Cortical activation and lamina terminalis functional connectivity during thirst and drinking in humans

M. J. Farrell, T. K. Bowala, M. Gavrilescu, P. A. Phillips, M. J. McKinley, R. M. McAllen, D. A. Denton and G. F. Egan
Am J Physiol Regul Integr Comp Physiol 301:R623-R631, 2011. First published 15 June 2011; doi: 10.1152/ajpregu.00817.2010 You might find this additional info useful... Supplementary material for this article can be found at: http://ajpregu.physiology.org/http://ajpregu.physiology.org/content/suppl/2011/08/02/ajpregu.0081 7.2010.DC1.html This article cites 46 articles, 17 of which you can access for free at: http://ajpregu.physiology.org/content/301/3/R623.full#ref-list-1 Updated information and services including high resolution figures, can be found at: http://ajpregu.physiology.org/content/301/3/R623.full Additional material and information about American Journal of Physiology - Regulatory, Integrative and Comparative Physiology can be found at: http://www.the-aps.org/publications/ajpregu This information is current as of November 23, 2012.
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American Journal of Physiology - Regulatory, Integrative and Comparative Physiology publishes original investigations that illuminate normal or abnormal regulation and integration of physiological mechanisms at all levels of biological organization, ranging from molecules to humans, including clinical investigations. It is published 12 times a year (monthly) by the American Physiological Society, 9650 Rockville Pike, Bethesda MD 20814-3991. Copyright © 2011 the American Physiological Society. ISSN: 0363-6119, ESSN: 1522-1490. Visit our website at http://www.the-aps.org/.

Bowala. 2012 Submitted 15 December 2010.1. Parkville. Parkville. Dentistry and Health Sciences. Indeed. it has been proposed that osmoreceptive units within the OVLT relay osmoregulatory signals to both the cingulate and insula to generate thirst (24). prefrontal cortex. Cerebral osmoreceptors that control both thirst and vasopressin secretion are located within the organum vasculosum of the lamina terminalis (OVLT) (31. 17–19). and areas in the prefrontal and temporal gyri (13.1152/ajpregu. Egan GF. increased blood osmolality. Human functional brain imaging studies of thirst have rarely identified activation in the ventral lamina terminalis (LT). insula. 35. Regional brain activations during dehydration. the telencephalic neural correlates of consciousness of thirst have only recently begun to be identified. rCBF measurements in the ventral lamina terminalis were correlated with whole brain rCBF measures to identify regions that correlated with the osmoreceptive region. Furthermore.1. Australia Downloaded from http://ajpregu. accepted in final form 3 June 2011 1 Farrell MJ.2010.ajpregu. BA24 of the midcingulate cortex. F. Gavrilescu M. Recently. 29). http://www.2 T. J. A. the demonstrated capacity of PASL fMRI to identify activations using images acquired 24 h apart suggests an ideal R623 0363-6119/11 Copyright © 2011 the American Physiological Society . The semiquantitative measures acquired with PASL are stable over extended periods up to 24 h (42). and their mode of function as osmoreceptors and Na receptors is delineated. 3Department of Physiology. and postdrinking were consistent with the network previously identified during systemic hypertonic infusions. Prahran. this study involved exercise-induced sweating in 15 people and measures of regional cerebral blood flow (rCBF) using a functional magnetic resonance imaging technique called pulsed arterial spin labeling. Alfred Hospital. 30. A. subthalamic elements involved in the genesis of thirst are well identified. Regions implicated in the experience of thirst were identified including cingulate cortex. Phillips. fMRI. which is particularly suited to the investigation of the OVLT. and cerebellum.00817. the parahippocampal gyrus. 19). and 6Baker Heart Research Institute. 38. Some of these cortically projecting thalamic neurons were shown to be activated by a thirst-producing stimulus (hypertonicity). Farrell.—The pattern of regional brain activation in humans during thirst associated with dehydration. With the objective of investigating the neuroanatomical correlates of dehydration and activation in the ventral lamina terminalis. Victoria. McAllen RM. 2Centre for Neuroscience. parahippocampus. 18. suggesting that functional connectivity of the ventral lamina terminalis is a dynamic process influenced by hydration status and ingestive behavior. Whereas. Egan1.1. precuneus. thirst. VIC 3010.2 M. there is little information available about associations between activation in osmoreceptive brain regions such as the organum vasculosum of the lamina terminalis and the brain regions implicated in thirst and its satiation in humans. 2011. 