]
  		Table 1. Summary of VOI analysis

 
Cluster analysis.   Cortical areas where signals increased or decreased throughout the challenge in both groups are shown in Fig. 4 and tabulated in Table 2. Regions of signal increase emerged bilaterally in primary cortical regions related to sensory and motor control in the frontal and parietal cortex bordering the central fissure and included supplementary sensory parietal areas. A smaller number of regions exhibited signal decreases in both groups, including areas deep within the posterior and superior surface of the right temporal lobe, and hippocampus, insula, and head of caudate. The frontal and parietal cortical representation of common increase was bilateral; the declining temporal signals emerged on the right side.



View larger version (71K):
[in this window]
[in a new window]
  		Fig. 4. Three-dimensional rendered brain images showing cortical areas of common responses in both control and CCHS groups, with regions of signal increase in green and signal decrease in blue. Degree of color saturation indicates proximity to the cortical surface, with more saturated values closer to the surface; the light blue shading on the right temporal cortex represents common signal decreases deep to the surface.

 

View this table:
[in this window]
[in a new window]
  		Table 2. Clusters of voxels with a significant signal increase or decrease in both groups

 
The areas in which signals differed significantly in controls from CCHS patients are shown in Figs. 5–7 and Table 3. Areas in which control values were greater than in CCHS patients included the posterior, mid, and anterior cingulate cortex, preferentially on the right side and extending to the frontal cortex, anterior dorsal thalamus and basal ganglia, right insula and superior temporal cortex, fastigial nucleus, and dorsal cerebellar cortex. CCHS patients showed significantly greater signal changes over control subjects in the dorsal pons and dorsal and medial midbrain, anterior cerebellar cortex, and isolated portions of the frontal, temporal, and parietal cortices and right hippocampus (Fig. 5). Although primary motor and sensory region responses were largely similar in the two groups, areas within the right parietal cortex and posterior temporal cortex showed increased signals in control subjects over CCHS patients (Fig. 6), principally on the surface.



View larger version (44K):
[in this window]
[in a new window]
  		Fig. 5. Coronal (C), sagittal (S), and axial (A) views of significant signal differences between groups, using a boxcar model (P < 0.1, corrected, RMANOVA P < 0.05). Clusters are pseudo-colored according to their significance level (t-statistic, key in figure) and overlaid onto average of all 27 subjects' anatomical images. Control values > CCHS, warm (orange-yellow) colors; areas within the fastigial nucleus (coronal, sagittal and axial 1), cingulate cortex, extending to frontal cortex, (sagittal 1, 3; axial 2, 3; coronal 3), right superior temporal cortex (axial 2, 3), right insula (axial 4, sagittal 3), anterior thalamus and basal ganglia (sagittal 2; coronal 3, 4; axial, 4). CCHS > controls, cool (blue-green) colors: dorsal pons and dorsal and medial midbrain, cerebellar cortex, basal ganglia and isolated portions of the frontal and parietal cortex (sagittal 2, 5; axial 2, 3, 4).

 


View larger version (38K):
[in this window]
[in a new window]
  		Fig. 7. Time trends of selected clusters of group difference in the superior temporal cortex (A), anterior cingulate (B), fastigial nucleus (C), and anterior cerebellar cortex (D). Display conventions are the same as for Fig. 5.

 

View this table:
[in this window]
[in a new window]
  		Table 3. Clusters of voxels with a significant difference in response between groups (Figure 1)

 


View larger version (72K):
[in this window]
[in a new window]
  		Fig. 6. Three-dimensional rendered brain images showing cortical areas where control responses were > CCHS (red) and CCHS response values were > controls (blue). Degree of color saturation indicates proximity to the cortical surface, with more saturated values closer to the surface.

 
Time trends for selected clusters overlapping regions of the superior temporal and anterior cingulate cortices, fastigial nucleus, and anterior cerebellum are shown in Fig. 7. The trends illustrate the absence of a response (anterior cerebellum, anterior cingulate cortex) in CCHS patients or a decline in response when control subjects increase signal (fastigial nucleus, superior temporal cortex).


