Stephen M. Oppenheimer

Cardiovascular effects of human insular cortex stimulation

Recent investigations indicate a site of cardiac representation within the left insular cortex of the rat. Moreover, the results of lesion studies suggest left-sided insular dominance for sympathetic cardiovascular effects. It is unclear whether similar representation exists within the human insular cortex. Five epileptic patients underwent intraoperative insular stimulation prior to temporal lobectomy for seizure control. On stimulation of the left insular cortex, bradycardia and depressor responses were more frequently produced than tachycardia and pressor effects (p < 0.005). The converse applied for the right insular cortex. We believe this to be the first demonstration of cardiovascular changes elicitable during insular stimulation in humans, and of lateralization of such responses for a cortical site. In humans, unlike the rat, there appears to be right-sided dominance for sympathetic effects. These findings may be of relevance in predicting the autonomie effects of stroke in humans and in the explanation of sudden unexpected epileptic death.

Left-insular cortex lesions perturb cardiac autonomic tone in humans

The insular cortex is involved in cardiac regulation. The left insula is predominantly responsible for parasympathetic cardiovascular effects. Damage to this area could shift cardiovascular balance towards increased basal sympathetic tone (a proarrhythmic condition) and contribute to the excess cardiac mortality following stroke. Acute left insular stroke increased basal cardiac sympathetic tone and was associated with a decrease in randomness of heart rate variability. In addition, phase relationships between heart rate and blood pressure were disturbed, implying a disruption of oscillators involved in cardiovascular control. The insula appears to be involved in human heart rate regulation and damage to it may encourage a pro-arrhythmic state.The insular cortex is involved in cardiac regulation. The left insula is predominantly responsible for parasympathetic cardiovascular effects. Damage to this area could shift cardiovascular balance towards increased basal sympathetic tone (a proarrhythmic condition) and contribute to the excess cardiac mortality following stroke. Acute left insular stroke increased basal cardiac sympathetic tone and was associated with a decrease in randomness of heart rate variability. In addition, phase relationships between heart rate and blood pressure were disturbed, implying a disruption of oscillators involved in cardiovascular control. The insula appears to be involved in human heart rate regulation and damage to it may encourage a pro-arrhythmic state.

Cerebrogenic cardiac arrhythmias: cortical lateralization and clinical significance.

That the brain may be involved in cardiovascular regulation has been acknowledged for over a century. That cardiac arrhythmias may result from cortical derangement has been less well recognized. That cortical cardiac representation may be lateralized is even more controversial. Recent evidence implicates several cortical structures, especially the insula, in cardiac rate and rhythm control. Experimental models indicate that insular lesions may be arrhythmogenic. Accumulating data show similar lesion effects in humans. In the rat, monkey and man sympathetic cardiovascular control is generally represented in the right insula, although pronounced insulo-insular connectivity has been demonstrated. Proarrhythmic shifts in cardiac sympathovagal balance occur after human stroke, including left insular lesions. This evidence implicates the cortex in the promotion and even generation of cardiovascular dysfunction under appropriate circumstances.

Insular cortex lesions alter baroreceptor sensitivity in the urethane-anesthetized rat

Cardiovascular representation has been demonstrated within the insular cortex and lateralization has been previously inferred. In this study, baroreceptor gain was investigated in response to the systemic injection of the pressor agent phenylephrine (PE) and the depressor agent sodium nitroprusside (SNP) in 57 urethane-anesthetized, male Sprague-Dawley rats before and after single lesion placement. Lesions mainly confined to the anterior insula (left or right) or the adjacent cortex were without significant effect on baroreceptor gain. Left posterior insular lesions, however, significantly increased baroreceptor gain (p<0.0001) whereas right posterior insular lesions had no effect on baroreceptor gain although heart rate and blood pressure were both significantly increased after lesion placement (p<0.05). These data suggest that: (1) the posterior insula (and not surrounding cortex or anterior insula) is primarily involved in cardiovascular control; (2) the left insular cortex may be chiefly concerned with parasympathetic cardiac regulation. Conversely, the right posterior insular cortex may regulate both cardiac and vasomotor sympathetic tone, as has been suggested in other species.

