Air hunger (uncomfortable urge to breathe) is a component of dyspnea (shortness of breath). Three human H(2)(15)O positron emission tomography (PET) studies have identified activation of phylogenetically ancient structures in limbic and paralimbic regions during dyspnea. Other studies have shown activation of these structures during other sensations that alert the organism to urgent homeostatic imbalance: pain, thirst, and hunger for food. We employed blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) to examine activation during air hunger. fMRI conferred several advantages over PET: enhanced signal-to-noise, greater spatial resolution, and lack of ionizing radiation, enabling a greater number of trials in each subject. Six healthy men and women were mechanically ventilated at 12-14 breaths/min. The primary experiment was conducted at mean end-tidal PCO(2) of 41 Torr. Moderate to severe air hunger was evoked during 42-s epochs of lower tidal volume (mean = 0.75 L). Subjects described the sensation as "like breath-hold," "urge to breathe," and "starved for air." In the baseline condition, air hunger was consistently relieved by epochs of higher tidal volume (mean = 1.47 L). A control experiment in the same subjects under a background of mild hypocapnia (mean end-tidal PCO(2) = 33 Torr) employed similar tidal volumes but did not evoke air hunger, controlling for stimulus variables not related to dyspnea. During each experiment, we maintained constant end-tidal PCO(2) and PO(2) to avoid systematic changes in global cerebral blood flow. Whole-brain images were acquired every 5 s (T2*, 56 slices, voxel resolution 3 x 3 x 3 mm). Activations associated with air hunger were determined using voxel-based interaction analysis of covariance that compared data between primary and control experiments (SPM99). We detected activations not seen in the earlier PET study using a similar air hunger stimulus (Banzett et al. 2000). Limbic and paralimbic loci activated in the present study were within anterior insula (seen in all 3 published studies of dyspnea), anterior cingulate, operculum, cerebellum, amygdala, thalamus, and basal ganglia. Elements of frontoparietal attentional networks were also identified. The consistency of anterior insular activation across subjects in this study and across published studies suggests that the insula is essential to dyspnea perception, although present data suggest that the insula acts in concert with a larger neural network.

To investigate the functional neuroanatomy of voluntary respiratory control, blood O2 level-dependent functional magnetic resonance imaging was performed in six healthy right-handed individuals during voluntary hyperpnea. Functional images of the whole brain were acquired during 30-s periods of spontaneous breathing alternated with 30-s periods of isocapnic hyperpnea [spontaneous vs. voluntary: tidal volume = 0.5 +/- 0.01 vs. 1.3 +/- 0.1 (SE) liters and breath duration = 4.0 +/- 0.4 vs. 3.2 +/- 0.4 (SE) s]. For the group, voluntary hyperpnea was associated with significant (P < 0.05, corrected for multiple comparisons) neural activity bilaterally in the primary sensory and motor cortices, supplementary motor area, cerebellum, thalamus, caudate nucleus, and globus pallidum. Significant increases in activity were also identified in the medulla (corrected for multiple comparisons on the basis of a small volume correction for a priori region of interest) in a superior dorsal position (P = 0.012). Activity within the medulla suggests that the brain stem respiratory centers may have a role in mediating the voluntary control of breathing in humans.

Ablation of preBötzinger complex (preBötC) neurons, critical for respiratory rhythm generation, resulted in a progressive, increasingly severe disruption of respiratory pattern, initially during sleep and then also during wakefulness in adult rats. Sleep-disordered breathing is highly prevalent in elderly humans and in some patients with neurodegenerative disease. We propose that sleep-disordered breathing results from loss of preBötC neurons and could underlie death during sleep in these populations.

Rett syndrome is a neurological disorder caused by mutation of the X-linked MECP2 gene. Mice lacking functional Mecp2 display a spectrum of Rett syndrome-like signs, including disturbances in motor function and abnormal patterns of breathing, accompanied by structural defects in central motor areas and the brainstem. Although routinely classified as a neurodevelopmental disorder, many aspects of the mouse phenotype can be effectively reversed by activation of a quiescent Mecp2 gene in adults. This suggests that absence of Mecp2 during brain development does not irreversibly compromise brain function. It is conceivable, however, that deep-seated neurological defects persist in mice rescued by late activation of Mecp2. To test this possibility, we have quantitatively analysed structural and functional plasticity of the rescued adult male mouse brain. Activation of Mecp2 in ∼70% of neurons reversed many morphological defects in the motor cortex, including neuronal size and dendritic complexity. Restoration of Mecp2 expression was also accompanied by a significant improvement in respiratory and sensory-motor functions, including breathing pattern, grip strength, balance beam and rotarod performance. Our findings sustain the view that MeCP2 does not play a pivotal role in brain development, but may instead be required to maintain full neurological function once development is complete.