32). Univ.5 M. Significantly. Victoria.6 and G. the correlation of rCBF between the ventral lamina terminalis and the cingulate cortex and insula was different for the states of thirst and recent drinking. thirst THIRST IS THE SUBJECTIVE COMPONENT of the genetically programmed behavior subserving the intention to drink in the face of dehydration. which means the technique can be used to investigate steady or slowly evolving states like thirst. BA29 and BA26 of the posterior cingulate cortex. South Australia. First published June 15. Australia. M. Moreover.1 P. Cortical activation and lamina terminalis functional connectivity during thirst and drinking in humans.1 D.4. McKinley. 2011. doi:10. CALL FOR PAPERS Mitochondrial Function/Dysfunction in Health and Disease Cortical activation and lamina terminalis functional connectivity during thirst and drinking in humans M. striatum. Gavrilescu.2 Howard Florey Institute. median preoptic nucleus (MnPO) (9. thus providing further evidence that the network is involved in monitoring body fluid and the experience of thirst.2010. 2011. Therefore. dorsomedial thalamus. J. McKinley MJ. of Melbourne.00817. the BA32 activity decreased below threshold within 3 min of drinking water with a corresponding loss of thirst sensation (13).au). University of Melbourne. Farrell.3 R. Australia. Bowala TK. tract tracing studies using pseudorabies virus have shown that polysynaptic efferent connections from all parts of the OVLT are relayed to insula and cingulate cortices via several medially located thalamic nuclei (24). and subfornical organ (23. The majority of thirst studies have used positron emission tomography (12.Am J Physiol Regul Integr Comp Physiol 301: R623–R631. Australia (e-mail: farrellm@unimelb. and 4Office of the Dean. which is limited in resolution to identify activation in a structure as small as the OVLT.org (BA) 32 of the anterior cingulate cortex. Denton. 13. A recently developed functional MRI (fMRI) technique with similar spatial resolution to BOLD fMRI is pulsed arterial spin labeling (PASL) (15). Am J Physiol Regul Integr Comp Physiol 301: R623–R631. suggesting a strong involvement of this region in the consciousness of thirst. nontagged image to give an estimate of rCBF. 39). 2011. doi:10.physiology. PASL magnetically labels arterial blood water before acquiring an image. and decreased blood volume is not known. significant numbers of osmotically stimulated neurons within the OVLT and MnPO project to these thalamic sites. First published June 15. Adelaide. Denton DA. which can be subtracted from a second.edu.1152/ajpregu. McAllen. Studies using systemic infusion of hypertonic saline to raise plasma sodium concentration and osmotic pressure have identified activations in Brodmann area Address for reprint requests and other correspondence: M. 5School of Medicine. K.org/ by guest on November 23. Phillips PA. Faculty of Medicine. Centre for Neuroscience. Flinders University. Furthermore. We previously reported on two of four case studies showing increased blood oxygen level-dependent (BOLD) signal in the anterior wall of the third ventricle during steep increases of thirst associated with systemic hypertonic infusion (17).

We hypothesized that fluid loss would lead to thirst activation in brain regions previously identified in response to systemic hypertonic infusion. Blood for analysis of hematocrit (1 ml) was collected into a heparinized tube to minimize red cell rupture. Hematocrit was measured with an impedance analyzer. The identification of connections from the OVLT to cortical regions via relay in the thalamus in animals has been achieved using techniques that are inapplicable to experiments involving humans. Drinking was interrupted by two 5-min scans (Post-Drink) 5 to 20 min after beginning drinking. salty.R624 CONNECTIVITY OF THE THIRST NETWORK method to investigate thirst arising from fluid loss and/or deprivation. Plasma AVP was quantified in rat blood using a commercial RIA kit (EuroDiagnostica.5 h after the initiation of drinking for two further scans that represented the control. Australia by using a 3-Tesla Magnetom Trio scanner (Siemens. participants were allowed free access to water. All participants provided written consent to participate in the study. Malmo. However. Ad libitum drinking commenced following the Maximum Thirst scans and continued for 150 min. Thirst ratings and blood chemistry levels. All blood samples were immediately transferred to ice after labeling.physiology. 1. 2012 The University of Melbourne Human Ethics Subcommittee and the Howard Florey Institute Human Ethics Committee approved this study. Sweden) (11). Fifteen healthy participants exercised on a stationary cycle at 60% of heart rate reserve (28) for 30 min. since the ROI method uses the time course of signals from the predefined region as an independent variable to determine common variance in all other regions of the brain. Erlangen. Blood for analysis of hematocrit (1 ml) was collected into a heparinized tube to minimize red cell rupture. After the conclusion of the Post-Drink scans. time ϭ 15 min). a standard bird cage head coil. echo time ϭ 20 ms. All blood samples were immediately transferred to ice after labeling. 