Acute Hypernatremia Increases Functional Connectivity of Sodium Sensing Regions in the Brain

Rodent studies have identified specialized sodium chloride (NaCl)-sensing neurons in the circumventricular organs (CVOs), which mediate NaCl-induced changes in sympathetic nerve activity, arginine vasopressin (AVP), thirst, and blood pressure (BP). In humans, acute hypernatremia has been shown to increase sympathetic nerve activity, AVP, thirst and BP. However, few human studies have investigated the network of NaCl sensing regions of the brain using functional magnetic resonance imaging (fMRI). OBJECTIVE: To determine how the functional connectivity of sodium sensing regions of the brain change during an acute hypernatremic perturbation. METHODS: Resting-state fMRI was performed on 9 healthy young adults (29±4 yrs, 5M) at baseline and during a 30 min 3% NaCl intravenous infusion at a rate of 0.15 ml/kg/min. Venous blood samples and perceived thirst (Likert scale, cm) were obtained before and immediately following the infusion. Serum electrolytes, plasma osmolality, hematocrit, and hemoglobin were assessed. Beat-to-beat blood pressure was measured continuously. Seed-based voxel-wise functional connectivity analysis was performed in AFNI using spherical seeds placed bilaterally in the subfornical organ (SFO), the organum vasculosum lamina terminalis (OVLT) as well as cortical sensory regions such as the insula. Functional connectivity was compared at baseline vs. early infusion (min 0-15) and baseline vs. late infusion (min 16-30) at p < 0.01, corrected for multiple comparisons with 3dClustSim. RESULTS: Thirst (∆1.9±2.0 cm), serum sodium (∆3.2±2.1 mmol/L), and plasma osmolality (∆6.9±4.7 mOsm/kg H2 O) all increased from baseline to post-infusion (p<0.05). Head motion was minimal and did not change throughout the stages of the infusion (mean motion = 0.11±0.10 mm, p>0.80). Hypertonic saline infusion increased local functional connectivity between the SFO and OVLT (Z score baseline=0.07±0.01, Z score late phase=0.17+0.01, p<0.01). A similar increase in functional connectivity was seen between the insula and somatosensory cortex. CONCLUSION: Acute hypernatremia increases local functional connectivity within the CVOs and between cortical sensory regions of the brain. © FASEB.