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1Wellcome Department of Imaging Neuroscience, Institute of Neurology, University College London, London WC1N 3BG; 2National Heart and Lung Institute, Imperial College London, London W6 8RP; 4Mackay Institute of Communication and Neuroscience, School of Life Sciences, Keele University, Staffordshire ST5 5BG, United Kingdom; and 3Department of Psychiatry, Massachusetts General Hospital and McLean Hospital, Harvard Medical School, Boston, Massachusetts 02115
Submitted 15 July 2002 ; accepted in final form 12 May 2003
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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respiratory control; brain stem; cortex; functional magnetic resonance imaging
The voluntary control of breathing is presumed to be of cortical origin. The neural basis for the corticomotor control of respiratory muscles in humans was first investigated during neurosurgery; electrical stimulation of the cortical surface induced a twitch of the diaphragm (20), indicating representation of the respiratory muscles within the primary motor cortex. Subsequently, studies using percutaneous electrical (24) and transcranial magnetic stimulation of the brain (36) have identified a fast-conducting pathway from the motor cortex to the diaphragm. Each hemisphere of the diaphragm is represented predominantly in the contralateral motor cortex (34). In addition, studies of brain activity using positron emission tomography (PET) have highlighted areas of the motor cortex, thalamus, and cerebellum that are associated with volitional breathing (7, 18, 43). These structures may also mediate the control of other behavioral breathing acts, for example, breathing for speech (35) and exercise (17), behavioral tasks in which breathing control may be modified by learning and experience (33).
Voluntary and behavioral respiratory motor tasks must be performed in the context of ongoing reflex demands on breathing. Even small increases in reflex chemical drive can perturb the accuracy of voluntary respiratory movements (11). However, the neural basis for the integration of reflex and behavioral breathing is unclear. Behavioral control of the respiratory spinal motor neurons may be mediated "directly" via corticospinal neurons or "indirectly" via the brain stem respiratory centers and their associated bulbospinal neurons. In animals, neurophysiological studies have demonstrated a pathway from the motor cortex to the spinal motor neurons innervating the respiratory muscles (1). Clinical observations in humans with damage to the upper spinal cord indicate two anatomically distinct pathways: a corticospinal pathway from the cortex to the respiratory motoneurons and a bulbospinal pathway from the medulla descending in the ventrolateral quadrant of the spinal cord to the respiratory motoneurons. Damage to the ventrolateral spinal cord during neurosurgery can result in the loss of reflex breathing, while the control of voluntary breathing is preserved (37, 44), presumably by the corticospinal tract. Observations from transcranial magnetic stimulation also suggest a direct functionally distinct corticospinal pathway in humans (9). However, the firing patterns of respiratory neurons within the medulla are closely correlated with breathing patterns modulated by respiratory behaviors in the cat (40) and mouse (5). These observations support a model in which the behavioral control of breathing is mediated by the respiratory centers in the medulla and by bulbospinal motoneurons (39).
Because of limited spatial resolution and a limited field of view, our previous respiratory-related PET studies provided an incomplete picture of the voluntary motor control of respiration. In particular, the ability to resolve separate sensorimotor foci in the cortex was limited, and we were unable to determine respiratory-related activity in the brain stem. More recently, we demonstrated the suitability of blood O2 level-dependent (BOLD) functional magnetic resonance imaging (fMRI) to determine cortical and brain stem motor-related activity associated with voluntary tongue contraction (10). The aim of the present study was to use the enhanced sensitivity and spatial resolution of BOLD fMRI to describe suprapontine activity associated with voluntary breathing, specifically voluntary hyperpnea. In addition, we wished to determine whether BOLD fMRI is a sensitive tool with which to identify activity within the medulla that may have a potential role in the behavioral control of breathing. We hypothesized that volitional hyperpnea would be associated with increased BOLD signal within sensorimotor areas of the cortex, subcortical nuclei, and medulla.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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Six healthy, right-handed individuals (20-35 yr of age, 5 men and 1 woman) were studied. All subjects gave informed consent according to the Declaration of Helsinki (1991) and were studied with ethical approval from the Riverside Ethics Committee and the Joint Ethical Committees of the Institute of Neurology (Imperial College London) and the National Hospital for Neurology and Neurosurgery (University College London).