5 ml of blood was withdrawn into a normal tube. Participants then left the scanner and returned 2. Interleaved control and tagged images were acquired with the following parameters: repetition time ϭ 3 s. corn chips) throughout the experimental protocol. the brain imaging technique of functional connectivity enables the assessment of correlations between activation in the OVLT and activation elsewhere in the human brain. Blood was drawn from the antecubital vein during the interval between each pair of functional imaging scans while participants were lying in the scanner. Participants were not selected on the basis of physical fitness. They abstained from drinking for a further 4. The functional connectivity region of interest (ROI) approach is appropriate for the identification of brain regions correlated with the OVLT. PASL images were acquired for each participant using a modified flowsensitive alternating inversion recovery sequence (43).ajpregu. A single voxel of interest (VOI) from the anterior wall of the third ventricle was used to investigate the functional connectivity of the LT. The functional connectivity technique identifies regions distributed throughout the brain that have correlated time series signal changes (21). For the other blood measures. A: subjects reported a moderate level of thirst after the first pair of functional brain imaging scans (Maximum Thirst. We also hypothesized that the ventral LT would show functional connectivity with the medial thalamus. followed by ad libitum drinking and two further 5-min Post-Drink scans 5 to 15 min later.org . flip angle ϭ 90. and no acquisition acceleration factor. MATERIALS AND METHODS vided as supplementary information (see Supplementary Material posted with the online version of this article). Magnetic resonance imaging. hydrated state. 0. Healthy participants were recruited for the study through advertisements posted in public places. Germany). Plasma osmolality was measured using the freezing point depression method. B: water imbibed correlated with changes in plasma osmolality from the Maximum Thirst scans to the control scans. snack food (potato crisps.05). This study used perfusion fMRI to investigate brain activation during thirst and drinking after fluid loss subsequent to exercise-related sweating. and cingulate cortex that would be greater during thirst and drinking compared with a nonthirsty. Defining the region according to each participant’s neuroanatomy enables accurate identification of the OVLT ROI. Experimental protocol. A tabulated time line of the experimental protocol is proAJP-Regul Integr Comp Physiol • VOL Fig. The sample consisted of 15 people with a median age of 23 yr (range 19 to 41 yr) of whom four were women. The thirst rating declined precipitately after drinking began and was low 150 min later.7-s Downloaded from http://ajpregu. 301 • SEPTEMBER 2011 • www. Melbourne. 5 ml of blood was withdrawn into a normal tube. MRI imaging was carried out at the Childrens’ MRI Centre.5 h before attending two scanning sessions. The first scanning session consisted of two 5-min fMRI scans of Maximum Thirst. For the other blood measures. Participants were given access to dry. Containers of water were weighed before and after each bout of drinking to establish the volume of water ingested throughout the experimental protocol. Participants provided thirst ratings after each pair of scans using a 0 to 10 rating scale.org/ by guest on November 23. insula. Blood samples showed that plasma osmolality decreased between the Post-Drink and control scans (*P Ͻ 0. Drinking prior to and between the Post-Drink scans occurred while participants were lying in the scanner with the aid of a cycling hydration pack.

29 3. The effects of head movement and physiological noise were accounted for by regressing the estimated motion parameters and two time courses extracted from CSF from the lateral ventricle and deep white matter as described in Fox et al.42 3.05 corrected for multiple comparisons.17 3.55 4. (42). and cerebrospinal fluid (CSF) images using SPM2 (www. the VOI incorporated the midline region but was occasionally offset such that a greater proportion of the voxel was in one or the other hemisphere.33 3.org/ by guest on November 23. The rCBF estimates extracted from each VOI were regressed Downloaded from http://ajpregu. Post-Drink.ucl. rapid gradient-echo acquisition in sagittal orientation (512 ϫ 512 matrix. are likely to involve relatively slow changes in brain activation during the 10 min of image acquisition for each of the phases of the study (Maximum Thirst. Brodmann area.68 3.23 3. an extra image of equilibrium tissue magnetization (M0) was acquired at the start of each PASL imaging run.uk) to preserve the grey matter border. AJP-Regul Integr Comp Physiol • VOL 301 • SEPTEMBER 2011 • www. Two runs of 98 PASL images were collected for each of the three functional states (Maximum Thirst.fil.63 3.29 3.50 3.12 3. Activations had a voxel inclusion value of Z ϭ 2.22 3. positive z values are superior. Positive x values are to the right. 