ABSRACTFew tasks are simpler to perform than a breath hold; however, the neural basis underlying this voluntary inhibitory behaviour, which must suppress spontaneous respiratory motor output, is unknown. Here, using blood oxygen level dependant functional magnetic resonance imaging (BOLD fMRI), we investigated the neural network responsible for volitional breath holding in 8 healthy humans. BOLD images of the whole brain (156 brain volumes, voxel resolution 3x3x3mm) were acquired every 5.2s. All breath holds were performed for 15 seconds at resting expiratory lung volume when respiratory musculature was presumed to be relaxed, which ensured that the protocol highlighted the inhibitory components underlying the breath hold. An experimental paradigm was designed to dissociate the time course of the whole-brain BOLD signal from the time course of the local, neural-related BOLD signal associated with the inhibitory task. We identified a bilateral network of cortical and subcortical structures including the insula, basal ganglia, frontal cortex, parietal cortex and thalamus, that are in common with response inhibition tasks, and in addition, activity within the pons. From these results we speculate that the pons has a role in integrating information from supra-brainstem structures, and in turn it exerts an inhibitory effect on medullary respiratory neurones to inhibit breathing during breath holding.2

Rationale: In adult rats, bilateral ablation of pre-Bötzinger complex (preBötC) neurokinin 1-expressing (NK1R) neurons leads to a progressive and irreversible disruption in breathing pattern, initially during sleep, eventually resulting in an ataxic breathing pattern during wakefulness. Objectives: Here we determine whether ablation of fewer preBötC NK1R neurons leads to a persistent pattern of disordered breathing during sleep but not during wakefulness. Methods: Adult male Sprague-Dawley rats (n 5 12) were instrumented to record diaphragmatic, abdominal, and neck EMG, and EEG. Fourteen days later, a second surgery was performed to stereotaxically microinject into the preBötC on one side the toxin saporin conjugated to substance P (SP-SAP), which selectively ablates NK1R neurons. Measurements and Main Results: Postinjection, rats were monitored within a plethysmograph until they were killed (Days 21-51). At Days 6-9 post-unilateral SP-SAP injection, respiratory pattern during sleep, particularly REM sleep, became increasingly disordered, characterized by an increase in frequency of central sleep apnea and hypopneas (36.8 6 7.4 episodes/h of REM vs. 6 6 2.0 episodes/h in preinjection controls; P , 0.05), whereas breathing during resting wakefulness remained stable. Unlike bilateral SP-SAP-injected rats, an ataxic breathing pattern did not develop during wakefulness. Rats that were monitored up to 51 days post-SP-SAP injection continued to have sleep-disordered breathing; breathing during wakefulness remained relatively stable. Histologic analysis of the ventrolateral medulla confirmed that NK1R neurons within the preBötC on the injected but not on the contralateral side of the medulla were ablated. Conclusions: Gradual loss of preBötC NK1R neurons may be an underlying factor of sleep-disordered breathing, in particular of central sleep apnea.

The aim of this study was to determine if episodic hypoxia evokes persistent increases of genioglossus muscle (GG) activity, termed long-term facilitation (LTF), in neonatal rats in vivo. Experiments were performed on anaesthetized, spontaneously breathing, intubated neonatal rats (postnatal days (P) 3-7), divided into three groups. The first group (n = 8) was subjected to three 5-min periods of hypoxia (5% O 2 -95% N 2 ) alternating with 5 min periods of room air. The second group (n = 8) was exposed to 15 min of continuous hypoxia. The third (n = 4) group was not exposed to hypoxia and served as a control. GG EMG activity and airflow were recorded before, during and for 60 min after episodic and continuous hypoxic exposure. During hypoxia, GG EMG burst amplitude and tidal volume (V T ) significantly increased compared to baseline levels (episodic protocol: mean ± S.E.M.; 324 ± 59% of control and 0.13 ± 0.007 versus 0.09 ± 0.005 ml, respectively; continuous protocol: 259 ± 30% of control and 0.16 ± 0.005 versus 0.09 ± 0.007 ml, respectively; P < 0.05). After the episodic protocol, GG EMG burst amplitude transiently returned to baseline; over the next 60 min, burst amplitude progressively increased to levels significantly greater than baseline (238 ± 40% at 60 min; P < 0.05), without any significant increase in V T and respiratory frequency (P > 0.05). After the continuous protocol, there was no lasting increase in GG EMG burst amplitude. We conclude that LTF of upper airway muscles is an adaptive respiratory behaviour present from birth.

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