Physiology & Behavior, Vol. 16, pp. 227-230. Pergamon Press and Brain Research Publ., 1976. Printed in the U.S.A.
BRIEF COMMUNICATION Cardiovascular Responses Elicited by Electrical Brain Stimulation in the
Rabbit I
D. A. POWELL, M. F. TKACIK, S. L. BUCHANAN AND W. L. MILLIGAN
Neuroscience Laboratory, VA Hospital, and University o f South Carolina, Columbia S C (Received 7 March 1975) POWELL, D. A., M. F. TKACIK, S. L. BUCHANAN AND W. L. MILLIGAN. Cardiovascular responses elicited by electrical brain stimulation in the rabbit. PHYSIOL. BEHAV. 16(2) 227-230, 1976. - Long and short trains of electrical stimulation at low and high pulse frequencies were delivered to diencephalic sites in the rabbit. Short train durations elicited BP increases accompanied by HR decreases at all sites, whereas long train durations elicited a variety of different BP and HR changes at different electrode sites. Fifty and 200 Hz pulse frequencies elicited significantly more pressor responses than did 5 Hz pulse frequency, which tended to convert pressor responses elicited by higher frequencies to depressor responses. Diencephalon
Cardiovascularactivity
Electrical brain stimulation
With regard to the second question, several earlier studies found that, at extremely low frequencies, the typically obtained BP increases could be converted to depressor responses in the cat and dog (e.g. [2,10]). Although pulse frequency was manipulated in 2 recent investigations in the rabbit [5,9], the extremely low frequencies [ 2 - 5 Hz] reported in earlier studies to produce depressor responses were not employed in these studies. In the present experiment frequencies of 5 Hz, 50 Hz, and 200 Hz were employed with stimulus trains of either 1.0 or 5 sec duration.
ELECTRICAL stimulation of central nervous tissue has contributed greatly to the elucidation of higher level control of cardiovascular processes and the role these processes play in behavior; see Cohen and MacDonald [3] for a recent review. The present investigation focused upon 2 issues relevant to this area of research. (a) First, can different cardiovascular responses be elicited from discrete areas of the diencephalon, and (b) secondly, are these different response topographies related to stimulus parameters. Recent studies of electrical stimulation of diencephalon and forebrain in the rabbit suggested that the primary cardiovascular response was a short latency but relatively long enduring pressor response accompanied either by bradycardia or a biphasic heart rate (HR) increase followed by a decrease [9, 11, 131. Francis, Sampson, Gerace and Schneiderman [5] recently reported, however, that all 4 combinations of HR and blood pressure (BP) changes could be elicited by longer trains of stimulation. Although train duration was manipulated in a prior study from our laboratory [9], only 8 electrode sites were studied and these tended to be concentrated in more posterior diencephalic regions. In the latter study the HR and BP topographies did not differ for long vs short train durations (viz., all consisted of pressor responses accompanied by HR decreases). Thus a major purpose of the present investigation was to assess systematically the effects of long train durations of electrical stimulation at more anterior sites in the diencephalon.