1-s postlabeling delay.ajpregu. PASL images were denoised prior to rCBF estimation because there is evidence that noise due to physiological processes and other factors can have a differential impact on the control and tagged images (37). which incorporates osmoreceptors and has been implicated in the control of fluid balance in animals.50 3. rCBF estimates were used to perform functional connectivity analysis because the stability of the measures makes it possible to identify low-frequency changes that would be confounded by signal drift if blood oxygen. Data preprocessing for functional connectivity estimation was performed as follows. negative x values are to the left.10 BA. In all cases. and negative z values are inferior of the anterior commissure.uk/spm).CONNECTIVITY OF THE THIRST NETWORK R625 label time. white matter. Structural tissue-dependent spin-lattice relaxation time (T1)weighted brain images were acquired prior to PASL imaging using a magnetization-prepared. The global CBF for each image was calculated as the average value across all voxels in the grey matter CBF image.10 3.14 32 23 31 46 8 9 45 45 11 4 4 3 2 40 40 40 7 7 21 21 39 22 13 Ϫ4 6 6 48 Ϫ40 36 40 52 42 36 Ϫ58 52 Ϫ44 44 56 Ϫ56 2 Ϫ6 60 Ϫ66 50 62 22 34 14 Ϫ22 Ϫ38 44 26 44 34 22 56 Ϫ12 Ϫ10 Ϫ14 Ϫ8 Ϫ46 Ϫ42 Ϫ40 Ϫ62 Ϫ54 Ϫ52 Ϫ44 Ϫ58 Ϫ26 16 16 40 30 30 14 38 28 Ϫ6 Ϫ2 Ϫ12 50 36 30 48 58 32 32 50 52 0 Ϫ4 28 6 Ϫ2 Ϫ6 3.physiology. Estimates of rCBF were made according to Wang et al. 176 ϫ 1-mm slices). for the creation of cerebral blood flow images.27 3.ac.28 mm in plane resolution. positive y values are anterior. whole brain coverage with 24 slices and 5-mm slice thickness.5 mm2. control).20 3.fmrib. control).16 3. Previous functional connectivity studies using arterial spin labeling data have indicated that rCBF estimates based on simple subtraction are contaminated by BOLD fluctuations due to differences in the BOLD weighting between the tagged and control images (7). field of view ϭ 210 ϫ 210 mm2.31 3. The PASL images for each participant were corrected for head movement.5 ϫ 0. VOI definition.80 3.89 3. and perfusion images were calculated using an established subtraction algorithm (1).10 3.52 3.12 3. Post-Drink.79 3. The anterior commissure was identified on the mean image of the motion-corrected time series of PASL images. The outcomes of the individual transformations are shown in supplementary information (see online publication of this article).35 3.36 3. The rCBF images were masked with each subject’s grey matter image and spatially smoothed with a 6-mm kernel as implemented in FSL 4.0 (http://www.001 Hz) was used to correct low-frequency signal drift. 0.3 and a cluster level probability of P Ͻ 0.27 40 40 7 21 22 46 Ϫ54 10 Ϫ54 58 Ϫ44 Ϫ50 Ϫ64 Ϫ32 Ϫ6 60 50 50 Ϫ6 Ϫ8 3. a sinc subtraction method was used to calculate rCBF values (1). VOIs were spatially transformed according to the coregistration of each participant’s mean PASL and T1-weighted images to further evaluate the accuracy of VOI placement.ox. This region was chosen because it is the site of the OVLT. negative y values are posterior.12 3.ac. 64 ϫ 64 matrix with 3. Maximum Thirst and Post-Drink activations Maximum Thirst Brain Region BA x y z Stat BA x Post-Drink y z Stat Anterior cingulate Cortex Midcingulate cortex Posterior cingulate cortex Middle frontal gyrus Superior frontal gyrus Inferior frontal gyrus Orbitofrontal cortex Precentral gyrus Postcentral gyrus Inferior parietal lobule Supramarginal gyrus Precuneus Middle temporal gyrus Superior temporal Gyrus Putamen Insula 32 23 23 46 10 9 10 45 47 11 11 8 4 8 40 32 Ϫ46 Ϫ28 52 Ϫ42 46 Ϫ46 40 Ϫ22 Ϫ38 44 56 16 56 22 26 54 46 18 30 30 22 14 26 10 0 Ϫ4 Ϫ12 Ϫ10 3. 2012 Table 1. The segmented images were transformed into the functional data space.56 3. The voxel that was closest to the midline and immediately ventral to the anterior commissure was chosen for each participant. (20a). The coordinates of peak activations are reported as distance in millimeters from the anterior commissure according to the standard brain of the Montreal Neurological Institute.70 3.10 3.ion. To account as far as possible for BOLD contamination. the slowly changing experience of thirst and gradual repletion of fluid loss through drinking behavior.48 3.53 3. Processes associated with fluid monitoring.27 3. All T1 images were segmented into grey matter. A single VOI was used from each participant for the functional connectivity analysis. A high-pass filter (f Ͼ 0. The values in the Stat column are Z statistics of the peak voxel in a cluster of activation.31 3.org .30 3.18 3.60 3. Consequently. level-dependent contrast images were used. Data preprocessing. In addition.