Characterization, distribution and lateralization of baroreceptor-related neurons in the rat insular cortex

The insular cortex contains a site of cardiovascular representation. Stimulation experiments suggest a discrete localization within the rostral posterior insula. In 34 urethane-anesthetized male Sprague-Dawley rats, we investigated whether cells responsive to baroreceptor stimulation with phenylephrine and sodium nitroprusside were selectively clustered within the insula compared with the surrounding frontoparietal cortex, the extent of distribution of these responsive cells within the insula, and whether there was any lateralization of response. In addition, we characterized the cells as SE (sympathoexcitatory), SI (sympathoinhibitory) or null cells using the criteria of Barman. Of the 128 insular cells investigated with extracellular recording techniques, 70% responded to baroreceptor manipulations compared to 32% of the 57 cells investigated outside the insula (P < 0.0001). The majority of the responsive cells were SE units and were distributed widely throughout the insular cortex including anterior areas not previously thought to be involved in cardiovascular control. Within the rostral posterior insula from which cardiovascular effects are mainly obtained in stimulation experiments, lateralization was identified, with significantly more cells responding to blood pressure changes being found within the right posterior insula than the left (P < 0.003). These data confirm the importance of the right posterior insula in the rat as a site of cardiovascular representation; identify a more extensive distribution of cells responsive to blood pressure changes within the insula than previous studies and imply more widespread convergence of visceral afferent information within the insula.

Characterization of baroreceptor-related neurons in the monkey insular cortex

Insular neurons responsive to baroreceptor challenge have been identified in the rat, but not previously in primates. Characterization of baroreceptor-related neurons was performed in 15 anesthetized monkeys (Macaca fascicularis) using extracellular single-unit recording techniques. 131 units were investigated within the insula and surrounding regions. Based on their responses to phenylephrine hydrochloride (PE) and sodium nitroprusside (SNP), three types of units were distinguished: 35/131 (27%) sympathoexcitatory (SE), 12/131 (9%) sympathoinhibitory (SI) and 84 (64%) null units. More baroreceptive units were found within the insula (38/73, 52%) than in surrounding areas (9/58, 16%) (p < 0.001). Lateralization was indicated with more baroreceptive units being encountered within the right insula (28/44, 64%) than the left (10/29, 34%) (p = 0.02). The majority of the responsive units were located within the dysgranular and granular insula in layers II, III and V/VI. These data suggest that cardiovascular representation may occur in the primate insula as has been shown in other species.

Baroreceptive and somatosensory convergent thalamic neurons project to the posterior insular cortex in the rat

Connectivity between the rat posterior insula and the ventrobasal thalamus has been demonstrated anatomically. Neurons convergent for baroreceptor and nociceptive input have also been identified in the homologous anterior insula of the primate. Whether similar convergent cells exist in the ventrobasal thalamus was investigated in 30 urethane anesthetized male Sprague--Dawley rats. Six classes of cells were identified in the right ventrobasal thalamus: (a) 83/159 (52%) baroreceptive and nociceptive convergent units; (b) 2/159 (1%) convergent cells responding to baroreceptor activation and light touch; (c) 44/159 (28%) purely nociceptive units; (d)10/159 (6%) purely baroreceptive units; (e) 1/159 (0.6%) cells responding to brush alone and (f) 19/159 (12%) unresponsive units. Of the viscerosomatic convergent cells, 66/85 (78%) were situated in the ventroposterolateral nucleus (VPL), 6/85 (7%) in the ventroposterolateral parvicellular nucleus (VPLpc), and 13/85 (15%) in the ventroposteromedial nucleus (VPM). Fifteen right ventrobasal thalamic units were antidromically activated and 34 units orthodromically activated by right posterior insular microstimulation. Cobalt injection into the right ventrobasal thalamus blocked the right insular response to baroreceptor activation by >70%. These data indicate: (a) baroreceptive and somatosensory nociceptive convergent units exist in the ventrobasal thalamus; (b) thalamic convergent neurons project directly to the ipsilateral posterior insula and receive reciprocal insulothalamic projections; and (c) a significant proportion of baroreceptor input relays to the posterior insula through the ipsilateral ventrobasal thalamus.

