The Journal of Neuroscience, February 11, 2009 • 29(6):1817–1825 • 1817 Behavioral/Systems/Cognitive Following One’s Heart: Cardiac Rhythms Gate Central Initiation of Sympathetic Reflexes Marcus A. Gray,1,2 Karin Rylander,4 Neil A. Harrison,3 B. Gunnar Wallin,4 and Hugo D. Critchley1 1Clinical Imaging Sciences Centre, Brighton and Sussex Medical School, University of Sussex, Brighton, East Sussex BN1 9RR, United Kingdom, 2Wellcome Trust Centre for Neuroimaging, University College London, London WC1N 3BG, United Kingdom, 3Institute of Cognitive Neuroscience, University College London, London WC1N 3AR, United Kingdom, and 4Institute of Neuroscience and Physiology, Department of Clinical Neurophysiology, Sahlgren University Hospital, SE-413 45 Gothenburg, Sweden Central nervous processing of environmental stimuli requires integration of sensory information with ongoing autonomic control of cardiovascular function. Rhythmic feedback of cardiac and baroreceptor activity contributes dynamically to homeostatic autonomic control. We examined how the processing of brief somatosensory stimuli is altered across the cardiac cycle to evoke differential changes in bodily state. Using functional magnetic resonance imaging of brain and noninvasive beat-to-beat cardiovascular monitoring, we show that stimuli presented before and during early cardiac systole elicited differential changes in neural activity within amygdala, anterior insula and pons, and engendered different effects on blood pressure. Stimulation delivered during early systole inhibited blood pressure increases. Individual differences in heart rate variability predicted magnitude of differential cardiac timing responses within periaque- ductal gray, amygdala and insula. Our findings highlight integration of somatosensory and phasic baroreceptor information at cortical, limbic and brainstem levels, with relevance to mechanisms underlying pain control, hypertension and anxiety. Key words: baroreceptor; blood pressure; PAG; amygdala; insula; fMRI; shock; anxiety; blood phobia; HF HRV Introduction baroreceptor feedback (McAllen and Malpas, 1997; Ja¨nig, 2006). The processing of environmental stimuli is influenced by visceral Unexpected somatosensory stimuli occurring during early car- state. The brain receives continuous afferent information about diac systole [200–400 ms after electrocardiogram (ECG) internal bodily functions. Cardiovascular homeostasis depends R-wave] further inhibit MSNA in ϳ60% of healthy subjects on such feedback; notably phasic signals from aortic arch and (Donadio et al., 2002a,b; Eder et al., 2009). In contrast, stimuli carotid sinus baroreceptors activated by blood-volume- presented at the ECG R-wave (hereafter called synchronous stim- distension during cardiac systole (Mancia and Mark, 1983). uli), i.e., before the systolic pressure wave, do not inhibit MSNA Baroreceptor firing modulates efferent autonomic responses in (Donadio et al., 2002a,b; Wallin, 2007). Thus, when stimuli are an organ-specific manner, inhibiting muscle sympathetic nerves administered after a delay relative to the ECG R-wave (hereafter while leaving skin sympathetic outflow unaltered (Wallin, 2007). delayed stimuli), baroreceptor impulses inhibit activity in sym- The central processing of painful stimuli is influenced by exper- pathetic nerves supplying muscle. This inhibition is exaggerated imentally increasing aortic baroreceptor firing via external neck in patients with blood phobia and syncope, suggesting that feed- pressure at specific phases of the cardiac cycle, reducing perceived back mechanisms supporting cardiac homeostasis shape an indi- pain and reflexive responses (e.g., limb withdrawal) (Brody and vidual’s affective style (Donadio et al., 2007). Stimulus timing Rau, 1994; Droste et al., 1994; Dworkin et al., 1994; Kardos et al., within the cardiac cycle also influences reflexive and/or subjective 1994; Mini et al., 1995; Angrilli et al., 1997; Edwards et al., 2001, impact of somatosensory stimulation; limb withdrawal and pain- 2002; Rau and Elbert, 2001). ful sensation are reduced to delayed versus synchronous stimuli Sympathetic outflow to muscle vascular beds [muscle sympa- (Elbert et al., 1988; Dworkin et al., 1994; Angrilli et al., 1997; thetic nerve activity (MSNA)] occurs in characteristic bursts, re- Edwards et al., 2002, 2003, 2008). flecting the cyclical inhibition of efferent brainstem cardiovascu- The role of baroreceptor-sensitive brainstem nuclei in the ho- lar nuclei, including the rostral ventrolateral medulla (RVLM) by meostatic regulation of blood pressure is well characterized (Gil- bey and Spyer, 1993; McAllen and Malpas, 1997; Spyer, 1999; Ja¨nig, 2006; Gilbey, 2007). However, the mechanisms though Received July 18, 2008; revised Dec. 