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Background: Cough is a defense mechanism that protects the airways and lungs in response to airway irritation. The sensory neurons involved in detecting airway irritants and the neural pathways mediating cough share similarities with those that encode pain from the body. Painful conditioning stimuli applied to one body site are known to reduce the perception of pain at another. However, whether the neural regulation of cough is influenced by painful stimuli is not known., Research Question: What are the behavioral and neural outcomes of painful conditioning stimuli on urge-to-cough (UTC) and cough evoked by inhaled capsaicin?, Study Design and Methods: Sixteen healthy participants underwent psychophysical testing and functional MRI while completing a series of capsaicin inhalations to induce UTC and cough. The responses associated with capsaicin inhalation without pain were compared with those after the application of painful conditioning stimuli., Results: Significant decreases were seen behaviorally of 18.7% ± 17.3% (P < .001) and 47.0% ± 30.8% (P < .001) in participants' UTC ratings and cough frequencies, respectively, during the application of pain. UTC ratings were reduced by 24.2% ± 36.5% (P < .005) and increased by 67% ± 40% (P < .001) for capsaicin and saline inhalation, respectively, during the scanning session. Painful conditioning stimuli were associated with widespread decreases in regional brain responses to capsaicin inhalation (P < .001). Several brain regions showed levels of reduced activation attributable to painful conditioning that correlated with related changes in behavioral responses during scanning (R 2  = 0.53)., Interpretation: Pain-related decreases of cough and UTC are accompanied by widespread changes in brain activity during capsaicin inhalation, suggesting that pain can modify the central processing of inputs arising from the airways. A mechanistic understanding of how cough and pain processing interact within the brain may help develop more effective therapies to reduce unwanted coughing., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: The authors declare no competing interest.

Cough is important for airway defence, and studies in healthy animals and humans have revealed multiple brain networks intimately involved in the perception of airway irritation, cough induction and cough suppression. Changes in cough sensitivity and/or the ability to suppress cough accompany pulmonary pathologies, suggesting a level of plasticity is possible in these central neural circuits. However, little is known about how persistent inputs from the lung might modify the brain processes regulating cough.In the present study, we used human functional brain imaging to investigate the central neural responses that accompany an altered cough sensitivity in cigarette smokers.In nonsmokers, inhalation of the airway irritant capsaicin induced a transient urge-to-cough associated with the activation of a distributed brain network that included sensory, prefrontal and motor cortical regions. Cigarette smokers demonstrated significantly higher thresholds for capsaicin-induced urge-to-cough, consistent with a reduced sensitivity to airway irritation. Intriguingly, this was accompanied by increased activation in brain regions known to be involved in both cough sensory processing (primary sensorimotor cortex) and cough suppression (dorsolateral prefrontal cortex and the midbrain nucleus cuneiformis). Activations in the prefrontal cortex were highest among participants with the least severe smoking behaviour, whereas those in the midbrain correlated with more severe smoking behaviour.These outcomes suggest that smoking-induced sensitisation of central cough neural circuits is offset by concurrently enhanced central suppression. Furthermore, central suppression mechanisms may evolve with the severity of smoke exposure, changing from initial prefrontal inhibition to more primitive midbrain processes as exposure increases., Competing Interests: Conflict of interest: A. Ando has nothing to disclose. Conflict of interest: S.B. Mazzone reports grants from The University of Melbourne (NHMRC grant 1078943), during the conduct of the study; grants and personal fees from Merck Sharpe & Dohme, outside the submitted work. Conflict of interest: M.J. Farrell reports grants from The University of Melbourne (NHMRC grant 1078943), during the conduct of the study., (Copyright ©ERS 2019.)

