ELECTROCARDIOGRAPHIC CHANGES

ELECTROCARDIOGRAPHIC CHANGES PRODUCED BY LOCALIZED H Y P O T H A L A M I C STIMULATIONS * t By S. J. WEINBERG, M.D., F.A.C.P., and JOAQUIN M. FUSTER, M.D., Los Angeles, California T H E background of our present knowledge of neurocardiac relationships has previously been summarized.1'2'3 The exact location of the diencephalic structures capable of influencing the electrocardiogram has heretofore not been determined. The investigation presented here was aimed at clarifying the possible role of the hypothalamus in the genesis of some electrocardiographic configurations of clinical interest. METHODS

In the present study the hypothalamus of the cat was explored throughout by means of the Horsley-Clarke apparatus. Three hundred seventy-five individual diencephalic points were electrically stimulated in 10 animals. The location of each point stimulated by the tip of the electrode was in all cases precisely defined by millimeter coordinates. Histologic verification of the electrode placements was accomplished by sectioning and staining the hypothalamus after each experiment. Ether anesthesia was employed for surgery, on termination of which intravenous curarization with Flaxedil and thorough procaine local anesthesia were given and maintained throughout the experiment. Concentric bipolar electrodes were used. The stimulation of each explored point lasted 30 seconds. The stimulus was a square wave current of 3 milliseconds pulse duration and 100 cycles per second, and did not exceed a maximum of 5 volts. These stimulation parameters were found to be most effective for the production of the changes observed. Continuous electrocardiographic tracings were taken in Lead II, using needle electrodes. A control electrocardiogram was run before each stimulation, and a period of recovery elapsed before another site in the hypothalamus was stimulated. * Received for publication January 4, 1960. Presented at the Forty-first Annual Session of The American College of Physicians, San Francisco, California, April 5, 1960. From the Departments of Medicine, Psychiatry and Anatomy, University of California at Los Angeles. t T h e work on which this paper is based was supported in part by private subscription of Mrs. Mary E. Osenbach. Requests for reprints should be addressed to S. J. Weinberg, M.D., 1015 Gayley Avenue, Los Angeles 24, California. 332

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RESULTS

Stimulation of various locations in the hypothalamus resulted in electrocardiographic manifestations. The majority of the changes observed were elicited by stimulation of the posterior and lateral regions of the hypothalamus. Wave components, rate, rhythm and pacemaker location were found to be susceptible to change by central stimulation. Relative sinus tachycardia was much more frequently observed than bradycardia as a consequence of hypothalamic stimulation. When sinus bradycardia could be elicited, it usually occurred late during stimulation or immediately following stimulation. Ventricular paroxysmal tachycardia was a frequent result of stimulation of the posterolateral hypothalamus. The sequence of events leading in certain instances to multifocal or unifocal ventricular tachycardia is initiated by a uniform increase in the size of the T wave. The increasing T wave may progress to become the upright component of the biphasic QRS, and the P wave is seen to merge with the Q R S (figure 1).

FIG. 1. a. Control, b. 17 seconds after start of stimulation.

A-V dissociation may occur at times. When it occurs and the ventricular rhythm remains regular, the auricular rhythm is usually regular. At onset of the dissociation the P - P interval may increase and then decrease, causing the P wave originating from a pseudonodal focus to wander on the Q R S (figure 2 d ) . This type of dissociation is more often seen in the late or poststimulation phase. Early during stimulation the accentuated T may obliterate the P wave, causing prematurity and irregular ventricular rhythm. In figure 3, following stimulation, the pacemaker is seen to step up from ventricle to node and then to its normal sinus locus. Energy transfer from hypothalamus to myocardium is capable of instituting several irritable foci. Sometimes a superimposed pacemaker in the ventricle flickers (figure 4 ) from one site to another in an orderly fashion. Thus we may have multifocal irregular ventricular rhythm, unifocal regular ventricular rhythm (figure 1), or multifocal ventricular regularity. The latter may take the


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FIG. 2. a. Control, b. 7 seconds after start of stimulation, c. 2 seconds after cessation of stimulation, d. 23 seconds after cessation of stimulation, e. Section of the posterior hypothalamus. The point stimulated is marked by dot.

FIG. 3. a. Control, b. Immediately after cessation of stimulation.