Physiological Monitoring
Subjects breathed through a circuit designed to maintain end-tidal PCO2 (PETCO2) to ±2 Torr of normocapnia (3). Inspiratory gas was kept mildly hyperoxic (30% inspired O2). Respired gases were sampled via a probe inserted into the mouthpiece, and PETCO2 and end-tidal PO2 (PETCO2) were determined by a quadrupole respiratory mass spectrometer (model MGA 2000, Case Medical). Changes in respiratory frequency and tidal volume (VT) were measured by a pneumotachograph (Collins) positioned in the expiratory line of the circuit and connected to a differential pressure transducer (Validyne). Airway pressure was determined via a probe inserted into the mouthpiece, which was connected to a differential pressure transducer (Validyne). All signals were recorded on a personal computer (Optiplex GX, Dell) via an analog-to-digital interface (model 1401 Plus, Cambridge Electronic Design, Cambridge, UK). All subjects wore a nose clip throughout the experiment. Monitoring apparatus taken into the scanner room contained no ferrous components.
Imaging
Brain images were acquired by using a Siemens Vision MRI scanner operating at 2 T at the Wellcome Department of Imaging Neuroscience, Institute of Neurology. All subjects underwent a positioning scan and then a T1 weighted "structural" scan to determine brain morphology. Subsequently, the functional images were acquired by using BOLD echo planar imaging. The T2* weighted functional sequences, consisting of 156 brain volumes, were acquired continuously throughout the breathing tasks. Each brain volume from cortex to upper spinal cord was collected in 5.2 s and consisted of 56 transverse slices with an isotropic voxel resolution of 3 mm and a matrix size of 64 x 64 pixels. Subjects lay in a supine position on the scanner bed. To minimize head movement artifacts, the head was held in place by firm padding, and subjects were attached to the breathing circuit via a personalized mouthpiece, which was securely attached to the head coil by using customized support. To minimize scanner noise, the subjects wore earplugs, which were connected to a microphone in the control room, enabling the subjects to hear verbal instructions.
Breathing Paradigm
Subjects carried out 12 periods of 31 s (i.e., 6 whole brain images per period) of isocapnic hyperpnea alternating with 31-s periods of spontaneous breathing. A verbal cue was given at the beginning and end of each hyperpnea period. The hyperpnea-breathing pattern was designed to increase ventilation by approximately three times resting breathing, predominantly through an increase in VT. Subjects underwent training to perform the hyperpnea without feedback on a previous occasion at the National Heart and Lung Institute, Charing Cross Campus, Imperial College School of Medicine.
Data Analysis
Ventilatory data were analyzed on a breath-by-breath basis (Spike 2, Cambridge Electronic Design). Functional imaging data were analyzed by using SPM99 software (Wellcome Department of Cognitive Neurology; http://www.fil.ion.ucl.ac.uk/spm). Before statistical analysis, the data underwent a number of preprocessing stages. To account for small head movements, images from each subject were realigned to the first image in the data series. To enable group analysis, the images were normalized into standard stereotaxic Montreal Neurological Institute space, resampled at a resolution of 2 x 2 x 2 mm, and spatially smoothed [filter size, full-width half-maximum = 6 mm (21)]. After the preprocessing, statistical tests were performed for the group and for each individual to determine BOLD signal changes that were significantly related to the breathing task. The data underwent a multiple linear regression time series analysis performed voxel by voxel to produce statistical maps of significant neural activity. For this, the data were fitted to a binary "boxcar" function, chosen to represent the signal changes occurring with the on-off periods of voluntary hyperpnea. This boxcar model was then convolved with a hemodynamic response function to represent the relation between neural activity and cerebral blood flow changes (22). The data were then temporally smoothed by application of a high-pass filter (cutoff set at 124 s, twice the experimental period) to remove low-frequency signal changes, such as signal drift, and a low-pass filter (4 s Gaussian) to remove high-frequency noise. To account for changes in BOLD signal intensity that might be due to changes in "global" signal intensity (e.g., changes in global cerebral blood flow), the average global signal intensity was included as a regressor of no interest. For the whole brain, a statistical threshold of P < 0.05 (corrected for multiple comparisons, T > 5) was set to determine statistical significance voxel by voxel. Our a priori hypothesis was that voluntary hyperpnea would be associated with increased neural activity within the medulla; consequently, we corrected for multiple comparisons on the basis of a small volume of interest [10-mm radius centered in the medulla; SPM99 software (47)]. A conjunction analysis was performed at a statistical threshold of P < 0.001 to determine activity common to all individuals. The positions of the local maxima are reported, in Montreal Neurological Institute space (see above), in terms of the x, y, and z coordinates relative to the anterior commissure, with the horizontal plane running through the anterior and posterior commissures (46). To determine the anatomic location of each maximum, the statistical maps were superimposed onto a group-mean structural image and onto the appropriate individual's structural image and identified with reference to standard anatomic atlases (14, 15, 27, 46).
