Ebbe Curtis Hoff

ECG changes resulting from cerebral stimulation

Abstract In order to assess the influences of the diencephalon and mesencephalon on the control of heart rhythm, 24 adult beagle dogs were lightly anesthetized with Surital sodium, and stimulating electrodes were guided stereotaxically into regions of the diencephalon and mesencephalon previously shown to elicit sympathetic responses. Symmetrical biphasic pulses of 1 to 2 Ma. were delivered to these loci while the ECG was recorded from Standard Lead II. Electrical stimulation elicited a spectrum of ectopic ventricular rhythms. Observed in sequence were ventricular tachycardia, both unifocal and multifocal, ventricular premature contractions in bigeminal pattern, and fusion contractions followed by a return to sinus rhythm. Although the entire spectrum was not evoked in all experiments, the sequence of these abnormal rhythms was consistently the same. When an initial stimulus failed to elicit a response, an increase in intensity usually evoked the entire spectrum. Bilateral vagotomy had no effect on the response; however, it was completely abolished by beta-adrenergic blockade with propranolol (1 mg. per kilogram). These data demonstrate that the type of arrhythmia observed is directly related to the intensity of sympathetic discharge, and that all abnormal ventricular complexes observed in the clinic can be elicited.

The development of the electrocardiogram of the embryonic heart

Abstract With the aid of three-stage amplification, electrocardiographic records were made from chick embryos during the early stages of heart development. The youngest embryo from which records were obtained successfully was a fifteen-somite chick. At this stage, which is reached on the average with about 33 to 36 hours of incubation, the nearly straight tubular heart consists almost entirely of ventricle. The electrical record obtained from it shows none of the deflections characteristic of the adult electrocardiogram, but takes the form of a curve which first drops below, and then rises above, the isoelectric line. This configuration is consistent with the posteroanterior direction of the progress of contraction shown by superimposed tracings of successive frames from micromoving pictures of the heart action at this stage. Slightly older embryos (sixteen to seventeen somites, average incubation age 37 to 40 hours) yield a record in which there appears a sharp downward deflection, followed by a rapid return to, or above, the isoelectric line. Because of its characteristic configuration and because morphologic studies indicate that the embryonic heart at this stage is practically all ventricle, we interpret this as representing the QRS complex. In the next three or four hours of development, fusion of the cardiac primordia progresses caudally, so that the atrial region becomes definitely differentiated and the sinus venosus begins to take shape posterior to the atrium. Records from embryos in this age range show the appearance of a downward deflection coming about two twenty-fifths of a second ahead of the QRS complex. This we interpret as an inverted P-wave. During the next day of development the ventricular loop is bent backward so that it comes to be in its adult position caudal to the sinoatrial part of the heart. With this shift in relative positions the P-wave appears above the isoelectric line. Thus by the fourth day of development the electrocardiogram has assumed practically its adult configuration. It is to be emphasized that not even wandering neuroblasts reach the heart until considerably later in development than the age range covered in these experiments. Furthermore, “conduction tissue” is not at these ages histologically distinguishable from the remainder of the cardiac muscle. Thus we can trace the appearance of all the major features of the adult electrocardiographic pattern in embryonic hearts so young that they completely lack either a nerve supply or a specialized sinoventricular conduction system.

ECG changes after cerebral stimulation. I. Anomalous atrioventricular excitation elicited by electrical stimulation of the mesencephalic reticular formation

Abstract Unipolar electrodes were stereotaxically implanted in the mesencephalic reticular formation of adult boxer dogs anesthetized with Surital sodium. Electrical stimulation (60 c.p.s. of alternating current) of a circumscribed area at the level of the pons produced an anomalous atrioventricular excitation similar to the WPW phenomenon observed in clinical medicine. Bilateral section of the vagosympathetic trunks had no effect on the production of this aberrant cardiac rhythm; however, it could no longer be elicited after section of the spinal cord at the level of the second cervical vertebra. These results demonstrate that the WPW-like complexes observed in this study are mediated exclusively by the sympathetic division of the antonomic nervous system. Electrical stimulation of the distal cut-end of the right vagosympathetic trunk, after the aberrant rhythm had been elicited by cerebral stimulation, abolished the abnormal response.

NEUROPHYSIOLOGICAL ASPECTS OF THE ACTION OF NICOTINE

The central nervous system effects of nicotine would command only academic interest were i t not the principal ingredient of a plant in general use throughout the world. I t is well known that the action of nicotine in the body is, indeed, complex. In both experimental and clinical studies these effects are manifested by either stimulation or depression of function, and this dual but opposite action appears to be directly related to the dosages used; for instance, small amounts usually exert a stimulating effect while larger dosages are depressant. In some experimental situations, however, it has been noted that the initial activation is followed by a depression. Experimental work, in our laboratories, has shown that small doses of nicotine, in the microgram range, mimic responses typically observed when electrical stimuli are delivered to cerebral structures known to mediate sympathetic action. For a number of years, we have been engaged on a research program, the object of which has been to clarify some of the mechanisms involved in higher central nervous system regulation and control of autonomic function. As an integral part of this program, we have examined the effects of electrical stimulation of the central nervous system upon renal circulation,’ skin temperature,’ gastric3 and salivary ~ e c r e t i o n , ~ ’ ~ and cardiac rate and r h ~ t h m . ~ ’ ~ Electrical stimuli delivered through stereotaxically placed electrodes to neural loci in the telencephalon, diencephalon, and mesencephalon have permitted us to identify, with a degree of precision, the activation of neural mechanisms which elevate systemic blood pressure, increase cardiac output, reduce renal flow, produce salivary and gastric secretion, and induce abnormal electrocardiographic complexes. I n our studies of these basic autonomic functions, we have used nicotine and other drugs as a method of further elucidating central processes regulating autonomic function and as a technique for determining the site of action of these compounds. In one such study, acute experiments were performed on ten adult cats, weighing between 2.5 and 4.0 kg., anesthetized with ether and immobilized with gallamine triethiodide (Flaxedil). Varying dosages of nicotine were ad-