METHOD
A n im als Fourteen male and female New Zealand albino rabbits, weighing approximately 3.0 kg each, were used. Two to 4 electrodes were implanted in each animal. From this sample 18 placements yielded cardiovascular changes which met the predetermined criterion of a 10% change from prestimulus baseline. Apparatus and Procedure Standard stereotaxic techniques were used to implant bipolar electrodes in the anterior hypothalamus, preoptic region, or septum. The implanted electrodes were chronically held in place by dental cement. Approximately 10 days later the medial ear artery was cannulated with a 3.0
t This research was supported by VA Institutional Research Funds, Project Number 5737-01. Reprints may be obtained from the authors, Neuroscience Laboratory, VA Hospital, Columbia, South Carolina 29201. 227
228 cm length of 30 ga Teflon catheter, which allowed for recording of blood pressure. A Bio-Medical Electronics stimulator with isolated output and constant current stimulus, was used to produce equal biphasic pulse pairs with no delay between the 2 pulses. The duration of the pair was 1/10 cycle irrespective of pulse frequency. Holding the pulse pair duration equal to a constant fraction of the cycle length maintained a constant average current across frequencies. Stimulus train durations o f either 1 or 5 sec were employed at pulse pair frequencies of 5, 50, or 200 Hz. The stimulus intensity was held constant for individual animals in that the intensity producing the largest magnitude HR and BP responses, without evoking gross body movement, was used. HR was measured by stainless steel safety pins inserted into the skin over the right front and left hind leg. BP was measured by connecting a Statham pressure transducer to the previously implanted catheter in the medial ear artery, and EMG was monitored from stainless steel needle electrodes placed in the animal's neck. HR, BP, and EMG were recorded on a Grass Model-5 polygraph with the BP channel calibrated to translate pen deflections into mm Hg. HR measures were based upon 5 beat intervals measured to the nearest ram. On each trial the baseline consisted of the mean duartion of 2 successive 5 beat intervals occurring prior to stimulus onset; the R-R duration of each of 10 successive blocks of 5 beats following stimulus onset was then compared with this baseline. This was accomplished by converting the duration of each 5 beat interval into beats per min. BP response topographies were obtained by comparing the mean BP in mm Hg at the midpoint of each successive pre- and post- 5 beat interval. The experiment was conducted in 2 phases. In the first phase HR thresholds were determined. During each experimental session the animal, restrained within a sound attenuated enclosure, was presented with increasing stimulus intensities (50 Hz, 5 sec train duration) until: (a) a HR change of 10% or greater (compared to a prestimulus baseline) was elicited, (b) 2 mA peak-to-peak current was reached, or (c) gross body movements were evoked, as monitored by the EMG channel of the polygraph. During Phase 2 after active HR electrodes were identified, the animals were cannulated, and BP and HR responses recorded as in phase 1. In this phase, however, stimulus intensity (using a 5 sec train duration - 50 Hz signal) was increased until it was just below the threshold for eliciting EMG responses. This intensity was then used in all further trials. Each of 3 pulse pair frequencies were studied with the 5 sec train duration in all animals at all active electrode sites. In addition, in 5 animals (8 sites), the 1 sec train duration was also studied at each frequency during Phase 2. Since substantial data exist on short pulse train elicited cardiovascular changes in the rabbit (e.g. [11,13]), an exhaustive study of these effects was not attempted in the present investigation. Four trials at each combination of frequency and train duration were administered in a predetermined random order during each experimental session. The intertrial interval was approximately 3 rain. Since the HR response was in many cases biphasic, and occasionally triphasic, the HR as well as BP response elicited by a given set of stimulus parameters was taken to be the largest magnitude change in a given direction during the first 50 poststimulus heart beats. This definition of the HR and BP response follows that used in previous studies [5,9]. Electrode tip placements were verified by standard histological techniques [ 9 ].
POWELL E T A L .
sp D
!
-
A4
1
i
.......
2
.....
FIG. 1. Electrode tip placements (closed circles) supertmposed on sections from the Atlas of Sawyer, Everett and Green [121. Abbreviations for areas in which electrode tips were located are as follows: (a) SP - Septal region; (b) MPO - Medial Preoptic area; (c) LPO - Lateral Preoptic area; (d) LHA - Lateral Hypothalamic area; (e) VMH - Ventromedial Hypothalamus, and (f) DMH Dorsomedial Hypothalamus.
