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The Insular Cortex and the Regulation of Cardiac Function

Stephen Oppenheimer, David Cechetto

10.1002/cphy.c140076

Source: null

Published online: March 2016

Full Article on Wiley Online Library



ABSTRACT

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. © 2016 American Physiological Society. Compr Physiol 6:1081‐1133, 2016.

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Figure 1. Figure 1. The T‐wave represents ventricular repolarization and is followed by the U‐wave (when present). The PQ interval denotes the time for the impulse to spread from the SA node across the atria and down the bundle of His and therefore represents the time from atrial depolarization onset to ventricular depolarization onset. The ST‐T interval coincides with ventricular repolarization. The QT interval corresponds to the duration of ventricular depolarization and repolarization. Reprinted with permission from “ECG signal processing, classification, and interpretation.” Gacek A, Pedrycz W (Eds.) Springer, London 2012 (92).
Figure 2. Figure 2. Four cases of cerebral hemorrhage with subendocardial hemorrhages noted on autopsy (sequentially displayed from left to right), and absence of coronary arterial disease in the first three cases. The ECGs show characteristic neurogenic repolarization changes with QT prolongation, peaked T wave inversion in the lateral leads, U waves (with T‐U fusion). Reproduced from Koskelo et al. Br Med J 1964 with permission from BMJ Publishing Group Ltd. (174).
Figure 3. Figure 3.

(A) Lateral view of the rat brain illustrating the granular (Ig), dysgranular (Id), and agranular (Ia) regions of the insular cortex. (B) Connections of the insular cortex in the rat with ascending visceral sensory regions, including the PBN, and the VMPpc and VPLpc of the thalamus. (C) Connections of the insular cortex in the rat with limbic regions, including the LHA, AMYG, and IL.

cs central sulcus csi central sulcus of the insular cortex Ig granular insular cortex Id dysgranular insular cortex Ia agranular insular cortex IFGo inferior frontal gyrus, opercular LF lateral frontal cortex LO lateral orbital cortex OLB olfactory bulb PaO parietal operculum PeR perirhinal cortex PIR piriform cortex PoG postcentral gyrus pos postcentral sulcus PPo planum polare PrG precentral gyrus prs precentral sulcus PTe planum temporale SI primary somatosensory cortex SII association somatosensory cortex TTG transverse temporal gyri

