Regional brain responses associated with the neural control of drinking in humans

© 2017 Dr. Pascal Dorian SakerDrinking in response to dehydration is a tightly regulated behaviour that accurately corrects the fluid deficit present within the body. The critical importance of this behaviour is underlined by its conservation across evolution along with the adverse health effects produced by its dysregulation. One of the most notable of these effects is water intoxication caused by excess water intake, exemplified by the polydipsia associated with schizophrenia. Given the everyday occurrence of drinking, our critical dependence upon it for survival, and the range of detrimental health effects associated with its dysfunction, understanding how drinking is regulated in response to hydration status represents a topic of considerable scientific and medical importance. Remarkably, despite its importance, this regulatory process has received little investigation in humans. Furthermore, as both the motivation to drink and the cessation of drinking are associated with the subjective states of thirst and satiation respectively, the fundamental relationship between these states, hydration status, and drinking behaviour remains unknown. This relationship can be investigated using functional magnetic resonance imaging (fMRI), an imaging modality capable of interrogating the fully integrated system of brain, body and behaviour. fMRI was therefore used in this PhD project to investigate the neural control of drinking in humans, with the aim of gaining novel insight into how dehydration status influences the regulation of fluid intake and its associated subjective states. Twenty healthy participants were recruited for the first study in this thesis. The experimental protocol consisted of inducing two opposing conditions of hydration in each participant: a state of thirst produced by exercise-related dehydration and a ‘post-satiation’ (over-sated) state that followed excess fluid intake. Participants were scanned during both conditions while they drank 5mL volumes of liquid and the pleasantness of this drinking was subsequently rated. The principle finding of the first study was a bilateral increase in primary motor cortex activation when water was swallowed during the over-sated condition relative to the thirsty condition. A difference in mean pleasantness ratings was also found between the thirsty and over-sated conditions, with drinking found to be pleasant during the thirsty condition and unpleasant during the over-sated condition. Finally, between-participant correlations of subjective ratings and brain activity revealed a positive association during the thirsty condition for pleasantness ratings and activity in the orbital frontal cortex (OFC) and the anterior cingulate cortex (ACC), while for the over-sated condition activity in the amygdala (amongst other regions) showed a negative association with unpleasantness ratings. For the second study, twenty healthy participants were again recruited. In this study subjective ratings of “swallowing effort” were added to the existing experimental protocol and brain activity prior to swallowing was examined. A threefold increase in swallowing difficulty was revealed psychometrically for the over-sated condition compared to the thirsty condition, while for the same contrast increased activity was observed in parietal, prefrontal, and motor cortices along with the striatum and thalamus. Between-participant correlations of subjective ratings and brain activity revealed a negative association during the over-sated condition between ratings of swallowing effort and activity in the prefrontal cortex and several nuclei in the pontine region of the brainstem. For the final study, data from the second experiment was reanalyzed and regional brain responses were investigated during a ten second period designated ‘drinking behaviour’, which consisted of a conjunction of pre-swallow and swallow events. Psychophysical interaction (PPI) analyses were also used to investigate the functional connectivity between an anterior mid cingulate cortex (aMCC) ‘seed’ and other brain regions. For the thirsty condition relative to the over-sated condition, greater activation was observed in the aMCC along with several swallowing-related regions. An increase in functional connectivity, relative to a non-drinking baseline, was also observed in the thirsty condition between the aMCC seed and these swallowing-related regions. When the thirsty and over-sated conditions were contrasted during drinking behaviour, a greater increase in functional connectivity compared to the non-drinking baseline was observed in the thirsty condition between the aMCC and two subcortical regions, the cerebellum and the rostroventral medulla, the latter containing nuclei responsible for the swallowing reflex. Finally, during drinking behaviour in the over-sated condition, ratings of swallowing effort showed a negative association with functional connectivity between the aMCC and two cortical regions, the sensorimotor cortex and the supramarginal gyrus. The three empirical chapters in this thesis present several important findings with the potential to inform knowledge of the neural control of fluid intake: the identification of swallowing inhibition following satiation; a disinhibitory counterresponse provided by the prefrontal cortex; and the identification of a brain region (the aMCC) likely to play an important role in regulating fluid intake in response to changes in hydration status. As these outcomes show considerable promise for improving our understanding of pathologicial and non-pathological cases of excess fluid intake, the work presented in this PhD thesis is likely to provide an important empirical foundation for future research in this emerging field