RESULTS
Electrode tip placements are shown in Fig. 1. As Francis, e t al. [ 5 ] reported, using long trains of stimulation resulted in all combinations of the 4 possible HR and BP changes from different sites in the septum, preoptic area, and anterior hypothalamus. The frequency of occurrence of each combination is shown in Table 1 for the 5 and 50 Hz conditions accompanied by the mean peak-to-peak current used to elicit these changes. The 200 Hz stimulus produced in all cases, except for one medial hypothalamic placement, a response that was similar in topography, but smaller in
CNS STIMULATION IN THE RABBIT
229
magnitude than the 50 Hz stimulus. With regard to the one exception, 200 Hz elicited a BP and HR decrease as did 5 Hz stimulation, while 50 Hz elicited a BP increase accompanied by a HR decrease. There was no systematic relationship between site of stimulation and the form of the response elicited. Both pressor and depressor responses were elicited from septal, as well as hypothalamic, placements. BP increases accompanied by HR decreases were obtained at all 8 sites in which 1 sec trains were used. At 3 of these sites the HR response was actually biphasic consisting of an initial brief HR acceleration followed by a larger and longer lasting deceleration. These findings are compatible with prior studies in which short stimulus trains were used [5, 9, 11, 13]. The 8 sites studied with the 1 sec train included 3 septals placements and 5 preoptic and hypothalamic placements. Although all 4 combinations of HR and BP changes were produced by all frequencies when the 5 sec duration was employed, more depressor responses were associated with the lower frequency stimulus than with higher frequencies. Thus, as can be seen in Table 1, 14 of the 18 sites elicited depressor responses with the 5 Hz stimulus whereas only 5 of 18 BP responses were decreases when the higher frequency (50 Hz) stimulus was employed. In 9 of the 14 instances, the 5 Hz stimulus converted a pressor response at
::;]
TABLE1 NUMBER OF SEPTAL AND ANTERIOR HYPOTHALAMIC SITES SHOWING FOUR DIFFERENT COMBINATIONSOF HEART RATE AND BLOODPRESSURECHANGESIN RESPONSETO 5 SEC TRAINS OF ELECTRICAL STIMULATION. MEAN STIMULUS INTENSITY REQUIRED TO ELICIT THE LARGESTMAGNITUDEBLOOD PRESSURE RESPONSE (UNACCOMPANIED BY MOVEMENT) IS ALSO SHOWN
HR
BP
5 Hz
50 Hz
Mean Stimulus Intensity
decrease decrease increase increase
decrease increase decrease increase
8 2 6 2
2 8 3 5
0.360 mA 0.480 mA 0.380 mA 0.520 mA
50 Hz to a depressor response. At the other 5 sites, both 5 and 50 Hz elicited depressor responses. There were no sites at which depressor responses were elicited at 50 Hz and pressor responses by 5 Hz. The binomial test for related samples [4] applied to these data yielded a 2 sided probability of 0.034, suggesting that the different frequen280
A
,,o
=1oI =oo.
heart
//~
O
D
a
Zv---&
rate=6o 25o Ii
--
5HZ 50HZ
c
~
190 180
160 0
,=o +15
÷20I pressure+, s
blood
.o
.o I
-5
=
/
-5
10l
-10
-15 ,
-15 -20
/
0
1
2
3
4
5
6
7
8
blocks of five heart beats
9
10
0
1
2
3
4
5
6
7
8
9
10
blocks of five heart beats
FIG. 2. Heart rate (top) and blood pressure (bottom) changes elicited by 5 sec trains of stimulation at the pulse frequencies shown. The left panel (A) shows changes elicited by a 0.4 mA stimulus to the dorsolateral preoptic area. The right panel (B) shows similar changes elicited by a 0.8 mA stimulus to the medial septal region.
230
POWELL E T A L .
