BOLD fMRI Identifies Limbic, Paralimbic, and Cerebellar Activation During Air Hunger

Abstract

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.

Cerebellar Vermis Involvement in Cocaine-Related Behaviors

“…Vermis activation also occurs in response to nondrug rewards or their anticipation (Rogers et al, 1999;Kunig et al, 2000;Martin-Solch et al, 2001;Knutson et al, 2003), painful or aversive stimuli or their anticipation (Paradiso et al, 1999;Casey et al, 2000;Becerra et al, 2001), and interoceptive stimuli triggered by vegetative regulatory functions including thirst (Egan et al, 2003), hunger (Tataranni et al, 1999), and respiratory stress (Evans et al, 2002). Together, those findings are consistent with the suggestion that the cerebellum and the vermis process multimodal sensory inputs to influence cortical excitability and enhance motor sequence learning and execution (Molinari et al, 2002).…”

A bilateral cortico-bulbar network associated with breath holding in humans, determined by functional magnetic resonance imaging

“…Interestingly, breath holding was not associated with increased activity within the cerebellum; cerebellar activity is commonly reported in human respiratory related imaging paradigms (Evans et al, 2002;McKay et al, 2003;Parsons et al, 2001) and in animals (Xu and Frazier, 2002) usually when task-related respiratory motor activity is increased.…”

“…The anterior cingulate is associated with many tasks that involve cognitive awareness (Frith et al, 1991), more specifically cognitive behaviours that elicit autonomic arousal (Critchley et al, 2001). Likewise, the insula has been implicated in the explicit awareness of internal bodily states (Cechetto, 1987;Craig, 2002;Critchley et al, 2001) and in the perception of dyspnoea (Banzett et al, 2000b;Evans et al, 2002) and hypercapnia (Corfield et al, 1995). Our post study de-brief determined that 'a need for more air' was the most common sensation/feeling experienced during breath holding but in all subjects this sensation was mild and was limited only to a short period towards the end of the breath hold.…”

“…Within the brainstem, animal models have shown that stimulation of pontine respiratory neurones can lead to apnoea, hypernoea or apneusis (Chamberlin, 2004;Fung and St John, 1994;Mutolo et al, 1998), while ablation of the preBötzinger complex (preBötC), a small region of the ventrolateral medulla, can lead to central sleep apnoea and ataxic breathing during wakefulness (Gray et al, 2001;McKay et al, 2005) We hypothesised that breath holding would be associated with an inhibitory network of subcortical structures including the pons. We were aware that our subjects would experience secondary effects, such as interoceptive awareness and an increasing desire for, and an anticipation of, the subsequent breath; therefore, we also hypothesised activity within areas associated with respiratory awareness and air hunger, such as the insula and cingulate cortices (Banzett et al, 2000b;Evans et al, 2002;Peiffer et al, 2001). …”

The air hunger response of four elite breath-hold divers

“…He was aware of these contractions, and his ratings of their intensity were proportional to PET CO 2 , but they were not a source of discomfort. This disjuncture between respiratory center drive and air hunger suggests that either the ascending pathways from medulla or cortical areas responsible for appreciation of air hunger are dysfunctional (Eldridge and Chen 1992;Evans et al 2002).…”