Although it has been established that the medulla oblongata is the primary cardiovascular control site (Guyenet 2006), studies in rodent models have highlighted the importance of certain forebrain structures involved with the modulation of efferent autonomic outflow (Cechetto and Saper 1987, Dampney 1994, Verberne and Owens 1998). In addition, clinical neuroimaging research has revealed that basal levels of autonomic tone may be disrupted in patients with stroke or epileptic seizures in higher regions of the brain such as the prefrontal and insular cortices, suggesting that cortical regions are involved in cardiovascular regulation (Oppenheimer, Gelb et al. 1992, Cheung and Hachinski 2000, Colivicchi, Bassi et al. 2004). Functional magnetic resonance imaging (fMRI) techniques have enabled the non-invasive assessment of cortical autonomic correlates in healthy, young conscious humans (King, Menon et al. 1999, Critchley, Corfield et al. 2000, Harper, Bandler et al. 2000, Henderson, Macey et al. 2002). A network of forebrain regions, termed the ‘cortical autonomic network’, has been shown to exert influence over autonomic outflow and cardiovascular control. These regions include the bilateral insular cortex (IC), amygdala, thalamus, medial prefrontal cortex (MPFC), anterior cingulate cortex (ACC), and most recently, the hippocampus (HC).
The IC and ACC are activated during a variety of cognitive maneuvers that elevate autonomic stimulation such as gambling (Critchley, Mathias et al. 2001), Stroop task (Gianaros, Derbyshire et al. 2005), mental arithmetic (Critchley, Corfield et al. 2000) and many more. The involvement of the ACC and IC in influencing sympathetic nerve activity are not only observed during cognitive tasks that induce mental arousal, but are also reported in situations of physical stress such as baroreceptor unloading (Kimmerly, O'Leary et al. 2005), and isometric exercise (Wong, Masse et al. 2007). Also, neuronal responses have been 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). Furthermore, studies in humans have supported a lateralization of insula effects on autonomic cardiovascular control, which is consistent
with evidence provided from anesthetized rodents. Specifically, HR and BP increase upon stimulation of the right IC, while left IC stimulation produces depressed cardiac and pressor responses (Oppenheimer, Gelb et al. 1992). Experimental studies indicate further that electrical stimulation of the posterior IC, increases HR and BP in anesthetized rats (Ruggiero, Mraovitch et al. 1987), with a large predominance of sympathoexcitatory neurons in the right posterior insula (Oppenheimer and Cechetto 1990, Zhang, Dougherty et al. 1999). Furthermore, during direct stimulation of the rodent brain, the superior IC is associated with tachycardia, whereas inferior portions produce bradycardia (Oppenheimer and Cechetto 1990).
The MPFC has been shown to have strong efferent connections with structures involved in autonomic function including the amygdala, hypothalamus, HC, periaqueductal gray, the NTS and the caudal and rostral ventrolateral medulla (Neafsey 1990, Chiba and Semba 1991, Hurley, Herbert et al. 1991, Verberne and Owens 1998, Vertes 2004). Recent studies conducted in animals and humans have revealed depressor sites within the ventral region of the MPFC that are heightened during periods of relaxation, including sleep and rest (Barnabi and Cechetto 2001, Critchley, Mathias et al. 2001). Furthermore, pharmacological blockade studies (Hollander and Bouman 1975, Mitchell, Reeves et al. 1989, Victor, Pryor et al. 1989) indicate that parasympathetic withdrawal represents the primary determinant of the rapid adjustments in HR that are initiated immediately at the onset of IHG exercise (Mitchell, Reeves et al. 1989, Wong, Masse et al. 2007), and has been shown to be associated with deactivation in the MPFC (Wong, Masse et al. 2007). These observations suggest that the MPFC is involved in mediating behavioural mechanisms that reduce the cardiovascular response to psychological or physical stress, while augmenting vagal efferent control of HR (Critchley, Wiens et al. 2004), thus supporting a direct relation between MPFC activity and cardiovagal control in young, healthy adults.
Emphasis on the role of the HC in cardiovascular dynamic responses to stress has received relatively little attention despite early studies which noted anatomical visceral sensory connections to the HC (Maclean 1952). More recently, retroviral tracing techniques have established the neuronal linkages and relays that connect brainstem
autonomic nuclei with the HC (Westerhaus and Loewy 2001, Castle, Comoli et al. 2005). Previously, Ruit and Neafsey (Ruit and Neafsey 1988) illustrated the ability of electrical stimulation of the ventral HC to depress cardiovascular activation, exposing an inverse relationship between HC activation and cardiovascular arousal. Of note, the cardiovascular outcomes in this electrical stimulation model required an intact MPFC. These findings confirm early evidence that electrical stimulation of the HC in anesthetized rats elicits a variety of visceral or autonomic modifications, such as decreases in HR and increases in pulse pressure (Kaada 1951, Kaada and Jasper 1952, Andy and Akert 1955, Liberson and Akert 1955, Anand and DUA 1956). These earlier findings are supported further by recent electroencephalography results from conscious rats that point to entrainment of theta rhythms between the HC and MPFC (Hyman, Hasselmo et al. 2011). Moreover, the necessity of an intact MPFC for electrical stimulation of the HC to elicit cardiovascular changes (Ruit and Neafsey 1988) supports data from conscious humans where cardiac dynamics are inversely related to MPFC activation state in functional neuroimaging studies (Gianaros, Van Der Veen et al. 2004, Wong, Kimmerly et al. 2007, Wong, Masse et al. 2007, Goswami, Frances et al. 2011, Norton, Luchyshyn et al. 2013).
Overall, these observations confirm a network of regions involved in mediating the cardiovascular response to psychological or physical stress, thus supporting a direct relation between cortical activity and cardiovagal control in young, healthy adults. The modulation of this autonomic network through the influence of positive and negative lifestyle factors such as fitness and age, respectively, is not known.