In response to dehydration, humans experience thirst. This subjective state is fundamental to survival as it motivates drinking, which subsequently corrects the fluid deficit. To elicit thirst, previous studies have manipulated blood chemistry to produce a physiological thirst stimulus. In the present study, we investigated whether a physiological stimulus is indeed required for thirst to be experienced. Functional MRI (fMRI) was used to scan fully hydrated participants while they imagined a state of intense thirst and while they imagined drinking to satiate thirst. Subjective ratings of thirst were significantly higher for imagining thirst compared with imagining drinking or baseline, revealing a successful dissociation of thirst from underlying physiology. The imagine thirst condition activated brain regions similar to those reported in previous studies of physiologically evoked thirst, including the anterior midcingulate cortex (aMCC), anterior insula, precentral gyrus, inferior frontal gyrus, middle frontal gyrus, and operculum, indicating a similar neural network underlies both imagined thirst and physiologically evoked thirst. Analogous brain regions were also activated during imagined drinking, suggesting the neural representation of thirst contains a drinking-related component. Finally, the aMCC showed an increase in functional connectivity with the insula during imagined thirst relative to imagined drinking, implying functional connectivity between these two regions is needed before thirst can be experienced. As a result of these findings, this study provides important insight into how the neural representation of subjective thirst is generated and how it subsequently motivates drinking behavior.

In humans, activity in the anterior midcingulate cortex (aMCC) is associated with both subjective thirst and swallowing. This region is therefore likely to play a prominent role in the regulation of drinking in response to dehydration. Using functional MRI, we investigated this possibility during a period of "drinking behavior" represented by a conjunction of preswallow and swallowing events. These events were examined in the context of a thirsty condition and an "oversated" condition, the latter induced by compliant ingestion of excess fluid. Brain regions associated with swallowing showed increased activity for drinking behavior in the thirsty condition relative to the oversated condition. These regions included the cingulate cortex, premotor areas, primary sensorimotor cortices, the parietal operculum, and the supplementary motor area. Psychophysical interaction analyses revealed increased functional connectivity between the same regions and the aMCC during drinking behavior in the thirsty condition. Functional connectivity during drinking behavior was also greater for the thirsty condition relative to the oversated 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 behavior in the oversated 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 results of this study provide evidence that the aMCC helps facilitate swallowing during a state of thirst and is therefore likely to contribute to the regulation of drinking after dehydration.

In humans, drinking replenishes fluid loss and satiates the sensation of thirst that accompanies dehydration. Typically, the volume of water drunk in response to thirst matches the deficit. Exactly how this accurate metering is achieved is unknown; recent evidence implicates swallowing inhibition as a potential factor. Using fMRI, this study investigated whether swallowing inhibition is present after more water has been drunk than is necessary to restore fluid balance within the body. This proposal was tested using ratings of swallowing effort and measuring regional brain responses as participants prepared to swallow small volumes of liquid while they were thirsty and after they had overdrunk. Effort ratings provided unequivocal support for swallowing inhibition, with a threefold increase in effort after overdrinking, whereas addition of 8% (wt/vol) sucrose to water had minimal effect on effort before or after overdrinking. Regional brain responses when participants prepared to swallow showed increases in the motor cortex, prefrontal cortices, posterior parietal cortex, striatum, and thalamus after overdrinking, relative to thirst. Ratings of swallowing effort were correlated with activity in the right prefrontal cortex and pontine regions in the brainstem; no brain regions showed correlated activity with pleasantness ratings. These findings are all consistent with the presence of swallowing inhibition after excess water has been drunk. We conclude that swallowing inhibition is an important mechanism in the overall regulation of fluid intake in humans.

The instinct of thirst was a cardinal element in the successful colonization by vertebrates of the dry land of the planet, which began in the Ordovician period about 400 million y ago. It is a commonplace experience in humans that drinking water in response to thirst following fluid loss is a pleasant experience. However, continuing to drink water once thirst has been satiated becomes unpleasant and, eventually, quite aversive. Functional MRI experiments reported here show pleasantness of drinking is associated with activation in the anterior cingulate cortex (Brodmann area 32) and the orbitofrontal cortex. The unpleasantness and aversion of overdrinking is associated with activation in the midcingulate cortex, insula, amygdala, and periaqueductal gray. Drinking activations in the putamen and cerebellum also correlated with the unpleasantness of water, and the motor cortex showed increased activation during overdrinking compared with drinking during thirst. These activations in motor regions may possibly reflect volitional effort to conduct compliant drinking in the face of regulatory mechanisms inhibiting intake. The results suggestive of a specific inhibitory system in the control of drinking are unique.

BACKGROUND:Polymorphisms in the serotonin transporter gene (5-HTTLPR) modulate amygdala activity in healthy individuals. Increased responses to negative stimuli in carriers of low transcription alleles have been proposed to contribute to the pathogenesis of depression. We sought to investigate the effects of genotype as well as diagnosis in patients with depression. METHODS:Subjects with recurrent depression (n=67) and matched healthy controls (n=49) participated in a fMRI task of implicit processing of sad facial stimuli. Effects of biallelic (short (S) and long (L) alleles) and triallelic (including rs25531 A/G single nucleotide variation) models of 5-HTTLPR polymorphisms on amygdala activity and connectivity were investigated. RESULTS:Significant effects were observed of both genotype and diagnosis on amygdala activity. Increased amygdala activity was associated with 5-HTTLPR genotype in low transcription allele carriers as well as with a diagnosis of depression. The connectivity analysis revealed a main effect of genotype with reduced connectivity to the subgenual region of the anterior cingulate in carriers of the low transcription alleles. There was also a main effect of diagnosis with reduced connectivity to the dorsal region of the anterior cingulate and to the dorsolateral prefrontal cortex in depression. There were no interaction effects between genotype and diagnosis in amygdala activity or connectivity. CONCLUSIONS:Significant independent effects of genotype and diagnosis on amygdala responsivity were revealed. The effects of genotype and diagnosis on amygdala connectivity showed a regional segregation, suggesting that 5-HTTLPR polymorphisms bias frontal-limbic connectivity while the development of depression involves more extensive neural disturbances. These findings point to the potential of connectivity maps as a diagnostic biomarker for depression.