Figure 4. Figure 4. (A) Lateral view of the primate insular cortex. In this view, the lateral fissure and the superior and inferior limiting sulci have been unfolded to view the entire insular cortex. This view illustrates the granular (Ig), dysgranular (Id), and agranular (Ia) regions of the insular cortex. (B) Connections of the insular cortex in the rat with ascending visceral sensory regions, including the PBN, and the VMPpc and VPLpc of the thalamus. (C) Connections of the insular cortex in the rat with limbic regions, including the LHA, AMYG, and IL. The abbreviations are as in Figure 3.
Figure 5. Figure 5. The human insula seen from the right. The overlying opercula have been retracted exposing the insula and its five principal gyri; b1, b2, b3, respectively, are the gyrus brevis primus, secundus and tertius; l1, l2, respectively, are the gyrus longus primus and secundus; of is the orbitofrontal operculum; ofp is the frontoparietal operculum; ot is the temporal operculum; scia, circular insular sulcus‐anterior; scii, circular insular sulcus inferior; scis, circular insular sulcus superior. Reprinted from Nieuwenhuys, (226) with permission from Elsevier.
Figure 6. Figure 6. Distribution of cardiac chronotropic sites within the rat insular cortex. The numbers beneath each section refer to its location with reference to the bregma. Filled circles represent sites from which phasic microstimulation elicited an increase in heart rate without change in respiration or blood pressure; filled triangles represent sites from which microstimulation elicited a decrease in heart rate without change in heart rate or blood pressure; open circles represent sites from where no cardiac or respiratory change was elicited on phasic microstimulation. Reprinted with permission from Oppenheimer et al. (232).
Figure 7. Figure 7. Phasic microstimulation of the cortex approximately 200 ms prior to the QRS complex of the ECG: (A) Serial ECG changes during phasic microstimulation of the sensorimotor cortex surrounding the insula in a control rat. No significant changes are observable after 8 h of continuous stimulation. No change is heart rate is noted with the stimulus, and no change in respiration or blood pressure occurred throughout the stimulation. The stimulus artifact present in all but the prestimulation trace (Prestim) is identified by the three arrows in A5; (B) serial ECGs during insular phasic microstimulation. Characteristic repolarization changes are seen with progressive ST depression, evolution of the U wave, QT interval prolongation and progressive degrees of heart block. Subsequently, interventricular conduction defects are noted, bradycardia with a ventricular escape rhythm, complete heart block, and then asystole. Inset is a coronal section diagram through the rat forebrain showing insular stimulation and control sites. Filled circles indicate insular stimulation sites; open squares indicate sites of electrode insertion without stimulation; stars indicate control stimulation sites in extrainsular locations. Reprinted with permission from Oppenheimer et al. (238).
Figure 8. Figure 8. (A) photomicrograph of a coronal section through a rat left ventricle (hematoxylin and eosin stain) following stimulation of the insular cortex demonstrating features of early myocytolysis: scattered foci of myocardial fibre disruption (thick arrows) and surrounding monocytic infiltration (thin arrows); and (B) photomicrograph of a sagittal section (Movats stain) of the membranous septum adjacent to the left ventricle (LV) and inferior to the right atrium (RA) showing a large subendocardial hemorrhage (thick arrow) close to the origin of the left branch of the bundle of His (L). Reprinted with permission from Oppenheimer et al. (238).
Figure 9. Figure 9. Takotsubo cardiomyopathy in insular infarction. (A) MRI showing infarction involving the left insular cortex and adjacent frontoparietal areas; (B) ECG on admission showing AF and neurogenic changes comprising T wave inversion, QT prolongation, and ST elevation predominantly in the anterolateral leads; (C)normal coronary angiogram of the vessels supplying the left ventricular myocardium; and (D) ventriculograph typical of Takotsubo cardiomyopathy, with the apex of the heart showing the rounded appearance contrasting with the systolic constriction of the left ventricular base. Reprinted with permission modified from Cho et al. (54).
Figure 10. Figure 10. fMRI patterns in the resting brain demonstrating both anteroposterior insular parcellation as well as lateralization differences: the right AI shows connectivity with brainstem, pons, right thalamus and left middle/posterior insula, right dorsolateral prefrontal cortex, right rostral ACC, and the right supramarginal gyrus. The left AI shows predominant connectivity at rest with right posterior insula, left dorsolateral prefrontal cortex, and bilaterally with the supplementary motor area. The right posterior insula shows little connectivity with left posterior insular regions, but the left posterior insula is connected with the cuneus/lingual gyrus and the superior temporal gyrus bilaterally, the right postcentral gyrus, the left thalamus, and the left pre‐ and postcentral gyri. Reprinted from Cauda et al. (31) with permission from Elsevier.


Figure 1. The T‐wave represents ventricular repolarization and is followed by the U‐wave (when present). The PQ interval denotes the time for the impulse to spread from the SA node across the atria and down the bundle of His and therefore represents the time from atrial depolarization onset to ventricular depolarization onset. The ST‐T interval coincides with ventricular repolarization. The QT interval corresponds to the duration of ventricular depolarization and repolarization. Reprinted with permission from “ECG signal processing, classification, and interpretation.” Gacek A, Pedrycz W (Eds.) Springer, London 2012 (92).


Figure 2. Four cases of cerebral hemorrhage with subendocardial hemorrhages noted on autopsy (sequentially displayed from left to right), and absence of coronary arterial disease in the first three cases. The ECGs show characteristic neurogenic repolarization changes with QT prolongation, peaked T wave inversion in the lateral leads, U waves (with T‐U fusion). Reproduced from Koskelo et al. Br Med J 1964 with permission from BMJ Publishing Group Ltd. (174).


Figure 3.

(A) Lateral view of the rat brain illustrating the granular (Ig), dysgranular (Id), and agranular (Ia) regions of the insular cortex. (B) Connections of the insular cortex in the rat with ascending visceral sensory regions, including the PBN, and the VMPpc and VPLpc of the thalamus. (C) Connections of the insular cortex in the rat with limbic regions, including the LHA, AMYG, and IL.

cs central sulcus csi central sulcus of the insular cortex Ig granular insular cortex Id dysgranular insular cortex Ia agranular insular cortex IFGo inferior frontal gyrus, opercular LF lateral frontal cortex LO lateral orbital cortex OLB olfactory bulb PaO parietal operculum PeR perirhinal cortex PIR piriform cortex PoG postcentral gyrus pos postcentral sulcus PPo planum polare PrG precentral gyrus prs precentral sulcus PTe planum temporale SI primary somatosensory cortex SII association somatosensory cortex TTG transverse temporal gyri



Figure 4. (A) Lateral view of the primate insular cortex. In this view, the lateral fissure and the superior and inferior limiting sulci have been unfolded to view the entire insular cortex. This view illustrates the granular (Ig), dysgranular (Id), and agranular (Ia) regions of the insular cortex. (B) Connections of the insular cortex in the rat with ascending visceral sensory regions, including the PBN, and the VMPpc and VPLpc of the thalamus. (C) Connections of the insular cortex in the rat with limbic regions, including the LHA, AMYG, and IL. The abbreviations are as in Figure 3.


