Forebrain lateralization of cardiovascular function: Physiology and clinical correlates

No satisfactory explanation exists for the phenomenon of functional cerebral lateralization. Anatomical separation probably allows more complete organization, specialization, and control but comes at a price: it requires fast, efficient communication between regions engaged in processing similar information. This cost seems appropriate for complex tasks, such as fine motor, visual, and language function. To many, however, lateralization of related facets of autonomic control is inconceivable. The generally subconscious regulation of the cardiovascular system, viscera, and skin is considered a product of mass patterning and lacking in refinement. Recent research reveals the considerable complexity behind the cortical organization and integration of cardiovascular function and that functional lateralization is indeed a feature of the autonomic nervous system. Stimulation and extracellular recordings in the human, primate, and rodent identified the insular cortex as a principal site of autonomic representation. In the rodent, microelectrode sampling of cells demonstrates statistically significant clustering of baroreceptorresponsive units within the right posterior insula when compared with other insular regions. Similar clustering is seen in the right anterior and mid-insula of the macaque monkey (an area neuroanatomically homologous with the posterior insula of the rodent). Stimulation of the right anterior insula in the human increases heart rate and diastolic blood pressure; on the left, identical stimulation produces bradycardia alone. These results are strikingly consistent with the earlier reversible inactivation studies of Zamrini et al: barbiturate infusion into the arterial supply of the right hemisphere during the Wada test decreased heart rate, whereas left hemisphere arterial infusion increased heart rate. Recent functional magnetic resonance imaging studies have further confirmed this laterality of function: baroreceptor stimulation increased neuronal activity within the insular cortex and was generally greater on the right. Ablation experiments in anesthetized rodents are consistent with these findings: lesions confined to the right posterior insular cortex significantly increase heart rate and blood pressure but are without effect on baroreceptor gain. Conversely, left posterior insular lesions significantly increase baroreceptor gain. Lesions in other insular or juxta-insular locations are without any significant cardiovascular effect. These findings, consistent across species, indicate that the left posterior insular cortex may be primarily involved with integration of parasympathetic cardiomotor activity; the right posterior insula regulates both cardiac and vasomotor sympathetic function. To complete this picture, we recently identified bidirectional interhemispheric projections between the cardiovascular-related regions of the rodent insula. These fibres are probably analogous to similar pathways that underlie the functional integration of other lateralized systems (for example, visual and sensorimotor). The report by Hilz et al in this issue of the Annals adds further compelling evidence in support of cortical lateralization of cardiovascular function. Using spectral analysis of both heart rate and blood pressure, and transfer function analysis of the relationship between spontaneous blood pressure fluctuations and heart rate they confirm the cardiovascular lateralization schema discussed above. In addition, inactivation of the left hemisphere decreased baroreceptor sensitivity. Interestingly, as noted earlier, lesioning the left insula increases baroreceptor sensitivity in the rat. The discrepancy may reflect species differences in organization and function of descending pathways, the effects of localized versus generalized hemisphere inactivation, or the modifying limitations of general anesthesia as used in the rat experiments. However, both inhibitory and excitatory pathways from the posterior insula to the lateral hypothalamic area (LHA) have been recently identified in our laboratory. These project to discrete LHA regions, which in turn project to cardiovascular control sites within the brainstem and spinal cord. It is not inconceivable that balance between these pathways may vary according to level of arousal, including the effect of anesthetic and other modifying drugs. The clinical import of lateralization of cortical representation of cardiovascular function is clear. The blood pressure instability, glycemic dysregulation, and cardiac functional changes increasingly recognized after stroke are very likely directly related to the involvement of specific brain regions (including the insula) in the infarct. Indeed, augmented sympathetic and decreased parasympathetic cardiac tone accompanies stroke involving the left insular cortex. This destabilizes the ventricular myocardium engendering a proarrhythmic state. An increased incidence of sympathetically mediated cardiac arrhythmias after strokes involving the left insular cortex has been observed. Sander and Klingelhoffer have recently shown that stroke involving the insular cortex abolished the normal nocturnal dip in blood pressure. In addition, the corrected QT interval was elevated but only in those patients whose stroke involved the insula. In these circumstances there was also a significantly elevated incidence of ventricular ectopy and tachyarrhythmias. Inappropriate activation of supratentorial cardiovascular regions during seizures EDITORIALS