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Overview.   Several brain sites in CCHS patients showed functional deficits, even when subjects were confronted with a voluntary breathing challenge that they were able to execute, albeit with certain differences in cardiovascular patterning. Voluntary motor and sensory areas in the primary cortex bordering the central sulcus showed only minor differences between groups, suggesting that functions within those areas are essentially intact. However, dorsal pontine and midbrain areas as well as sites within the anterior cerebellar cortex and the hippocampus were recruited more in CCHS than controls, indicating possible compensatory actions in those areas for the significantly lower signals in multiple other sites. Of interest among the altered responses were delays in the dorsal and ventral medulla. Among those sites showing diminished responses in CCHS, the cingulate cortex, head of caudate, lenticular nuclei, insula, superior temporal cortex, fastigial nucleus, and lateral cerebellar cortex were prominent. The response patterns differed only late in the response in the cerebellar fastigial nucleus, unlike other sites.

Interpretation and limitations.   The BOLD signal is an indirect measure of neural synaptic activity, with several potential confounds and limitations on following rapid responses (31). These limitations pose restrictions on interpretation of results.

The removal of all patterns matching global effects means that the findings do not include signal trends matching those global patterns. The consequence of correction for global effects is the potential for false negative rather than erroneous detection, i.e., the lack of detection of BOLD responses corresponding to neural activations when such activation precisely follows the global trend.

The CCHS group was ventilator dependent during sleep but not waking. The syndrome is characterized by variation in symptomatology, and it is possible that CCHS patients who are ventilator dependent 24 h/day may differ in their neural responses. Patients who are entirely dependent on mechanical ventilation may lack development of voluntary neural structures necessary for the loading challenge, and those deficits may be especially expressed in more rostral brain regions found here.

Voluntary motor regions.   Responses in voluntary primary motor cortex were similar in both groups, a finding consistent with the apparent capability of CCHS patients to breathe on command. The activated regions within sensory and motor cortices included areas more ventrally sited than those previously reported for a hyperpnea task (40), likely because the expiratory loading task requires more extensive recruitment of upper airway musculature and afferent processes. Striatal areas, implicated by others in voluntary breathing (15), also participated.

The caudate (head) and lenticular nuclei showed diminished responses in CCHS patients. In addition, other nonvoluntary motor areas, e.g., the dorsal pons, dorsal midbrain, anterior cerebellar cortex, and cerebellar dentate nuclei, showed increased signal in CCHS patients. The latter areas, in particular the cerebellar dentate nuclei, perform sensorimotor coordination roles below the level of conscious intent. Deficiencies appeared in motor areas but primarily in basal ganglia and cerebellar and pontine regions associated with automatic motor corrective action.

Medulla, pons, and midbrain.   Both the dorsal and ventral medulla showed delayed response onsets in CCHS patients, suggesting an inability of the dorsal medulla to activate rapidly to afferent information mediated by the nucleus of the solitary tract (NTS, sited within the dorsal medulla), although other functions are controlled within this dorsal region. Such a delay may underlie deficits in rapid modulation of cardiorespiratory interactions in CCHS patients. The dorsal pons showed a rapid-onset elevated response in CCHS subjects, unlike controls. A case study previously suggested elevated activity in the dorsal pontine parabrachial complex of CCHS patients (50). Because increased signal represents enhanced synaptic activity (31), pontine respiratory phase-switching structures may be activated more in this task in CCHS than in control subjects and may be compensating for impaired dorsal and ventral medullary action. The medullary abnormalities may result from decreased density of neurons and myelinated nerve fibers (30, 43) or may reflect processes altered by aberrant PHOX2B gene expression, which shows a high incidence of mutation in CCHS patients (2) and appears to play a major role in visceral sensory structures, including the NTS (9). The potential for PHOX2B mutations to affect breathing control by alterations in NTS function would appear to be of special significance in this study, because substantial aberrations in signal were found from this region in CCHS patients.

Cerebellum.   The anterior lateral cerebellar cortex and dentate nuclei increased signal in CCHS patients over controls and likely act in unison with the dorsal pons and midbrain to provide compensatory motor efforts to overcome integrative sensorimotor control deficits in CCHS patients. The enhanced cerebellar action may interact with the basal ganglia, causing the relative decline in CCHS signal in those structures as well.

