Ventral medial prefrontal cortex and cardiovagal control in conscious humans Savio W. Wong, a Nicholas Massé, a Derek S. Kimmerly, a Ravi S. Menon, b and J. Kevin Shoemaker a,c, ⁎ a Neurovascular Research Laboratory, School of Kinesiology, The University of Western Ontario, London, ON, Canada N6A 3K7 b Robarts Research Institute, London, Ontario, Canada N6A 5C1 c Department of Physiology and Pharmacology, The University of Western Ontario, London, Ontario, Canada N6A 5C1 Received 19 September 2006; revised 28 October 2006; accepted 11 December 2006 Available online 30 December 2006 The autonomic nervous system plays a critical role in regulating the cardiovascular responses to mental and physical stress. Recent neuroimaging studies have demonstrated that sympathetic outflow to the heart is modulated by the activity of the anterior cingulate cortex (ACC). However, the cortical modulation of cardiovagal activity is still unclear in humans. The present study used functional MRI to investigate the cortical network involved in cardiovagal control. Seventeen healthy individuals performed graded handgrip exercise while heart rate (HR) and cortical activity were recorded. Muscle sympathetic nerve activity (MSNA), mean arterial pressure (MAP) and HR were measured while participants repeated the same protocol in a parallel experiment session. The handgrip exercise elevated HR and MAP without concurrent elevations in MSNA supporting earlier conclusions that the cardiovascular responses are mainly modulated by vagal withdrawal. The imaging data showed activation in the insular cortex, thalamus, parietal cortices and cerebellum during the exercise period. Consistently across all the participants, the HR response correlated with the deactivation in the ventral medial prefrontal cortex (vMPFC), which has substantial anatomical connection with the subcortical autonomic structures. The deactivation of the vMPFC was independent of the motor control and was observed commonly in both left and right hand exercise. Stronger vMPFC deactivation was observed when participants completed a higher intensity exercise that elicited a larger HR response. Our findings support the hypothesis that the vMPFC is involved in modulating the vagal efferent outflow to the heart and the suppression of its activity elevates cardiovascular arousal in conscious humans. © 2006 Elsevier Inc. All rights reserved. Keywords: Sympathetic nervous system; Parasympathetic nervous system; Ventral medial prefrontal cortex; Insula; Heart rate Introduction In humans, the balance between sympathetic and parasympathetic regulation of the cardiovascular system is crucial to blood pressure stability and long-term health. The sympathetic nervous system (SNS) elevates heart rate (HR) and blood pressure (BP) by augmenting adrenergic activity whereas the parasympathetic nervous system (PNS) slows the heart through its cholinergic activity focused at the sinoatrial node. Clinical studies revealed that these autonomic responses could be disrupted in patients with stroke or epileptic seizures in the prefrontal cortex (Cheung and Hachinski, 2000; Colivicchi et al., 2004; Jackson, 1931), suggesting that there is a close relationship between cortical functions and cardiovascular health. Brainstem nuclei involved in the autonomic reflex have been well-characterized (Loewy and Spyer, 1990). Additionally, the importance of cortical sites in modulating SNS and PNS activity has become the focus of current research. Clinical and experi- mental studies have exposed a network of forebrain regions with important influence over autonomic outflow and cardiovascular control. These include the insular cortex (IC), medial prefrontal cortex (MPFC), amygdala and thalamus (Neafsey, 1990; Saper, 2002; Verberne and Owens, 1998). Of these regions, the IC and MPFC have received considerable attention. Autonomic responses, including changes in HR and BP, were evoked by electrical stimulation within discrete regions of the MPFC (Burns and Wyss, 1985; Fisk and Wyss, 1997; Owens and Verberne, 2001; Verberne, 1996) and IC (Cechetto and Chen, 1990; Oppenheimer et al., 1992; Ruggiero et al., 1987; Yasui et al., 1991). Also, neuronal responses were recorded in the IC when HR and BP changes were elicited by stimulation of the vagus nerve (Barnabi and Cechetto, 2001) and baroreflex afferents (Cechetto and Saper, 1987). Anatomically, the MPFC has a larger number of direct connections with subcortical autonomic structures than the IC (Verberne and Owens, 1998). In rats and monkeys, the major prefrontal projections to subcortical autonomic structures (i.e. hypothalamus and periaqueductal gray) arise from the MPFC (An et al., 1998; Ongur et al., 1998). www.elsevier.com/locate/ynimg NeuroImage 35 (2007) 698 – 708 ⁎ Corresponding author. Neurovascular Research Laboratory, School of Kinesiology, Room 3110 Thames Hall, The University of Western Ontario, London, ON, Canada N6A 3K7. Fax: +1 519 661 2008. E-mail address: kshoemak@uwo.ca (J.K. Shoemaker). Available online on ScienceDirect (www.sciencedirect.com). 1053-8119/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.neuroimage.2006.12.027