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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The ventilatory data for one subject collected during the scanning
experiment are illustrated in Fig.
1. The 13 periods of spontaneous breathing alternating with the 12
periods of voluntary hyperpnea are clearly observed on the traces.
VT increased from 
0.5 to 1.5 liters. There was also a
clear increase in the amplitude of the pressure changes associated with the
voluntary breathing condition, indicating the increased respiratory effort
associated with hyperpnea. PETCO2 remained
constant throughout the scanning period.
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Table 1 summarizes the mean data for the six subjects. There is a threefold increase in VT (P < 0.001) from spontaneous to voluntary breathing and also a slight increase in breathing frequency (P > 0.05); voluntary breathing was not associated with any change in PETO2 (P > 0.05) or PETCO2 (P > 0.05).
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Neural Activity Associated With Voluntary Hyperpnea
Group analysis. An overall view of the neural activity is illustrated as a maximum intensity projection within a "glass brain" in Fig. 2. The coordinates and statistical values of the most significant maxima for each anatomic location are listed in Table 2 and illustrated in Fig. 3.
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The most significant activity identified in this study was within the supplementary motor cortex (SMA). Activity in the SMA was observed bilaterally close to the midline; the clusters extended laterally and deep into the sulcus.
In the superior precentral gyrus, significant bilateral activity was identified, with a cluster of local maxima located posteriorly, extending deep into the gyrus (Fig. 3A) and a second smaller discrete cluster of activity located in an anterior position in the gyrus (Fig. 3B). Bilateral activity was also present in the inferior precentral gyrus (Fig. 3C).
Within the superior postcentral gyrus, bilateral activations extended deep into the cortex. The identified increases in activity within the sensorimotor cortices described above were observed bilaterally, with the most significant maxima located on the left.
Smaller discrete clusters were also observed bilaterally within the anterior thalamic nuclei, globus pallidum, caudate nuclei, and inferior parietal gyri. On the right, discrete clusters were identified within the premotor cortex, midcingulate gyrus, superior frontal gyrus, anterior middle frontal gyrus, and superior temporal gyrus.
Significant signal change was identified inferior to the posterior cingulate gyrus, in the vicinity of the internal cerebral vein. Within the cerebellum, activity was dispersed bilaterally over the cerebellar cortices, with clusters observed deep within the cerebellum.
Individual analyses. In all individuals, when corrected for multiple comparisons (P < 0.05), increased neural activity was observed bilaterally within the superior sensorimotor cortices. In four of the six individuals, the anatomic spatial extent of activity within the superior sensorimotor cortices was almost identical. Although the other two individuals likely contributed to the main effects observed for the group, their activity in this region was limited to small discrete bilateral maxima. In all six subjects, activity was observed bilaterally in the cerebellum, but the location of the maxima varied between subjects. Activity within the cingulate gyrus was identified in four of the six individuals, and, in the thalamus, discrete clusters of activity were identified in three of the individuals. However, activity was observed in these areas in all subjects at a lower statistical threshold (P < 0.001) uncorrected for multiple comparisons. A conjunction analysis uncorrected for multiple comparisons (P < 0.001) showed similar activations common to all individuals within the sensorimotor cortices, thalamic nuclei, and cerebellum.