4, 2008; accepted Dec. 7, 2008. This work was performed at the Wellcome Trust Centre for Neuroimaging (WTCN), Queen Square, London, and which baroreceptor activity influences sensory and emotional supported by a Wellcome Trust Programme Grant (H.D.C.), a Swedish Medical Research Council Grant (12170), and processing is poorly understood. Neuroimaging studies implicate funding to the WTCN. We thank Peter Aston and Eric Featherstone at the WTCN for help with the recording of anterior insular and anterior cingulate cortex (ACC) in mediat- physiological data within the fMRI environment. ing cardiac influences on conscious feeling states (Craig, 2002; Correspondence should be addressed to Marcus A. Gray, Clinical Imaging Sciences Centre, Brighton and Sussex Medical School, University of Sussex, Brighton, East Sussex BN1 9RR, UK. E-mail: [email protected]. Critchley, 2005; Gianaros et al., 2007). The amygdala, via direct DOI:10.1523/JNEUROSCI.3363-08.2009 connections with pontine autonomic nuclei, is further implicated Copyright © 2009 Society for Neuroscience 0270-6474/09/291817-09$15.00/0 in translating psychological stress into bodily arousal, including 1818 • J. Neurosci., February 11, 2009 • 29(6):1817–1825 Gray et al. • Cardiac Cycle: Neural and Physiological Responses patterns of blood pressure reactivity (Gi- anaros et al., 2008). We therefore hypoth- esized the activity of brainstem autonomic nuclei, amygdala, anterior insula and ACC would reflect cardiac timing influences on physiological reactions to somatosensory stimuli. We simultaneously recorded neu- ral activity and physiological (beat-to-beat blood pressure) responses to unpredict- able electrical stimulation of the skin at different times within the cardiac cycle to investigate the central mechanisms through which sensory and baroreceptor information interact. Materials and Methods Participants. Eleven healthy right-handed adults (7 female, 4 male, mean Ϯ SD age 27.2 Ϯ 7.2 years) with no history of psychiatric, neuro- logical or cardiovascular illness or psychotropic or cardiovascular medication gave informed written consent to take part in this study which was approved by the Joint Research Ethics Committee of the Institute of Neurology and the National Hospital for Neurology and Neu- rosurgery, Queen Square, UK. Informed con- sent was obtained after full explanation of the study and procedures. Procedure. The scanning study was designed to investigate ECG R-wave synchronous and delayed stimuli. Immediately before scanning, ECG and pulse oximetry (Nonin 8600 FO Se- ries, Nonin Medical Inc.) data were recorded in a psychophysiology laboratory with the partic- ipant in a reclined position, to determine mean pulse transit time, calculated as time between ECG R-wave and peak finger pulse oximetry waveform. In the MRI scanner, participants were then fitted with three ECG electrodes (mid Figure 1. Physiological data recording. During fMRI recording we acquired ECG, pulse oximetry, stimulus event markers, sternum, 5 cm above and below left nipple). An beat-to-beat blood pressure, and skin conductance data. Blood pressure changes are relative to the average blood pressure inflatable finger cuff and infrared plethysmo- recorded during the three cardiac cycles before stimuli (highlighted by red box). SaO2, oxygen saturation; CI, cardiac interval; BP, graph were fitted to the index finger of the sub- blood pressure. ject’s left hand, allowing measurements of beat- to-beat finger arterial blood pressure with a chronous with the ECG R-wave (estimated using mean pulse transit time Portapres device (Finapres Medical Systems) adapted in-house to be MR from preceding pulse oximetry waveform) or delayed [100–500 ms compatible. Finally, the electrocutaneous shock electrode was applied to (mean 284.8, SD ϭ 105.1 ms) after the ECG R-wave (see Fig. 1). Shocks the back of the right hand using a customised optically isolated MR were 10 ms square waves, set at a subject defined intensity of “strong, but compatible system incorporating a Digitimer DS7A stimulator. The not painful” (mean intensity 5 mA, 60 V). Participants were instructed to stimulation electrode consisted of a central cathode (diameter 0.5 mm) simply focus on a central fixation cross and wait for sensory stimuli. On surrounded by a ring anode (diameter 6 mm) (Katsarava et al., 2006), average, each subject was presented with 27.1 synchronous (SD ϭ 6.59) 2 providing a stimulation area of 19.6 mm . Participants underwent func- and 29.5 delayed shocks (SD ϭ 8.13). tional magnetic resonance imaging (fMRI) of the brain while synchro- MRI acquisition and image preprocessing. Functional echo-planar data- nous or delayed electrical shocks were delivered to the dorsum of the sets sensitive to BOLD (blood oxygen level