org/ by guest on November 23.uk/fsl).3. 26) for group mean results (4.physiology.0001 to 0. and control periods. and precuneus activations were present during thirst. C: bilateral orbitofrontal cortices (OFC) activations were present during thirst. The statistical maps from single subjects were registered to the Montreal Neurological Institute template (8) by using linear registration (25.3. and the right insula. which revealed the absence of significant differences [F(1. D: the difference in blood flow in the rostral cingulate cortex from the Post-Drink period minus control period correlated with the volume of water that participants drank. Statistical comparisons were performed by contrasting Maximum Thirst and Post-Drink with control. The statistical analysis of the rCBF images was performed using FEAT (www.ac.ox. The rCBF change scores were tested for correlation with drinking volumes and vasopressin levels measured during the Post-Drink period.05 corrected for multiple comparisons. Pearson correlation coefficients were calculated to assess the relationship between rCBF and drinking volumes and blood chemistry. The global CBF values were averaged for each condition and compared using repeatedmeasures ANOVA. respectively. Reference to divisions of the cingulate cortex is according to the terms used by Vogt (41). left posterior insula.007 (range 0. The average R2 for the correlation between the VOIs and ventricle signals was 0. AJP-Regul Integr Comp Physiol • VOL 301 • SEPTEMBER 2011 • www. Maximum Thirst and Post-Drink scans contrasted with control scans showed increased rCBF. The Post-Drink period showed activations in right frontal operculum. The nomenclature used to describe brain activation is based on the terms used by the Harvard-Oxford atlases of cortical and subcortical structures (14). Statistical analysis. 2012 Fig. Changes of rCBF in regions of activation were calculated by subtracting the mean level of rCBF measured during the control period from the mean level of the Post-Drink period.org . A: rostral (R) anterior cingulate cortex (ACC). and middle temporal gyrus. Activations during Post-Drink were in the posterior and midanterior.fmrib. and the global signal (as a covariate of no interest). but not the rostral regions of the cingulate cortex. The functional connectivity estimation used three regressors of interest corresponding to the Maximum Thirst. 46). for each subject from the ventral LT VOI time course. Repeated-measures ANOVA was used to test for time effects on behavioral and blood measures. but activation was confined to the right hemisphere Post-Drink and was contiguous with a cluster in the inferior frontal gyrus.R626 CONNECTIVITY OF THE THIRST NETWORK against time courses from the ventricles to ensure that preprocessing had removed any shared variance between the VOI and CSF. 2. B: thirst activations were in frontal operculi. The statistical model for each participant comprised regressors for Maximum Thirst. The control condition was included as an implicit baseline.14) ϭ 0. posterior cingulate cortex (CC). Functional connectivity analysis was performed with times series of rCBF estimates. PostDrink.02). and both middle temporal gyri. The time series of the VOI were variance Downloaded from http://ajpregu. Post hoc pairwise comparisons were undertaken with dependent t-tests. Logical map of thirst and Post-Drink brain activation and correlations of regional cerebral blood flow (rCBF) with drinking behavior and vasopressin levels. not significant]. The group level Z-maps for each contrast of interest were thresholded using a voxel level threshold Z Ͼ 2.ajpregu. Post-Drink. E: levels of vasopressin measured in the blood from samples collected during the Post-Drink scans were correlated with changes in the levels rCBF between the Post-Drink and control periods in the posterior cingulate cortex (F). and a cluster level probability P Ͻ 0. Background images (black dots) are the average of all participants’ T1-weighted images after transformation to the Montreal Neurological Institute’s template. left posterior insula.