Medullary activity. Our a priori hypothesis, that voluntary breathing would be associated with activity within the medulla, allowed a small volume correction to be performed on an area centered in the medulla (0, -37, -56) with a 10-mm radius. For the group, a discrete cluster of significant activity was observed within the superior dorsal medulla (P = 0.012; Fig. 3D) extending bilaterally from the midline.
In four of the six individual analyses, activity within the medulla survived the small volume correction. In three of the individuals, the clusters appeared to have an anatomic location similar to the identified cluster in the group analysis. In another individual, the cluster was located laterally in the caudal medulla.
Time course of signal changes. The time course of the signal
changes, associated with voluntary hyperpnea within the motor cortex and
medulla, was similar. However, the magnitude of the signal change within the
motor cortex was 20% larger than that within the medulla. This is
illustrated for a single subject in Fig.
4.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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Primary Sensorimotor Cortices
One of our main findings with respect to supra-brain stem structures is the identification of two distinct clusters of activity within the primary motor cortex. It is known that the motor cortex is involved in the generation of voluntary movements; an early imaging example of this with the use of PET is activation of the motor cortex during a simple, repetitive arm movement (6). With respect to breathing, Foerster (20) first determined a site of thoracic muscle representation within the superior motor cortex and anterior to this location, a site representing the diaphragm. More recently, significant foci within the superior motor cortex have been identified in respiratory-related PET studies from our laboratories (7, 18, 43) and in an fMRI study (16). However, none of these imaging studies report more than one distinct cluster within the superior motor cortex. From Foerster's stimulation studies, we hypothesize that, in our study, diaphragmatic movements are associated with the anterior cluster of activity identified within the superior motor cortex and thoracic muscle activity is associated with the significant foci in the posterior location.
In the present study, respiratory-related activity was also identified inferiorly within the motor cortex, at a site that Ramsay et al. (43) showed to be associated with volitional expiration. A further study has shown this area to be active during vocalization (35), which is normally associated with active expiration. Our hyperpnea task involves the recruitment of predominantly inspiratory muscles, but it is probable that expiratory muscles were recruited during the task, which would explain the activity we have identified within the inferior motor cortex.
In the present study, significant activity was also identified bilaterally in the sensory cortex, immediately adjacent to the motor cortical foci. These were not identified in the respiratory-related PET studies (7, 43), presumably because the PET experimental design controlled for afferent feedback from the lung and chest wall by matching the subject's breathing pattern (frequency and volume) with positive-pressure ventilation (see Study Design).
SMA and Premotor Cortex
In our study, we identified extensive activity bilaterally within the SMA. The SMA is functionally divided into an anterior portion, involved in the planning and selection of motor action (19, 42), and a posterior portion, associated with execution and imagination of movements (42, 45). The respiratory-related task performed by the subjects in this study was a learned task requiring precision and control in planning and executing the movement, thereby explaining activation of the SMA. Also, in common with the previous imaging studies (7, 16, 43), voluntary hyperpnea in this study was associated with a lateralization of premotor activity to the right. This activity may be attributed to a greater degree of attention (41) associated with volitional inspiration or volitional expiration.
Other Cortical Areas
Other cortical areas activated in this study were the cingulate, inferior parietal gyri, right superior temporal gyrus, and right superior and middle frontal gyri. The anterior cingulate is known to play a crucial role in the initiation and motivation of movements with a specific goal (13). Recently, a PET study reported that the anterior cingulate might be important in integrating peripheral cardiovascular changes with cognitive effort, motor preparedness, and emotional states (12). The peripheral cardiovascular changes during hyperpnea in this study were not measured; however, subjects were cognitively aware that they were increasing the effort of breathing while performing the hyperpnea task, and this may be accompanied by a change in emotional state. Furthermore, a previous PET study from our laboratory (8) identified significant bilateral activity within the cingulate associated with CO2 simulated breathing. Activity within the frontal and parietal cortices may represent components of the frontoparietal network associated with motor planning and attention (42), required by the subjects to attend to the learned hyperpnea task.