The late-developing cerebellar fastigial nucleus responses may relate to cardiovascular aspects of the task; breathing against a load leads to rapid elevation of blood pressure and concurrent heart rate slowing, with a subsequent fall in blood pressure and increase in heart rate after release (13). The CCHS patients initially slowed heart rate, but that response reversed later in the challenge, unlike controls. The fastigial nucleus plays essential roles in mediating compensatory responses to blood pressure challenges (6, 32) and regulation of phrenic output (60, 61). CCHS is associated with lower resting blood pressure during waking but little or no "dipping" during sleep (56), suggesting a weakened or missing aspect of autonomic regulation.

Vermal areas increased responses in CCHS over control subjects; this region is activated to extreme expiratory loading (47). The increased signal in the vermis observed in the present study likely represents compensatory motoric efforts required to complete the task.

Hippocampus.   The hippocampus increases activity on initiation of inspiration after a sigh in animals (48). The structure may contribute to enhanced drive to initiate respiratory efforts in these CCHS patients to overcome delays in deficient fast-responding physiological actions.

Parietal cortex.   Control subjects showed large signal increases over CCHS patients in the right parietal and posterior temporal cortices, regions associated with integration of spatial sensorimotor relationships. Although higher order perceptual processes are not generally believed to be significantly disturbed in CCHS patients, there is evidence of below-average motor and eye-hand coordination performance (54). Integration of internal movement cues for spatial navigation of directed motor behavior has been proposed as a posterior cingulate cortex function (25), and the parietal cortex would provide aspects of internal spatial sensory cues for such movement. The deficient responses in both parietal and cingulate cortex may contribute to inadequate motor coordination.

Cingulate cortex.   The cingulate cortex differences ranged over the entire structure and extended to the medial frontal cortex. Anterior cingulate regions have been implicated in roles for behaviors related to intentions to move (24), responses based on reward (4, 28, 44), or general aspects of conflict between potential actions (10, 12, 39). A significant role for participation in aspects of sympathetic outflow rather than cognitive conflict resolution has also been suggested for the dorsal anterior cingulate (8). The anterior cingulate contains neurons that discharge with both respiratory and cardiac patterning (17) and responds to a range of blood pressure manipulations (23, 27), including elicitation of large rises in blood pressure and heart rate on stimulation (3). Stimulation of the anterior portion also elicits upper airway action in respiratory-related behaviors, such as vocalization (58). The region shows recruitment to respiratory tasks that involve dyspnea (47) and has extensive projections to insular cortex, hippocampal, and hypothalamic areas (5, 57). The anterior cingulate has been implicated in structural and response deficits in other breathing disorders, especially obstructive sleep apnea and heart failure, the latter syndrome associated with Cheyne-Stokes and obstructed breathing (22, 23, 34).

The expiratory loading task may have elicited dyspnea, and CCHS patients show an absence of affect to the perception of breathlessness (46, 53). However, the onset of the differences in cingulate responses emerged early, whereas the perception of dyspnea would be expected to appear late in the challenge, and nearly the entire extent of the cingulate appeared to be involved; only a portion of the cingulate cortex has been implicated in dyspnea reactions (14, 47). The challenge would elevate blood pressure and thus recruit sympathetic activation earlier noted to be associated with dorsal anterior cingulate cortex action. More caudal portions of the cingulate cortex project differently from anterior portions, preferentially targeting primary motor cortex, rather than premotor areas receiving anterior cingulate fibers (59). It may be the case that multiple physiological characteristics, including regulation of sympathetic outflow, intention to move, and resolution of the decision to move, all show deficiencies in CCHS patients.

Because the cingulate cortex is affected in multiple respiratory disorders, the structure may play a general role in motor patterning for breathing that is not normally considered in respiratory regulation. Expiratory loading includes aspects of intent of action, emotional responses to restriction of airflow, associated autonomic responses, and choice of appropriate respiratory muscle action. Autonomic responses are impaired in CCHS patients to the expiratory loading as well as other breathing challenges (26, 36), but the capability to voluntarily intend to breathe and consciously perform that action is apparently intact. The principal defect in the cingulate may lie with regulation of autonomic characteristics of the response, with secondary defects in aspects of intentional movement control. The cingulate cortex likely acts in concert with the insular cortex to which it projects, a region associated with regulation of autonomic outflow (41, 62).