Effects of Pentobarbital and Ether upon Vasomotor Responses from Cerebral Cortex of the Dog.

Summary 1. Electrical stimulation of the anterior cerebral cortex of the dog under pentobarbital anesthesia gives predominantly depressor responses. 2. Under ether anesthesia the response is usually pressor. Some stimuli are followed by a rise of blood pressure of one of 2 minutes duration, while others are accompanied by only 15 to 20 seconds of pressure elevation. 3. The mode of action of these anesthetics in affecting the cortically induced blood pressure response is not understood.

Interneuronal connections of the mammalian spinal cord and their examination by experimental degeneration; a review of more recent findings.

SummaryThe structure of the interneuronal connections of the mammalian spinal cord is considered and the degeneration of the boutons or endfeet of Held and Auerbach is described. Degeneration of the boutons provides a method that has been advocated and used for tracing fiber tracts to their termination wuhin the central grey matter. The validity of this method has been questioned by some and these objections are discussed. Evidence is presented that the bouton represents a locus of especial sensitivity to forward degeneration and is protected from retrograde changes, and bouton degeneration is shown to be correlated with functional and biochemical disturbances.

SALIVATION AS A COMPONENT OF THE VISCERAL RESPONSE TO CEREBRAL STIMULATION

Pavlovs classical investigations clearly implicate higher levels of the central nervous system in the regulation of salivary secretion. Bernards puncture of the floor of the fourth ventricle marked the beginning of a voluminous literature on medullary salivary centers and bulbar reflexes mediated through the chorda tympani, glossopharyngeal, and vagus nerves. Recent studies of Velo and Hoffl represent an attempt to determine more precisely the nervous influences on salivary secretion from the cerebral cortex and from the periphery. In cats under ether and gallamine triethiodide (Flaxedil) these investigators evoked submandibular salivation in response to electrical stimulation of the central cut-end of the sciatic nerve and cortical loci on the sigmoid gyrus and gyms proreus. These responses could be obtained with only the sympathetic or parasympathetic innervation of the gland intact. Submandibular salivation mediated only through the chorda tympani was investigated by stimulating cortical loci in animals with complete third cervical segment cord transection or bilateral cervical sympathectoiny plus clamping of both adrenal glands and by stimulation of the central cut-end of the sciatic and other peripheral nerves in animals in which the sympathetics in the neck had been severed and the adrenal glands clamped. Submandibular salivation was also measured in response to stimulation of cortical loci and the central cut-end of the sciatic nerve before and after section of both lingual nerves (central to the terminal branching of the chorda tympani) and clamping of the adrenal glands. It was found that the ascending path in the cord for both parasympathetic and sympathetic effects runs in the dorsal part of the lateral funiculus. In acute experiments the relay for both effects takes place between the upper cervical level of the spinal cord and the niidcollicular level of the brainstem. This parallels observations of Sell et aL,2 who obtained activity in sympathetic nerves to the heart and kidneys in response to stimulation of the central ends of the sciatic, brachial, and splanchnic nerves and observed in acute experiments lasting from one to two hours that these responses were eliminated by cord severance a t the second or third cervical levels. These workers concluded froin these cord sections that all sympathetic responses originate from a center above the second cervical level. A possible segmental activation of sympathetic salivary responses may have been masked by autonomic spinal shock. Velo and Hoff observed that the excitable cortical area overlaps those yielding vasomotor responses, adrenal inedullary activity, and bladder contractions. The descending pathway for the sympathetic effects runs in the spinal cord a t the cervical level a t the junction of the dorsal and ventral parts of the lateral funiculus, a region also containing descending vasomotor fibers. Since Carroll et aL3 have more recently reported salivation in acute experi-

Cerebral autonomic control systems and their pharmacological evaluation

Abstract Stimulation of isocortical, limbic, diencephalic and mesencephalic loci has produced changes in cardiac dynamics, systemic blood pressure, coronary, superior mesenteric and renal arterial blood flow, skin temperature, salivation, gut motility, renal function, epinephrine activity and hematopoiesis. These responses are selectively modified by psychoactive drugs. Hypothetically, the infantile ego protects against cerebrally-induced autonomic overactivity in the infant who is capable of responding mainly by visceral action. Alcohol allows regression to the infantile level through depression of the reticular activating system. Other drugs, such as chlordiazepoxide, act by tension reduction (through effects on cerebral autonomic mechanisms) without impairing contact with reality and are, therefore, useful for infantile ego deflation while fostering receptivity by psychotherapy.