Subcortical Activity
Subcortical activity was identified in the thalamus, globus pallidum, caudate, and cerebellum. These areas are typically associated with the voluntary control of movement (29, 42) and in a previous PET study were shown to be active when associated with hyperpnea during and immediately after exercise (17). In addition, previous volitional breathing studies have also identified activity within the thalamus, cerebellum (7, 43), and globus pallidus (16) associated with the movement of respiratory musculature. Findings of the aforementioned studies (7, 16, 17, 43) and the more extensive results of this study enable us to reasonably conclude that the voluntary control of respiration is similar to the control of other general voluntary movements requiring activity throughout an integrated network of cortical and subcortical structures.
Brain Stem Activity
Anatomic localization. In this study, we report activity in the
superior dorsal medulla, spreading bilaterally from the midline. Previous
studies of behavioral breathing
(7,
16-18,
35,
43) have had a more limited
field of view that has not included the medulla; we believe that our study is
the first report of behavioral respiratory-related activity within the human
medulla. Because the BOLD technique detects signal changes in the venules and
small veins draining a region of activation, signal changes may not be
anatomically superimposed directly on the activated nuclei. Corfield et al.
(10) used voluntary tongue
contraction to identify activity specifically within the hypoglossal nucleus;
the BOLD signal change occurred within a region of the dorsal medulla similar
to that in the present study but was located more dorsally on either side of
the midline and extended in a rostrocaudal direction of up to 2 cm. With
reference to the sections in the brain atlases of Haines
(27) and Duvernoy
(14), the increase in BOLD
signal seen here is most likely due to increased activity in respiratory
neurons associated with the nucleus of the solitary tract or the nucleus
ambiguus.
Functional significance. The presence of medullary activity in the present study suggests that the medullary respiratory centers play some part in the mediation of volitional breathing. Although evidence indicates that the corticospinal pathway can functionally bypass the brain stem respiratory centers (see the introduction), these results suggest that the corticospinal pathway does not solely mediate the cortical control of breathing. If this were the case, we would have predicted no increase in activity within the medulla. The present findings would be consistent with a corticomotor-related excitation or inhibition at the medullary respiratory centers.
However, an alternative explanation for our medullary activity may be that of sensory input from the lungs and chest wall. Inflation of the lungs excites sensory vagal afferents of the lungs, airways, and muscles of the chest wall. The vagal fibers project to and terminate onto the respiratory neurons of the nucleus of the solitary tract, where they have an excitatory or inhibitory effect on these neurons (4, 30). Evidence has shown that afferents of intercostal nerves project to the cerebral cortex (23); however, it is not known whether this projection is relayed via the brain stem. We did not control for proprioceptive input in this study (see Study Design); therefore, the increased activity may be explained by sensory afferents having an excitatory or inhibitory synaptic effect on cells within the respiratory centers.
A previous respiratory-related fMRI study has reported activity in the pons (a region of the brain stem also containing respiratory-related neurons) in response to inspiratory resistive loading (25). In our study, we did not identify pontine activity, perhaps because the load of breathing in this study was not sufficient to induce activity within the pons.
Study Design
The activation-related signal changes associated with voluntary hyperpnea reflect a differential increase in activity, i.e., the increase in neural activity produced by the hyperpnea compared with the neural activity present in the control state of spontaneous eupneic breathing. Consequently, the pattern of reported activity reflects the overall sensorimotor activity associated with voluntary hyperpnea; it will include the increased motor-related activity producing the hyperpnea and the increased sensory-related activity produced by increased afferent activity arising from the lungs and chest wall. Additionally, signals in motor structures may reflect increased motor-related output and/or increased input from activity in sensory-related areas.
This control state differs from that used in previous imaging studies of voluntary hyperpnea in which the level of hyperpnea was matched by a control state of "passive" positive-pressure ventilation at an elevated VT (7, 16, 18, 43). This latter control state was used because it accounts for differences in lung inflation; therefore, the reported activations are predominantly motor related. However, such a control is not without problems; although the pump muscles may be relaxed during the passive ventilation, this relaxation is a motor-related task, achieved behaviorally, by undefined cortical structures. Additionally, mechanical ventilation produces a positive pressure in the mouth and upper airways, which requires active stabilization of these structures; mechanical ventilation is therefore associated with sensory and motor activations that are not directly related to the intended control state. As a result, it is likely that some breathing-related neural activity that is common to both conditions will not be observed.