cies associated with the 5 vs 50 Hz conditions were significant. Two animals in which BP increases at higher frequencies were converted to depressor responses by low frequency stimulation are shown in Fig. 2. The left panel of this figure shows the HR and BP changes elicited by a 0.4 mA stimulus in the dorso-lateral preoptic area. As can be seen, all frequencies of stimulation ehcited a monophasic HR decrease, but the BP response was a depressor response at 5 Hz and a monophasic pressor response at 200 Hz and 50 H z A similar finding is shown in the right panel, where the 50 Hz and 200 Hz, 0.8 mA stimulus resulted in pressor responses but the 5 Hz stimulus elicited a depressor response. This electrode was located in the medial septal area. In this case the HR response was a biphasic increase followed by a decrease at higher frequencies but a monophasic decrease with the 5 Hz stimulus. In most cases, where the 5 Hz stimulus converted the BP changes to a depressor response, the magnitude of the latter was somewhat smaller than the magnitude of the pressor response elicited by the 50 Hz stimulus. DISCUSSION The present data are compatible with the results of several previous studies. First, it was found that short trains of high frequency stimulation resulted in BP increases accompanied by HR decreases at several different sites in the anterior diencephalon, as was reported previously [5, 9, 1 1 ]. Secondly, it was also found that, by utilizing longer trains of stimulation, several different kinds of cardiovascular changes could be elicited, as was reported by Francis, et al. [5]. However, in the latter study it was reported that these changes were not related to pulse frequency. Similarly, in a prior study from our laboratory [9], it was found that pulse frequency was not related to the form of the cardiovascular response elicited. However, neither of these experiments used frequencies below 10 Hz. It was found in the present experiment that when pulse
frequency was lowered to 5 Hz, significantly more BP decreases were obtained than when a 50 Hz stimulus was employed. These findings are thus compatible with the earlier studies which reported that parasympathetic like responses were more sensitive to lower frequencies of stimulation in other species (e.g. [ 2,10]. Although these responses have been described as parasympathetic (e.g. [2,8] ), it is possible that they are due to sympathetic inhibition. It has also been suggested that discrete sympathetic and parasympathetic zones exist in the diencephalon [ 1,2]. However, the lack of correspondence between cardiovascular response patterns and site of stimulation in the present study as well as others in the rabbit [ 5,11] and cat [ 10], suggests that this may not be the case, at least with regard to the cardiovascular system. Such responses may be due to sympathetic inhibition. Pitts, et al. [10], for example, found that low frequency (2 Hz) diencephalic stimulation resulted in depressor responses accompanied by decreased rates of firing in the cardiac sympathetic nerves. Although low pulse frequencies tended to elicit depressor responses in the present study, it should also be emphasized that all combinations of HR and BP changes were elicited by both low and high frequencies when the 5 sec train duration was employed. These different patterns of cardiovascular responding suggest, as has been pointed out by others (e.g. [5]), that longer trains of stimulation, via polysynaptic pathways, modulate medullary reflex centers and thus interfere with vagal compensatory adjustment in various ways. Short duration trains, which do not endure long enough to effect such modulation, thus elicit pressor responses accompanied by HR decreases, a response that has been shown to be primarily due to the action of the buffer reflexes [6 7, 10, 11]. A host of recent experiments have shown that diencephalic stimulation does indeed modulate lower cardiovascular centers in the cat and dog (e.g. [6,7] ).
REFERENCES 1. Akert, K. Diencephalon. In: Electrical Stimulation of the Brain, edited by D. E. Sheer. Austin: University of Texas Press, 1961, pp. 288-310. 2. Andy, O. J., K. Koshino, S. R. Nelson, D. L. Sparks, G. C. Warren and A. Sanford. Septal influences on autonomic function. In: Limbic System Mechanisms and Autonomic Function, edited by C. H. Hockman. Springfield: Thomas, 1972, pp. 41-59. 3. Cohen, D. H. and R. L. MacDonald. A selective review of central neural pathways involved in cardiovascular control. In: Cardiovascular Psychophysiology, edited by P. A. Obrist, A. H. Black, J. Brener and L. V. Dicara. Chicago: Aldine, 1974, pp. 33-59. 4. Edwards, A. E. Experimental Design in Psychological Research. New York: Holt, Rinehart and Winston, 1964. 5. Francis, J. S., L. D. Sampson, T. Gerace and N. Schneiderman. Cardiovascular responses of rabbits to ESB: Effects of anesthetization, stimulus frequency and pulse-train duration. Physiol. Behav. 11: 195-203, 1973. 6. Gebber, G. L. and D. W. Snyder. Hypothalamic control of baroceptor reflexes. Am. J. Physiol. 218: 124-131, 1970.