The Insular Cortex and the Regulation of Cardiac Function.

Cortical representation of the heart challenges the orthodox view that cardiac regulation is confined to stereotyped, preprogrammed and rigid responses to exteroceptive or interoceptive environmental stimuli. The insula has been the region most studied in this regard; the results of clinical, experimental, and functional radiological studies show a complex interweave of activity with patterns dynamically varying regarding lateralization and antero-posterior distribution of responsive insular regions. Either acting alone or together with other cortical areas including the anterior cingulate, medial prefrontal, and orbito-frontal cortices as part of a concerted network, the insula can imbue perceptions with autonomic color providing emotional salience, and aiding in learning and behavioral decision choice. In these functions, cardiovascular input and the right anterior insula appear to play an important, if not pivotal role. At a more basic level, the insula gauges cardiovascular responses to exteroceptive and interoceptive stimuli, taking into account memory, cognitive, and reflexive constructs thereby ensuring appropriate survival responses and maintaining emotional and physiological homeostasis. When acquired derangements to the insula occur after stroke, during a seizure or from abnormal central processing of interoceptive or exteroceptive environmental cues as in psychiatric disorders, serious consequences can arise including cardiac electrophysiological, structural and contractile dysfunction and sudden cardiac death.

Protective effects of beta-blockers in cerebrovascular disease

Objective: Because activated sympathetic tone is associated with poorer outcome after stroke, we investigated whether beta-blocker treatment was associated with lesser stroke severity and improved outcome. Method: We prospectively studied 111 patients with stroke. Stroke severity on presentation gauged by Canadian Neurologic Scale (CanNS) and medication use verified from medical records. Power spectral analysis of heart rate variability estimated cardiac sympathovagal tone. Coagulation and inflammatory activity were assessed. Results: On multiple linear regression, beta-blocker use was the sole independent predictor of less severe stroke on presentation (95% CI: 0.12 to 1.86: p = 0.03). When CanNS was dichotomized, multiple logistic regression revealed that beta-blocker use (odds ratio [OR] 3.70, 95% CI: 1.24 to 11.01, p = 0.02) and female gender (OR 2.96, 95% CI: 1.14 to 7.69, p = 0.03) were independent predictors of CanNS score >8.5. There was no difference in blood pressure and blood glucose between these two groups. Beta-blocker treatment was associated with lower sympathovagal tone (p = 0.001), thrombin (p = 0.009), hemoglobin A1C levels (p = 0.02), and erythrocyte sedimentation rate (p = 0.003). Conclusion: Beta-blocker use is associated with less severe stroke on presentation and may be cerebroprotective due to a sympatholytic effect associated with decreased thrombin, inflammation, and hemoglobin A1C.

Cerebrogenic cardiac arrhythmias

That the brain may be involved in cardiovascular regulation has been acknowledged for over a century. That cardiac arrhythmias may result from cortical derangement has been less well recognized. That cortical cardiac representation may be lateralized is even more controversial. Recent evidence implicates several cortical structures, especially the insula, in cardiac rate and rhythm control. Experimental models indicate that insular lesions may be arrhythmogenic. Accumulating data show similar lesion effects in humans. In the rat, monkey and man sympathetic cardiovascular control is generally represented in the right insula, although pronounced insulo-insular connectivity has been demonstrated. Proarrhythmic shifts in cardiac sympathovagal balance occur after human stroke, including left insular lesions. This evidence implicates the cortex in the promotion and even generation of cardiovascular dysfunction under appropriate circumstances.