Figure 5. The human insula seen from the right. The overlying opercula have been retracted exposing the insula and its five principal gyri; b1, b2, b3, respectively, are the gyrus brevis primus, secundus and tertius; l1, l2, respectively, are the gyrus longus primus and secundus; of is the orbitofrontal operculum; ofp is the frontoparietal operculum; ot is the temporal operculum; scia, circular insular sulcus‐anterior; scii, circular insular sulcus inferior; scis, circular insular sulcus superior. Reprinted from Nieuwenhuys, (226) with permission from Elsevier.


Figure 6. Distribution of cardiac chronotropic sites within the rat insular cortex. The numbers beneath each section refer to its location with reference to the bregma. Filled circles represent sites from which phasic microstimulation elicited an increase in heart rate without change in respiration or blood pressure; filled triangles represent sites from which microstimulation elicited a decrease in heart rate without change in heart rate or blood pressure; open circles represent sites from where no cardiac or respiratory change was elicited on phasic microstimulation. Reprinted with permission from Oppenheimer et al. (232).


Figure 7. Phasic microstimulation of the cortex approximately 200 ms prior to the QRS complex of the ECG: (A) Serial ECG changes during phasic microstimulation of the sensorimotor cortex surrounding the insula in a control rat. No significant changes are observable after 8 h of continuous stimulation. No change is heart rate is noted with the stimulus, and no change in respiration or blood pressure occurred throughout the stimulation. The stimulus artifact present in all but the prestimulation trace (Prestim) is identified by the three arrows in A5; (B) serial ECGs during insular phasic microstimulation. Characteristic repolarization changes are seen with progressive ST depression, evolution of the U wave, QT interval prolongation and progressive degrees of heart block. Subsequently, interventricular conduction defects are noted, bradycardia with a ventricular escape rhythm, complete heart block, and then asystole. Inset is a coronal section diagram through the rat forebrain showing insular stimulation and control sites. Filled circles indicate insular stimulation sites; open squares indicate sites of electrode insertion without stimulation; stars indicate control stimulation sites in extrainsular locations. Reprinted with permission from Oppenheimer et al. (238).


Figure 8. (A) photomicrograph of a coronal section through a rat left ventricle (hematoxylin and eosin stain) following stimulation of the insular cortex demonstrating features of early myocytolysis: scattered foci of myocardial fibre disruption (thick arrows) and surrounding monocytic infiltration (thin arrows); and (B) photomicrograph of a sagittal section (Movats stain) of the membranous septum adjacent to the left ventricle (LV) and inferior to the right atrium (RA) showing a large subendocardial hemorrhage (thick arrow) close to the origin of the left branch of the bundle of His (L). Reprinted with permission from Oppenheimer et al. (238).


Figure 9. Takotsubo cardiomyopathy in insular infarction. (A) MRI showing infarction involving the left insular cortex and adjacent frontoparietal areas; (B) ECG on admission showing AF and neurogenic changes comprising T wave inversion, QT prolongation, and ST elevation predominantly in the anterolateral leads; (C)normal coronary angiogram of the vessels supplying the left ventricular myocardium; and (D) ventriculograph typical of Takotsubo cardiomyopathy, with the apex of the heart showing the rounded appearance contrasting with the systolic constriction of the left ventricular base. Reprinted with permission modified from Cho et al. (54).


Figure 10. fMRI patterns in the resting brain demonstrating both anteroposterior insular parcellation as well as lateralization differences: the right AI shows connectivity with brainstem, pons, right thalamus and left middle/posterior insula, right dorsolateral prefrontal cortex, right rostral ACC, and the right supramarginal gyrus. The left AI shows predominant connectivity at rest with right posterior insula, left dorsolateral prefrontal cortex, and bilaterally with the supplementary motor area. The right posterior insula shows little connectivity with left posterior insular regions, but the left posterior insula is connected with the cuneus/lingual gyrus and the superior temporal gyrus bilaterally, the right postcentral gyrus, the left thalamus, and the left pre‐ and postcentral gyri. Reprinted from Cauda et al. (31) with permission from Elsevier.
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Article Title: The Insular Cortex and the Regulation of Cardiac Function
 

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Stephen Oppenheimer, David Cechetto. The Insular Cortex and the Regulation of Cardiac Function. Compr Physiol 2016, null: 1081-1133. doi: 10.1002/cphy.c140076