as a proportion of body wt.001] (Fig. Contrasts of parameter estimates were transformed to Z scores.74. inferior frontal gyri (IFG).4 mosm/kg. and MR images are presented to indicate the anatomy of the lamina terminalis (LT) and the location of a voxel of interest (VOI) from 1 participant.7. P Ͻ 0. namely the OFC. autoradiographic.3 and a clustercorrected level of P Ͻ 0. 1) and no significant differences in levels of hematocrit (mean ϭ 39. while decreased levels of vasopressin after drinking correlated with increased levels of Post-Drink activation in Downloaded from http://ajpregu. An average of 367 Ϯ 245 ml (0. There were no significant differences between the Maximum Thirst and PostDrink activation maps at the whole brain volume-corrected level. The unbiased global CBF estimate was then used as a regressor of no interest in the statistical model for each participant.01) (Fig. The Post-Drink period decreases in rCBF in the ACC correlated with volume of water drunk (Fig. and anterior insula (Table 1. Condition-specific connectivity maps were also calculated by contrasting parameter estimates from the Maximum Thirst and PostDrink periods with the control period. MFG. Group level connectivity maps were calculated across all three conditions to identify the network of brain regions correlated with the ventral LT VOI.org .005).58. B: both the dorsal and ventral parts of the LT contain ANG II receptors as indicated by binding of the radioligand 125 I-[Sar1. SFG. IFG. Additional blood parameters in a subset of the group (n ϭ 11). we calculated an unbiased estimator of the global CBF per scan using a two-step masking method as described in Andersson (3).3 Ϯ 4. RESULTS was confined to the right hemisphere. Changes in osmolality between Maximum Thirst and control also correlated with levels of ad libitum drinking (r ϭ 0.2%). Histological. Fig. 3. FEAT was used for general linear modeling to produce parameter estimates for the fit of each voxel to the signal from the VOI. anterior insula and inferior parietal lobules (IPL) (Table 1.physiology. The mean hematocrit value was lower than would be expected. There were also no significant decreases of rCBF during Maximum Thirst and Post-Drink periods compared with control. while activation was observed in the PCC and precuneus. The final two 5-min periods of fMRI data was then acquired (control). superior frontal gyri (SFG). and an unbiased estimate of the global CBF was then calculated using all grey matter voxels outside this group map. middle frontal gyri (MFG). given the proportion of men in the sample. The ventral portion of the LT extends between the anterior commissure and optic chiasm (ox) either side of the third ventricle (v).3. and it also occurred in the right putamen. Maximum Thirst activation in the middle temporal gyrus (MTG) and posterior insula occurred in the left hemisphere. as well as the precuneus. A group level map of regions significantly correlated (P Ͻ 0.05). Analysis of blood samples taken after each scan showed no significant changes in vasopressin levels across the course of the experimental protocol (mean ϭ 1. P Ͻ 0. 301 • SEPTEMBER 2011 • www. Inspection of individual values revealed two male participants with hematocrit values below the normal range. 2).8 Ϯ 4. Post-Drink activation was observed in the right hemisphere in many of the regions activated bilaterally during Maximum Thirst. Participants reported a maximum level of thirst after a further 4. 1).ajpregu. in the first step general linear modeling was performed for each participant without correction for global CBF variations.56 Ϯ 0.CONNECTIVITY OF THE THIRST NETWORK R627 normalized for the connectivity analysis.4% body wt) during 30 min of exercise. respectively). which was terminated after two 5-min periods of PASL perfusion fMRI image acquisition. Thirst thereafter remained at low levels during 2 h of free access to water when participants drank 916 Ϯ 245 ml of water.05) with the VOI across all three conditions was calculated. Therefore.4 to 286. The participants lost an average of 787 Ϯ 250 g (1.org/ by guest on November 23. r ϭ Ϫ0. Histology of anterior wall of third ventricle and localization of voxel for functional connectivity analysis. and axial views (E). Midline activation during Maximum Thirst was observed in the posterior and anterior cingulate cortices (PCC and ACC. revealed a decrease from Post-Drink to control in osmolality [288.33% body wt) of water was ingested during 5 min of ad libitum drinking prior to two 5-min periods of fMRI data acquisition (Post-Drink). P Ͼ 0. sagittal (D). while activation in the superior temporal gyrus AJP-Regul Integr Comp Physiol • VOL Fig. P Ͼ 0. Briefly. The ACC was not activated during the Post-Drink period.05.33 Ϯ 0.05] (Fig. Fig. Maximum Thirst and Post-Drink activation. The VOI of 1 subject is shown (orange) on their MR T1-weighted image in coronal (C).2. particularly so. 2). 2012 Physiology and behavior.Ile8]ANG II. t(11) ϭ 2. Activation was bilateral in the inferior parietal lobules and MTG during the Post-Drink period. P Ͻ 0. 2B. Murphy (34) suggested that adjusting for the global signal variations can bias the results by inducing spurious negative correlations.9 Ϯ 3. 1).23 pg/ml). Thirst ratings decreased to preexercise levels after participants were given free access to water [t(14) ϭ 7.2 Ϯ 0. A: a human brain coronal section stained with Luxol fast blue and Cresyl violet shows the dorsal part of the LT between the fornix (f) and anterior commissure (ac). and all group maps were threshold using a voxel inclusion level of Z Ͼ 2. The total volume of ad libitum drinking. and on the average EPI scan (F) at the midline immediately ventral to the anterior commissure. correlated with proportional weight loss subsequent to exercise (r ϭ 0. The contrast between the Maximum Thirst and control periods revealed bilateral activation in the orbitofrontal cortices (OFC).5 h of fluid deprivation (Maximum Thirst).