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form of a normal beat, followed by a unifocal ventricular beat (figure 5b), a type of sequence commonly seen clinically in cases of psychogenic bigeminy. Apparently, at onset of hypothalamic stimulation, the lower nodal or ventricular pacemaker is too weak to effect more than an alternation with the sinus node, resulting in bigeminy. Later, the ectopic pacemaker takes

FIG. 4. a. Control (for b and c ) . b. 26 seconds after start of stimulation, c. Immediately after cessation of stimulation, d. Control (for e ) . e. 42 seconds after cessation of stimulation.

over completely, or in partnership with other ventricular foci. Two ventricular foci may act alternately (figure 4e), or each of two foci may regularly and alternately cause two consecutive contractions of the heart (figure 4b), or a normal sinus focus and a ventricular focus may set up a trigeminy and a trigeminy-bigeminy (figure 5b), or a quadrigeminy. Figures 6b and 6d show spindle formations of different lengths occurring in a unifocal ven-


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FIG. 5. a. Control, b. 12 seconds after start of stimulation, c. 17 seconds after start of stimulation, d. 9 seconds after cessation of stimulation.

tricular tachycardia during stimulations in adjacent posterior hypothalamic loci. At another locus in the same animal (figure 6f), alternations in size of the S waves occur within a spindle during stimulation. A reduction in the QRS voltage is sometimes observed after central electrical stimulation. More often, however, an increase in QRS voltage

FIG. 6. a. Control (for b). b. 17 seconds after start of stimulation, c. Control (for d). d. 17 seconds after start of stimulation, e. Control (for f). f. 11 seconds after start of stimulation.


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results. Repolarization may be affected variously. An S T elevation, or an inversion of the T wave, may be observed during stimulation. A well defined U wave was encountered in three instances during and after stimulation, two of the loci stimulated being in the anterior and one in the posterior hypothalamus. P wave changes and auricular extrasystoles were not common, although they occurred in some instances. Elevation of the P wave was minor in the few cases in which it was observed. Marked diminution of the P was seen at times in conjunction with a late nodal rhythm (figure 3 ) , where normal P impulse formation was completely suppressed. When A-V dissociation occurred together with irregular multifocal ventricular rhythm (figure 2 ) , P waves were irregular in both amplitude and rhythm. The alterations in the duration of P-R and Q R S intervals were analyzed for their possible interest in relation to the pathogenesis of the WilsonWolff-Parkinson-White syndrome. It may be seen in the control record of figure 2a that the P-R interval is 0.08 sec. and the Q R S interval is 0.03 sec. During and following one-half minute of electrical stimulation in a locus in the posterior hypothalamus, A-V dissociation occurs. One observes a pseudonodal focus, a wandering sinus pacemaker (figure 2 d ) , and initial nodal beats (three beats are starred) in which P-R is now 0.07 sec. and Q R S is 0.05 sec. The configurations may simulate right bundle branch block, placing these beats within the criteria of classification in the Wilson-Wolff-Parkinson-White syndrome. When the electrode was shifted 3 mm. in the hypothalamus and the same electrical stimulus was applied, a remarkable sequel occurred in which alternate beats exhibited a narrowing of the P R interval, a widening of the Q R S interval, and T inversion. When the electrode tip was shifted another millimeter and another stimulation was effected, the bigeminal effect faded and the phenomenon of shortening of P-R, broadening of Q R S and T inversion was most striking every fourth beat. This grouping of effects was not uncommon in our series of experiments. At times the P wave was seen on the ascending limb of the Q R S complex, another type of Wilson-Wolff-Parkinson-White phenomenon as classified by Ohnell.11 In control experiments, Flaxedil, injected intravenously, in no instance resulted in electrocardiographic change. Intravenous pentobarbital was found to block the hypothalamic electrical stimulatory effects on the electrocardiogram. DISCUSSION

The variety of electrocardiographic manifestations in this study indicates the complexity of the control exerted by the hypothalamus upon the heart, a complexity perhaps not fully apprehended in previous investigations bearing upon the problem. 7 ' 15 ' 16 ' 17 The pathways involved in the transmission of