7. Hockman, C. H. and J. Talesnik. Central nervous system modulation of baroceptor input. Am. J. PhysioL 221: 515-519, 1971. 8. Malmo, R. B. Classical and instrumental conditioning with septal stimulation as reinforcement. J. comp. physiol. Psychol. 60: 1-8, 1965. 9. Milligan, W. L. and D. A. Powell. CNS stimulation: Effects of stimulus parameters on cardiovascular changes and behavior in the rabbit. Physiol. Psychol. 3: 59-64, 1975. 10. Pitts, R. F., M. G. Larrabee and D. W. Bronk. An analysis of hypothalamic cardiovascular control. Am. J. Physiol. 134: 359-383, 1941. 11. Powell, D. A., S. Goldberg, G. W. Dauth, E. Schneiderman and N. Schneiderman. Adrenergic and cholinergic blockade of cardiovascular responses to subcortical electrical stimulation in unanesthetized rabbits. PhysioL Behav. 8: 927-936, 1972. 12. Sawyer, C. H., J. W. Everett and J. D. Green. The rabbit diencephalon in stereotaxic coordinates. J. comp. Neurol. 101: 801-824, 1954. 13. Schneiderman, N. The relationship between learned and unlearned cardiovascular responses. In: Cardiovascular Psychophysiology, edited by P. A. Obrist, A. H. Black, J. Brener and L. V. DiCara. Chicago: Aldine, 1974, pp. 190-210.
BRIEF COMMUNICATION Cardiovascular Responses Elicited by Electrical Brain Stimulation in the
Rabbit I
D. A. POWELL, M. F. TKACIK, S. L. BUCHANAN AND W. L. MILLIGAN
Neuroscience Laboratory, VA Hospital, and University o f South Carolina, Columbia S C (Received 7 March 1975) POWELL, D. A., M. F. TKACIK, S. L. BUCHANAN AND W. L. MILLIGAN. Cardiovascular responses elicited by electrical brain stimulation in the rabbit. PHYSIOL. BEHAV. 16(2) 227-230, 1976. - Long and short trains of electrical stimulation at low and high pulse frequencies were delivered to diencephalic sites in the rabbit. Short train durations elicited BP increases accompanied by HR decreases at all sites, whereas long train durations elicited a variety of different BP and HR changes at different electrode sites. Fifty and 200 Hz pulse frequencies elicited significantly more pressor responses than did 5 Hz pulse frequency, which tended to convert pressor responses elicited by higher frequencies to depressor responses. Diencephalon
Cardiovascularactivity
Electrical brain stimulation
With regard to the second question, several earlier studies found that, at extremely low frequencies, the typically obtained BP increases could be converted to depressor responses in the cat and dog (e.g. [2,10]). Although pulse frequency was manipulated in 2 recent investigations in the rabbit [5,9], the extremely low frequencies [ 2 - 5 Hz] reported in earlier studies to produce depressor responses were not employed in these studies. In the present experiment frequencies of 5 Hz, 50 Hz, and 200 Hz were employed with stimulus trains of either 1.0 or 5 sec duration.
ELECTRICAL stimulation of central nervous tissue has contributed greatly to the elucidation of higher level control of cardiovascular processes and the role these processes play in behavior; see Cohen and MacDonald [3] for a recent review. The present investigation focused upon 2 issues relevant to this area of research. (a) First, can different cardiovascular responses be elicited from discrete areas of the diencephalon, and (b) secondly, are these different response topographies related to stimulus parameters. Recent studies of electrical stimulation of diencephalon and forebrain in the rabbit suggested that the primary cardiovascular response was a short latency but relatively long enduring pressor response accompanied either by bradycardia or a biphasic heart rate (HR) increase followed by a decrease [9, 11, 131. Francis, Sampson, Gerace and Schneiderman [5] recently reported, however, that all 4 combinations of HR and blood pressure (BP) changes could be elicited by longer trains of stimulation. Although train duration was manipulated in a prior study from our laboratory [9], only 8 electrode sites were studied and these tended to be concentrated in more posterior diencephalic regions. In the latter study the HR and BP topographies did not differ for long vs short train durations (viz., all consisted of pressor responses accompanied by HR decreases). Thus a major purpose of the present investigation was to assess systematically the effects of long train durations of electrical stimulation at more anterior sites in the diencephalon.