Cough is an important protective mechanism for clearing the airways but becomes a troublesome, and often difficult to treat, symptom in respiratory disease. Although cough can be produced as a reflex in response to the presence of irritants within the airways, emerging research demonstrates an unappreciated complexity in the peripheral and central neural systems that regulate cough. This complexity includes multiple primary sensory neurons that can induce or facilitate reflex coughing, different ascending central circuits in the brain that contribute to cough sensory discrimination and the perception of the urge-to-cough, and several descending brain systems for inducing, facilitating and inhibiting cough responses. Consequently, the mechanisms responsible for cough becoming dysregulated in disease are not likely homogeneous across all patients with chronic cough. The available data suggests that changes in primary sensory neuron excitability, altered central nervous system integration of sensory inputs and changes in descending control mechanisms may each contribute to the development of cough hypersensitivity., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: Cognitive behavioral therapies decrease pain and improve mood and function in people with osteoarthritis. This study assessed the effects of coping strategies on the central processing of knee pain in people with osteoarthritis of the knees., Methods: Mechanical pressure was applied to exacerbate knee pain in 28 people with osteoarthritis of the knee. Reports of pain intensity and functional magnetic resonance imaging measures of pain-related brain activity were recorded with and without the concurrent use of pain coping skills., Results: Coping skills led to a significant reduction in pain report (Coping = 2.64 ± 0.17, Not Coping = 3.28 ± 0.15, P < 0.001). These strategies were associated with increased activation in pain modulatory regions of the brain (medial prefrontal and rostral anterior cingulate cortices, Pcorrected < 0.05) and decreased pain-related activation in regions that process noxious input (midcingulate cortex, supplementary motor area, secondary somatosensory cortex, and anterior parietal lobule, Pcorrected < 0.05). The magnitude of the decrease in pain report during the use of pain coping strategies was found to be proportional to the decrease in pain-related activation in brain regions that code the aversive/emotional dimension of pain (anterior insula, inferior frontal gyrus, orbitofrontal cortex, Pcorrected < 0.05) but did not differ between groups with and without training in coping skills. However, training in coping skills reduced the extent to which brain responses to noxious input were influenced by anxiety., Conclusions: The results of this study support previous reports of pain modulation by cognitive pain coping strategies and contribute to the current understanding of how analgesia associated with the use of pain coping strategies is represented in the brain.

Sweating events occur in response to mental stress (psychogenic) or with increased body temperature (thermogenic). We previously found that both were linked to activation of common brain stem regions, suggesting that they share the same output pathways: a putative common premotor nucleus was identified in the rostral-lateral medulla (Farrell MJ, Trevaks D, Taylor NA, McAllen RM. Am J Physiol Regul Integr Comp Physiol 304: R810-R817, 2013). We therefore looked in higher brain regions for the neural basis that differentiates the two types of sweating event. Previous work has identified hemispheric activations linked to psychogenic sweating, but no corresponding data have been reported for thermogenic sweating. Galvanic skin responses were used to measure sweating events in two groups of subjects during either psychogenic sweating (n = 11, 35.3 ± 11.8 yr) or thermogenic sweating (n = 11, 34.4 ± 10.2 yr) while regional brain activation was measured by BOLD signals in a 3-Tesla MRI scanner. Common regions activated with sweating events in both groups included the anterior and posterior cingulate cortex, insula, premotor cortex, thalamus, lentiform nuclei, and cerebellum (P(corrected) < 0.05). Psychogenic sweating events were associated with significantly greater activation in the dorsal midcingulate cortex, parietal cortex, premotor cortex, occipital cortex, and cerebellum. No hemispheric region was found to show statistically significantly greater activation with thermogenic than with psychogenic sweating events. However, a discrete cluster of activation in the anterior hypothalamus/preoptic area was seen only with thermogenic sweating events. These findings suggest that the expected association between sweating events and brain regions implicated in "arousal" may apply selectively to psychogenic sweating; the neural basis for thermogenic sweating events may be subcortical., (Copyright © 2015 the American Physiological Society.)