Hypoxic vs. developmental injury.   CCHS patients are often exposed to hypoxic episodes of varying severity, as a consequence of failed ventilation during sleep or other circumstances, and these episodes can damage neural tissue. The areas classically associated with hypoxic damage include Purkinje cells in the cerebellar cortex, hippocampal structures, especially the CA1 area, and certain cortical areas (37, 49). Several of these structures showed different fMRI signal patterns to the challenge in CCHS patients. It was not possible in the present studies to distinguish between abnormalities caused by preexisting neural maldevelopment and neural tissue damage resulting from hypoxia. Recently developed spectroscopic and other magnetic resonance procedures may, however, assist that differentiation in the future.

Global signal changes.   Any challenge that induces the pronounced cardiovascular changes found here has the potential to modify global perfusion of the brain; those global signals could interact with regional signal changes. There was a mild decrease in the global signal in both groups. There was no significant group difference, but, nevertheless, to control for such a potential confound, we removed global effects by removing, on a voxel-by-voxel basis, any pattern that followed the global signal (35). The risk of such a detrending technique is an increase in false negatives, i.e., not detecting responses that follow the pattern of the global signal.

An earlier examination of global BOLD signal patterns showed that the extent of vascular reactivity was diminished to hypercapnic, hypoxic, and hyperoxic stimuli in CCHS patients and that rapidly acting global reactions were deficient. Impaired reactivity to autoregulatory processes could potentially include the localized BOLD responses and be reflected in the regional response differences we found. However, the responses in CCHS patients were not uniform in magnitude or direction relative to controls; CCHS patients showed some regional signal responses that were larger than controls and in other areas the same or smaller than those of the nonpatient group. Moreover, very rapid responses emerged in CCHS patients within selected regions, arguing against the possibility of a uniform muted regional responsiveness.

In summary, the purpose of the study was to determine neural regions responsible for abnormal short-term, cardiorespiratory integrative deficiencies in CCHS to expiratory loading whereas adequate longer latency and voluntary respiratory responses are retained. The primary voluntary motor cortex responses in CCHS were essentially intact, but response delays occurred in the dorsal and ventral medulla, and different patterns emerged in the cerebellum and dorsal pons. More rapid sensorimotor integration may have been affected by altered medullary, cerebellar, and pontine response timing. Autonomic deficits likely developed from deficits in the fastigial nucleus, localized portions of the cingulate cortex, and insula. Aberrant responses in parietal and other portions of the cingulate cortex suggest broader problems in spatial-motor patterning.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
ACKNOWLEDGMENTS
 REFERENCES
 
This research was supported by National Institute of Child Health & Human Development Grant HD-22695.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
REFERENCES
 
We thank Dr. Munawar Saeed, Amy Kim, and Claire Valderama for technical support and Dr. Rajesh Kumar for editorial assistance.


   FOOTNOTES
 

Address for reprint requests and other correspondence: R. M. Harper, Dept. of Neurobiology, Univ. of California, Los Angeles, CA 90095-1763 (E-mail: rharper{at}ucla.edu).

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
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 

