In recent years, considerable progress has been made in determining the role of the cortex in autonomic control in health and disease. Characteristics of the cardiovascular responses elicited from the insular cortex have been determined as well as the efferent and afferent pathways, the nature of the responses, the control of tonic sympathetic activity, and the neurotransmitters mediating these responses. Very early experiments demonstrated that "sham rage'' could be induced in cats following crude decortication. Upon innocuous stimulation, such as stroking the fur, cats would demonstrate all the somatomotor and autonomic manifestations (piloerection, dilatation of the pupils, retraction of the nictitating membrane, panting, and tachycardia) of rage. Ablation of the orbitoinsular region of the frontal lobes in cats resulted in a syndrome similar to that of complete decortication or complete removal of the frontal lobes. These studies suggested that the insular cortex might play a role in the tonic regulation of autonomic (particularly sympathetic) responses. Stimulation studies have supported this view. Electrical stimulation of the insular cortex in a variety of mammals, including humans, elicits changes in blood pressure, heart rate, respiration, piloerection, pupillary dilatation, gastric moti-lity, peristaltic activity, salivation, and adrenaline secretion. Phasic microstimulation of the rat insular cortex linked to the R wave of the electrocardiogram (ECG) evokes tachycardia or bradycardia responses without accompanying changes in blood pressure or respiration, and prolonged stimulation in the insular cortex generates progressive degrees of heart block and increased plasma norepinephrine and can cause death in asystole. Accompanying cardiac structural changes are myocytolysis and subendocardial hemorrhages in the vicinity of the origin of the bundle of His, suggesting increased cardiac sympathetic activity. Finally, the efferent pathways and neurotransmitters for these autonomic responses from the insular cortex have been determined. It is clear that a mandatory synapse is located in the lateral hypothalamic area and that the primary neurotransmitter in this region is glutamate acting at NMDA receptors.
The insular cortex is considered to be the visceral sensory cortex on the basis of anatomical and physiological evidence. The earliest demonstration of general visceral input to a cortical level was an investigation in cats that showed that stimulation of the cephalic end of the severed cervical vagus nerve resulted in an increase in the rate and amplitude of cortical electrical activity in the orbitoinsular region. Recent anatomical results in the rat have indicated that the insular cortex might be organized in a viscerotopic manner. The recording of individual neurons in response to activation of specific visceral receptors demonstrated that neurons responding to gustatory inputs were located in the dysgranular region of the insular cortex. General visceral inputs were primarily located in the granular region of the insular cortex in the rat. In this region, there was a separation between the regions receiving gastric inputs compared to the cardiopulmonary responsive neurons. The distribution of arterial bar-oreceptor responsive neurons was extensively mapped in the rat insular cortex, which demonstrated that significantly more neurons responding to blood pressure changes were located in the right insular cortex than in the left. This granular insular cortex in which the cardiopulmonary information terminates may be the critical region in the lateral frontal cortex mediating central autonomic manifestations of emotional behavior as predicted by the early experiments demonstrating sham rage.
Gustatory or taste input is considered to be a special visceral sensation. Gustatory input is relayed ipsilat-erally from the thalamus to the primary gustatory area, which is located near the face region in the primary somatosensory cortex. Although a cell in the gustatory cortex can be activated by any number of taste stimuli, it will have a preference for one of the four basic taste qualities (sour, sweet, bitter, and acidic). The detection and subsequent identification of a particular taste is not mediated by individual cells in the cortex; rather, the quality of the taste is determined by the pattern of firing in a group of activated cells. The anterior insular cortex (secondary gustatory cortex) also receives gustatory input and this area integrates the gustatory information with input from the olfactory system. Information from both the primary gustatory area and the insula is integrated with other sensory information in the orbitofrontal cortex.
Recent evidence has shown for the first time that it is possible to obtain a clear representation of visceral sensation in the human insular cortex similar to that observed in the rodent. fMRI was used to identify regions of the human brain that were activated in response to a series of tests designed to stimulate cardiopulmonary and gustatory receptors. Cardiopul-monary activation included maximal inspiration, Valsalva's maneuver, and maximal handgrip to elevate arterial blood pressure. These maneuvers consistently resulted in discrete changes in activity in the anterior insular cortex, with a time course corresponding to the changes in arterial blood pressure and heart rate they produced (Fig. 7). Gustatory stimuli, such as salt and sucrose perfusion of the tongue, resulted in activation of the inferior anterior insular cortex.
Several investigations have indicated that the insular cortex may mediate the cardiovascular consequences
of stroke. Middle cerebral artery occlusion (MCAO) in the cat and rat results in an increase in blood pressure, norepinephrine level, sympathetic nerve activity, myo-cytolysis, and death. These changes resemble those seen clinically and are obtained only when the insular cortex is included in the infarct. Asymmetry of responses elicited from the cerebral cortex is an important topic in many types of behavioral investigations. There is evidence that stimulation of the insular cortex in the human also elicits different results from each hemisphere. In the MCAO model in the rat, right-sided stroke results in a significantly higher increase in mean arterial blood pressure, sympathetic nerve activity, and plasma norepinephrine and an increase in the QT interval of the ECG. Finally, the animal stroke model has clearly shown that the cardiovascular consequences of stroke are more severe with increasing age. The aged animals had significantly increased mortality following the stroke and prior to death exhibited significantly elevated sympathetic nerve activity, plasma norepinephrine concentration, and prolonged QT interval of the ECG. Clinical studies have confirmed the importance of the insular cortex in mediating the cardiovascular consequences of stroke. Plasma norepinephrine levels, changes in circadian blood pressure, and incidence of cardiac arrhythmias correlate highly with percentage insular infarction. These investigations also confirm observations of right hemispheric dominance for sympathetic effects. There is some indication that the left insular cortex is predominantly responsible for parasympathetic effects since left insular stimulation in humans results in more frequent parasympathetic responses (bradycardia) compared to right insular stimulation, which yielded increased blood pressure and heart rate (sympathetic effects). Recently, it was shown in a group of patients with lesions mainly confined to the left insular cortex that there was an increased basal cardiac tone associated with a decrease in heart rate variability.
Anatomical and functional data clearly indicate that another cortical site in the medial prefrontal cortex plays an important role in determining the autonomic responses of the organism to complex behaviors. This medial prefrontal cortical area is considered to be visceral motor cortex. Compared to the insular cortex, considerably less is known regarding the specific role of the medial prefrontal cortex in autonomic control. A variety of autonomic responses can be elicited by stimulation of the medial prefrontal cortex. In fact, complete cessation ofheartbeat may occur in monkeys during stimulation of the medial frontal cortex. The medial prefrontal cortex has extensive connections with both the limbic and the autonomic systems of the brain. It receives inputs from the insular and entorh-inal cortices, the hippocampus, amygdala, the visceral relay nuclei of the thalamus, and pontine and medullary autonomic control sites. The medial prefrontal cortex has descending projections to many autonomic sites, including the insular cortex, the amygdala, the visceral relay nuclei of the thalamus, hypothalamus, and brain stem autonomic control nuclei.
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