Complex sensations accompany the activation of sensory neurons within the respiratory system, yet little is known about the organization of sensory pathways in the brain that mediate these sensations. In the present study, we employ anterograde viral neuroanatomical tract tracing with isogenic self-reporting recombinants of HSV-1 strain H129 to map the higher brain regions in receipt of vagal sensory neurons arising from the trachea versus the lungs, and single-cell PCR to characterize the phenotype of sensory neurons arising from these two divisions of the respiratory tree. The results suggest that the upper and lower airways are predominantly innervated by sensory neurons derived from the somatic jugular and visceral nodose cranial ganglia, respectively. This coincides with central circuitry that is predominately somatic-like, arising from the trachea, and visceral-like, arising from the lungs. Although some convergence of sensory pathways was noted in preautonomic cell groups, this was notably absent in thalamic and cortical regions. These data support the notion that distinct afferent subtypes, via distinct central circuits, subserve sensations arising from the upper versus lower airways. The findings may explain why sensations arising from different levels of the respiratory tree are qualitatively and quantitatively unique.

Coughing and the urge-to-cough are important mechanisms that protect the patency of the airways, and are coordinated by the brain. Inhaling a noxious substance leads to a widely distributed network of responses in the brain that are likely to reflect multiple functional processes requisite for perceiving, appraising, and behaviorally responding to airway challenge. The broader brain network responding to airway challenge likely contains subnetworks that are involved in the component functions required for coordinated protective behaviors. Functional connectivity analyses were used to determine whether brain responses to airway challenge could be differentiated regionally during inhalation of the tussive substance capsaicin. Seed regions were defined according to outcomes of previous activation studies that identified regional brain responses consistent with cough suppression, stimulus intensity coding, and perception of urge-to-cough. The subnetworks during continuous inhalation of capsaicin recapitulated the distributed regions previously implicated in discrete functional components of airway challenge. The outcomes of this study highlight the central representation of airways defence as a distributed network., (Copyright © 2014 Wiley Periodicals, Inc.)

Cough is a complex respiratory behavior essential for airway protection, consisting of sensory, motor, affective and cognitive attributes. Accordingly, the cough neural circuitry extends beyond a simple pontomedullary reflex arc to incorporate a network of neurons that are also widely distributed throughout the subcortical and cortical brain. Studies have described discrete regional responses in the brain that likely give rise to sensory discriminative processes, voluntary and urge-related cough control mechanisms and aspects of the emotive responses following airways irritation and coughing. Data from these studies highlight the central nervous system as a plausible target for therapeutic intervention and, consistent with this, a careful appraisal of the many and varied clinical disorders of coughing control would argue that more diversified therapies are needed to treat patients with cough dysfunction. In this paper we explore these concepts in detail to highlight unanswered questions and stimulate discussion for potential research of cough in the future., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

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.

Rationale: Antitussive therapies are accompanied by a substantial placebo effect, indicating that inhibitory circuits in the brain have a significant capacity to regulate cough neural processing. However, essentially nothing is known about the identity of these inhibitory circuits or how they reduce coughing. Understanding these processes may help develop more effective antitussive therapies in the future., Objectives: To identify regional changes in human brain activity related to the urge-to-cough after placebo antitussive administration., Methods: Seventeen healthy participants undertook functional magnetic resonance imaging while completing a series of inhalations of capsaicin to induce the urge-to-cough. The resultant brain responses associated with capsaicin inhalation without any treatment were compared with those induced by capsaicin after placebo antitussive administration., Measurements and Main Results: There was a significant decrease in participants' ratings of urge-to-cough after the placebo antitussive administration. Brain activity associated with capsaicin inhalation was less in the somatosensory, primary motor, insula, and cingulate cortices during placebo antitussive trials compared with no treatment control subjects. By contrast, placebo trials were associated with increased activation in the prefrontal and left parietal cortices., Conclusions: Placebo-related decreases in urge-to-cough are accompanied by commensurate decreases in several brain regions activated during capsaicin inhalation, suggesting that beliefs about treatment can modify the central processing of inputs arising from the airways. The prefrontal cortex and posterior parietal cortex are likely to play an active role in the modification of airway sensory processing after administration of a placebo.