ajpregu.05 corrected for multiple comparisons. Fig.23 3.physiology. positive y values are anterior. 2012 Table 2.5 Ϯ 18.47. P Ͻ 0. First.67 3. as well as regions in the frontal. Fig.37 3.4 ml·100 gϪ1·minϪ1.25 3.30 3.10 3.76 3.9 ml·100 gϪ1·minϪ1. 3). Activations had a voxel inclusion value of Z ϭ 2.39 4. The patterns of activation in BA32 provide evidence of this region’s role in the conscious experience of thirst. Functional connectivity of the ventral lamina terminalis Brain Region BA x y z Stat Ventral Lamina Terminalis Network Midcingulate cortex Posterior cingulate cortex Precueous Middle frontal gyrus Orbitofrontal gyrus Parahippocampus Middle temporal gyrus Thalamus Caudate nucleus Ventral striatum Cerebellum 24 23 7 10 47 46 30 30 21 Ϫ4 Ϫ6 8 8 Ϫ22 38 12 Ϫ10 Ϫ54 4 Ϫ10 12 Ϫ8 10 40 Ϫ38 Ϫ28 Maximum Thirst Anterior cingulate cortex Middle frontal gyrus Superior temporal gyrus Middle temporal gyrus 32 10 22 21 10 8 Ϫ50 Ϫ48 Post-Drink Inferior frontal gyrus Orbitofrontal gyrus Postcentral gyrus Parietal operculum (SII) Superior temporal gyrus Insula Putamen Ventral striatum 46 47 47 47 22 13 13 13 Ϫ48 Ϫ40 Ϫ34 40 Ϫ64 Ϫ44 Ϫ60 Ϫ32 Ϫ42 36 22 Ϫ14 42 40 34 32 Ϫ16 Ϫ22 Ϫ24 20 Ϫ12 12 18 16 Ϫ2 0 Ϫ14 Ϫ16 16 16 6 0 8 Ϫ2 2 Ϫ6 3. The ventral LT functional connectivity network included bilateral cerebellum.23 3.85 4. The mean rCBF levels for the VOI did not differ significantly during the three experimental conditions (means Ϯ SD.24 4. Functional connectivity of the ventral LT.70 4. Activation in the cingulate cortex during thirst and drinking.4 Ϯ 14. 4). P Ͻ 0.org . The network of rCBF changes involving the ventral LT is dynamic. and negative z values are inferior of the anterior commissure. Activation of BA32 during thirst has now been ob- Downloaded from http://ajpregu.44 Ϫ6 Ϫ54 Ϫ60 58 20 36 Ϫ44 Ϫ46 Ϫ26 Ϫ14 16 14 8 8 Ϫ44 Ϫ58 Ϫ82 34 24 36 Ϫ16 Ϫ22 Ϫ12 0 4 Ϫ10 12 8 12 Ϫ6 Ϫ6 Ϫ34 Ϫ38 Ϫ42 3. 2F.51 3.20 3.2 Ϯ 18. Fig. and anterior insula.18 3. The rCBF time course for a VOI incorporating the ventral portion of the LT was correlated with rCBF changes throughout the brain for each participant (Fig.58 3. and a similar trend was seen for the PCC (Fig. Brodmann Area. bilateral OFC.37 3. IFG.23 3. increased rCBF in BA32 occurred during the Maximum Thirst period. limbic and paralimbic cortices. as well as the left posterior insula. and caudate (Table 2.R628 CONNECTIVITY OF THE THIRST NETWORK the insula (Fig. r ϭ Ϫ0.52 3. negative y values are posterior. MFG.55.98 4.18 3. DISCUSSION This study has identified thirst activations after fluid loss that correspond to previous findings after systemic hypertonic infusion. and bilateral parahippocampi (Table 2. showing increased functional connectivity during the experience of thirst and after drinking.10 42 54 Ϫ20 Ϫ16 12 Ϫ4 0 Ϫ42 3. bilateral ventral striatum. 4).05).org/ by guest on November 23. Values in the Stat column are Z statistics of the peak voxel in a cluster of activation. the medial thalamus bilaterally.The coordinates of peak activations are reported as distance in millimeters from the anterior commissure according to the standard brain of the Montreal Neurological Institute. 2D.11 BA.79 3.22 3. r ϭ Ϫ0.39 3.17 3. AJP-Regul Integr Comp Physiol • VOL 301 • SEPTEMBER 2011 • www. The Post-Drink period showed significantly increased correlation of the ventral LT bilaterally with the OFC. Comparisons of the Maximum Thirst and PostDrink periods with the control period showed significantly increased correlation during Maximum Thirst of the ventral LT with the right ACC. bilateral caudate nuclei. and left superior temporal gyrus (Table 2.62 4. venteromedial prefrontal cortex. 4).07 3. temporal. The PCC and ACC were also activated across the three periods of image acquisition. Maximum Thirst: 39. negative x values are to the left.41 3. including Maximum Thirst activation in BA32 that fell below threshold after drinking. The study also revealed functional connectivity of the ventral LT with the medial thalamus. Positive x values are to the right. positive z values are superior. Post-Drink: 32. superior temporal gyrus.08).2 ml·100 gϪ1·minϪ1). and parietal cortices. venteromedial prefrontal cortex.90 3.3 and a cluster level probability of P Ͻ 0.56 4. control: 36.