  1. American Thoracic Society. Idiopathic congenital central hypoventilation syndrome: diagnosis and management. Am J Respir Crit Care Med 160: 368–373, 1999.[Free Full Text]
  2. Amiel J, Laudier B, Attie-Bitach T, Trang H, de Pontual L, Gener B, Trochet D, Etchevers H, Ray P, Simonneau M, Vekemans M, Munnich A, Gaultier C, and Lyonnet S. Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome. Nat Genet 33: 459–461, 2003.[CrossRef][Web of Science][Medline]
  3. Burns SM and Wyss JM. The involvement of the anterior cingulate cortex in blood pressure control. Brain Res 340: 71–77, 1985.[CrossRef][Web of Science][Medline]
  4. Bussey TJ, Everitt BJ, and Robbins TW. Dissociable effects of cingulate and medial frontal cortex lesions on stimulus-reward learning using a novel Pavlovian autoshaping procedure for the rat: implications for the neurobiology of emotion. Behav Neurosci 111: 908–919, 1997.[CrossRef][Web of Science][Medline]
  5. Caceres A and Taleisnik S. Pathways by which stimuli originating in the cingulate cortex inhibiting LH secretion reach the hypothalamus. Neuroendocrinology 32: 317–324, 1981.[Web of Science][Medline]
  6. Chen CH, Williams JL, and Lutherer LO. Cerebellar lesions alter autonomic responses to transient isovolaemic changes in arterial pressure in anaesthetized cats. Clin Auton Res 4: 263–272, 1994.[CrossRef][Medline]
  7. Commare MC, Francois B, Estournet B, and Barois A. Ondine's curse: a discussion of five cases. Neuropediatrics 24: 313–318, 1993.[Web of Science][Medline]
  8. Critchley HD, Mathias CJ, Josephs O, O'Doherty J, Zanini S, Dewar BK, Cipolotti L, Shallice T, and Dolan RJ. Human cingulate cortex and autonomic control: converging neuroimaging and clinical evidence. Brain 126: 2139–2152, 2003.[Abstract/Free Full Text]
  9. Dauger S, Pattyn A, Lofaso F, Gaultier C, Goridis C, Gallego J, and Brunet JF. PHOX2B controls the development of peripheral chemoreceptors and afferent visceral pathways. Development 130: 6635–6642, 2003.[Abstract/Free Full Text]
  10. Dehaene S, Artiges E, Naccache L, Martelli C, Viard A, Schurhoff F, Recasens C, Martinot MLP, Leboyer M, and Martinot JL. Conscious and subliminal conflicts in normal subjects and patients with schizophrenia: the role of the anterior cingulate. Proc Natl Acad Sci USA 100: 13722–13727, 2003.[Abstract/Free Full Text]
  11. Dejours P. [The regulation of ventilation during muscular exercise in man]. J Physiol (Paris) 51: 929–935, 1959.[Medline]
  12. Durston S, Davidson MC, Thomas KM, Worden MS, Tottenham N, Martinez A, Watts R, Ulug AM, and Casey BJ. Parametric manipulation of conflict and response competition using rapid mixed-trial event-related fMRI. Neuroimage 20: 2135–2141, 2003.[CrossRef][Web of Science][Medline]
  13. Eckberg DL. Parasympathetic cardiovascular control in human disease: a critical review of methods and results. Am J Physiol Heart Circ Physiol 239: H581–H593, 1980.[Abstract/Free Full Text]
  14. Evans KC, Banzett RB, Adams L, McKay L, Frackowiak RSJ, and Corfield DR. BOLD fMRI identifies limbic, paralimbic, and cerebellar activation during air hunger. J Neurophysiol 88: 1500–1511, 2002.[Abstract/Free Full Text]
  15. Evans KC, Shea SA, and Saykin AJ. Functional MRI localisation of central nervous system regions associated with volitional inspiration in humans. J Physiol 520: 383–392, 1999.[Abstract/Free Full Text]
  16. Friston KJ, Holmes AP, Worsley K, Poline JB, Frith CD, and Frackowiak RS. Statistic parametric maps in functional imaging: a general linear approach. Hum Brain Mapp 2: 189–210, 1995.[Medline]
  17. Frysinger RC and Harper RM. Cardiac and respiratory relationships with neural discharge in the anterior cingulate cortex during sleep-walking states. Exp Neurol 94: 247–263, 1986.[CrossRef][Web of Science][Medline]
  18. Gozal D, Marcus CL, Shoseyov D, and Keens TG. Peripheral chemoreceptor function in children with the congenital central hypoventilation syndrome. J Appl Physiol 74: 379–387, 1993.[Abstract/Free Full Text]
  19. Gozal D, Marcus CL, Ward SL, and Keens TG. Ventilatory responses to passive leg motion in children with congenital central hypoventilation syndrome. Am J Respir Crit Care Med 153: 761–768, 1996.[Abstract]
  20. Gozal D and Simakajornboon N. Passive motion of the extremities modifies alveolar ventilation during sleep in patients with congenital central hypoventilation syndrome. Am J Respir Crit Care Med 162: 1747–1751, 2000.[Abstract/Free Full Text]
