| Summary: | Understanding respiratory control is crucial for improving the management of respiratory disease, and the accompanying breathlessness endured by its sufferers. A body of animal evidence supports the role of the midbrain periaqueductal gray (PAG) in modulating ascending and descending respiratory information, with the PAG subdivisions acting within a network that may contribute to the threatening perception of breathlessness. In this Thesis we used ultra high field magnetic resonance imaging (MRI) at 7 Tesla to firstly identify activity within the columns of the PAG during the simple respiratory task of breath holding in humans, matching those previously reported in animals for slowed ventilatory responses. Extending this investigation to the perception of breathlessness, we then used a classical fear-conditioning paradigm to investigate anticipation and response to an aversive inspiratory resistive loading stimulus. We found activity in the lateral PAG (lPAG) during slowed breathing against an inspiratory resistance, and activity in the ventrolateral PAG (vlPAG) during anticipation of resistive loading. These results align with the proposed threat perception model in animals; with the vlPAG involved in passive responses to inescapable stress, while the lPAG is involved in active responses to threat. Lastly, we investigated the role and connections of the PAG columns within the wider cortical breathlessness network, and any plastic changes evoked by exercise. Functional and connectivity results suggest the PAG column activities in breathlessness are influenced by top-down cortical networks, with the vlPAG involved in the affective emotional dimension of breathlessness, while the lPAG is involved in the sensory component. In a comparison between athlete and sedentary subjects, athletes displayed increased functional activity in the vlPAG and prefrontal cortex during anticipation of breathlessness, indicating possible affective changes in perception rather than a global 'de-sensitisation' to breathlessness. Therefore, in this Thesis we have identified the columns of the PAG to be intricately involved with respiratory control and perception of breathlessness. It appears the PAG may be a critical point of distinction between aspects of breathlessness perception, with the vlPAG a possible area of adaptation of affective breathlessness in athletes, or conversely (mal)adaptation and a target for treatment in patients with chronic respiratory disease.
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