Clinical and physiological considerations
In many species the insular cortex plays a pivotal role in the integration of autonomic function. Viscerotopic organization has been demonstrated in the insula of the rat [
6]. Cardiac chronotropic organization was subsequently identified in the rostral posterior insula [
32]. Phasic microstimulation of the rat left insula resulted in QT prolongation, ST depression, pronounced bradycardia, complete heart block and idioventricular rhythm ending in asystole [
33]. Myocytolysis was apparent on cardiac examination and plasma noradrenaline levels were elevated, without a change in adrenaline (which in the rat indicates neural rather than adrenal origin).Neither was provoked by stimulation of peri-insular sensory cortex.Thus, cerebral stimulation can reproducibly generate lethal cardiac arrhythmias and pathology resembling changes seen after stroke or sudden unexpected death in epilepsy.
Lesions confined mainly to the right posterior insula of the rat increase blood pressure and heart rate without altering baroreceptor sensitivity [
54]. Conversely, left posterior insular lesions do not alter cardiovascular variables, but increase baroreceptor sensitivity. Previously, we had shown that damage to the right hemisphere in a rat middle cerebral artery occlusion model increased both QT interval and plasma norepinephrine [
16]. Chemical lesions confined to the right insula also increase heart rate and blood pressure [
4].
Direct recording from cardiac sympathetic nerves is difficult; however surrogate measures of sympathovagal balance may be assessed from spectral analysis of heart rate.We have shown in the rat that right posterior insular stimulation increases cardiac sympathetic tone in the absence of heart rate, blood pressure or respiration changes [
36]. Interestingly, baroreceptor sensitivity decreased, a finding also linked to increased mortality after stroke [
40].
These laterality issues are of interest because of previous observations that in the human, right carotid amylobarbital infusion produces bradycardia, and left carotid infusion is accompanied by tachycardia [
53].Additionally, an increased incidence of supraventricular tachycardia was reported in patients with right middle cerebral artery stroke [
22]. Our investigations in the human indicate that left caudal anterior insular stimulation during surgery for intractable epilepsy increases the frequency of bradycardia and depressor responses, whereas stimulation of a similar region of the right anterior insula is associated with heart rate and diastolic blood pressure elevation [
34].Although both types of response were elicitable from either insula, the proportion varied, and the degree of bradycardia was greater on left insular stimulation. These data indicate that in the human at least, some lateralization of cardiovascular representation may exist with sympathetic predominance of cardiovascular regulation being a right insular function, and parasympathetic cardiac neural regulation relating to the left insula.
Recently we reported a series of patients with lesions confined to the left insula [
35]. Consistent with the hypothesis of left insular cardioinhibitory representation, these patients had a higher basal heart rate than age-gender matched controls. Cardiac autonomic balance was shifted towards sympathetic predominance and mirrored the effects of rising from sitting to standing in the control group. ISE and approximate entropy data indicated a decrease in heart rate complexity. Interestingly 40% of these patients developed ECG changes not seen on premorbid traces, comprising tachycardia, T wave inversion, prominent U waves and QTc prolongation. None reported a cardiac history. No similar changes were seen in controls.The abnormalities resolved within 2 months of stroke. A similar case has also been reported of an arrhythmia resolving after evacuation of a left insular hematoma [
46].We have also encountered a patient who developed transient ST depression 3 days after left insular infarction in the absence of cardiac history, coronary artery disease, or echocardiographic abnormalities [
8].
Others have indicated a significant role for the right insular cortex in cardiovascular decompensation after stroke. Tokgozoglu [
50] showed that compared to age-gender matched controls total spectral energy was reduced after ischemic stroke as noted previously by others. However, this was particularly marked in patients with stroke involving the right middle cerebral artery, or the insular cortex. Sudden death was observed in 11%, but occurred more often after right MCA lesions. Naver [
29] indicated that heart rate variability entrained to deep breathing (a parasympathetic relationship) was reduced with right sided stroke, whereas peripheral sympathetic influences were equally distributed between the two sides. Sympathetic skin response and pulse rate variation (parasympathetic measure) were suppressed in patients with both right or left hemisphere lesions compared with controls [
11]. This effect was more marked with right hemisphere lesions, although the authors failed to show a statistical difference when right and left sides were compared. On the other hand, Li [
26] indicated that supraventricular arrhythmias were more frequently encountered after right insular infarction compared with strokes in other locations. Interestingly, ST abnormalities were more frequent after left insular involvement in comparison with controls or strokes in other locations. Sander [
43] showed that right hemisphere infarction reduced circadian blood pressure variability and increased nocturnal blood pressure compared to left hemisphere infarcts. Additionally, higher serum noradrenaline levels, longer QTc prolongation and more cardiac arrhythmias were observed after right hemisphere infarction. In general, changes were greatest when there was insular involvement, under which circumstances no laterality effects were observed.
Whereas these changes indicate that left insular lesions may disrupt interactions of central oscillators regulating cardiac rhythmicity, there is some inconsistency in the data. Certainly, right rostral posterior insular stimulation in the rat increases cardiac sympathetic tone; however, lesions involving this region also increase heart rate and blood pressure. These seemingly incompatible effects may relate to anesthetic effects on descending inhibitory and excitatory pathways. Under baseline anesthesia conditions inhibitory pathways (probably insular efferents to the lateral hypothalamic area [
37]) may be maximally operational, and this inhibition is released by insular lesioning. On the other hand, stimulation recruits excitatory pathways, possibly quiescent under basal anesthetic conditions. Human investigations were conducted in minimally anesthetized individuals and so the relationships may differ. In the rat, prolonged left insular stimulation results in both cardiac parasympathetic and sympathetic activation [
33]. The major cardiac effect, however, appears related to parasympathetic upregulation (bradyarrhythmias and complete heart block).