  21. Haddad GG, Mazza NM, Defendini R, Blanc WA, Driscoll JM, Epstein MA, Epstein RA, and Mellins RB. Congenital failure of automatic control of ventilation, gastrointestinal motility and heart rate. Medicine (Baltimore) 57: 517–526, 1978.[Medline]
  22. Harper RM, Macey PM, Henderson LA, Woo MA, Macey KE, Frysinger RC, Alger JR, Nguyen KP, and Yan-Go FL. fMRI responses to cold pressor challenges in control and obstructive sleep apnea subjects. J Appl Physiol 94: 1583–1595, 2003.[Abstract/Free Full Text]
  23. Henderson LA, Woo MA, Macey PM, Macey KE, Frysinger RC, Alger JR, Yan-Go F, and Harper RM. Neural responses during Valsalva maneuvers in obstructive sleep apnea syndrome. J Appl Physiol 94: 1063–1074, 2003.[Abstract/Free Full Text]
  24. Isomura Y, Ito Y, Akazawa T, Nambu A, and Takada M. Neural coding of "attention for action" and "response selection" in primate anterior cingulate cortex. J Neurosci 23: 8002–8012, 2003.[Abstract/Free Full Text]
  25. Katayama K, Takahashi N, Ogawara K, and Hattori T. Pure topographical disorientation due to right posterior cingulate lesion. Cortex 35: 279–282, 1999.[Web of Science][Medline]
  26. Kim AH, Macey PM, Woo MA, Yu PL, Keens TG, Gozal D, and Harper RM. Cardiac responses to pressor challenges in congenital central hypoventilation syndrome. Somnologie 6: 109–115, 2002.[CrossRef]
  27. King AB, Menon RS, Hachinski V, and Cechetto DF. Human forebrain activation by visceral stimuli. J Comp Neurol 413: 572–582, 1999.[CrossRef][Web of Science][Medline]
  28. Kirsch P, Schienle A, Stark R, Sammer G, Blecker C, Walter B, Ott U, Burkart J, and Vaitl D. Anticipation of reward in a nonaversive differential conditioning paradigm and the brain reward system: an event-related fMRI study. Neuroimage 20: 1086–1095, 2003.[CrossRef][Web of Science][Medline]
  29. Littell RC, Milliken GA, Stroup WW, and Wolfinger RD. SAS System for Mixed Models. Cary, NC: SAS Institute, 1996.
  30. Liu HM, Loew JM, and Hunt CE. Congenital central hypoventilation syndrome: a pathologic study of the neuromuscular system. Neurology 28: 1013–1019, 1978.[Abstract/Free Full Text]
  31. Logothetis NK, Pauls J, Augath M, Trinath T, and Oeltermann A. Neurophysiological investigation of the basis of the fMRI signal. Nature 412: 150–157, 2001.[CrossRef][Medline]
  32. Lutherer LO, Lutherer BC, Dormer KJ, Janssen HF, and Barnes CD. Bilateral lesions of the fastigial nucleus prevent the recovery of blood pressure following hypotension induced by hemorrhage or administration of endotoxin. Brain Res 269: 251–257, 1983.[CrossRef][Web of Science][Medline]
  33. Macey PM, Henderson LA, Macey KE, Alger JR, Frysinger RC, Woo MA, Harper RK, Yan-Go FL, and Harper RM. Brain morphology associated with obstructive sleep apnea. Am J Respir Crit Care Med 166: 1382–1387, 2002.[Abstract/Free Full Text]
  34. Macey PM, Macey KE, Henderson LA, Alger JR, Frysinger RC, Woo MA, Yan-Go F, and Harper RM. Functional magnetic resonance imaging responses to expiratory loading in obstructive sleep apnea. Respir Physiol Neurobiol 138: 275–290, 2003.[CrossRef][Web of Science][Medline]
  35. Macey PM, Macey KE, Kumar R, and Harper RM. A method for removal of global effects from fMRI time series. Neuroimage 22: 360–366, 2004.[CrossRef][Web of Science][Medline]
  36. Macey PM, Valderama C, Kim AH, Woo MA, Gozal D, Keens TG, Harper RK, and Harper RM. Temporal trends of cardiac and respiratory responses to ventilatory challenges in congenital central hypoventilation syndrome. Pediatr Res 55: 953–959, 2004.[CrossRef][Web of Science][Medline]
  37. Mallard EC, Waldvogel HJ, Williams CE, Faull RL, and Gluckman PD. Repeated asphyxia causes loss of striatal projection neurons in the fetal sheep brain. Neuroscience 65: 827–836, 1995.[CrossRef][Web of Science][Medline]
  38. Marcus CL, Bautista DB, Amihyia A, Ward SL, and Keens TG. Hypercapneic arousal responses in children with congenital central hypoventilation syndrome. Pediatrics 88: 993–998, 1991.[Abstract/Free Full Text]
  39. Mathalon DH, Whitfield SL, and Ford JM. Anatomy of an error: ERP and fMRI. Biol Psychol 64: 119–141, 2003.[CrossRef][Web of Science][Medline]
  40. McKay LC, Evans KC, Frackowiak RSJ, and Corfield DR. Neural correlates of voluntary breathing in humans. J Appl Physiol 95: 1170–1178, 2003.[Abstract/Free Full Text]