the mid-ACC. We have previously undertaken a series of experiments that combined systemic hypertonic saline infusions with measures of rCBF by using positron emission tomography to test for thirst and drinking activation (11. An initial bout of drinking had an immediate effect on thirst ratings in this study. the parahippocampi bilaterally (B). The osmolality of the blood shows apparent decreases within 5 to 10 min after ad libitum drinking (36). served under a variety of conditions: systemic hypertonic infusion (13). such as the pharynx and esophagus. fluid deprivation (10).ajpregu. whereas neural inflow from the 7th. The Post-Drink period showed greater levels of correlation in postererolateral orbitofrontal cortices (G). bilateral anterior insuli. 9th. 40. in that the thirst period involves significant increases relative to baseline and the postdrinking period does not (13. are important for the satiation of thirst in humans. Studies of human physiology and behavior indicate that sensory inputs from drinking water influence the experience of thirst more rapidly than the chemistry of the blood. in humans it would appear that passage of water through the pharynx and esophagus is sufficient to resolve thirst and that distension of the stomach is not required for satiation of thirst after drinking. and in the present study involving exercise-induced fluid loss combined with fluid deprivation. the rostral ACC showed significantly greater correlation with the ventral LT during Maximum Thirst compared with control. 16). Brain regions showing levels of rCBF that correlated with rCBF in the ventral LT. whereby inflow from osmoreceptors to limbic cortex is implicated in the initiation and persistence of this experience. E: greater levels of correlation with the LT occurred during Maximum Thirst in the rostral (R) ACC. decreases of rCBF in BA32 after drinking were not sufficient to constitute a statistically significant difference relative to the Maximum Thirst period. Indeed. but 25 min elapse before osmolality shows statistically significant decreases relative to the peak in dehydrated humans (20). whereas the impact of drinking on activation in BA32 was less dramatic. which means that the identification of brain activation associated with hydration status. 18. Brain networks correlating with the ventral LT were compared during Maximum Thirst and Post-Drink periods with the control period. In this study and all other studies involving functional brain imaging of thirst. whereas infusion of water into the stomach via a nasogastric tube is associated with a significant decrease in thirst only after 25 min (20). participants drinking the largest volumes of water had levels of rCBF in BA32 after drinking that were close to control-state levels. and inferior frontal gyri. but the size and inconsistency of the decrease is not detectable with the methods used so far. 15. and that inputs from structures. whereas participants who drank smaller amounts showed larger Post-Drink levels of rCBF compared with control. 19). left posterior insula. Unlike some other species (5. Osmostimulation of the LT continues until water drunk is absorbed from the gut 15 to 20 min after ingestion. and drinking is difficult to do using standard functional brain imaging protocols. and 10th cranial nerves arising from the act of drinking may diminish activity in BA32. The ventral LT network included: nuclei in the dorsal and ventral striatum (A). the medial dorsal thalamus.physiology. Indeed. and the precuneus and cerebellum (D). VMPFC. The significant reduction of thirst in humans that follows ad libitum drinking is still observed when water is extracted from the stomach.org/ by guest on November 23. The combined observations of Maximum Thirst activation and increased functional connectivity with the ventral LT suggest that BA32 subserves neural processes involved in the conscious experience of thirst. 4.org . 2012 Fig. levels of rCBF in BA32 during Maximum Thirst and Post-Drink periods could be described as showing a consistent distinction. and left middle temporal gyrus (H). Second. AJP-Regul Integr Comp Physiol • VOL The relationship between drinking volumes and activation in BA32 is likely to be dependent on inputs from visceral structures involved in the ingestion of water. and the left middle temporal gyrus (F) . the venteromedial prefrontal cortex (VMPFC) (C). A parsimonious explanation for the distinction is that drinking initiates a decrease in BA32 activation. the posterior cingulate. 45).CONNECTIVITY OF THE THIRST NETWORK R629 Downloaded from http://ajpregu. Further experiments will be required to test for relationships between afferent inflow from the viscera and levels of activation in the cingulate cortex. thirst. Manipulation of blood chemistry and thirst cannot be done quickly. The use of arterial spin 301 • SEPTEMBER 2011 • www. the variability of responses in BA32 suggest that the region is influenced by drinking because differences in rCBF between the Post-Drink and control periods were negatively correlated to the volume of water drunk. In other words.

The network of brain regions activated by thirst in the current experiment replicates a number of findings from our earlier studies that is notable for two reasons. polysynaptic connections could exist between these regions and the LT. mice. DISCLOSURES No conflicts of interest. Mathers Charitable Foundation. middle temporal gyrus. We have shown that regions activated during thirst AJP-Regul Integr Comp Physiol • VOL also have increased rCBF after drinking commences and that postdrinking activation in the insula and posterior cingulate cortex correlates with levels of vasopressin in the blood. 3. Nevertheless. Leksell LG. Kleberg. MTG). the Post-Drink period was characterized by a resolution of thirst after drinking volumes that were ϳ40% of the total ad libitum volume during the course of the experiment. The VOI included the ventral portion of the LT that is the site of the OVLT but may have also included the MnPO (9.R630 CONNECTIVITY OF THE THIRST NETWORK labeling images in the present study to estimate rCBF has permitted an alternative thirst induction method based on dehydration. However. Brain Res 99: 261–275. Future studies are required to ascertain the duration of activation and increased functional connectivity that succeeds the onset of regulatory drinking. The consistency of cortical regions activated during hypertonic and dehydrative thirst suggests that these regions do not show differentiated responses to different afferent blood volume signals of hydration status. 22. The rCBF changes observed in this study during the Post-Drinking period indicate a sustained. Kleberg Foundation and the G. Activations identified during the Post-Drink period could represent processes involved in the ongoing monitoring of hydration status. links the LT and ACC (24). differentially correlated network of responses associated with the sequelae of drinking after fluid loss. 39). is functionally connected with cortical regions involved in thirst and drinking including the cingulate cortex (BA32) and the insula. and Helen C. Participants reported a near absence of thirst after the first bout of ad libitum drinking. Jr. Harold and Leila Y. REFERENCES 1. Aguirre GK. caudate nucleus. Egan are National Health and Medical Research Council (Australia) Fellows. Conclusion. are declared by the author(s). Andersson JL. The prolonged period of regulatory drinking in humans and in other species including rats. 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