METHOD
A n im als Fourteen male and female New Zealand albino rabbits, weighing approximately 3.0 kg each, were used. Two to 4 electrodes were implanted in each animal. From this sample 18 placements yielded cardiovascular changes which met the predetermined criterion of a 10% change from prestimulus baseline. Apparatus and Procedure Standard stereotaxic techniques were used to implant bipolar electrodes in the anterior hypothalamus, preoptic region, or septum. The implanted electrodes were chronically held in place by dental cement. Approximately 10 days later the medial ear artery was cannulated with a 3.0
t This research was supported by VA Institutional Research Funds, Project Number 5737-01. Reprints may be obtained from the authors, Neuroscience Laboratory, VA Hospital, Columbia, South Carolina 29201. 227
228 cm length of 30 ga Teflon catheter, which allowed for recording of blood pressure. A Bio-Medical Electronics stimulator with isolated output and constant current stimulus, was used to produce equal biphasic pulse pairs with no delay between the 2 pulses. The duration of the pair was 1/10 cycle irrespective of pulse frequency. Holding the pulse pair duration equal to a constant fraction of the cycle length maintained a constant average current across frequencies. Stimulus train durations o f either 1 or 5 sec were employed at pulse pair frequencies of 5, 50, or 200 Hz. The stimulus intensity was held constant for individual animals in that the intensity producing the largest magnitude HR and BP responses, without evoking gross body movement, was used. HR was measured by stainless steel safety pins inserted into the skin over the right front and left hind leg. BP was measured by connecting a Statham pressure transducer to the previously implanted catheter in the medial ear artery, and EMG was monitored from stainless steel needle electrodes placed in the animal's neck. HR, BP, and EMG were recorded on a Grass Model-5 polygraph with the BP channel calibrated to translate pen deflections into mm Hg. HR measures were based upon 5 beat intervals measured to the nearest ram. On each trial the baseline consisted of the mean duartion of 2 successive 5 beat intervals occurring prior to stimulus onset; the R-R duration of each of 10 successive blocks of 5 beats following stimulus onset was then compared with this baseline. This was accomplished by converting the duration of each 5 beat interval into beats per min. BP response topographies were obtained by comparing the mean BP in mm Hg at the midpoint of each successive pre- and post- 5 beat interval. The experiment was conducted in 2 phases. In the first phase HR thresholds were determined. During each experimental session the animal, restrained within a sound attenuated enclosure, was presented with increasing stimulus intensities (50 Hz, 5 sec train duration) until: (a) a HR change of 10% or greater (compared to a prestimulus baseline) was elicited, (b) 2 mA peak-to-peak current was reached, or (c) gross body movements were evoked, as monitored by the EMG channel of the polygraph. During Phase 2 after active HR electrodes were identified, the animals were cannulated, and BP and HR responses recorded as in phase 1. In this phase, however, stimulus intensity (using a 5 sec train duration - 50 Hz signal) was increased until it was just below the threshold for eliciting EMG responses. This intensity was then used in all further trials. Each of 3 pulse pair frequencies were studied with the 5 sec train duration in all animals at all active electrode sites. In addition, in 5 animals (8 sites), the 1 sec train duration was also studied at each frequency during Phase 2. Since substantial data exist on short pulse train elicited cardiovascular changes in the rabbit (e.g. [11,13]), an exhaustive study of these effects was not attempted in the present investigation. Four trials at each combination of frequency and train duration were administered in a predetermined random order during each experimental session. The intertrial interval was approximately 3 rain. Since the HR response was in many cases biphasic, and occasionally triphasic, the HR as well as BP response elicited by a given set of stimulus parameters was taken to be the largest magnitude change in a given direction during the first 50 poststimulus heart beats. This definition of the HR and BP response follows that used in previous studies [5,9]. Electrode tip placements were verified by standard histological techniques [ 9 ].