Unlabelled: The diversity of chronic pain syndromes and the methods employed to study them make integrating experimental findings challenging. This study performed coordinate-based meta-analyses using voxel-based morphometry imaging results to examine gray matter volume (GMV) differences between chronic pain patients and healthy controls. There were 12 clusters where GMV was decreased in patients compared with controls, including many regions thought to be part of the "pain matrix" of regions involved in pain perception, but also including many other regions that are not commonly regarded as pain-processing areas. The right hippocampus and parahippocampal gyrus were the only regions noted to have increased GMV in patients. Functional characterizations were implemented using the BrainMap database to determine which behavioral domains were significantly represented in these regions. The most common behavioral domains associated with these regions were cognitive, affective, and perceptual domains. Because many of these regions are not classically connected with pain and because there was such significance in functionality outside of perception, it is proposed that many of these regions are related to the constellation of comorbidities of chronic pain, such as fatigue and cognitive and emotional impairments. Further research into the mechanisms of GMV changes could provide a perspective on these findings., Perspective: Quantitative meta-analyses revealed structural differences between brains of individuals with chronic pain and healthy controls. These differences may be related to comorbidities of chronic pain., (Copyright © 2013 American Pain Society. Published by Elsevier Inc. All rights reserved.)

The perception of airways irritation is represented in a distributed brain network. However, the functional roles of sub-regions of this network are yet to be determined. The aim of this study was to measure brain activation in healthy participants as they inhaled two doses of capsaicin to identify dose-dependent and dose-independent responses. Blood oxygen level-dependent functional magnetic resonance imaging (fMRI) measures of brain responses during inhalation of saline, and a low and high dose of capsaicin were made from 16 healthy participants. Subjective ratings of the urge-to-cough were also made during capsaicin challenges. The majority of brain regions that were activated during capsaicin inhalation, including insula and mid cingulate cortex, showed graduated responses to the two doses of capsaicin. Prefrontal and parietal regions had dose-independent activation, whereas premotor regions and the cerebellum activated exclusively at the high dose of capsaicin. Activation in the somatosensory and mid-cingulate cortices correlated with ratings of urge-to-cough. In the brainstem, capsaicin produced dose-dependent activations in respiratory-related regions of the dorsal pons and lateral medulla. These data show dissociable response patterns to capsaicin inhalation that may represent different regional processes involved in monitoring and assessing stimulus intensity, determining the spatial localization of the stimulus and suppressing motor responses., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: This review summarizes the scientific literature addressing the effects of aging on pain processing in the brain., Design: A literature search was undertaken using PubMed and search terms including pain, aging, and brain., Settings and Patients: Studies including healthy older people and older people with painful disorders were reviewed., Measures: Publications reporting the outcomes of neuroimaging techniques including positron emission tomography, structural and functional magnetic resonance imaging, and electroencephalography in samples incorporating older people were reviewed., Results: Age-related decreases in regional brain volume occur in structures implicated in pain processing, and are most pronounced in the prefrontal cortex and hippocampus, whereas age-related atrophy in brainstem regions involved in pain modulation is less pronounced. Functional brain imaging has revealed decreased pain activation in the putamen and insula among older people during extrinsic stimuli, but any effects of aging on the processing of clinical pain are yet to be reported., Conclusions: The network of brain regions involved in pain processing are subject to age-related changes in structure, but that the functional implications of these changes are yet to be determined., (Wiley Periodicals, Inc.)