In practice, the transition from voluntary hyperpnea to mechanical
ventilation, and vice versa, requires data to be acquired discontinuously, in
discrete sessions. This is a suitable protocol for activation-related studies
using PET, but it is a less ideal design for BOLD fMRI studies, where
low-frequency noise and signal drift, occurring between sessions, may
predominate over activation-related signal changes. The on-off block design
with a repeat time of 1 min, as used in the present study, is a robust
approach for fMRI studies, which results in increased sensitivity. Evans et
al. (16) carried out an fMRI
study of voluntary hyperpnea, in a session-by-session way, using mechanical
ventilation to diminish sensory feedback; although they did report activity
associated with volitional breathing, the activations are weaker than those
reported here.
In summary, no one study design is optimal; each has strengths and weaknesses. The present protocol was optimized to have good signal-to-noise characteristics, and it lacks the confounds associated with mechanical ventilation. However, it retains sensory-related signals associated with the voluntary hyperpnea that prevent the reported activations from being interpreted as exclusively motor related.
Other Methodological Issues
An increase in the BOLD fMRI signal will occur as a result of increases in global or local cerebral perfusion that result in a decrease in deoxyhemoglobin concentration (31, 38). Changes in breathing pattern, such as hyperpnea, alter the partial pressure of gases within the blood. Because CO2 is a vasodilator, any changes in PCO2 will ultimately have an effect on global cerebral blood flow and will therefore affect global signal changes. The global signal changes may confound the detection of local signal changes associated with the task if the time courses of the two signals correlate. To minimize such an effect in this study, PETCO2 levels were clamped to ±2 Torr. To further exclude any nonspecific changes related to the global signal, the time course of the mean global signal intensity was included within the model as an effect of no interest.
BOLD fMRI is highly sensitive but is susceptible to motion-induced signal changes. Motion artifacts may be caused by head movements or may be related to tissue movements correlated to the cardiac and respiratory cycles. If movements correlate with the task, they may produce an artifactual activation-related signal (28). Imaging activity within the brain stem is potentially more problematic than imaging cortical activity, because the anatomic structures within the brain stem are smaller and tissue movements and signal variance are greater. However, our previous work indicates that robust motor-related signal changes can be determined in the medulla by using fMRI (10). In the present study, we corrected for head-related movement by realigning all the functional brain images for each subject to a reference image. To further correct for the potential effects of head movement, we constructed a second statistical model that included the parameters used for realignment as effects of no interest. This model is highly conservative, inasmuch as it would remove signal changes related to head movement that correlate with the hyperpnea task; therefore, it may remove "real" signal changes related to neural activity. This approach gave an anatomically identical pattern of activation to the statistical model without the realignment parameters, suggesting little effect of movement on our study. We have therefore reported the results of the first model only.
The characteristics (Fig. 4)
of the signal changes within the medulla are similar to the signal changes
within the motor cortex; however, signal changes within the medulla related to
voluntary hyperpnea are 20% smaller. This might result from a larger
tissue inhomogeneity in the medulla than in the motor cortex with a different
ratio of gray to white matter. The weaker signal within the brain stem,
together with an increased signal variance, may explain why medullary activity
reaches significance in only half of the individuals.
Conclusion
We have identified distinct cortical and subcortical structures that are associated with voluntary hyperpnea. In addition, we have successfully imaged activation-related signal changes in the medulla, highlighting a potential role of the medullary respiratory centers in behavioral respiratory control in humans. We have not identified the precise role of the medullary respiratory centers in mediating this control, and this remains the objective of further study.
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DISCLOSURES |
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ACKNOWLEDGMENTS |
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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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) and fitted statistical model
(
) have been adjusted to remove effects of covariates of no interest.
Horizontal bar, period of voluntary hyperpnea. Inset: statistical
model in which raw boxcar is convolved with the hemodynamic response function
(a), and this function is adjusted to remove effects of no interest
mentioned above (b).