POWELL E T A L .
sp D
!
-
A4
1
i
.......
2
.....
FIG. 1. Electrode tip placements (closed circles) supertmposed on sections from the Atlas of Sawyer, Everett and Green [121. Abbreviations for areas in which electrode tips were located are as follows: (a) SP - Septal region; (b) MPO - Medial Preoptic area; (c) LPO - Lateral Preoptic area; (d) LHA - Lateral Hypothalamic area; (e) VMH - Ventromedial Hypothalamus, and (f) DMH Dorsomedial Hypothalamus.
RESULTS
Electrode tip placements are shown in Fig. 1. As Francis, e t al. [ 5 ] reported, using long trains of stimulation resulted in all combinations of the 4 possible HR and BP changes from different sites in the septum, preoptic area, and anterior hypothalamus. The frequency of occurrence of each combination is shown in Table 1 for the 5 and 50 Hz conditions accompanied by the mean peak-to-peak current used to elicit these changes. The 200 Hz stimulus produced in all cases, except for one medial hypothalamic placement, a response that was similar in topography, but smaller in
CNS STIMULATION IN THE RABBIT
229
magnitude than the 50 Hz stimulus. With regard to the one exception, 200 Hz elicited a BP and HR decrease as did 5 Hz stimulation, while 50 Hz elicited a BP increase accompanied by a HR decrease. There was no systematic relationship between site of stimulation and the form of the response elicited. Both pressor and depressor responses were elicited from septal, as well as hypothalamic, placements. BP increases accompanied by HR decreases were obtained at all 8 sites in which 1 sec trains were used. At 3 of these sites the HR response was actually biphasic consisting of an initial brief HR acceleration followed by a larger and longer lasting deceleration. These findings are compatible with prior studies in which short stimulus trains were used [5, 9, 11, 13]. The 8 sites studied with the 1 sec train included 3 septals placements and 5 preoptic and hypothalamic placements. Although all 4 combinations of HR and BP changes were produced by all frequencies when the 5 sec duration was employed, more depressor responses were associated with the lower frequency stimulus than with higher frequencies. Thus, as can be seen in Table 1, 14 of the 18 sites elicited depressor responses with the 5 Hz stimulus whereas only 5 of 18 BP responses were decreases when the higher frequency (50 Hz) stimulus was employed. In 9 of the 14 instances, the 5 Hz stimulus converted a pressor response at
::;]
TABLE1 NUMBER OF SEPTAL AND ANTERIOR HYPOTHALAMIC SITES SHOWING FOUR DIFFERENT COMBINATIONSOF HEART RATE AND BLOODPRESSURECHANGESIN RESPONSETO 5 SEC TRAINS OF ELECTRICAL STIMULATION. MEAN STIMULUS INTENSITY REQUIRED TO ELICIT THE LARGESTMAGNITUDEBLOOD PRESSURE RESPONSE (UNACCOMPANIED BY MOVEMENT) IS ALSO SHOWN
HR
BP
5 Hz
50 Hz
Mean Stimulus Intensity
decrease decrease increase increase
decrease increase decrease increase
8 2 6 2
2 8 3 5
0.360 mA 0.480 mA 0.380 mA 0.520 mA
50 Hz to a depressor response. At the other 5 sites, both 5 and 50 Hz elicited depressor responses. There were no sites at which depressor responses were elicited at 50 Hz and pressor responses by 5 Hz. The binomial test for related samples [4] applied to these data yielded a 2 sided probability of 0.034, suggesting that the different frequen280
A
,,o
=1oI =oo.
heart
//~
O
D
a
Zv---&
rate=6o 25o Ii
--
5HZ 50HZ
c
~
190 180
160 0
,=o +15
÷20I pressure+, s
blood
.o
.o I
-5
=
/
-5
10l
-10
-15 ,
-15 -20
/
0
1
2
3
4
5
6
7
8
blocks of five heart beats
9
10
0
1
2
3
4
5
6
7
8
9
10
blocks of five heart beats
FIG. 2. Heart rate (top) and blood pressure (bottom) changes elicited by 5 sec trains of stimulation at the pulse frequencies shown. The left panel (A) shows changes elicited by a 0.4 mA stimulus to the dorsolateral preoptic area. The right panel (B) shows similar changes elicited by a 0.8 mA stimulus to the medial septal region.