  41. Oppenheimer S. The insular cortex and the pathophysiology of stroke-induced cardiac changes. Can J Neurol Sci 19: 208–211, 1992.[Web of Science][Medline]
  42. Oren J, Kelly DH, and Shannon DC. Long-term follow-up of children with congenital central hypoventilation syndrome. Pediatrics 80: 375–380, 1987.[Abstract/Free Full Text]
  43. Ozawa Y and Okado N. Alteration of serotonergic receptors in the brain stems of human patients with respiratory disorders. Neuropediatrics 33: 142–149, 2002.[CrossRef][Web of Science][Medline]
  44. Parkinson JA, Willoughby PJ, Robbins TW, and Everitt BJ. Disconnection of the anterior cingulate cortex and nucleus accumbens core impairs Pavlovian approach behavior: further evidence for limbic cortical-ventral striatopallidal systems. Behav Neurosci 114: 42–63, 2000.[CrossRef][Web of Science][Medline]
  45. Paton JY, Swaminathan S, Sargent CW, Hawksworth A, and Keens TG. Ventilatory response to exercise in children with congenital central hypoventilation syndrome. Am Rev Respir Dis 147: 1185–1191, 1993.[Web of Science][Medline]
  46. Paton JY, Swaminathan S, Sargent CW, and Keens TG. Hypoxic and hypercapnic ventilatory responses in awake children with congenital central hypoventilation syndrome. Am Rev Respir Dis 140: 368–372, 1989.[Web of Science][Medline]
  47. Peiffer C, Poline JB, Thivard L, Aubier M, and Samson Y. Neural substrates for the perception of acutely induced dyspnea. Am J Respir Crit Care Med 163: 951–957, 2001.[Abstract/Free Full Text]
  48. Poe GR, Kristensen MP, Rector DM, and Harper RM. Hippocampal activity during transient respiratory events in the freely behaving cat. Neuroscience 72: 39–48, 1996.[CrossRef][Web of Science][Medline]
  49. Ranck JB Jr and Windle WF. Brain damage in the monkey, macaca mulatta, by asphyxia neonatorum. Exp Neurol 1: 130–154, 1959.[CrossRef][Web of Science][Medline]
  50. Saito Y, Ito M, Ozawa Y, Obonai T, Kobayashi Y, Washizawa K, Ohsone Y, Takami T, Oku K, and Takashima S. Changes of neurotransmitters in the brainstem of patients with respiratory-pattern disorders during childhood. Neuropediatrics 30: 133–140, 1999.[Web of Science][Medline]
  51. Shea SA. Life without ventilatory chemosensitivity. Respir Physiol 110: 199–210, 1997.[CrossRef][Web of Science][Medline]
  52. Shea SA, Andres LP, Shannon DC, and Banzett RB. Ventilatory responses to exercise in humans lacking ventilatory chemosensitivity. J Physiol 468: 623–640, 1993.[Abstract/Free Full Text]
  53. Shea SA, Andres LP, Shannon DC, Guz A, and Banzett RB. Respiratory sensations in subjects who lack a ventilatory response to CO2. Respir Physiol 93: 203–219, 1993.[CrossRef][Web of Science][Medline]
  54. Silvestri JM, Weese-Mayer DE, and Nelson MN. Neuropsychologic abnormalities in children with congenital central hypoventilation syndrome. J Pediatr 120: 388–393, 1992.[CrossRef][Web of Science][Medline]
  55. Spengler CM, Banzett RB, Systrom DM, Shannon DC, and Shea SA. Respiratory sensations during heavy exercise in subjects without respiratory chemosensitivity. Respir Physiol 114: 65–74, 1998.[CrossRef][Web of Science][Medline]
  56. Trang H, Boureghda S, Denjoy I, Alia M, and Kabaker M. 24-hour BP in children with congenital central hypoventilation syndrome. Chest 124: 1393–1399, 2003.[CrossRef][Medline]
  57. Vogt BA and Pandya DN. Cingulate cortex of the rhesus monkey: II. Cortical afferents. J Comp Neurol 262: 271–289, 1987.[CrossRef][Web of Science][Medline]
  58. Von Cramon D and Jurgens U. The anterior cingulate cortex and the phonatory control in monkey and man. Neurosci Biobehav Rev 7: 423–425, 1983.[CrossRef][Web of Science][Medline]
  59. Wang Y, Shima K, Sawamura H, and Tanji J. Spatial distribution of cingulate cells projecting to the primary, supplementary, and pre-supplementary motor areas: a retrograde multiple labeling study in the macaque monkey. Neurosci Res 39: 39–49, 2001.[CrossRef][Web of Science][Medline]
  60. Xu F and Frazier DT. Modulation of respiratory motor output by cerebellar deep nuclei in the rat. J Appl Physiol 89: 996–1004, 2000.[Abstract/Free Full Text]
  61. Xu F and Frazier DT. Respiratory-related neurons of the fastigial nucleus in response to chemical and mechanical challenges. J Appl Physiol 82: 1177–1184, 1997.[Abstract/Free Full Text]
  62. Yasui Y, Breder CD, Saper CB, and Cechetto DF. Autonomic responses and efferent pathways from the insular cortex in the rat. J Comp Neurol 303: 355–374, 1991.[CrossRef][Web of Science][Medline]