Patients with Alzheimer's disease (AD) are administered fewer analgesics and report less clinical pain compared with their cognitively-intact peers, prompting much speculation about the likely impact of neurodegeneration on pain perception and processing. This study used functional connectivity analysis to examine the impact of AD on the integrated functioning of brain regions mediating the sensory, emotional, and cognitive aspects of pain. Fourteen patients with AD and 15 controls attended two experimental sessions. In an initial psychophysical testing session, a random staircase procedure was used to assess sensitivity to noxious mechanical pressure applied to the thumbnail. In a subsequent brain imaging session, fMRI data were collected as participants received noxious or innocuous thumbnail pressure, delivered at intensities corresponding with previously identified subjective pain thresholds. Two approaches to functional connectivity analysis were utilised. A seed-based correlation method was first used to identify regions showing significant functional connectivity with the right dorsolateral prefrontal cortex (DLPFC). Functional connectivity between a network of 17 predefined pain processing regions was then assessed. Between-group comparisons revealed enhanced functional connectivity between the DLPFC and the anterior mid cingulate cortex, periaqueductal grey, thalamus, hypothalamus, and several motor areas in patients with AD compared with control group. Likewise, inter-regional functional connectivity across most regions of the predefined pain network was shown to be greater in the patient group, with the enhanced functional connectivity centred on three nodes: the DLPFC-R, hypothalamus, and PAG. The results of this study support previous research suggesting an interplay between pain and cognitive processes in patients with AD., (Copyright © 2010 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.)

Compared with young adults, older people report more chronic pain complaints, and show reduced tolerance to experimental pain. Atrophy of brain parenchyma in normal ageing is well documented, with grey matter reduction occurring across many regions known to be involved in pain processing. However, the functional consequences of these changes, in particular their contribution toward age-related differences in pain perception and report, are yet to be elucidated. The present study investigated the effects of ageing on supraspinal pain processing by comparing regional brain responses to noxious pressure stimulation in 15 young (aged 26+/-3 years) and 15 older (aged 79+/-4 years) adults. Both groups showed significant pain-related activity in a common network of areas including the insula, cingulate, posterior parietal and somatosensory cortices. However, compared with older adults, young subjects showed significantly greater activity in the contralateral putamen and caudate, which could not be accounted for by increased age-associated shrinkage in these regions. The age-related difference in pain-evoked activity seen in the present study may reflect reduced functioning of striatal pain modulatory mechanisms with advancing age., (Copyright 2008 Elsevier Inc. All rights reserved.)

This study used arterial spin labeling (ASL) fMRI to measure brain perfusion in a group of healthy men under conditions that closely resembled customary sexual behavior. Serial perfusion measures for 30 min during two self-limited periods of partnered penis stimulation, and during post-stimulatory periods, revealed novel sexual activity-related cerebral blood flow (rCBF) changes, mainly in subcortical parts of the brain. Ventral pallidum rCBF was highest during the onset of penile erection, and lowest after the termination of penis stimulation. The perceived level of sexual arousal showed the strongest positive association with rCBF in the right basal forebrain. In addition, our results demonstrate that distinct subregions of the hypothalamus and cingulate cortex subserve opposite functions during human male sexual behavior. The lateral hypothalamus and anterior part of the middle cingulate cortex showed increased rCBF correlated with penile erection. By contrast, the anteroventral hypothalamus and subgenual anterior cingulate cortex exhibited rCBF changes correlated with penile detumescence after penile stimulation. Continuous rapid and high-resolution brain perfusion imaging during normal sexual activity has provided novel insights into the central mechanisms that control male sexual arousal., (Copyright (c) 2009 Elsevier Inc. All rights reserved.)

Several indications suggest that supramedullary brain regions receive sensory information from the airways and provide motor control to the brainstem neurons that control coughing. However, the organization of this circuitry has not been described in any detail. In this short review we will discuss how state-of-the-art functional brain imaging techniques in humans and animals will enable unprecedented insights into the supramedullary brain regions that help control coughing. In addition we will describe the likely similarities between cough-related higher brain networks and those involved in the processing of other aversive sensory modalities, such as pain.

