Basic research models for the study of underlying mechanisms of electrical neuromodulation and ischemic heart-brain interactions

PROJECT 4: BIDIRECTIONAL HUMORAL AND NERVOUS HEART-BRAIN INTERACTIONS

With respect to the emotional component of angina, we thought to study alternative pathways of communication between the heart and the brain. This idea occurred as a consequence of observations that many patients who suffer serious cardiac events, such as CABG or myocardial infarction, are confronted with a period of emotional problems following these events. So, from our experimental projects, the question became relevant as to whether emotional alterations in behavior following a cardiac life event may be executed by a humoral pathway from the heart to the brain, since, vice versa, the brain controls the heart through both nervous and humoral pathways. In other words, is it feasible that both humoral and neural pathways are involved, bidirectionally, in interactions between the brain and the heart?

Cardiac disease, proinflammatory cytokines, and blood-brain barrier damage

Cardiac ischemia, the underlying cause of cardiac pain in angina pectoris, triggers a cascade of events that release numerous substances in the myocardium and circulation, all of which are potential candidates for nociceptor activation and initiation of behavioral and autonomic responses to cardiac pain. Some of the substances that are released into the circulation may play a role in the humoral communication between heart and brain, but when released chronically, these substances may induce neuropathological modifications. Anxiety disorders and depression are cerebral disorders that are frequently comorbid with ischemic heart diseases. The latter are attributed to noncoping behavior, but our own experiments (as part of the program) showed that immune activation after tissue damage in the heart generates regional blood-brain barrier damage (Project 4) that could be an underlying organic basis for comorbid neuropsychiatric disorders. The incentive for this project in general was the observation that myocardial infarction is accompanied by behavioral and neuronal abnormalities.

In this project we established whether release of proinflammatory cytokines after tissue damage in the heart is a possible inducer of comorbid neuropsychiatric diseases.

As a model for immune activation, we studied the effects of intravenous injections of the proinflammatory recombinant tumor necrosis factor–alpha (TNF-α) on cerebral endothelial leakage, induction of neuronal damage, and motor and cognitive function in rats. Determinants of selectivity of blood-brain barrier damage were assessed with a molecular biological approach in which we studied regional differences of TNF-α–induced expression in the cerebral endothelial cells of the immediate early gene c-fos and proteins involved in leukocyte docking (intercellular adhesion molecules [ICAMs]) and TNF-α receptors.

To examine the mechanisms by which this interaction occurs, we induced myocardial infarction in a group of rats and then performed immunohistochemistry of the brain. This experiment revealed regional serum protein extravasation, pointing to leakage of the blood-brain barrier. This process occurred in certain cortical, subcortical, and hindbrain areas in discrete patches. The leakage was colocalized with expression of the immune activation marker ICAM-1. To assess the involvement of the immune system in the effects shown, a second group of rats was injected with TNF-α, as the major proinflammatory cytokine. This procedure rendered the same results. It was concluded that myocardial infarction may interfere with the integrity of the blood-brain barrier and possibly with brain functioning through activation of the immune system. The relevance for pathophysiological processes may provide a substrate for further research in unraveling the emotional consequences of serious cardiac events.

In the state of immune activation that follows myocardial ischemic events, various cytokines are released from the myocardium into the plasma. These cyto kines potentiate the cytotoxicity of TNF-α. In the next experiment we were able to demonstrate that intravenous injection of TNF-α induces a selective and regional neural IgG and endothelial ICAM-1 immunoreactivity. The expression of TNF-α–induced changes in the brain suggests that TNF-α is capable of inducing blood-brain barrier dysfunction. It is hypothesized that through dysfunction of the blood-brain barrier, the released cytokines bind to specific cognitive centers in the brain and thus may lead to emotional disturbances following cardiac events.¹⁴

Having identified some specific centers involved in cardiovascular control, we further studied the effects of electrical and chemical stimulation of a specific brain center on the heart.

PROJECT 5: EFFECT OF BRAIN STIMULATION ON CORONARY FLOW

From a clinical PET study performed in patients with end-stage CAD during active spinal cord stimulation therapy, as well as from our PRV experiments and the literature, we concluded that the periaqueductal gray plays a central role in the regulation of different cardiovascular responses and in the integration of motor output from the limbic system.^6,7 Subsequently, the peri aqueductal gray has been thought to be one of the pivotal cerebral centers involved in executing electrical neuromodulation effects.

We investigated the function of the periaqueductal gray in regulation of the coronary flow of the heart. Depending on the stimulation site, electrical stimulation in the periaqueductal gray resulted in increases and decreases in coronary flow and conductance. These effects were organized topographically. The sites producing increases in coronary flow and conductance were found in both the dorsolateral and the ventrolateral periaqueductal gray. The sites producing decreases were restricted mainly to the ventrolateral portion. Similar topographic distributions were observed for the sites producing changes in carotid conductance and heart rate, but not for those producing changes in blood pressure and carotid flow. It is hypothesized that the topographic distribution of coronary vasoconstrictive and vasodilatory responses from the periaqueductal gray may enable optimal adjustments of the coronary perfusion. These optimal adjustments can then accommodate variations in myocardial oxygen demands accompanying different behavioral modes.

CONCLUSION

From all our experiments, mainly performed in rats (but sometimes also in a cat model due to the existence of a stereotactic brain atlas for the cat), we have learned about heart-brain communication through the use of electrical neuromodulation. In the last decade we have further studied heart-brain interactions in the International Working Group on Neurocardiology (IWGN), making use of canine and rabbit models. The main focus of the IWGN is on neural hierarchy in cardiac control. These projects are discussed by one of us (R.D.F.) elsewhere in these proceedings. In brief, the importance for the heart of the intracardiac neuron system and controlling centers at the C1 spinal level,^15–17 in conjunction with the induction of myocardial ischemia, will be highlighted. For a more extensive overview of recent work performed by the IWGN, see the reviews by Foreman et al¹⁸ and Wu et al.¹⁹