This article has been cited by other articles:


Home page
 Am. J. Respir. Crit. Care Med.Home page
J. Huang, C. L. Marcus, P. Bandla, M. S. Schwartz, M. E. Pepe, J. M. Samuel, H. B. Panitch, R. M. Bradford, Y. P. Mosse, J. M. Maris, et al.
Cortical Processing of Respiratory Occlusion Stimuli in Children with Central Hypoventilation Syndrome
Am. J. Respir. Crit. Care Med., October 1, 2008; 178(7): 757 - 764.
[Abstract] [Full Text] [PDF]

Home page
 Proc Am Thorac SocHome page
D. E. O'Donnell, R. B. Banzett, V. Carrieri-Kohlman, R. Casaburi, P. W. Davenport, S. C. Gandevia, A. F. Gelb, D. A. Mahler, and K. A. Webb
Pathophysiology of Dyspnea in Chronic Obstructive Pulmonary Disease: A Roundtable
Proceedings of the ATS, May 1, 2007; 4(2): 145 - 168.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
P. M. Macey, M. A. Woo, K. E. Macey, T. G. Keens, M. M. Saeed, J. R. Alger, and R. M. Harper
Hypoxia reveals posterior thalamic, cerebellar, midbrain, and limbic deficits in congenital central hypoventilation syndrome
J Appl Physiol, March 1, 2005; 98(3): 958 - 969.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurophysiol.Home page
R. M. Harper, P. M. Macey, M. A. Woo, K. E. Macey, T. G. Keens, D. Gozal, and J. R. Alger
Hypercapnic Exposure in Congenital Central Hypoventilation Syndrome Reveals CNS Respiratory Control Mechanisms
J Neurophysiol, March 1, 2005; 93(3): 1647 - 1658.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow All Versions of this Article:
97/5/1897    most recent
00359.2004v1
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (10)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Macey, K. E.
Right arrow Articles by Harper, R. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Macey, K. E.
Right arrow Articles by Harper, R. M.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2004 by the American Physiological Society.