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the stimulus from the hypothalamus to the heart muscle are probably those described by Beattie et al.16 Cardiac effects obtained in the present study late during stimulation, or after stimulation had ceased, may be reflex phenomena, involving the medulla and other cardioregulatory centers. The secondary effects are often cardio-inhibitory (figure 3 ) , and frequently include runs of nodal rhythm. Because distortion or inversion of the P wave was not seen, except by encroachment of an enlarging T wave, it may be inferred that the preponderant influence flows from hypothalamus to the ventricular myocardium. Often the vicinity of the A-V node appears to be heavily affected. The very early occurrence of adventitious foci, manifest by irregularities in the T wave and the common early enlargement of the T wave, might lead to the presumption that the occasional concurrent auricular extrasystoles could involve a retrograde phenomenon. The reduction in the voltage of the Q R S complex, which we have observed to follow some stimulation, does not seem to be the result of myocardial fatigue. The phenomenon resembles that which occurs after injection of quinidine into the third cerebral ventricle. 3 It is also known to follow clinical quinidine excess. Areas of greatest sensitivity in production of cardiac effects were found generally in the posterior and lateral hypothalamus. More extensive details of anatomic localization in the brain will be treated in another publication. 18 The same areas were reported by Manning and Peiss 8 and Rushmer and Smith 9 to increase myocardial contractility when stimulated. The electrocardiographic manifestations may be classified as initial or secondary, depending upon the time of appearance after onset of diencephalic stimulation. The initial effects, seen early during stimulation, frequently included wave augmentation, Q R S amplitude change, extrasystoles principally from nodal and ventricular foci, and runs of (pseudo) nodal and ventricular tachycardia. The secondary effects, such as relative bradycardia, rhythmic grouping and pacemaker shifts, including the Wilson-Wolff-ParkinsonWhite phenomenon, were probably the result of delayed reflex activation of accessory cardioregulatory centers within the nervous system. Within the initial group we may see both irregular (multifocal) and regular (unifocal) ventricular rhythm with varying degree of A-V dissociation. One cannot therefore differentiate between a "true" and a "pseudo" ventricular tachycardia on the basis of the regularity of the rhythm. The observations in the present study would appear to support, within the limits imposed by species difference, the conclusion of Schrire and Vogelpoel 10 that, if the Q R S is of normal duration, the tachycardia is supraventricular. However, in the bidirectional type of "pseudo" ventricular tachycardia, with a slurred S-T segment (figure 5d), the QRS dimension is not easily apparent, and where preexcitation occurs (figure 2 ) , a bundle branch block may be simulated. The duration of the Q R S may also be indistinct where the P wave, in a wandering pacemaker sequence, is superimposed upon the


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S-T segment (figure 6 ) , a pattern likely to be mistakenly called "retrograde conduction." The records were analyzed for criteria bearing upon possible extracardiac etiology of the Wilson-Wolff-Parkinson-White syndrome, or as designated by Hejtmancik and Herrmann, 6 the electrocardiographic syndrome of short P-R interval and broad QRS complexes. The progressive shortening of the P-R interval appears to be a form of centrally controlled dissociation, and it is interesting to note in this connection that Wolff et al.,12 as well as Fenichel, 13 felt that both the short P R and the Q R S block of the much discussed Wilson-Wolff-Parkinson-White syndrome were due to the influence of extracardiac nerves. The capability of a single hypothalamic site to produce the Wilson-Wolff-Parkinson-White phenomenon associated with paroxysmal tachycardia is of significance, as Hejtmancik and Herrmann have demonstrated, 6 the clinical association of the Wilson-Wolff-ParkinsonWhite syndrome and paroxysmal arrhythmias is quite common. Furthermore, organic heart disease is often absent in the Wilson-Wolff-ParkinsonWhite syndrome. Our investigation supports the contention of Ranson 4 that the hypothalamus is devoid of parasympathetic centers, though possibly not of parasympathetic pathways from the "prehypothalamus," and that the posterior hypothalamus may be considered to contain a sympathetic center or centers. The concept of anterior hypothalamic cardiovascular inhibition, balanced by posterior hypothalamic stimulatory function, receives only weak corroboration. One would expect to produce primary sinus inhibition with bradycardia or standstill if the anterior hypothalamus contained cardioinhibitory centers. Bradycardia, when present, occurred late in stimulation or after stimulation, presumably from activation of other areas within the central nervous system, perhaps the same areas which produce prolonged cardiac standstill during encephalography. 14 There is evidence indicating that sympathetic and possibly also the parasympathetic nerve fibers reach all parts of the heart, 2 largely by accompanying the blood vessels. However, the intracardiac mechanisms resulting in the electrocardiographic changes observed in our experiments have not been determined. SUMMARY

Through the use of the Horsley-Clarke technic in a series of cats the hypothalamus was explored by means of electrical stimulations and simultaneous electrocardiographic recordings. The manifestations, obtained by stimulation of histologically confirmed points, chiefly in the lateral and posterior hypothalamus, included marked alterations in the wave components QRS and T, changes in rhythm such as bigeminy and trigeminy, A-V dissociation, extrasystoles, paroxysmal nodal and ventricular tachycardias, and the Wilson-Wolff-Parkinson-White configuration.