Rationale: Coughing in humans is typically preceded by a desire (or urge) to cough. The neural circuitry involved in sensing airway irritation and generating the urge-to-cough in humans is essentially unknown., Objectives: The aim of the present study was to use functional brain imaging to describe the supramedullary regions that are activated in humans during capsaicin inhalation., Methods: Experiments were performed on 10 healthy subjects (5 males, 5 females). Capsaicin doses were individually tailored to evoke a transient and reversible urge-to-cough. Blood oxygen level-dependent (BOLD) functional magnetic resonance measures were collected during repeated 24-second challenges with capsaicin or saline inhalation and subjects were asked to rate the urge-to-cough intensity of each challenge., Measurements and Main Results: Capsaicin inhalation reliably evoked an urge-to-cough, which was associated with activations in a variety of brain regions, including the insula cortex, anterior midcingulate cortex, primary sensory cortex, orbitofrontal cortex, supplementary motor area, and cerebellum., Conclusions: These data provide the first insights into the cortical neuronal network involved in sensing airway irritation and modulating coughing in humans.

People with Alzheimer's disease are administered fewer analgesics and report less clinical pain than cognitively intact peers with similar painful diseases or injuries, prompting speculation about the likely impact of neurodegeneration on central pain processing. The present study measured pain ratings and functional MRI (fMRI) brain responses following mechanical pressure simulation in 14 patients with Alzheimer's disease and 15 age-matched controls. Contrary to the prevailing hypothesis that this disease is likely to differentially reduce emotional responses to pain, we show that activity in both medial and lateral pain pathways is preserved. Moderate pain was evoked with similar stimuli in both groups, and was associated with a common network of pain-related activity incorporating cingulate, insula and somatosensory cortices. Between-group analyses showed no evidence of diminished pain-related activity in Alzheimer's disease patients compared with controls. In fact, compared with controls, patients showed greater amplitude and duration of pain-related activity in sensory, affective and cognitive processing regions consistent with sustained attention to the noxious stimulus. The results of this study show that pain perception and processing are not diminished in Alzheimer's disease, thereby raising concerns about the current inadequate treatment of pain in this highly dependent and vulnerable patient group.

The capacity of pain to alert against potential injury or focus attention on damaged tissue is enhanced by the intrinsically aversive nature of the experience. Finding methods to relieve pain will ultimately be facilitated by deeper understanding of the processes that contribute to the experience, and functional brain imaging has contributed substantially toward that end. An impressive body of literature has identified a distributed network of pain-related activity in the brain that is subject to considerable modulation by different stimulus parameters, contextual factors, and clinical conditions. The fundamental substrates of the pain network are yet to be distilled from the highly variable results of studies published thus far. Qualitative reviews of the pain-imaging literature have been contributory, but lack the greater surety of quantitative methods. We employ the activation likelihood estimation (ALE) meta-analytic technique to establish the most consistent activations among studies reporting brain responses subsequent to the application of noxious heat. A network of pain-related activity was replicated for stimuli to either upper limb that included two discernible regions of the mid-anterior cingulate cortex, bilateral thalami, insula, and opercula cortices, posterior parietal cortex, premotor cortex, supplementary motor area, and cerebellum. The findings of the meta-analysis resonate with other streams of information that continue to enhance our understanding of pain in the brain. The results also point toward new areas of research that may be fruitful for the exploration of central pain processing.

This study used positron-emission tomography to establish the patterns of brain activity involved in the isolated and concurrent experiences of thirst and pain. Ten subjects were scanned while experiencing pain evoked with noxious pressure, while experiencing thirst after the infusion of hypertonic saline, and while experiencing pain when thirsty. After the onset of thirst, noxious pressure evoked more intense sensations of pain. Noxious pressure did not change subjective ratings of thirst. Thirst caused activation in the anterior cingulate (Brodmann area 32) and the insula. Enhanced pain responses were associated with increased activity in cortical regions that are known to correlate with pain intensity, and also with unique activity in the pregenual anterior cingulate and ventral orbitofrontal cortex. These findings suggest a role for limbic and prefrontal cortices in the modulation of pain during the experience of thirst. [ABSTRACT FROM AUTHOR]