230
POWELL E T A L .
cies associated with the 5 vs 50 Hz conditions were significant. Two animals in which BP increases at higher frequencies were converted to depressor responses by low frequency stimulation are shown in Fig. 2. The left panel of this figure shows the HR and BP changes elicited by a 0.4 mA stimulus in the dorso-lateral preoptic area. As can be seen, all frequencies of stimulation ehcited a monophasic HR decrease, but the BP response was a depressor response at 5 Hz and a monophasic pressor response at 200 Hz and 50 H z A similar finding is shown in the right panel, where the 50 Hz and 200 Hz, 0.8 mA stimulus resulted in pressor responses but the 5 Hz stimulus elicited a depressor response. This electrode was located in the medial septal area. In this case the HR response was a biphasic increase followed by a decrease at higher frequencies but a monophasic decrease with the 5 Hz stimulus. In most cases, where the 5 Hz stimulus converted the BP changes to a depressor response, the magnitude of the latter was somewhat smaller than the magnitude of the pressor response elicited by the 50 Hz stimulus. DISCUSSION The present data are compatible with the results of several previous studies. First, it was found that short trains of high frequency stimulation resulted in BP increases accompanied by HR decreases at several different sites in the anterior diencephalon, as was reported previously [5, 9, 1 1 ]. Secondly, it was also found that, by utilizing longer trains of stimulation, several different kinds of cardiovascular changes could be elicited, as was reported by Francis, et al. [5]. However, in the latter study it was reported that these changes were not related to pulse frequency. Similarly, in a prior study from our laboratory [9], it was found that pulse frequency was not related to the form of the cardiovascular response elicited. However, neither of these experiments used frequencies below 10 Hz. It was found in the present experiment that when pulse
frequency was lowered to 5 Hz, significantly more BP decreases were obtained than when a 50 Hz stimulus was employed. These findings are thus compatible with the earlier studies which reported that parasympathetic like responses were more sensitive to lower frequencies of stimulation in other species (e.g. [ 2,10]. Although these responses have been described as parasympathetic (e.g. [2,8] ), it is possible that they are due to sympathetic inhibition. It has also been suggested that discrete sympathetic and parasympathetic zones exist in the diencephalon [ 1,2]. However, the lack of correspondence between cardiovascular response patterns and site of stimulation in the present study as well as others in the rabbit [ 5,11] and cat [ 10], suggests that this may not be the case, at least with regard to the cardiovascular system. Such responses may be due to sympathetic inhibition. Pitts, et al. [10], for example, found that low frequency (2 Hz) diencephalic stimulation resulted in depressor responses accompanied by decreased rates of firing in the cardiac sympathetic nerves. Although low pulse frequencies tended to elicit depressor responses in the present study, it should also be emphasized that all combinations of HR and BP changes were elicited by both low and high frequencies when the 5 sec train duration was employed. These different patterns of cardiovascular responding suggest, as has been pointed out by others (e.g. [5]), that longer trains of stimulation, via polysynaptic pathways, modulate medullary reflex centers and thus interfere with vagal compensatory adjustment in various ways. Short duration trains, which do not endure long enough to effect such modulation, thus elicit pressor responses accompanied by HR decreases, a response that has been shown to be primarily due to the action of the buffer reflexes [6 7, 10, 11]. A host of recent experiments have shown that diencephalic stimulation does indeed modulate lower cardiovascular centers in the cat and dog (e.g. [6,7] ).
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