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ACKNOWLEDGMENTS

We are indebted to the Department of Biophysics, and specifically to Professor A. W. Bellamy and Professor M. Verzeano, for technical advice and for making available some of their facilities. SUMMARIO IN INTERLINGUA

Le objectivo del presente studio esseva determinar qual areas del mesencephalo es possibilemente de signification predominante in le genese de specific configurationes electrocardiographic e de anormal rhythmos cardiac que es de interesse clinic. Tal areas in le cerebro ha non usque nunc essite identificate, ben que on ha studiate relationes neuro-cardiac depost multe annos e ab varie punctos de vista. Con le uso del technica de Horsley-Clarke, 375 histologicamente confirmate punctos diencephalic esseva stimulate electricamente in un serie de cattos, e le effectos electrocardiographic de ille stimulation esseva registrate. Iste effectos— veniente primarimente ab areas in le hypothalamo lateral e posterior—includeva tachycardias sinusal, nodal, e ventricular, marcate alterationes del voltage e del conformation de componentes undal in QRS e T, dissociation atrio-ventricular, alterationes del rhythmo (tal como bi- e trigeminia), e un configuration simile a illo describite per Wilson, Wolff, Parkinson, e White. Le resultatos indica que le hypothalamo postero-lateral exerce un profunde influentia super le stato functional del myocardio. Phenomenos de dissociation atrioventricular resultante ab le stimulation electric del diencephalo pare intrainar le concomitante excitation de altere areas in le systema nervose, con un inhibition reflexe del nodo sinusal. BIBLIOGRAPHY 1. Weinberg, S. J.: Hypothalamic dysfunction. A review of experimental, and clinical observations of cardiac and renal aspects, California Med. 77: 253-268, 1952. 2. Schiitz, E.: Physiologie des Herzens, Chapter 16, 1958, Springer, Berlin. 3. Weinberg, S. J., and Haley, T. J.: Centrally mediated effects of cardiac drugs: strophanthin-K, quinidine, and procaine amide, Circul. Res. 3 : 103-108 (Jan.) 1955. 4. Ranson, S. W., quoted in Boon, A. A.: Comparative anatomy and physio-pathology of the autonomic hypothalamic centres, Acta psychiat. et neurol. Suppl. 18: 53-129, 1938. 5. Mitchell, G. A. G.: Anatomy of the autonomic nervous system, 1953, E. and S. Livingstone, Ltd., Edinburgh and London, p. 111. 6. Hejtmancik, M. R., and Herrmann, G. R.: The electrocardiographic syndrome of the short P-R interval and broad QRS complexes, Am. Heart J. 54: 708-721. 7. Weinberg, S. J., and Haley, T. J.: Effect of chlorpromazine on cardiac arrhythmias induced by intra-cerebral injection of tryptamide-strophanthidin, Arch, internat. de pharmacodyn. et de therap. 105: 209-220, 1956. 8. Manning, J. W., Jr., and Peiss, C. N.: Cardiovascular responses elicited by electrical stimulation of the hypothalamus, Federation Proc. 17: 136 (Mar.) 1958. 9. Rushmer, R. F., and Smith, O.: Hypothalamic influence on left ventricular performance, Federation Proc. 17: 136, 1958. 10. Schrire, V., and Vogelpoel, L.: The clinical and electrocardiographic differentiation of supraventricular and ventricular tachycardia with regular rhythm, Am. Heart J. 49: 162-187, 1955. 11. Ohnell, R. F.: Pre-excitation, a cardiac abnormality, Acta med. scandinav. Suppl. 152: 149-152, 1944. 12. Wolff, L., Parkinson, J., and White, P.: Bundle-branch block with short P-R interval in healthy young people prone to paroxysmal tachycardia, Am. Heart J. 5: 685-704 (Aug.) 1930.


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13. Fenichel, N. M.: Analysis of QRS complex of electrocardiogram, Am. Heart J. 7: 514-531 (Apr.) 1932. 14. Weinberg, S. J., and Bushard, M. C.: Alterations in renal function in man during intra-cranial air studies. Alterations in cardiac function, Arch. Int. Med. 86: 857871 (Dec.) 1950. 15. White, J. C.: Autonomic discharge from stimulation of the hypothalamus in man, A. Research Nerv. and Ment. Dis., Proc. 20: 854-863, 1940. 16. Beattie, J., Brow, G. R., and Long, C. N. H.: Physiological and anatomical evidence for existence of nerve tracts connecting the hypothalamus with spinal sympathetic centres, Proc. Roy. Soc, London, s. B 106: 253-275 (May) 1930. 17. Van Bogaert, A.: Hypothalamus et reactions cardio-vasculaires d'origine centrale, Arch, internat. de pharmacodyn. et de therap. 52: 137-176, 1936. 18. Fuster, J. M., and Weinberg, S. J.: Bioelectrical changes of the heart cycle induced by stimulation of diencephalic regions, Exper. Neurol. 2: 26-39, 1960.
